Clinical Review

New imaging tools along with adaptations to existing technologies have been emerging in recent years, with the potential to improve hair diagnostics and treatment monitoring. We provide an overview of 4 noninvasive hair imaging technologies: global photography, trichoscopy, reflectance confocal microscopy (RCM), and optical coherence tomography (OCT). For each instrument, we discuss current and future applications in clinical practice and research along with advantages and disadvantages.

Global Photography

Global photography allows for the analysis of hair growth, volume, distribution, and density through serial standardized photographs.¹ Global photography was first introduced for hair growth studies in 1987 and soon after was used for hair and scalp assessments in finasteride clinical trials.²

Hair Assessment—Washed, dried, and combed hair, without hair product, are required for accurate imaging; wet conditions increase reflection and promote hair clumping, thus revealing more scalp and depicting the patient as having less hair.¹ Headshots are taken from short distances and use stereotactic positioning devices to create 4 global views: vertex, midline, frontal, and temporal.³ Stereotactic positioning involves fixing the patient’s chin and forehead as well as mounting the camera and flash device to ensure proper magnification. These adjustments ensure lighting remains consistent throughout consecutive study visits.⁴ Various grading scales are available for use in hair growth clinical studies to increase objectivity in the analysis of serial global photographs. A blinded evaluator should assess the before and after photographs to limit experimenter bias. Global photography often is combined with quantitative software analysis for improved detection of hair changes.¹

Advancements—Growing interest in improving global photography has resulted in various application-based, artificial intelligence (AI)–mediated tools to simplify photograph collection and analysis. For instance, new hair analysis software utilizes AI algorithms to account for facial features in determining the optimal angle for capturing global photographs (Figure 1), which simplifies the generation of global photography images through smartphone applications and obviates the need for additional stereotactic positioning equipment.^5,6

Limitations—Clinicians should be aware of global photography’s requirements for consistency in lighting, camera settings, film, and image processing, which can limit the accuracy of hair assessment over time if not replicated correctly.^7,8 Emerging global photography software has helped to overcome some of these limitations.

Global photography is less precise when a patient’s hair loss is less than 50%, as it is difficult to discern subtle hair changes. Thus, global photography provides limited utility in assessing minimal to moderate hair loss.⁹ Currently, global photography largely functions as an adjunct tool for other hair analysis methods rather than as a stand-alone tool.

Trichoscopy

Trichoscopy (also known as dermoscopy of the hair and scalp) may be performed with a manual dermoscope (with 10× magnification) or a digital videodermatoscope (up to 1000× magnification).^10-12 Unlike global photography, trichoscopy provides a detailed structural analysis of hair shafts, follicular openings, and perifollicular and interfollicular areas.¹³ Kinoshita-Ise and Sachdeva¹³ provided an in-depth, updated review of trichoscopy terminology with their definitions and associated conditions (with prevalence), which should be referenced when performing trichoscopic examination.

Hair Assessment—Trichoscopic assessment begins with inspection of follicular openings (also referred to as “dots”), which vary in color depending on the material filling them—degrading keratinocytes, keratin, sebaceous debris, melanin, or fractured hairs.¹³ The structure of hair shafts also is examined, showing broken hairs, short vellus hairs, and comma hairs, among others. Perifollicular areas are examined for scale, erythema, blue-gray dots, and whitish halos. Interfollicular areas are examined for pigment pattern as well as vascularization, which often presents in a looping configuration under dermoscopy. A combination of dot colorization, hair shaft structure, and perifollicular and interfollicular findings inform diagnostic algorithms of hair and scalp conditions. For example, central centrifugal cicatricial alopecia, the most common alopecia seen in Black women, has been associated with a combination of honeycomb pigment pattern, perifollicular whitish halo, pinpoint white dots, white patches, and perifollicular erythema.¹³

Advantages—Perhaps the most useful feature of trichoscopy is its ability to translate visualized features into simple diagnostic algorithms. For instance, if the clinician has diagnosed the patient with noncicatricial alopecia, they would next focus on dot colors. With black dots, the next step would be to determine whether the hairs are tapered or coiled, and so on. This systematic approach enables the clinician to narrow possible diagnoses.² An additional advantage of trichoscopy is that it examines large surface areas noninvasively as compared to hair-pull tests and scalp biopsy.^14,15 Trichoscopy allows temporal comparisons of the same area for disease and treatment monitoring with more diagnostic detail than global photography.¹⁶ Trichoscopy also is useful in selecting biopsy locations by discerning and avoiding areas of scar tissue.¹⁷

Limitations—Diagnosis via the trichoscopy algorithm is limiting because it is not comprehensive of all hair and scalp disease.¹⁸ Additionally, many pathologies exhibit overlapping follicular and interfollicular patterning. For example, almost all subtypes of scarring alopecia present with hair loss and scarred follicles once they have progressed to advanced stages. Further studies should identify more specific patterns of hair and scalp pathologies, which could then be incorporated into a diagnostic algorithm.¹³

Advancements—The advent of hair analysis software has expanded the role of videodermoscopy by rapidly quantifying hair growth parameters such as hair count, follicular density, and follicular diameter, as well as interfollicular distances (Figure 2).^14,17 Vellus and terminal hairs are differentiated according to their thickness and length.¹⁷ Moreover, the software can analyze the same area of the scalp over time by either virtual tattoos, semipermanent markings, or precise location measurements, increasing intra- and interclass correlation. The rate of hair growth, hair shedding, and parameters of anagen and telogen hairs can be studied by a method termed phototrichogram whereby a transitional area of hair loss and normal hair growth is identified and trimmed to less than 1 mm from the skin surface.¹⁹ A baseline photograph is taken using videodermoscopy. After approximately 3 days, the identical region is photographed and compared with the initial image to observe changes in the hair. Software programs can distinguish the growing hair as anagen and nongrowing hair as telogen, calculating the anagen-to-telogen ratio as well as hair growth rate, which are essential measurements in hair research and clinical studies. Software programs have replaced laborious and time-consuming manual hair counts and have rapidly grown in popularity in evaluating patterned hair loss.

Reflectance Confocal Microscopy

Reflectance confocal microscopy is a noninvasive imaging tool that visualizes skin and its appendages at near-histologic resolution (lateral resolution of 0.5–1 μm). It produces grayscale horizontal images that can be taken at levels ranging from the stratum corneum to the superficial papillary dermis, corresponding to a depth of approximately 100 to 150 µm. Thus, a hair follicle can be imaged starting from the follicular ostia down to the reachable papillary dermis (Figure 3).²⁰ Image contrast is provided by differences in the size and refractive indices of cellular organelles.^21,22 There are 2 commercially available RCM devices: VivaScope 1500 and VivaScope 3000 (Caliber Imaging & Diagnostics, Inc).

VivaScope 1500, a wide-probe microscope, requires the attachment of a plastic window to the desired imaging area. The plastic window is lined with medical adhesive tape to prevent movement during imaging. The adhesive tape can pull on hair upon removal, which is not ideal for patients with existing hair loss. Additionally, the image quality of VivaSope 1500 is best in flat areas and areas where hair is shaved.^20,23,24 Despite these disadvantages, VivaScope 1500 has successfully shown utility in research studies, which suggests that these obstacles can be overcome by experienced users. The handheld VivaScope 3000 is ergonomically designed and suitable for curved surfaces such as the scalp, with the advantage of not requiring any adhesive. However, the images acquired from the VivaScope 3000 cover a smaller surface area.

Structures Visualized—Structures distinguished with RCM include keratinocytes, melanocytes, inflammatory cells, hair follicles, hair shafts, adnexal infundibular epithelium, blood vessels, fibroblasts, and collagen.²³ Real-time visualization of blood flow also can be seen.

Applications of RCM—Reflectance confocal microscopy has been used to study scalp discoid lupus, lichen planopilaris, frontal fibrosing alopecia, folliculitis decalvans, chemotherapy-induced alopecia (CIA), alopecia areata, and androgenetic alopecia. Diagnostic RCM criteria for such alopecias have been developed based on their correspondence to histopathology. An RCM study of classic lichen planopilaris and frontal fibrosing alopecia identified features of epidermal disarray, infundibular hyperkeratosis, inflammatory cells, pigment incontinence, perifollicular fibrosis, bandlike scarring, melanophages in the dermis, dilated blood vessels, basal layer vacuolar degeneration, and necrotic keratinocytes.²⁵ Pigment incontinence in the superficial epidermis, perifollicular lichenoid inflammation, and hyperkeratosis were characteristic RCM features of early-stage lichen planopilaris, while perifollicular fibrosis and dilated blood vessels were characteristic RCM features of late-stage disease. The ability of RCM features to distinguish different stages of lichen planopilaris shows its potential in treating early disease and preventing irreversible hair loss.

Differentiating between scarring and nonscarring alopecia also is possible through RCM. The presence of periadnexal, epidermal, and dermal inflammatory cells, in addition to periadnexal sclerosis, are defining RCM features of scarring alopecia.²⁶ These features are absent in nonscarring alopecias. Reflectance confocal microscopy additionally has been shown to be useful in the treatment monitoring of lichen planopilaris and discoid lupus erythematosus.²⁰ Independent reviewers, blinded to the patients’ identities, were able to characterize and follow features of these scarring alopecias by RCM. The assessed RCM features were comparable to those observed by histopathologic evaluation: epidermal disarray, spongiosis, exocytosis of inflammatory cells in the epidermis, interface dermatitis, peri- and intra-adnexal infiltration of inflammatory cells, dilated vessels in the dermis, dermal infiltration of inflammatory cells and melanophages, and dermal sclerosis. A reduction in inflammatory cells across multiple skin layers and at the level of the adnexal epithelium correlated with clinical response to treatment. Reflectance confocal microscopy also was able to detect recurrence of inflammation in cases where treatment had been interrupted before clinical signs of disease recurrence were evident. The authors thus concluded that RCM’s sensitivity can guide timing of treatment and avoid delays in starting or restarting treatment.²⁰

Reflectance confocal microscopy also has served as a learning tool for new subclinical understandings of alopecia. In a study of CIA, the disease was found to be a dynamic process that could be categorized into 4 distinct phases distinguishable by combined confocal and dermoscopic features. This study also identified a new feature observable on RCM images—a CIA dot—defined as a dilated follicular infundibulum containing mashed, malted, nonhomogeneous material and normal or fragmented hair. This dot is thought to represent the initial microscopic sign of direct toxicity of chemotherapy on the hair follicle. Chemotherapy-induced alopecia dots persist throughout chemotherapy and subsequently disappear after chemotherapy ends.²⁷

Limitations and Advantages—Currently, subtypes of cicatricial alopecias cannot be characterized on RCM because inflammatory cell types are not distinguished from each other (eg, eosinophils vs neutrophils). Another limitation of RCM is the loss of resolution below the superficial papillary dermis (a depth of approximately 150 µm); thus, deeper structures, such as the hair bulb, cannot be visualized.

Unlike global photography and trichoscopy, which are low-cost methods, RCM is much more costly, ranging upwards of several thousand dollars, and it may require additional technical support fees, making it less accessible for clinical practice. However, RCM imaging continues to be recommended as an intermediate step between trichoscopy and histology for the diagnosis and management of hair disease.²⁶ If a biopsy is required, RCM can aid in the selection of a biopsy site, as areas with active inflammation are more informative than atrophic and fibrosed areas.²³ The role of RCM in trichoscopy can be expanded by designing a more cost-effective and ergonomically suited scope for hair and scalp assessment.

Optical Coherence Tomography

Optical coherence tomography is a noninvasive handheld device that emits low-power infrared light to visualize the skin and adnexal structures. Optical coherence tomography relies on the principle of interferometry to detect phase differences in optical backscattering at varying tissue depths.^28,29 It allows visualization up to 2 mm, which is 2 to 5 times deeper than RCM.³⁶ Unlike RCM, which has cellular resolution, OCT has an axial resolution of 3 to 15 μm, which allows only for the detection of structural boundaries.³⁰ There are various OCT modalities that differ in lateral and axial resolutions and maximum depth. Commercial software is available that measures changes in vascular density by depth, epidermal thickness, skin surface texture, and optical attenuation—the latter being an indirect measurement of collagen density and skin hydration.

Structures Visualized—Hair follicles can be well distinguished on OCT images, and as such, OCT is recognized as a diagnostic tool in trichology (Figure 4).³¹ Follicular openings, interfollicular collagen, and outlines of the hair shafts are visible; however, detailed components of the follicular unit cannot be visualized by OCT. Keratin hyperrefractivity identifies the hair shaft. Additionally, the hair matrix is denoted by a slightly granular texture in the dermis. Dynamic OCT produces colorized images that visualize blood flow within vessels.

Applications of OCT—Optical coherence tomography is utilized in investigative trichology because it provides highly reproducible measurements of hair shaft diameters, cross-sectional surface areas, and form factor, which is a surrogate parameter for hair shape. The cross-section of hair shafts provides insight into local metabolism and perifollicular inflammation. Cross-sections of hair shafts in areas of alopecia areata were found to be smaller than cross-sections in the unaffected scalp within the same individual.³² Follicular density can be manually quantified on OCT images, but there also is promise for automated quantification. A recent study by Urban et al³³ described training a convolutional neural network to automatically count hair as well as hair-bearing and non–hair-bearing follicles in OCT scans. These investigators also were able to color-code hair according to height, resulting in the creation of a “height” map.

Optical coherence tomography has furthered our understanding of the pathophysiology of cicatricial and nonscarring alopecias. Vazquez-Herrera et al³⁴ assessed the inflammatory and cicatricial stages of frontal fibrosing alopecia by OCT imaging. Inflammatory hairlines, which are seen in the early stages of frontal fibrosing alopecia, exhibited a thickened dermis, irregular distribution of collagen, and increased vascularity in both the superficial and deep dermal layers compared to cicatricial and healthy scalp. Conversely, late-stage cicatricial areas exhibited a thin dermis and collagen that appeared in a hyperreflective, concentric, onion-shaped pattern around remnant follicular openings. Vascular flow was reduced in the superficial dermis of a cicatricial scalp but increased in the deep dermal layers compared with a healthy scalp. The attenuation coefficients of these disease stages also were assessed. The attenuation coefficient of the inflammatory hairline was higher compared with normal skin, likely as a reflection of inflammatory infiltrate and edema, whereas the attenuation coefficient of cicatricial scalp was lower compared with normal skin, likely reflecting the reduced water content of atrophic skin.³⁴ This differentiation of early- and late-stage cicatricial alopecias has implications for early treatment and improved prognosis. Additionally, there is potential for OCT to assist in the differentiation of alopecia subtypes, as it can measure the epidermal thickness and follicular density and was previously used to compare scarring and nonscarring alopecia.³⁵

Advantages and Limitations—Similar to RCM, OCT may be cost prohibitive for some clinicians. In addition, OCT cannot visualize the follicular unit in cellular detail. However, the extent of OCT’s capabilities may not be fully realized. Dynamic OCT is a new angiographic type of OCT that shows potential in monitoring early subclinical responses to novel alopecia therapies, such as platelet-rich plasminogen, which is hypothesized to stimulate hair growth through angiogenesis. Additionally, OCT may improve outcomes of hair transplantation procedures by allowing for visualization of the subcutaneous angle of hair follicles. Blind extraction of hair follicles in follicular unit extraction procedures can result in inadvertent transection and damage to the hair follicle; OCT could help identify good candidates for follicular unit extraction, such as patients with hair follicles in parallel arrangement, who are predicted to have better results.³⁶

Conclusion

The field of trichology will continue to evolve with the emergence of noninvasive imaging technologies that diagnose hair disease in early stages and enable treatment monitoring with quantification of hair parameters. As discussed in this review, global photography, trichoscopy, RCM, and OCT have furthered our understanding of alopecia pathophysiology and provided objective methods of treatment evaluation. The capabilities of these tools will continue to expand with advancements in add-on software and AI algorithms.

New imaging tools along with adaptations to existing technologies have been emerging in recent years, with the potential to improve hair diagnostics and treatment monitoring. We provide an overview of 4 noninvasive hair imaging technologies: global photography, trichoscopy, reflectance confocal microscopy (RCM), and optical coherence tomography (OCT). For each instrument, we discuss current and future applications in clinical practice and research along with advantages and disadvantages.

Global Photography

Global photography allows for the analysis of hair growth, volume, distribution, and density through serial standardized photographs.¹ Global photography was first introduced for hair growth studies in 1987 and soon after was used for hair and scalp assessments in finasteride clinical trials.²

Hair Assessment—Washed, dried, and combed hair, without hair product, are required for accurate imaging; wet conditions increase reflection and promote hair clumping, thus revealing more scalp and depicting the patient as having less hair.¹ Headshots are taken from short distances and use stereotactic positioning devices to create 4 global views: vertex, midline, frontal, and temporal.³ Stereotactic positioning involves fixing the patient’s chin and forehead as well as mounting the camera and flash device to ensure proper magnification. These adjustments ensure lighting remains consistent throughout consecutive study visits.⁴ Various grading scales are available for use in hair growth clinical studies to increase objectivity in the analysis of serial global photographs. A blinded evaluator should assess the before and after photographs to limit experimenter bias. Global photography often is combined with quantitative software analysis for improved detection of hair changes.¹

Advancements—Growing interest in improving global photography has resulted in various application-based, artificial intelligence (AI)–mediated tools to simplify photograph collection and analysis. For instance, new hair analysis software utilizes AI algorithms to account for facial features in determining the optimal angle for capturing global photographs (Figure 1), which simplifies the generation of global photography images through smartphone applications and obviates the need for additional stereotactic positioning equipment.^5,6

Limitations—Clinicians should be aware of global photography’s requirements for consistency in lighting, camera settings, film, and image processing, which can limit the accuracy of hair assessment over time if not replicated correctly.^7,8 Emerging global photography software has helped to overcome some of these limitations.

Global photography is less precise when a patient’s hair loss is less than 50%, as it is difficult to discern subtle hair changes. Thus, global photography provides limited utility in assessing minimal to moderate hair loss.⁹ Currently, global photography largely functions as an adjunct tool for other hair analysis methods rather than as a stand-alone tool.

Trichoscopy

Trichoscopy (also known as dermoscopy of the hair and scalp) may be performed with a manual dermoscope (with 10× magnification) or a digital videodermatoscope (up to 1000× magnification).^10-12 Unlike global photography, trichoscopy provides a detailed structural analysis of hair shafts, follicular openings, and perifollicular and interfollicular areas.¹³ Kinoshita-Ise and Sachdeva¹³ provided an in-depth, updated review of trichoscopy terminology with their definitions and associated conditions (with prevalence), which should be referenced when performing trichoscopic examination.

Hair Assessment—Trichoscopic assessment begins with inspection of follicular openings (also referred to as “dots”), which vary in color depending on the material filling them—degrading keratinocytes, keratin, sebaceous debris, melanin, or fractured hairs.¹³ The structure of hair shafts also is examined, showing broken hairs, short vellus hairs, and comma hairs, among others. Perifollicular areas are examined for scale, erythema, blue-gray dots, and whitish halos. Interfollicular areas are examined for pigment pattern as well as vascularization, which often presents in a looping configuration under dermoscopy. A combination of dot colorization, hair shaft structure, and perifollicular and interfollicular findings inform diagnostic algorithms of hair and scalp conditions. For example, central centrifugal cicatricial alopecia, the most common alopecia seen in Black women, has been associated with a combination of honeycomb pigment pattern, perifollicular whitish halo, pinpoint white dots, white patches, and perifollicular erythema.¹³

Advantages—Perhaps the most useful feature of trichoscopy is its ability to translate visualized features into simple diagnostic algorithms. For instance, if the clinician has diagnosed the patient with noncicatricial alopecia, they would next focus on dot colors. With black dots, the next step would be to determine whether the hairs are tapered or coiled, and so on. This systematic approach enables the clinician to narrow possible diagnoses.² An additional advantage of trichoscopy is that it examines large surface areas noninvasively as compared to hair-pull tests and scalp biopsy.^14,15 Trichoscopy allows temporal comparisons of the same area for disease and treatment monitoring with more diagnostic detail than global photography.¹⁶ Trichoscopy also is useful in selecting biopsy locations by discerning and avoiding areas of scar tissue.¹⁷

Limitations—Diagnosis via the trichoscopy algorithm is limiting because it is not comprehensive of all hair and scalp disease.¹⁸ Additionally, many pathologies exhibit overlapping follicular and interfollicular patterning. For example, almost all subtypes of scarring alopecia present with hair loss and scarred follicles once they have progressed to advanced stages. Further studies should identify more specific patterns of hair and scalp pathologies, which could then be incorporated into a diagnostic algorithm.¹³

Advancements—The advent of hair analysis software has expanded the role of videodermoscopy by rapidly quantifying hair growth parameters such as hair count, follicular density, and follicular diameter, as well as interfollicular distances (Figure 2).^14,17 Vellus and terminal hairs are differentiated according to their thickness and length.¹⁷ Moreover, the software can analyze the same area of the scalp over time by either virtual tattoos, semipermanent markings, or precise location measurements, increasing intra- and interclass correlation. The rate of hair growth, hair shedding, and parameters of anagen and telogen hairs can be studied by a method termed phototrichogram whereby a transitional area of hair loss and normal hair growth is identified and trimmed to less than 1 mm from the skin surface.¹⁹ A baseline photograph is taken using videodermoscopy. After approximately 3 days, the identical region is photographed and compared with the initial image to observe changes in the hair. Software programs can distinguish the growing hair as anagen and nongrowing hair as telogen, calculating the anagen-to-telogen ratio as well as hair growth rate, which are essential measurements in hair research and clinical studies. Software programs have replaced laborious and time-consuming manual hair counts and have rapidly grown in popularity in evaluating patterned hair loss.

Reflectance Confocal Microscopy

Reflectance confocal microscopy is a noninvasive imaging tool that visualizes skin and its appendages at near-histologic resolution (lateral resolution of 0.5–1 μm). It produces grayscale horizontal images that can be taken at levels ranging from the stratum corneum to the superficial papillary dermis, corresponding to a depth of approximately 100 to 150 µm. Thus, a hair follicle can be imaged starting from the follicular ostia down to the reachable papillary dermis (Figure 3).²⁰ Image contrast is provided by differences in the size and refractive indices of cellular organelles.^21,22 There are 2 commercially available RCM devices: VivaScope 1500 and VivaScope 3000 (Caliber Imaging & Diagnostics, Inc).

VivaScope 1500, a wide-probe microscope, requires the attachment of a plastic window to the desired imaging area. The plastic window is lined with medical adhesive tape to prevent movement during imaging. The adhesive tape can pull on hair upon removal, which is not ideal for patients with existing hair loss. Additionally, the image quality of VivaSope 1500 is best in flat areas and areas where hair is shaved.^20,23,24 Despite these disadvantages, VivaScope 1500 has successfully shown utility in research studies, which suggests that these obstacles can be overcome by experienced users. The handheld VivaScope 3000 is ergonomically designed and suitable for curved surfaces such as the scalp, with the advantage of not requiring any adhesive. However, the images acquired from the VivaScope 3000 cover a smaller surface area.

Structures Visualized—Structures distinguished with RCM include keratinocytes, melanocytes, inflammatory cells, hair follicles, hair shafts, adnexal infundibular epithelium, blood vessels, fibroblasts, and collagen.²³ Real-time visualization of blood flow also can be seen.

Applications of RCM—Reflectance confocal microscopy has been used to study scalp discoid lupus, lichen planopilaris, frontal fibrosing alopecia, folliculitis decalvans, chemotherapy-induced alopecia (CIA), alopecia areata, and androgenetic alopecia. Diagnostic RCM criteria for such alopecias have been developed based on their correspondence to histopathology. An RCM study of classic lichen planopilaris and frontal fibrosing alopecia identified features of epidermal disarray, infundibular hyperkeratosis, inflammatory cells, pigment incontinence, perifollicular fibrosis, bandlike scarring, melanophages in the dermis, dilated blood vessels, basal layer vacuolar degeneration, and necrotic keratinocytes.²⁵ Pigment incontinence in the superficial epidermis, perifollicular lichenoid inflammation, and hyperkeratosis were characteristic RCM features of early-stage lichen planopilaris, while perifollicular fibrosis and dilated blood vessels were characteristic RCM features of late-stage disease. The ability of RCM features to distinguish different stages of lichen planopilaris shows its potential in treating early disease and preventing irreversible hair loss.

Differentiating between scarring and nonscarring alopecia also is possible through RCM. The presence of periadnexal, epidermal, and dermal inflammatory cells, in addition to periadnexal sclerosis, are defining RCM features of scarring alopecia.²⁶ These features are absent in nonscarring alopecias. Reflectance confocal microscopy additionally has been shown to be useful in the treatment monitoring of lichen planopilaris and discoid lupus erythematosus.²⁰ Independent reviewers, blinded to the patients’ identities, were able to characterize and follow features of these scarring alopecias by RCM. The assessed RCM features were comparable to those observed by histopathologic evaluation: epidermal disarray, spongiosis, exocytosis of inflammatory cells in the epidermis, interface dermatitis, peri- and intra-adnexal infiltration of inflammatory cells, dilated vessels in the dermis, dermal infiltration of inflammatory cells and melanophages, and dermal sclerosis. A reduction in inflammatory cells across multiple skin layers and at the level of the adnexal epithelium correlated with clinical response to treatment. Reflectance confocal microscopy also was able to detect recurrence of inflammation in cases where treatment had been interrupted before clinical signs of disease recurrence were evident. The authors thus concluded that RCM’s sensitivity can guide timing of treatment and avoid delays in starting or restarting treatment.²⁰

Reflectance confocal microscopy also has served as a learning tool for new subclinical understandings of alopecia. In a study of CIA, the disease was found to be a dynamic process that could be categorized into 4 distinct phases distinguishable by combined confocal and dermoscopic features. This study also identified a new feature observable on RCM images—a CIA dot—defined as a dilated follicular infundibulum containing mashed, malted, nonhomogeneous material and normal or fragmented hair. This dot is thought to represent the initial microscopic sign of direct toxicity of chemotherapy on the hair follicle. Chemotherapy-induced alopecia dots persist throughout chemotherapy and subsequently disappear after chemotherapy ends.²⁷

Limitations and Advantages—Currently, subtypes of cicatricial alopecias cannot be characterized on RCM because inflammatory cell types are not distinguished from each other (eg, eosinophils vs neutrophils). Another limitation of RCM is the loss of resolution below the superficial papillary dermis (a depth of approximately 150 µm); thus, deeper structures, such as the hair bulb, cannot be visualized.

Unlike global photography and trichoscopy, which are low-cost methods, RCM is much more costly, ranging upwards of several thousand dollars, and it may require additional technical support fees, making it less accessible for clinical practice. However, RCM imaging continues to be recommended as an intermediate step between trichoscopy and histology for the diagnosis and management of hair disease.²⁶ If a biopsy is required, RCM can aid in the selection of a biopsy site, as areas with active inflammation are more informative than atrophic and fibrosed areas.²³ The role of RCM in trichoscopy can be expanded by designing a more cost-effective and ergonomically suited scope for hair and scalp assessment.

Optical Coherence Tomography

Optical coherence tomography is a noninvasive handheld device that emits low-power infrared light to visualize the skin and adnexal structures. Optical coherence tomography relies on the principle of interferometry to detect phase differences in optical backscattering at varying tissue depths.^28,29 It allows visualization up to 2 mm, which is 2 to 5 times deeper than RCM.³⁶ Unlike RCM, which has cellular resolution, OCT has an axial resolution of 3 to 15 μm, which allows only for the detection of structural boundaries.³⁰ There are various OCT modalities that differ in lateral and axial resolutions and maximum depth. Commercial software is available that measures changes in vascular density by depth, epidermal thickness, skin surface texture, and optical attenuation—the latter being an indirect measurement of collagen density and skin hydration.

Structures Visualized—Hair follicles can be well distinguished on OCT images, and as such, OCT is recognized as a diagnostic tool in trichology (Figure 4).³¹ Follicular openings, interfollicular collagen, and outlines of the hair shafts are visible; however, detailed components of the follicular unit cannot be visualized by OCT. Keratin hyperrefractivity identifies the hair shaft. Additionally, the hair matrix is denoted by a slightly granular texture in the dermis. Dynamic OCT produces colorized images that visualize blood flow within vessels.

Applications of OCT—Optical coherence tomography is utilized in investigative trichology because it provides highly reproducible measurements of hair shaft diameters, cross-sectional surface areas, and form factor, which is a surrogate parameter for hair shape. The cross-section of hair shafts provides insight into local metabolism and perifollicular inflammation. Cross-sections of hair shafts in areas of alopecia areata were found to be smaller than cross-sections in the unaffected scalp within the same individual.³² Follicular density can be manually quantified on OCT images, but there also is promise for automated quantification. A recent study by Urban et al³³ described training a convolutional neural network to automatically count hair as well as hair-bearing and non–hair-bearing follicles in OCT scans. These investigators also were able to color-code hair according to height, resulting in the creation of a “height” map.

Optical coherence tomography has furthered our understanding of the pathophysiology of cicatricial and nonscarring alopecias. Vazquez-Herrera et al³⁴ assessed the inflammatory and cicatricial stages of frontal fibrosing alopecia by OCT imaging. Inflammatory hairlines, which are seen in the early stages of frontal fibrosing alopecia, exhibited a thickened dermis, irregular distribution of collagen, and increased vascularity in both the superficial and deep dermal layers compared to cicatricial and healthy scalp. Conversely, late-stage cicatricial areas exhibited a thin dermis and collagen that appeared in a hyperreflective, concentric, onion-shaped pattern around remnant follicular openings. Vascular flow was reduced in the superficial dermis of a cicatricial scalp but increased in the deep dermal layers compared with a healthy scalp. The attenuation coefficients of these disease stages also were assessed. The attenuation coefficient of the inflammatory hairline was higher compared with normal skin, likely as a reflection of inflammatory infiltrate and edema, whereas the attenuation coefficient of cicatricial scalp was lower compared with normal skin, likely reflecting the reduced water content of atrophic skin.³⁴ This differentiation of early- and late-stage cicatricial alopecias has implications for early treatment and improved prognosis. Additionally, there is potential for OCT to assist in the differentiation of alopecia subtypes, as it can measure the epidermal thickness and follicular density and was previously used to compare scarring and nonscarring alopecia.³⁵

Advantages and Limitations—Similar to RCM, OCT may be cost prohibitive for some clinicians. In addition, OCT cannot visualize the follicular unit in cellular detail. However, the extent of OCT’s capabilities may not be fully realized. Dynamic OCT is a new angiographic type of OCT that shows potential in monitoring early subclinical responses to novel alopecia therapies, such as platelet-rich plasminogen, which is hypothesized to stimulate hair growth through angiogenesis. Additionally, OCT may improve outcomes of hair transplantation procedures by allowing for visualization of the subcutaneous angle of hair follicles. Blind extraction of hair follicles in follicular unit extraction procedures can result in inadvertent transection and damage to the hair follicle; OCT could help identify good candidates for follicular unit extraction, such as patients with hair follicles in parallel arrangement, who are predicted to have better results.³⁶

Conclusion

The field of trichology will continue to evolve with the emergence of noninvasive imaging technologies that diagnose hair disease in early stages and enable treatment monitoring with quantification of hair parameters. As discussed in this review, global photography, trichoscopy, RCM, and OCT have furthered our understanding of alopecia pathophysiology and provided objective methods of treatment evaluation. The capabilities of these tools will continue to expand with advancements in add-on software and AI algorithms.

New imaging tools along with adaptations to existing technologies have been emerging in recent years, with the potential to improve hair diagnostics and treatment monitoring. We provide an overview of 4 noninvasive hair imaging technologies: global photography, trichoscopy, reflectance confocal microscopy (RCM), and optical coherence tomography (OCT). For each instrument, we discuss current and future applications in clinical practice and research along with advantages and disadvantages.

Global Photography

Global photography allows for the analysis of hair growth, volume, distribution, and density through serial standardized photographs.¹ Global photography was first introduced for hair growth studies in 1987 and soon after was used for hair and scalp assessments in finasteride clinical trials.²

Hair Assessment—Washed, dried, and combed hair, without hair product, are required for accurate imaging; wet conditions increase reflection and promote hair clumping, thus revealing more scalp and depicting the patient as having less hair.¹ Headshots are taken from short distances and use stereotactic positioning devices to create 4 global views: vertex, midline, frontal, and temporal.³ Stereotactic positioning involves fixing the patient’s chin and forehead as well as mounting the camera and flash device to ensure proper magnification. These adjustments ensure lighting remains consistent throughout consecutive study visits.⁴ Various grading scales are available for use in hair growth clinical studies to increase objectivity in the analysis of serial global photographs. A blinded evaluator should assess the before and after photographs to limit experimenter bias. Global photography often is combined with quantitative software analysis for improved detection of hair changes.¹

Advancements—Growing interest in improving global photography has resulted in various application-based, artificial intelligence (AI)–mediated tools to simplify photograph collection and analysis. For instance, new hair analysis software utilizes AI algorithms to account for facial features in determining the optimal angle for capturing global photographs (Figure 1), which simplifies the generation of global photography images through smartphone applications and obviates the need for additional stereotactic positioning equipment.^5,6

Limitations—Clinicians should be aware of global photography’s requirements for consistency in lighting, camera settings, film, and image processing, which can limit the accuracy of hair assessment over time if not replicated correctly.^7,8 Emerging global photography software has helped to overcome some of these limitations.

Global photography is less precise when a patient’s hair loss is less than 50%, as it is difficult to discern subtle hair changes. Thus, global photography provides limited utility in assessing minimal to moderate hair loss.⁹ Currently, global photography largely functions as an adjunct tool for other hair analysis methods rather than as a stand-alone tool.

Trichoscopy

Trichoscopy (also known as dermoscopy of the hair and scalp) may be performed with a manual dermoscope (with 10× magnification) or a digital videodermatoscope (up to 1000× magnification).^10-12 Unlike global photography, trichoscopy provides a detailed structural analysis of hair shafts, follicular openings, and perifollicular and interfollicular areas.¹³ Kinoshita-Ise and Sachdeva¹³ provided an in-depth, updated review of trichoscopy terminology with their definitions and associated conditions (with prevalence), which should be referenced when performing trichoscopic examination.

Hair Assessment—Trichoscopic assessment begins with inspection of follicular openings (also referred to as “dots”), which vary in color depending on the material filling them—degrading keratinocytes, keratin, sebaceous debris, melanin, or fractured hairs.¹³ The structure of hair shafts also is examined, showing broken hairs, short vellus hairs, and comma hairs, among others. Perifollicular areas are examined for scale, erythema, blue-gray dots, and whitish halos. Interfollicular areas are examined for pigment pattern as well as vascularization, which often presents in a looping configuration under dermoscopy. A combination of dot colorization, hair shaft structure, and perifollicular and interfollicular findings inform diagnostic algorithms of hair and scalp conditions. For example, central centrifugal cicatricial alopecia, the most common alopecia seen in Black women, has been associated with a combination of honeycomb pigment pattern, perifollicular whitish halo, pinpoint white dots, white patches, and perifollicular erythema.¹³

Advantages—Perhaps the most useful feature of trichoscopy is its ability to translate visualized features into simple diagnostic algorithms. For instance, if the clinician has diagnosed the patient with noncicatricial alopecia, they would next focus on dot colors. With black dots, the next step would be to determine whether the hairs are tapered or coiled, and so on. This systematic approach enables the clinician to narrow possible diagnoses.² An additional advantage of trichoscopy is that it examines large surface areas noninvasively as compared to hair-pull tests and scalp biopsy.^14,15 Trichoscopy allows temporal comparisons of the same area for disease and treatment monitoring with more diagnostic detail than global photography.¹⁶ Trichoscopy also is useful in selecting biopsy locations by discerning and avoiding areas of scar tissue.¹⁷

Limitations—Diagnosis via the trichoscopy algorithm is limiting because it is not comprehensive of all hair and scalp disease.¹⁸ Additionally, many pathologies exhibit overlapping follicular and interfollicular patterning. For example, almost all subtypes of scarring alopecia present with hair loss and scarred follicles once they have progressed to advanced stages. Further studies should identify more specific patterns of hair and scalp pathologies, which could then be incorporated into a diagnostic algorithm.¹³

Advancements—The advent of hair analysis software has expanded the role of videodermoscopy by rapidly quantifying hair growth parameters such as hair count, follicular density, and follicular diameter, as well as interfollicular distances (Figure 2).^14,17 Vellus and terminal hairs are differentiated according to their thickness and length.¹⁷ Moreover, the software can analyze the same area of the scalp over time by either virtual tattoos, semipermanent markings, or precise location measurements, increasing intra- and interclass correlation. The rate of hair growth, hair shedding, and parameters of anagen and telogen hairs can be studied by a method termed phototrichogram whereby a transitional area of hair loss and normal hair growth is identified and trimmed to less than 1 mm from the skin surface.¹⁹ A baseline photograph is taken using videodermoscopy. After approximately 3 days, the identical region is photographed and compared with the initial image to observe changes in the hair. Software programs can distinguish the growing hair as anagen and nongrowing hair as telogen, calculating the anagen-to-telogen ratio as well as hair growth rate, which are essential measurements in hair research and clinical studies. Software programs have replaced laborious and time-consuming manual hair counts and have rapidly grown in popularity in evaluating patterned hair loss.

Reflectance Confocal Microscopy

Reflectance confocal microscopy is a noninvasive imaging tool that visualizes skin and its appendages at near-histologic resolution (lateral resolution of 0.5–1 μm). It produces grayscale horizontal images that can be taken at levels ranging from the stratum corneum to the superficial papillary dermis, corresponding to a depth of approximately 100 to 150 µm. Thus, a hair follicle can be imaged starting from the follicular ostia down to the reachable papillary dermis (Figure 3).²⁰ Image contrast is provided by differences in the size and refractive indices of cellular organelles.^21,22 There are 2 commercially available RCM devices: VivaScope 1500 and VivaScope 3000 (Caliber Imaging & Diagnostics, Inc).

VivaScope 1500, a wide-probe microscope, requires the attachment of a plastic window to the desired imaging area. The plastic window is lined with medical adhesive tape to prevent movement during imaging. The adhesive tape can pull on hair upon removal, which is not ideal for patients with existing hair loss. Additionally, the image quality of VivaSope 1500 is best in flat areas and areas where hair is shaved.^20,23,24 Despite these disadvantages, VivaScope 1500 has successfully shown utility in research studies, which suggests that these obstacles can be overcome by experienced users. The handheld VivaScope 3000 is ergonomically designed and suitable for curved surfaces such as the scalp, with the advantage of not requiring any adhesive. However, the images acquired from the VivaScope 3000 cover a smaller surface area.

Structures Visualized—Structures distinguished with RCM include keratinocytes, melanocytes, inflammatory cells, hair follicles, hair shafts, adnexal infundibular epithelium, blood vessels, fibroblasts, and collagen.²³ Real-time visualization of blood flow also can be seen.

Applications of RCM—Reflectance confocal microscopy has been used to study scalp discoid lupus, lichen planopilaris, frontal fibrosing alopecia, folliculitis decalvans, chemotherapy-induced alopecia (CIA), alopecia areata, and androgenetic alopecia. Diagnostic RCM criteria for such alopecias have been developed based on their correspondence to histopathology. An RCM study of classic lichen planopilaris and frontal fibrosing alopecia identified features of epidermal disarray, infundibular hyperkeratosis, inflammatory cells, pigment incontinence, perifollicular fibrosis, bandlike scarring, melanophages in the dermis, dilated blood vessels, basal layer vacuolar degeneration, and necrotic keratinocytes.²⁵ Pigment incontinence in the superficial epidermis, perifollicular lichenoid inflammation, and hyperkeratosis were characteristic RCM features of early-stage lichen planopilaris, while perifollicular fibrosis and dilated blood vessels were characteristic RCM features of late-stage disease. The ability of RCM features to distinguish different stages of lichen planopilaris shows its potential in treating early disease and preventing irreversible hair loss.

Differentiating between scarring and nonscarring alopecia also is possible through RCM. The presence of periadnexal, epidermal, and dermal inflammatory cells, in addition to periadnexal sclerosis, are defining RCM features of scarring alopecia.²⁶ These features are absent in nonscarring alopecias. Reflectance confocal microscopy additionally has been shown to be useful in the treatment monitoring of lichen planopilaris and discoid lupus erythematosus.²⁰ Independent reviewers, blinded to the patients’ identities, were able to characterize and follow features of these scarring alopecias by RCM. The assessed RCM features were comparable to those observed by histopathologic evaluation: epidermal disarray, spongiosis, exocytosis of inflammatory cells in the epidermis, interface dermatitis, peri- and intra-adnexal infiltration of inflammatory cells, dilated vessels in the dermis, dermal infiltration of inflammatory cells and melanophages, and dermal sclerosis. A reduction in inflammatory cells across multiple skin layers and at the level of the adnexal epithelium correlated with clinical response to treatment. Reflectance confocal microscopy also was able to detect recurrence of inflammation in cases where treatment had been interrupted before clinical signs of disease recurrence were evident. The authors thus concluded that RCM’s sensitivity can guide timing of treatment and avoid delays in starting or restarting treatment.²⁰

Reflectance confocal microscopy also has served as a learning tool for new subclinical understandings of alopecia. In a study of CIA, the disease was found to be a dynamic process that could be categorized into 4 distinct phases distinguishable by combined confocal and dermoscopic features. This study also identified a new feature observable on RCM images—a CIA dot—defined as a dilated follicular infundibulum containing mashed, malted, nonhomogeneous material and normal or fragmented hair. This dot is thought to represent the initial microscopic sign of direct toxicity of chemotherapy on the hair follicle. Chemotherapy-induced alopecia dots persist throughout chemotherapy and subsequently disappear after chemotherapy ends.²⁷

Limitations and Advantages—Currently, subtypes of cicatricial alopecias cannot be characterized on RCM because inflammatory cell types are not distinguished from each other (eg, eosinophils vs neutrophils). Another limitation of RCM is the loss of resolution below the superficial papillary dermis (a depth of approximately 150 µm); thus, deeper structures, such as the hair bulb, cannot be visualized.

Unlike global photography and trichoscopy, which are low-cost methods, RCM is much more costly, ranging upwards of several thousand dollars, and it may require additional technical support fees, making it less accessible for clinical practice. However, RCM imaging continues to be recommended as an intermediate step between trichoscopy and histology for the diagnosis and management of hair disease.²⁶ If a biopsy is required, RCM can aid in the selection of a biopsy site, as areas with active inflammation are more informative than atrophic and fibrosed areas.²³ The role of RCM in trichoscopy can be expanded by designing a more cost-effective and ergonomically suited scope for hair and scalp assessment.

Optical Coherence Tomography

Optical coherence tomography is a noninvasive handheld device that emits low-power infrared light to visualize the skin and adnexal structures. Optical coherence tomography relies on the principle of interferometry to detect phase differences in optical backscattering at varying tissue depths.^28,29 It allows visualization up to 2 mm, which is 2 to 5 times deeper than RCM.³⁶ Unlike RCM, which has cellular resolution, OCT has an axial resolution of 3 to 15 μm, which allows only for the detection of structural boundaries.³⁰ There are various OCT modalities that differ in lateral and axial resolutions and maximum depth. Commercial software is available that measures changes in vascular density by depth, epidermal thickness, skin surface texture, and optical attenuation—the latter being an indirect measurement of collagen density and skin hydration.

Structures Visualized—Hair follicles can be well distinguished on OCT images, and as such, OCT is recognized as a diagnostic tool in trichology (Figure 4).³¹ Follicular openings, interfollicular collagen, and outlines of the hair shafts are visible; however, detailed components of the follicular unit cannot be visualized by OCT. Keratin hyperrefractivity identifies the hair shaft. Additionally, the hair matrix is denoted by a slightly granular texture in the dermis. Dynamic OCT produces colorized images that visualize blood flow within vessels.

Applications of OCT—Optical coherence tomography is utilized in investigative trichology because it provides highly reproducible measurements of hair shaft diameters, cross-sectional surface areas, and form factor, which is a surrogate parameter for hair shape. The cross-section of hair shafts provides insight into local metabolism and perifollicular inflammation. Cross-sections of hair shafts in areas of alopecia areata were found to be smaller than cross-sections in the unaffected scalp within the same individual.³² Follicular density can be manually quantified on OCT images, but there also is promise for automated quantification. A recent study by Urban et al³³ described training a convolutional neural network to automatically count hair as well as hair-bearing and non–hair-bearing follicles in OCT scans. These investigators also were able to color-code hair according to height, resulting in the creation of a “height” map.

Optical coherence tomography has furthered our understanding of the pathophysiology of cicatricial and nonscarring alopecias. Vazquez-Herrera et al³⁴ assessed the inflammatory and cicatricial stages of frontal fibrosing alopecia by OCT imaging. Inflammatory hairlines, which are seen in the early stages of frontal fibrosing alopecia, exhibited a thickened dermis, irregular distribution of collagen, and increased vascularity in both the superficial and deep dermal layers compared to cicatricial and healthy scalp. Conversely, late-stage cicatricial areas exhibited a thin dermis and collagen that appeared in a hyperreflective, concentric, onion-shaped pattern around remnant follicular openings. Vascular flow was reduced in the superficial dermis of a cicatricial scalp but increased in the deep dermal layers compared with a healthy scalp. The attenuation coefficients of these disease stages also were assessed. The attenuation coefficient of the inflammatory hairline was higher compared with normal skin, likely as a reflection of inflammatory infiltrate and edema, whereas the attenuation coefficient of cicatricial scalp was lower compared with normal skin, likely reflecting the reduced water content of atrophic skin.³⁴ This differentiation of early- and late-stage cicatricial alopecias has implications for early treatment and improved prognosis. Additionally, there is potential for OCT to assist in the differentiation of alopecia subtypes, as it can measure the epidermal thickness and follicular density and was previously used to compare scarring and nonscarring alopecia.³⁵

Advantages and Limitations—Similar to RCM, OCT may be cost prohibitive for some clinicians. In addition, OCT cannot visualize the follicular unit in cellular detail. However, the extent of OCT’s capabilities may not be fully realized. Dynamic OCT is a new angiographic type of OCT that shows potential in monitoring early subclinical responses to novel alopecia therapies, such as platelet-rich plasminogen, which is hypothesized to stimulate hair growth through angiogenesis. Additionally, OCT may improve outcomes of hair transplantation procedures by allowing for visualization of the subcutaneous angle of hair follicles. Blind extraction of hair follicles in follicular unit extraction procedures can result in inadvertent transection and damage to the hair follicle; OCT could help identify good candidates for follicular unit extraction, such as patients with hair follicles in parallel arrangement, who are predicted to have better results.³⁶

Conclusion

The field of trichology will continue to evolve with the emergence of noninvasive imaging technologies that diagnose hair disease in early stages and enable treatment monitoring with quantification of hair parameters. As discussed in this review, global photography, trichoscopy, RCM, and OCT have furthered our understanding of alopecia pathophysiology and provided objective methods of treatment evaluation. The capabilities of these tools will continue to expand with advancements in add-on software and AI algorithms.

Brachioradial pruritus (BRP) is a neuropathic condition typically characterized by localized dysesthesia of the dorsolateral arms.¹ This dysesthesia has been described as a persistent painful itching, burning, tingling, or stinging sensation^2-4 and has a median duration of expression of 24 months.^5,6 The condition may be unilateral or bilateral in nature but tends to have a predilection for a bilateral distribution along the C5 to C6 dermatomes.^1,7,8 There are no primary skin lesions associated with BRP; however, excoriations, prurigo nodules, and lichenification may arise secondary to scratching of the irritated skin.^1,4,5,9 Brachioradial pruritus tends to have a predilection for adult females (3:1 ratio) with lighter skin. The mean age at diagnosis is 59 years, but cases have been reported in patients aged 12 to 84 years.^1,5 The diagnosis of BRP is based on clinical signs and symptoms, though the ice-pack sign tends to be pathognomonic for the diagnosis.^10,11 Although there is no clear evidence on the exact cause of BRP, there are 2 prevalent theories: cervical radiculopathy secondary to cervical spine pathology and/or excessive exposure to UV radiation (UVR) in the summer months.^3-5,12 Brachioradial pruritus remains poorly described in the literature, and even its origin is under debate. As such, the clinician may have difficulty deciding on the best course of management. The goal of this article is to identify and discuss known treatment options for BRP (Table).

Etiology 

Cervical Spine Pathology—A correlation appears to exist between BRP and cervical spine changes seen on plain film radiographs at the levels of C3 to C7, with increased incidence at the C5 to C6 levels. These plain film radiographs typically show degenerative joint disease and neural foraminal stenosis at levels that correlate to the dermatomal distribution of BRP.^1,7,10,12-14 In addition to plain film radiography, some studies have utilized magnetic resonance imaging to view the cervical spine and have documented evidence of intervertebral disc protrusion/bulging, central canal stenosis, neuroforaminal stenosis, and spondylosis at the affected regions.^5,15-17 Moreover, supporting the theory that the cervical spine is responsible for the emergence of BRP, Marziniak et al¹⁷ investigated 41 patients with BRP utilizing magnetic resonance tomography to find that 33 patients (80.5%) had changes in nerve compression, and 8 patients (19.5%) had degenerative changes. In addition to these findings, they found that there was a significant correlation (P<.01) between the dermatomal expression of BRP and the location of cervical anatomical changes.¹⁷ Further validating the relationship between cervical spine pathology and BRP is a case study of a patient who saw rapid and complete resolution of the pruritus following spinal decompression surgery.¹⁰ Another case study described an intramedullary tumor found in a patient with BRP that was diagnosed as an ependymoma after magnetic resonance imaging revealed an intramedullary lesion within the spinal cord between C4 and C7. The location of the tumor and dermatomal pattern of the neuropathic itch pointed to a possible association between nerve compression and BRP.¹⁴ Electromyography studies performed on individuals with BRP have shown an increase in polyphasic units, decreased motor units, and/or denervation changes along the C5/C6 or C6 nerve roots, which provides additional support for the theory of cervical spine pathology as a causative factor for BRP.¹⁶

UVR Exposure—Another etiologic theory for BRP is that UVR exposure may be responsible for the genesis of pruritus. Previously known as solar pruritus, BRP was deemed a clinical condition, as there was increased prevalence in patients living in warmer climates, such as Florida.⁹ Wallengren and Dahlbäck¹⁸ reported that sun exposure is a notable factor in the onset of BRP, as they saw an increase in symptoms during the late summer and a decrease in symptoms over the winter months.To further support the theory that UVR is linked to BRP, several studies have shown that the utilization of sun protection is linked to a reduction of symptoms, specifically in patients who showed seasonal variations of their symptoms.^9,12,19 Additionally, a study by Mirzoyev and Davis⁵ retrospectively reviewed 111 patients diagnosed with BRP. Of these patients, 84 (75.7%) presented with bilateral symptoms, and 54 (48.6%) reported prolonged sun exposure. Both of these findings demonstrate correlation between UVR and BRP.⁵ Interestingly, UV light exposure is known to release β-endorphin in the skin and may theoretically provide an area of exploration between UVR and cervical spine theories.

Conservative Treatment 

Chiropractic Manipulation—Because one etiologic theory includes disease of the cervical spine, there is evidence that targeting this region with treatment is beneficial.⁷ Two case reports found in the literature noted that cervical spine manipulation and cervical traction yielded positive results.^20,21 It has been established that pain generated by disc lesions can be the result of local nociceptive fiber activation, direct mechanical compression of the nerve roots, or inflammatory mediators.²² There are several postulated models describing the hypoalgesic effects of spinal manipulation, which contains both biomechanical and neurophysiological mechanisms. Biomechanical changes theorized to elicit analgesia include restoration of faulty biomechanical movement patterns, breaking up of periarticular adhesions, and reflexogenic muscle inhibition of hypertonic musculature. Hypothesized neurophysiological effects of joint manipulation include an increase in afferent information overwhelming the nociceptive input, reduction of temporal summation, and autonomic activation leading to non–opioid-induced hypoalgesia.²³ Cervical traction is another plausible treatment for BRP, wherein the physiological effects of traction allow for a separation of vertebral bodies and expansion of the intervertebral foramen circumference, thus decreasing compression of the nerve roots.²⁴

Acupuncture—Neurogenic pruritus, including BRP, is a group of conditions that have been treated using acupuncture. Acupuncture treatment consists of intramuscular needle stimulation and has been found to alleviate itching in patients with neurogenic pruritus. In 1 retrospective case series, acupuncture was used to treat 16 patients who were identified as having segmental pruritus. Acupuncture targeted the spasmed paravertebral muscles of the affected dermatomal levels as well as other regions of the body, and it was found that 12 patients (75%) experienced full resolution of symptoms. However, relapse did occur in 6 patients (37%) within 1 to 12 months following treatment.²⁵ Multiple theories exist as to why acupuncture may help. One is that it relieves muscle spasms, which in turn relieves neural irritation of the spinal nerves as they traverse the respective paraspinal musculature. Another is that acupuncture decreases nociception by stimulating release of opioid peptides in the dorsal horn.²⁶ A third proposed theory is that acupuncture acts on the afferent nerve fibers responsible for transmitting pain—Aδ and C fibers—activating these afferent nerves to produce an analgesic effect.²⁷

Physiotherapy—The literature suggests that possible first-line therapies for neurogenic pruritus, including BRP and notalgia paresthetica, consist of noninvasive nondermatologic treatments that target cervical spine disease. Notalgia paresthetica and BRP have similar proposed mechanisms of nerve impingement; therefore, they often are grouped together when discussing proposed manual treatment options. Physiotherapy treatment includes cervical muscle strengthening, increased range of motion, application of cervical soft collars, massage, transcutaneous electronic nerve stimulation, and cervical traction.⁷ A study of 12 patients by Raison-Peyron et al²⁸ in 1999 discussed the use of spinal and paraspinal ultrasound or radiation physiotherapy. Six patients underwent this treatment, and the symptoms subsided in 4 cases.²⁸ Another study by Fleischer et al²⁹ in 2011 discussed improvement in 2 patients with notalgia paresthetica by exercise involving active range of motion and strengthening.

Photoprotection—Avoidance of UVR exposure has been beneficial to some patients to reduce symptoms. Use of sunscreen and long-sleeved UV-protective clothing during outdoor activities or the warmer summer months may be beneficial.¹

Medication—Because of the nonspecific clinical presentation of BRP, initial treatment often involves prescription of first-line antipruritic agents, including steroid creams and systemic antihistamines, both of which generally fail to provide symptom relief.^1,30 Medications with neurologic mechanisms of action appear to provide potentially superior outcomes. Neuroleptics, including gabapentin and pregabalin, are typical therapeutic agents for neurogenic pruritus and inhibit nociceptive pain propagation.³¹ Intervention with pregabalin in 3 patients with BRP achieved complete symptom relief in all patients, with initial improvement occurring in as little as 1 week.⁸Mirogabalin, operating under a similar mechanism, has shown preliminary success in treating BRP, causing anecdotal patient improvement within 4 months of initial dosage.³² Prolonged 1-month intravenous naloxone treatment also appars to be promising, offering symptom improvement of at least 80% six months posttreatment.¹⁵ 

Topical interventions for BRP and related neurogenic pruritus have shown limited success. A case series evaluating capsaicin for pruritus offered only transient relief, likely because of its temporary hyperstimulatory and desensitizing effect on neuropeptides.^7,33 In small populations, the use of topical antidepressants has yielded cutaneous and pathological relief for BRP. A case study of a 70-year-old woman evaluated the efficacy of a combination cream of ketamine and amitriptyline (a tricyclic antidepressant) yielding moderate pruritus improvement and notable improvement of secondary brachial skin lesions.³⁴ Oral steroids also have shown success in the treatment of chronic pruritus; however, limited research is available on the efficacy of such medications for BRP, and the long-term use of oral steroids is limited by many side effects.³⁰ 

Interventional Pain Procedure—A 2018 case series investigated 3 patients with a clinical diagnosis of BRP who were treated between 2010 and 2016 with epidural steroid injection using computed tomography guidance of the cervical spine.³⁵ The authors reported that 2 patients had near-complete resolution after 1 interventional procedure. The third patient had a total of 3 injections, with mild to moderate relief that continued to improve on mexiletine.³⁵ Another case in 2010 of a 56-year-old man with BRP documented use of a series of 2 epidural steroid injections that resulted in clinical resolution of symptoms.³⁶

Surgery—There are multiple case studies in the literature that discuss anterior cervical discectomy and fusion (ACDF) as a last resort in patients with refractory BRP of discogenic cause. In 2022, Morosanu et al³⁷ described a case of a 63-year-old woman with BRP in the C5–C6 distribution who had an associated disc protrusion at this level following magnetic resonance imaging. The patient underwent a C5/C6 ACDF after conservative and medical treatment failed, and at 3-month follow up her symptoms had resolved entirely.³⁷ Another case report described a 56-year-old man who ultimately underwent ACDF after failed multimodal treatment attempts, with instant improvement in symptoms. Four months after surgery, the patient reported a 95% improvement of symptoms.¹⁹ An older case in 2008 discussed the use of ACDF in a 64-year-old woman with severe distress and an identifiable surgical target. The patient’s symptoms resolved completely within 1 week after surgery.¹⁰

Conclusion 

The pathogenesis of BRP continues to be an area of debate—it may be secondary to cervical spine disease or UVR. This review found there is more research pointing to cervical spine disease. There is an abundance of literature discussing both conservative and invasive treatment strategies, both of which carry benefits. Further research is needed to better establish the etiology of BRP so that formal treatment guidelines may be established. 

Neuropathic itch can be a frustrating condition for providers and patients, and many treatment modalities often are tried before arriving at a helpful treatment for a particular patient. Clinicians who may encounter BRP in practice benefit from up-to-date literature reviews that provide a summary of management strategies.

Brachioradial pruritus (BRP) is a neuropathic condition typically characterized by localized dysesthesia of the dorsolateral arms.¹ This dysesthesia has been described as a persistent painful itching, burning, tingling, or stinging sensation^2-4 and has a median duration of expression of 24 months.^5,6 The condition may be unilateral or bilateral in nature but tends to have a predilection for a bilateral distribution along the C5 to C6 dermatomes.^1,7,8 There are no primary skin lesions associated with BRP; however, excoriations, prurigo nodules, and lichenification may arise secondary to scratching of the irritated skin.^1,4,5,9 Brachioradial pruritus tends to have a predilection for adult females (3:1 ratio) with lighter skin. The mean age at diagnosis is 59 years, but cases have been reported in patients aged 12 to 84 years.^1,5 The diagnosis of BRP is based on clinical signs and symptoms, though the ice-pack sign tends to be pathognomonic for the diagnosis.^10,11 Although there is no clear evidence on the exact cause of BRP, there are 2 prevalent theories: cervical radiculopathy secondary to cervical spine pathology and/or excessive exposure to UV radiation (UVR) in the summer months.^3-5,12 Brachioradial pruritus remains poorly described in the literature, and even its origin is under debate. As such, the clinician may have difficulty deciding on the best course of management. The goal of this article is to identify and discuss known treatment options for BRP (Table).

Etiology 

Cervical Spine Pathology—A correlation appears to exist between BRP and cervical spine changes seen on plain film radiographs at the levels of C3 to C7, with increased incidence at the C5 to C6 levels. These plain film radiographs typically show degenerative joint disease and neural foraminal stenosis at levels that correlate to the dermatomal distribution of BRP.^1,7,10,12-14 In addition to plain film radiography, some studies have utilized magnetic resonance imaging to view the cervical spine and have documented evidence of intervertebral disc protrusion/bulging, central canal stenosis, neuroforaminal stenosis, and spondylosis at the affected regions.^5,15-17 Moreover, supporting the theory that the cervical spine is responsible for the emergence of BRP, Marziniak et al¹⁷ investigated 41 patients with BRP utilizing magnetic resonance tomography to find that 33 patients (80.5%) had changes in nerve compression, and 8 patients (19.5%) had degenerative changes. In addition to these findings, they found that there was a significant correlation (P<.01) between the dermatomal expression of BRP and the location of cervical anatomical changes.¹⁷ Further validating the relationship between cervical spine pathology and BRP is a case study of a patient who saw rapid and complete resolution of the pruritus following spinal decompression surgery.¹⁰ Another case study described an intramedullary tumor found in a patient with BRP that was diagnosed as an ependymoma after magnetic resonance imaging revealed an intramedullary lesion within the spinal cord between C4 and C7. The location of the tumor and dermatomal pattern of the neuropathic itch pointed to a possible association between nerve compression and BRP.¹⁴ Electromyography studies performed on individuals with BRP have shown an increase in polyphasic units, decreased motor units, and/or denervation changes along the C5/C6 or C6 nerve roots, which provides additional support for the theory of cervical spine pathology as a causative factor for BRP.¹⁶

UVR Exposure—Another etiologic theory for BRP is that UVR exposure may be responsible for the genesis of pruritus. Previously known as solar pruritus, BRP was deemed a clinical condition, as there was increased prevalence in patients living in warmer climates, such as Florida.⁹ Wallengren and Dahlbäck¹⁸ reported that sun exposure is a notable factor in the onset of BRP, as they saw an increase in symptoms during the late summer and a decrease in symptoms over the winter months.To further support the theory that UVR is linked to BRP, several studies have shown that the utilization of sun protection is linked to a reduction of symptoms, specifically in patients who showed seasonal variations of their symptoms.^9,12,19 Additionally, a study by Mirzoyev and Davis⁵ retrospectively reviewed 111 patients diagnosed with BRP. Of these patients, 84 (75.7%) presented with bilateral symptoms, and 54 (48.6%) reported prolonged sun exposure. Both of these findings demonstrate correlation between UVR and BRP.⁵ Interestingly, UV light exposure is known to release β-endorphin in the skin and may theoretically provide an area of exploration between UVR and cervical spine theories.

Conservative Treatment 

Chiropractic Manipulation—Because one etiologic theory includes disease of the cervical spine, there is evidence that targeting this region with treatment is beneficial.⁷ Two case reports found in the literature noted that cervical spine manipulation and cervical traction yielded positive results.^20,21 It has been established that pain generated by disc lesions can be the result of local nociceptive fiber activation, direct mechanical compression of the nerve roots, or inflammatory mediators.²² There are several postulated models describing the hypoalgesic effects of spinal manipulation, which contains both biomechanical and neurophysiological mechanisms. Biomechanical changes theorized to elicit analgesia include restoration of faulty biomechanical movement patterns, breaking up of periarticular adhesions, and reflexogenic muscle inhibition of hypertonic musculature. Hypothesized neurophysiological effects of joint manipulation include an increase in afferent information overwhelming the nociceptive input, reduction of temporal summation, and autonomic activation leading to non–opioid-induced hypoalgesia.²³ Cervical traction is another plausible treatment for BRP, wherein the physiological effects of traction allow for a separation of vertebral bodies and expansion of the intervertebral foramen circumference, thus decreasing compression of the nerve roots.²⁴

Acupuncture—Neurogenic pruritus, including BRP, is a group of conditions that have been treated using acupuncture. Acupuncture treatment consists of intramuscular needle stimulation and has been found to alleviate itching in patients with neurogenic pruritus. In 1 retrospective case series, acupuncture was used to treat 16 patients who were identified as having segmental pruritus. Acupuncture targeted the spasmed paravertebral muscles of the affected dermatomal levels as well as other regions of the body, and it was found that 12 patients (75%) experienced full resolution of symptoms. However, relapse did occur in 6 patients (37%) within 1 to 12 months following treatment.²⁵ Multiple theories exist as to why acupuncture may help. One is that it relieves muscle spasms, which in turn relieves neural irritation of the spinal nerves as they traverse the respective paraspinal musculature. Another is that acupuncture decreases nociception by stimulating release of opioid peptides in the dorsal horn.²⁶ A third proposed theory is that acupuncture acts on the afferent nerve fibers responsible for transmitting pain—Aδ and C fibers—activating these afferent nerves to produce an analgesic effect.²⁷

Physiotherapy—The literature suggests that possible first-line therapies for neurogenic pruritus, including BRP and notalgia paresthetica, consist of noninvasive nondermatologic treatments that target cervical spine disease. Notalgia paresthetica and BRP have similar proposed mechanisms of nerve impingement; therefore, they often are grouped together when discussing proposed manual treatment options. Physiotherapy treatment includes cervical muscle strengthening, increased range of motion, application of cervical soft collars, massage, transcutaneous electronic nerve stimulation, and cervical traction.⁷ A study of 12 patients by Raison-Peyron et al²⁸ in 1999 discussed the use of spinal and paraspinal ultrasound or radiation physiotherapy. Six patients underwent this treatment, and the symptoms subsided in 4 cases.²⁸ Another study by Fleischer et al²⁹ in 2011 discussed improvement in 2 patients with notalgia paresthetica by exercise involving active range of motion and strengthening.

Photoprotection—Avoidance of UVR exposure has been beneficial to some patients to reduce symptoms. Use of sunscreen and long-sleeved UV-protective clothing during outdoor activities or the warmer summer months may be beneficial.¹

Medication—Because of the nonspecific clinical presentation of BRP, initial treatment often involves prescription of first-line antipruritic agents, including steroid creams and systemic antihistamines, both of which generally fail to provide symptom relief.^1,30 Medications with neurologic mechanisms of action appear to provide potentially superior outcomes. Neuroleptics, including gabapentin and pregabalin, are typical therapeutic agents for neurogenic pruritus and inhibit nociceptive pain propagation.³¹ Intervention with pregabalin in 3 patients with BRP achieved complete symptom relief in all patients, with initial improvement occurring in as little as 1 week.⁸Mirogabalin, operating under a similar mechanism, has shown preliminary success in treating BRP, causing anecdotal patient improvement within 4 months of initial dosage.³² Prolonged 1-month intravenous naloxone treatment also appars to be promising, offering symptom improvement of at least 80% six months posttreatment.¹⁵ 

Topical interventions for BRP and related neurogenic pruritus have shown limited success. A case series evaluating capsaicin for pruritus offered only transient relief, likely because of its temporary hyperstimulatory and desensitizing effect on neuropeptides.^7,33 In small populations, the use of topical antidepressants has yielded cutaneous and pathological relief for BRP. A case study of a 70-year-old woman evaluated the efficacy of a combination cream of ketamine and amitriptyline (a tricyclic antidepressant) yielding moderate pruritus improvement and notable improvement of secondary brachial skin lesions.³⁴ Oral steroids also have shown success in the treatment of chronic pruritus; however, limited research is available on the efficacy of such medications for BRP, and the long-term use of oral steroids is limited by many side effects.³⁰ 

Interventional Pain Procedure—A 2018 case series investigated 3 patients with a clinical diagnosis of BRP who were treated between 2010 and 2016 with epidural steroid injection using computed tomography guidance of the cervical spine.³⁵ The authors reported that 2 patients had near-complete resolution after 1 interventional procedure. The third patient had a total of 3 injections, with mild to moderate relief that continued to improve on mexiletine.³⁵ Another case in 2010 of a 56-year-old man with BRP documented use of a series of 2 epidural steroid injections that resulted in clinical resolution of symptoms.³⁶

Surgery—There are multiple case studies in the literature that discuss anterior cervical discectomy and fusion (ACDF) as a last resort in patients with refractory BRP of discogenic cause. In 2022, Morosanu et al³⁷ described a case of a 63-year-old woman with BRP in the C5–C6 distribution who had an associated disc protrusion at this level following magnetic resonance imaging. The patient underwent a C5/C6 ACDF after conservative and medical treatment failed, and at 3-month follow up her symptoms had resolved entirely.³⁷ Another case report described a 56-year-old man who ultimately underwent ACDF after failed multimodal treatment attempts, with instant improvement in symptoms. Four months after surgery, the patient reported a 95% improvement of symptoms.¹⁹ An older case in 2008 discussed the use of ACDF in a 64-year-old woman with severe distress and an identifiable surgical target. The patient’s symptoms resolved completely within 1 week after surgery.¹⁰

Conclusion 

The pathogenesis of BRP continues to be an area of debate—it may be secondary to cervical spine disease or UVR. This review found there is more research pointing to cervical spine disease. There is an abundance of literature discussing both conservative and invasive treatment strategies, both of which carry benefits. Further research is needed to better establish the etiology of BRP so that formal treatment guidelines may be established. 

Neuropathic itch can be a frustrating condition for providers and patients, and many treatment modalities often are tried before arriving at a helpful treatment for a particular patient. Clinicians who may encounter BRP in practice benefit from up-to-date literature reviews that provide a summary of management strategies.

Brachioradial pruritus (BRP) is a neuropathic condition typically characterized by localized dysesthesia of the dorsolateral arms.¹ This dysesthesia has been described as a persistent painful itching, burning, tingling, or stinging sensation^2-4 and has a median duration of expression of 24 months.^5,6 The condition may be unilateral or bilateral in nature but tends to have a predilection for a bilateral distribution along the C5 to C6 dermatomes.^1,7,8 There are no primary skin lesions associated with BRP; however, excoriations, prurigo nodules, and lichenification may arise secondary to scratching of the irritated skin.^1,4,5,9 Brachioradial pruritus tends to have a predilection for adult females (3:1 ratio) with lighter skin. The mean age at diagnosis is 59 years, but cases have been reported in patients aged 12 to 84 years.^1,5 The diagnosis of BRP is based on clinical signs and symptoms, though the ice-pack sign tends to be pathognomonic for the diagnosis.^10,11 Although there is no clear evidence on the exact cause of BRP, there are 2 prevalent theories: cervical radiculopathy secondary to cervical spine pathology and/or excessive exposure to UV radiation (UVR) in the summer months.^3-5,12 Brachioradial pruritus remains poorly described in the literature, and even its origin is under debate. As such, the clinician may have difficulty deciding on the best course of management. The goal of this article is to identify and discuss known treatment options for BRP (Table).

Etiology 

Cervical Spine Pathology—A correlation appears to exist between BRP and cervical spine changes seen on plain film radiographs at the levels of C3 to C7, with increased incidence at the C5 to C6 levels. These plain film radiographs typically show degenerative joint disease and neural foraminal stenosis at levels that correlate to the dermatomal distribution of BRP.^1,7,10,12-14 In addition to plain film radiography, some studies have utilized magnetic resonance imaging to view the cervical spine and have documented evidence of intervertebral disc protrusion/bulging, central canal stenosis, neuroforaminal stenosis, and spondylosis at the affected regions.^5,15-17 Moreover, supporting the theory that the cervical spine is responsible for the emergence of BRP, Marziniak et al¹⁷ investigated 41 patients with BRP utilizing magnetic resonance tomography to find that 33 patients (80.5%) had changes in nerve compression, and 8 patients (19.5%) had degenerative changes. In addition to these findings, they found that there was a significant correlation (P<.01) between the dermatomal expression of BRP and the location of cervical anatomical changes.¹⁷ Further validating the relationship between cervical spine pathology and BRP is a case study of a patient who saw rapid and complete resolution of the pruritus following spinal decompression surgery.¹⁰ Another case study described an intramedullary tumor found in a patient with BRP that was diagnosed as an ependymoma after magnetic resonance imaging revealed an intramedullary lesion within the spinal cord between C4 and C7. The location of the tumor and dermatomal pattern of the neuropathic itch pointed to a possible association between nerve compression and BRP.¹⁴ Electromyography studies performed on individuals with BRP have shown an increase in polyphasic units, decreased motor units, and/or denervation changes along the C5/C6 or C6 nerve roots, which provides additional support for the theory of cervical spine pathology as a causative factor for BRP.¹⁶

UVR Exposure—Another etiologic theory for BRP is that UVR exposure may be responsible for the genesis of pruritus. Previously known as solar pruritus, BRP was deemed a clinical condition, as there was increased prevalence in patients living in warmer climates, such as Florida.⁹ Wallengren and Dahlbäck¹⁸ reported that sun exposure is a notable factor in the onset of BRP, as they saw an increase in symptoms during the late summer and a decrease in symptoms over the winter months.To further support the theory that UVR is linked to BRP, several studies have shown that the utilization of sun protection is linked to a reduction of symptoms, specifically in patients who showed seasonal variations of their symptoms.^9,12,19 Additionally, a study by Mirzoyev and Davis⁵ retrospectively reviewed 111 patients diagnosed with BRP. Of these patients, 84 (75.7%) presented with bilateral symptoms, and 54 (48.6%) reported prolonged sun exposure. Both of these findings demonstrate correlation between UVR and BRP.⁵ Interestingly, UV light exposure is known to release β-endorphin in the skin and may theoretically provide an area of exploration between UVR and cervical spine theories.

Conservative Treatment 

Chiropractic Manipulation—Because one etiologic theory includes disease of the cervical spine, there is evidence that targeting this region with treatment is beneficial.⁷ Two case reports found in the literature noted that cervical spine manipulation and cervical traction yielded positive results.^20,21 It has been established that pain generated by disc lesions can be the result of local nociceptive fiber activation, direct mechanical compression of the nerve roots, or inflammatory mediators.²² There are several postulated models describing the hypoalgesic effects of spinal manipulation, which contains both biomechanical and neurophysiological mechanisms. Biomechanical changes theorized to elicit analgesia include restoration of faulty biomechanical movement patterns, breaking up of periarticular adhesions, and reflexogenic muscle inhibition of hypertonic musculature. Hypothesized neurophysiological effects of joint manipulation include an increase in afferent information overwhelming the nociceptive input, reduction of temporal summation, and autonomic activation leading to non–opioid-induced hypoalgesia.²³ Cervical traction is another plausible treatment for BRP, wherein the physiological effects of traction allow for a separation of vertebral bodies and expansion of the intervertebral foramen circumference, thus decreasing compression of the nerve roots.²⁴

Acupuncture—Neurogenic pruritus, including BRP, is a group of conditions that have been treated using acupuncture. Acupuncture treatment consists of intramuscular needle stimulation and has been found to alleviate itching in patients with neurogenic pruritus. In 1 retrospective case series, acupuncture was used to treat 16 patients who were identified as having segmental pruritus. Acupuncture targeted the spasmed paravertebral muscles of the affected dermatomal levels as well as other regions of the body, and it was found that 12 patients (75%) experienced full resolution of symptoms. However, relapse did occur in 6 patients (37%) within 1 to 12 months following treatment.²⁵ Multiple theories exist as to why acupuncture may help. One is that it relieves muscle spasms, which in turn relieves neural irritation of the spinal nerves as they traverse the respective paraspinal musculature. Another is that acupuncture decreases nociception by stimulating release of opioid peptides in the dorsal horn.²⁶ A third proposed theory is that acupuncture acts on the afferent nerve fibers responsible for transmitting pain—Aδ and C fibers—activating these afferent nerves to produce an analgesic effect.²⁷

Physiotherapy—The literature suggests that possible first-line therapies for neurogenic pruritus, including BRP and notalgia paresthetica, consist of noninvasive nondermatologic treatments that target cervical spine disease. Notalgia paresthetica and BRP have similar proposed mechanisms of nerve impingement; therefore, they often are grouped together when discussing proposed manual treatment options. Physiotherapy treatment includes cervical muscle strengthening, increased range of motion, application of cervical soft collars, massage, transcutaneous electronic nerve stimulation, and cervical traction.⁷ A study of 12 patients by Raison-Peyron et al²⁸ in 1999 discussed the use of spinal and paraspinal ultrasound or radiation physiotherapy. Six patients underwent this treatment, and the symptoms subsided in 4 cases.²⁸ Another study by Fleischer et al²⁹ in 2011 discussed improvement in 2 patients with notalgia paresthetica by exercise involving active range of motion and strengthening.

Photoprotection—Avoidance of UVR exposure has been beneficial to some patients to reduce symptoms. Use of sunscreen and long-sleeved UV-protective clothing during outdoor activities or the warmer summer months may be beneficial.¹

Medication—Because of the nonspecific clinical presentation of BRP, initial treatment often involves prescription of first-line antipruritic agents, including steroid creams and systemic antihistamines, both of which generally fail to provide symptom relief.^1,30 Medications with neurologic mechanisms of action appear to provide potentially superior outcomes. Neuroleptics, including gabapentin and pregabalin, are typical therapeutic agents for neurogenic pruritus and inhibit nociceptive pain propagation.³¹ Intervention with pregabalin in 3 patients with BRP achieved complete symptom relief in all patients, with initial improvement occurring in as little as 1 week.⁸Mirogabalin, operating under a similar mechanism, has shown preliminary success in treating BRP, causing anecdotal patient improvement within 4 months of initial dosage.³² Prolonged 1-month intravenous naloxone treatment also appars to be promising, offering symptom improvement of at least 80% six months posttreatment.¹⁵ 

Topical interventions for BRP and related neurogenic pruritus have shown limited success. A case series evaluating capsaicin for pruritus offered only transient relief, likely because of its temporary hyperstimulatory and desensitizing effect on neuropeptides.^7,33 In small populations, the use of topical antidepressants has yielded cutaneous and pathological relief for BRP. A case study of a 70-year-old woman evaluated the efficacy of a combination cream of ketamine and amitriptyline (a tricyclic antidepressant) yielding moderate pruritus improvement and notable improvement of secondary brachial skin lesions.³⁴ Oral steroids also have shown success in the treatment of chronic pruritus; however, limited research is available on the efficacy of such medications for BRP, and the long-term use of oral steroids is limited by many side effects.³⁰ 

Interventional Pain Procedure—A 2018 case series investigated 3 patients with a clinical diagnosis of BRP who were treated between 2010 and 2016 with epidural steroid injection using computed tomography guidance of the cervical spine.³⁵ The authors reported that 2 patients had near-complete resolution after 1 interventional procedure. The third patient had a total of 3 injections, with mild to moderate relief that continued to improve on mexiletine.³⁵ Another case in 2010 of a 56-year-old man with BRP documented use of a series of 2 epidural steroid injections that resulted in clinical resolution of symptoms.³⁶

Surgery—There are multiple case studies in the literature that discuss anterior cervical discectomy and fusion (ACDF) as a last resort in patients with refractory BRP of discogenic cause. In 2022, Morosanu et al³⁷ described a case of a 63-year-old woman with BRP in the C5–C6 distribution who had an associated disc protrusion at this level following magnetic resonance imaging. The patient underwent a C5/C6 ACDF after conservative and medical treatment failed, and at 3-month follow up her symptoms had resolved entirely.³⁷ Another case report described a 56-year-old man who ultimately underwent ACDF after failed multimodal treatment attempts, with instant improvement in symptoms. Four months after surgery, the patient reported a 95% improvement of symptoms.¹⁹ An older case in 2008 discussed the use of ACDF in a 64-year-old woman with severe distress and an identifiable surgical target. The patient’s symptoms resolved completely within 1 week after surgery.¹⁰

Conclusion 

The pathogenesis of BRP continues to be an area of debate—it may be secondary to cervical spine disease or UVR. This review found there is more research pointing to cervical spine disease. There is an abundance of literature discussing both conservative and invasive treatment strategies, both of which carry benefits. Further research is needed to better establish the etiology of BRP so that formal treatment guidelines may be established. 

Neuropathic itch can be a frustrating condition for providers and patients, and many treatment modalities often are tried before arriving at a helpful treatment for a particular patient. Clinicians who may encounter BRP in practice benefit from up-to-date literature reviews that provide a summary of management strategies.

Pigmented purpuric dermatoses (PPDs) are characterized by petechiae, dusky macules representative of postinflammatory hyperpigmentation and dermal hemosiderin, and purpura generally localized to the lower extremities. They typically represent a spectrum of lymphocytic capillaritis, variable erythrocyte extravasation from papillary dermal blood vessels, and deposition of hemosiderin, yielding the classic red to orange to golden-brown findings on gross examination. Clinical overlap exists, but variants include Schamberg disease (SD), Majocchi purpura, Gougerot-Blum purpura, eczematoid purpura of Doucas and Kapetanakis (DK), and lichen aureus.¹ Other forms are rarer, including linear, granulomatous, quadrantic, transitory, and familial variants. It remains controversial whether PPD may precede or have an association with cutaneous T-cell lymphoma.² Dermoscopy usually shows copper-red pigmentation in the background, oval red dots, linear vessels, brown globules, and follicular openings. Although these findings may be useful in PPD diagnosis, they are not applicable in differentiating among the variants.

Pigmented purpuric dermatoses can easily be mistaken for stasis dermatitis or cellulitis, as these may occur concomitantly or in populations at risk for all 3 conditions, such as women older than 50 years with recent trauma or infection in the affected area. Tissue biopsy and clinical laboratory evaluation may be required to differentiate between PPD from leukocytoclastic vasculitis or the myriad causes of retiform purpura. Importantly, clinicians also should differentiate PPD from the purpuric eruptions of the lower extremities associated with COVID-19 infection.

Pigmented Purpuric Dermatoses

Schamberg Disease—In 1901, Jay Frank Schamberg, a distinguished professor of dermatology in Philadelphia, Pennsylvania, described “a peculiar progressive pigmentary disease of the skin” in a 15-year-old adolescent boy.³ Schamberg disease is the most common PPD, characterized by pruritic spots resembling cayenne pepper (Figure 1) with orange-brown pigmented macules on the legs and feet.⁴ Although platelet dysfunction, coagulation deficiencies, or dermal atrophy may contribute to hemorrhaging that manifests as petechiae or ecchymoses, SD typically is not associated with any laboratory abnormalities, and petechial eruption is not widespread.⁵ Capillary fragility can be assessed by the tourniquet test, in which pressure is applied to the forearm with a blood pressure cuff inflated between systolic and diastolic blood pressure for 5 to 10 minutes. Upon removing the cuff, a positive test is indicated by 15 or more petechiae in an area 5 cm in diameter due to poor platelet function. A positive result may be seen in SD.⁶

Histologically, SD is characterized by patchy parakeratosis, mild spongiosis of the stratum Malpighi, and lymphoid capillaritis (Figure 2).⁷ In addition to CD3⁺, CD4⁺, CD8⁺, CD1a⁺, and CD36⁺ lymphocytes, histology also may contain dendritic cells and cellular adhesion molecules (intercellular adhesion molecule 1, epithelial cell adhesion molecule 1) within the superficial perivascular infiltrate.⁸ There is no definitive therapy, but first-line interventions include emollients, topical steroids, and oral antihistamines. Nonpharmacologic management includes compression or support stockings, elevation of the lower extremities, and avoidance of offending medications (if identifiable).¹

Majocchi Purpura—Domenico Majocchi was a renowned Italian dermatologist who described an entity in 1898 that he called purpura annularis telangiectodes, now also known as Majocchi purpura.⁹ It is more common in females, young adults, and children. Majocchi purpura has rarely been reported in families with a possible autosomal-dominant inheritance.¹⁰ Typically, bluish-red annular macules with central atrophy surrounded by hyperpigmentation may be seen on the lower extremities, potentially extending to the upper extremities.¹ Treatment of Majocchi purpura remains a challenge but may respond to narrowband UVB phototherapy. Emollients and topical steroids also are used as first-line treatments. Biopsy demonstrates telangiectasia, pericapillary infiltration of mononuclear lymphocytes, and papillary dermal hemosiderin.¹¹

Gougerot-Blum Purpura—In 1925, French dermatologists Henri Gougerot and Paul Blum described a pigmented purpuric lichenoid dermatitis known as Gougerot-Blum purpura,¹² a rare PPD characterized by lichenoid papules that eventually coalesce into plaques of various colors, along with red-brown hyperpigmentation.⁴ As with other PPD variants, the legs are most involved, with rare extension to the trunk or thighs. The plaques may resemble and be mistaken for Kaposi sarcoma, cutaneous vasculitis, traumatic purpura, or mycosis fungoides. Dermoscopic examination reveals small, polygonal or round, red dots underlying brown scaly patches.¹³ Gougerot-Blum purpura is found more commonly in adult men and rarely affects children.⁴ Histologically, a lichenoid and superficial perivascular infiltrate composed of lymphocytes and macrophages is seen. Various therapies have been described, including topical steroids, antihistamines, psoralen plus UVA phototherapy, and cyclosporin A.¹⁴

Eczematoid Purpura of Doucas and Kapetanakis—In 1949, Greek dermatologists Christopher Doucas and John Kapetanakis observed several cases of purpuric dermatosis similar in form to the “pigmented purpuric lichenoid dermatitis” of Gougerot-Blum purpura¹² and to the “progressive pigmentary dermatitis” of Schamberg disease.³ After observing a gradual disappearance of the classic yellow color from hemosiderin deposition, Doucas and Kapetanakis described a new bright red eruption with lichenification.¹⁵ Eczematoid purpura of Doucas and Kapetanakis is rare and predominantly seen in middle-aged males. Hyperpigmented or dark brown macules may develop bilaterally on the legs, progressing to the thighs and upper extremities. Unlike the other types of PPD, DK is extensive and severely pruritic.⁴

Although most PPD can be drug induced, DK has shown the greatest tendency for pruritic erythematous plaques following drug usage including but not limited to amlodipine, aspirin, acetaminophen, thiamine, interferon alfa, chlordiazepoxide, and isotretinoin. Additionally, DK has been associated with a contact allergy to clothing dyes and rubber.⁴ On histology, epidermal spongiosis may be seen, correlating with the eczematoid clinical findings. Spontaneous remission also is more common compared to the other PPDs. Treatment consists of topical corticosteroids and antihistamines.¹⁶

Lichen Aureus—Lichen aureus was first observed by the dermatologist R.H. Martin in 1958.¹⁷ It is clinically characterized by closely aggregated purpuric papules with a distinctive golden-brown color more often localized to the lower extremities and sometimes in a dermatomal distribution. Lichen aureus affects males and females equally, and similar to Majocchi purpura can be seen in children.⁴ Histopathologic examination reveals a prominent lichenoid plus superficial and deep perivascular lymphocytic infiltrate, extravasated erythrocytes, papillary dermal edema, hemosiderophages, and an unaffected epidermis. In rare cases, perineural infiltrates may be seen. Topical steroids usually are ineffective in lichen aureus treatment, but responses to psoralen plus UVA therapy also have been noted.¹⁷

Differential Diagnosis

COVID-19–Related Cutaneous Changes—Because COVID-19–related pathology is now a common differential diagnosis for many cutaneous eruptions,one must be mindful of the possibility for patients to have PPD, cutaneous changes from underlying COVID-19, or both.¹⁸ The microvascular changes from COVID-19 infection can be variable.¹⁹ Besides the presence of erythema along a distal digit, manifestations can include reticulated dusky erythema mimicking livedoid vasculopathy or inflammatory purpura.¹⁹

Retiform Purpura—Retiform purpura may occur in the setting of microvascular occlusion and can represent the pattern of underlying dermal vasculature. It is nonblanching and typically stellate or branching.²⁰ The microvascular occlusion may be a result of hypercoagulability or may be secondary to cutaneous vasculitis, resulting in thrombosis and subsequent vascular occlusion.²¹ There are many reasons for hypercoagulability in retiform purpura, including disseminated intravascular coagulation in the setting of COVID-19 infection.²² The treatment of retiform purpura is aimed at alleviating the underlying cause and providing symptomatic relief. Conversely, the PPDs generally are benign and require minimal workup.

Leukocytoclastic Vasculitis—The hallmark of leukocytoclastic vasculitis is palpable purpura, often appearing as nonblanchable papules, typically in a dependent distribution such as the lower extremities (Figure 3). Although it primarily affects children, Henoch-Schönlein purpura is a type of leukocytoclastic vasculitis with lesions potentially similar in appearance to those of PPD.²³ Palpable purpura may be painful and may ulcerate but rarely is pruritic. Leukocytoclastic vasculitis represents perivascular infiltrates composed of neutrophils, lymphocytes, and occasionally eosinophils, along with karyorrhexis, luminal fibrin, and fibrinoid degeneration of blood vessel walls, often resulting from immune complex deposition. Leukocytoclastic vasculitis may affect blood vessels of any size and requires further clinical and laboratory evaluation for infection (including COVID-19), hypercoagulability, autoimmune disease, or medication-related reactions.²⁴

Stasis Dermatitis—Stasis dermatitis, a chronic inflammatory condition stemming from retrograde venous flow due to incompetent venous valves, mimics PPD. Stasis dermatitis initially appears as demarcated erythematous plaques, fissures, and scaling of the lower legs bilaterally, usually involving the medial malleolus.²⁵ With time, the affected region develops overlying brawny hyperpigmentation and fibrosis (Figure 4). Pruritus or pain are common features, while fissures and superficial erosions may heal and recur, leading to lichenification.

Although both commonly appear on the lower extremities, duplex ultrasonography may be helpful to distinguish PPDs from stasis dermatitis since the latter occurs in the context of chronic venous insufficiency, varicose veins, soft tissue edema, and lymphedema.²⁵ Additionally, pruritus, lichenification, and edema often are not seen in most PPD variants, although stasis dermatitis and PPD may occur in tandem. Conservative treatment involves elevation of the extremities, compression, and topical steroids for symptomatic relief.

Cellulitis—The key characteristics of cellulitis are redness, swelling, warmth, tenderness, fever, and leukocytosis. A history of trauma, such as a prior break in the skin, and pain in the affected area suggest cellulitis. Several skin conditions present similarly to cellulitis, including PPD, and thus approximately 30% of cases are misdiagnosed.²⁶ Cellulitis rarely presents in a bilateral or diffusely scattered pattern as seen in PPDs. Rather, it is unilateral with smooth indistinct borders. Variables suggestive of cellulitis include immunosuppression, rapid progression, and previous occurrences. Hyperpigmented plaques or thickening of the skin are more indicative of a chronic process such as stasis dermatitis or lipodermatosclerosis rather than acute cellulitis. Purpura is not a typical finding in most cases of soft tissue cellulitis. Treatment may be case specific depending on severity, presence or absence of sepsis, findings on blood cultures, or other pathologic evaluation. Antibiotics are directed to the causative organism, typically Streptococcus and Staphylococcus species, although coverage against various gram-negative organisms may be indicated.²⁷

Caution With Teledermatology

COVID-19 has established the value of telemedicine in providing access to health care services for at-risk or underserved individuals. The PPDs are benign, often asymptomatic, and potentially identifiable with teledermatology alone; however, they also can easily be mistaken for COVID-19–related eruptions, vasculitis, other types of purpura, stasis dermatitis, or other complications of lower extremity stasis and lymphedema, especially in an aging population. If tissue biopsy is required, as in the workup of vasculitis, the efficacy of telemedicine becomes more questionable. It is important to delineate the potentially confusing PPDs from other potentially dangerous or life-threatening inflammatory dermatoses.²⁸

Pigmented purpuric dermatoses (PPDs) are characterized by petechiae, dusky macules representative of postinflammatory hyperpigmentation and dermal hemosiderin, and purpura generally localized to the lower extremities. They typically represent a spectrum of lymphocytic capillaritis, variable erythrocyte extravasation from papillary dermal blood vessels, and deposition of hemosiderin, yielding the classic red to orange to golden-brown findings on gross examination. Clinical overlap exists, but variants include Schamberg disease (SD), Majocchi purpura, Gougerot-Blum purpura, eczematoid purpura of Doucas and Kapetanakis (DK), and lichen aureus.¹ Other forms are rarer, including linear, granulomatous, quadrantic, transitory, and familial variants. It remains controversial whether PPD may precede or have an association with cutaneous T-cell lymphoma.² Dermoscopy usually shows copper-red pigmentation in the background, oval red dots, linear vessels, brown globules, and follicular openings. Although these findings may be useful in PPD diagnosis, they are not applicable in differentiating among the variants.

Pigmented purpuric dermatoses can easily be mistaken for stasis dermatitis or cellulitis, as these may occur concomitantly or in populations at risk for all 3 conditions, such as women older than 50 years with recent trauma or infection in the affected area. Tissue biopsy and clinical laboratory evaluation may be required to differentiate between PPD from leukocytoclastic vasculitis or the myriad causes of retiform purpura. Importantly, clinicians also should differentiate PPD from the purpuric eruptions of the lower extremities associated with COVID-19 infection.

Pigmented Purpuric Dermatoses

Schamberg Disease—In 1901, Jay Frank Schamberg, a distinguished professor of dermatology in Philadelphia, Pennsylvania, described “a peculiar progressive pigmentary disease of the skin” in a 15-year-old adolescent boy.³ Schamberg disease is the most common PPD, characterized by pruritic spots resembling cayenne pepper (Figure 1) with orange-brown pigmented macules on the legs and feet.⁴ Although platelet dysfunction, coagulation deficiencies, or dermal atrophy may contribute to hemorrhaging that manifests as petechiae or ecchymoses, SD typically is not associated with any laboratory abnormalities, and petechial eruption is not widespread.⁵ Capillary fragility can be assessed by the tourniquet test, in which pressure is applied to the forearm with a blood pressure cuff inflated between systolic and diastolic blood pressure for 5 to 10 minutes. Upon removing the cuff, a positive test is indicated by 15 or more petechiae in an area 5 cm in diameter due to poor platelet function. A positive result may be seen in SD.⁶

Histologically, SD is characterized by patchy parakeratosis, mild spongiosis of the stratum Malpighi, and lymphoid capillaritis (Figure 2).⁷ In addition to CD3⁺, CD4⁺, CD8⁺, CD1a⁺, and CD36⁺ lymphocytes, histology also may contain dendritic cells and cellular adhesion molecules (intercellular adhesion molecule 1, epithelial cell adhesion molecule 1) within the superficial perivascular infiltrate.⁸ There is no definitive therapy, but first-line interventions include emollients, topical steroids, and oral antihistamines. Nonpharmacologic management includes compression or support stockings, elevation of the lower extremities, and avoidance of offending medications (if identifiable).¹

Majocchi Purpura—Domenico Majocchi was a renowned Italian dermatologist who described an entity in 1898 that he called purpura annularis telangiectodes, now also known as Majocchi purpura.⁹ It is more common in females, young adults, and children. Majocchi purpura has rarely been reported in families with a possible autosomal-dominant inheritance.¹⁰ Typically, bluish-red annular macules with central atrophy surrounded by hyperpigmentation may be seen on the lower extremities, potentially extending to the upper extremities.¹ Treatment of Majocchi purpura remains a challenge but may respond to narrowband UVB phototherapy. Emollients and topical steroids also are used as first-line treatments. Biopsy demonstrates telangiectasia, pericapillary infiltration of mononuclear lymphocytes, and papillary dermal hemosiderin.¹¹

Gougerot-Blum Purpura—In 1925, French dermatologists Henri Gougerot and Paul Blum described a pigmented purpuric lichenoid dermatitis known as Gougerot-Blum purpura,¹² a rare PPD characterized by lichenoid papules that eventually coalesce into plaques of various colors, along with red-brown hyperpigmentation.⁴ As with other PPD variants, the legs are most involved, with rare extension to the trunk or thighs. The plaques may resemble and be mistaken for Kaposi sarcoma, cutaneous vasculitis, traumatic purpura, or mycosis fungoides. Dermoscopic examination reveals small, polygonal or round, red dots underlying brown scaly patches.¹³ Gougerot-Blum purpura is found more commonly in adult men and rarely affects children.⁴ Histologically, a lichenoid and superficial perivascular infiltrate composed of lymphocytes and macrophages is seen. Various therapies have been described, including topical steroids, antihistamines, psoralen plus UVA phototherapy, and cyclosporin A.¹⁴

Eczematoid Purpura of Doucas and Kapetanakis—In 1949, Greek dermatologists Christopher Doucas and John Kapetanakis observed several cases of purpuric dermatosis similar in form to the “pigmented purpuric lichenoid dermatitis” of Gougerot-Blum purpura¹² and to the “progressive pigmentary dermatitis” of Schamberg disease.³ After observing a gradual disappearance of the classic yellow color from hemosiderin deposition, Doucas and Kapetanakis described a new bright red eruption with lichenification.¹⁵ Eczematoid purpura of Doucas and Kapetanakis is rare and predominantly seen in middle-aged males. Hyperpigmented or dark brown macules may develop bilaterally on the legs, progressing to the thighs and upper extremities. Unlike the other types of PPD, DK is extensive and severely pruritic.⁴

Although most PPD can be drug induced, DK has shown the greatest tendency for pruritic erythematous plaques following drug usage including but not limited to amlodipine, aspirin, acetaminophen, thiamine, interferon alfa, chlordiazepoxide, and isotretinoin. Additionally, DK has been associated with a contact allergy to clothing dyes and rubber.⁴ On histology, epidermal spongiosis may be seen, correlating with the eczematoid clinical findings. Spontaneous remission also is more common compared to the other PPDs. Treatment consists of topical corticosteroids and antihistamines.¹⁶

Lichen Aureus—Lichen aureus was first observed by the dermatologist R.H. Martin in 1958.¹⁷ It is clinically characterized by closely aggregated purpuric papules with a distinctive golden-brown color more often localized to the lower extremities and sometimes in a dermatomal distribution. Lichen aureus affects males and females equally, and similar to Majocchi purpura can be seen in children.⁴ Histopathologic examination reveals a prominent lichenoid plus superficial and deep perivascular lymphocytic infiltrate, extravasated erythrocytes, papillary dermal edema, hemosiderophages, and an unaffected epidermis. In rare cases, perineural infiltrates may be seen. Topical steroids usually are ineffective in lichen aureus treatment, but responses to psoralen plus UVA therapy also have been noted.¹⁷

Differential Diagnosis

COVID-19–Related Cutaneous Changes—Because COVID-19–related pathology is now a common differential diagnosis for many cutaneous eruptions,one must be mindful of the possibility for patients to have PPD, cutaneous changes from underlying COVID-19, or both.¹⁸ The microvascular changes from COVID-19 infection can be variable.¹⁹ Besides the presence of erythema along a distal digit, manifestations can include reticulated dusky erythema mimicking livedoid vasculopathy or inflammatory purpura.¹⁹

Retiform Purpura—Retiform purpura may occur in the setting of microvascular occlusion and can represent the pattern of underlying dermal vasculature. It is nonblanching and typically stellate or branching.²⁰ The microvascular occlusion may be a result of hypercoagulability or may be secondary to cutaneous vasculitis, resulting in thrombosis and subsequent vascular occlusion.²¹ There are many reasons for hypercoagulability in retiform purpura, including disseminated intravascular coagulation in the setting of COVID-19 infection.²² The treatment of retiform purpura is aimed at alleviating the underlying cause and providing symptomatic relief. Conversely, the PPDs generally are benign and require minimal workup.

Leukocytoclastic Vasculitis—The hallmark of leukocytoclastic vasculitis is palpable purpura, often appearing as nonblanchable papules, typically in a dependent distribution such as the lower extremities (Figure 3). Although it primarily affects children, Henoch-Schönlein purpura is a type of leukocytoclastic vasculitis with lesions potentially similar in appearance to those of PPD.²³ Palpable purpura may be painful and may ulcerate but rarely is pruritic. Leukocytoclastic vasculitis represents perivascular infiltrates composed of neutrophils, lymphocytes, and occasionally eosinophils, along with karyorrhexis, luminal fibrin, and fibrinoid degeneration of blood vessel walls, often resulting from immune complex deposition. Leukocytoclastic vasculitis may affect blood vessels of any size and requires further clinical and laboratory evaluation for infection (including COVID-19), hypercoagulability, autoimmune disease, or medication-related reactions.²⁴

Stasis Dermatitis—Stasis dermatitis, a chronic inflammatory condition stemming from retrograde venous flow due to incompetent venous valves, mimics PPD. Stasis dermatitis initially appears as demarcated erythematous plaques, fissures, and scaling of the lower legs bilaterally, usually involving the medial malleolus.²⁵ With time, the affected region develops overlying brawny hyperpigmentation and fibrosis (Figure 4). Pruritus or pain are common features, while fissures and superficial erosions may heal and recur, leading to lichenification.

Although both commonly appear on the lower extremities, duplex ultrasonography may be helpful to distinguish PPDs from stasis dermatitis since the latter occurs in the context of chronic venous insufficiency, varicose veins, soft tissue edema, and lymphedema.²⁵ Additionally, pruritus, lichenification, and edema often are not seen in most PPD variants, although stasis dermatitis and PPD may occur in tandem. Conservative treatment involves elevation of the extremities, compression, and topical steroids for symptomatic relief.

Cellulitis—The key characteristics of cellulitis are redness, swelling, warmth, tenderness, fever, and leukocytosis. A history of trauma, such as a prior break in the skin, and pain in the affected area suggest cellulitis. Several skin conditions present similarly to cellulitis, including PPD, and thus approximately 30% of cases are misdiagnosed.²⁶ Cellulitis rarely presents in a bilateral or diffusely scattered pattern as seen in PPDs. Rather, it is unilateral with smooth indistinct borders. Variables suggestive of cellulitis include immunosuppression, rapid progression, and previous occurrences. Hyperpigmented plaques or thickening of the skin are more indicative of a chronic process such as stasis dermatitis or lipodermatosclerosis rather than acute cellulitis. Purpura is not a typical finding in most cases of soft tissue cellulitis. Treatment may be case specific depending on severity, presence or absence of sepsis, findings on blood cultures, or other pathologic evaluation. Antibiotics are directed to the causative organism, typically Streptococcus and Staphylococcus species, although coverage against various gram-negative organisms may be indicated.²⁷

Caution With Teledermatology

COVID-19 has established the value of telemedicine in providing access to health care services for at-risk or underserved individuals. The PPDs are benign, often asymptomatic, and potentially identifiable with teledermatology alone; however, they also can easily be mistaken for COVID-19–related eruptions, vasculitis, other types of purpura, stasis dermatitis, or other complications of lower extremity stasis and lymphedema, especially in an aging population. If tissue biopsy is required, as in the workup of vasculitis, the efficacy of telemedicine becomes more questionable. It is important to delineate the potentially confusing PPDs from other potentially dangerous or life-threatening inflammatory dermatoses.²⁸

Pigmented purpuric dermatoses (PPDs) are characterized by petechiae, dusky macules representative of postinflammatory hyperpigmentation and dermal hemosiderin, and purpura generally localized to the lower extremities. They typically represent a spectrum of lymphocytic capillaritis, variable erythrocyte extravasation from papillary dermal blood vessels, and deposition of hemosiderin, yielding the classic red to orange to golden-brown findings on gross examination. Clinical overlap exists, but variants include Schamberg disease (SD), Majocchi purpura, Gougerot-Blum purpura, eczematoid purpura of Doucas and Kapetanakis (DK), and lichen aureus.¹ Other forms are rarer, including linear, granulomatous, quadrantic, transitory, and familial variants. It remains controversial whether PPD may precede or have an association with cutaneous T-cell lymphoma.² Dermoscopy usually shows copper-red pigmentation in the background, oval red dots, linear vessels, brown globules, and follicular openings. Although these findings may be useful in PPD diagnosis, they are not applicable in differentiating among the variants.

Pigmented purpuric dermatoses can easily be mistaken for stasis dermatitis or cellulitis, as these may occur concomitantly or in populations at risk for all 3 conditions, such as women older than 50 years with recent trauma or infection in the affected area. Tissue biopsy and clinical laboratory evaluation may be required to differentiate between PPD from leukocytoclastic vasculitis or the myriad causes of retiform purpura. Importantly, clinicians also should differentiate PPD from the purpuric eruptions of the lower extremities associated with COVID-19 infection.

Pigmented Purpuric Dermatoses

Schamberg Disease—In 1901, Jay Frank Schamberg, a distinguished professor of dermatology in Philadelphia, Pennsylvania, described “a peculiar progressive pigmentary disease of the skin” in a 15-year-old adolescent boy.³ Schamberg disease is the most common PPD, characterized by pruritic spots resembling cayenne pepper (Figure 1) with orange-brown pigmented macules on the legs and feet.⁴ Although platelet dysfunction, coagulation deficiencies, or dermal atrophy may contribute to hemorrhaging that manifests as petechiae or ecchymoses, SD typically is not associated with any laboratory abnormalities, and petechial eruption is not widespread.⁵ Capillary fragility can be assessed by the tourniquet test, in which pressure is applied to the forearm with a blood pressure cuff inflated between systolic and diastolic blood pressure for 5 to 10 minutes. Upon removing the cuff, a positive test is indicated by 15 or more petechiae in an area 5 cm in diameter due to poor platelet function. A positive result may be seen in SD.⁶

Histologically, SD is characterized by patchy parakeratosis, mild spongiosis of the stratum Malpighi, and lymphoid capillaritis (Figure 2).⁷ In addition to CD3⁺, CD4⁺, CD8⁺, CD1a⁺, and CD36⁺ lymphocytes, histology also may contain dendritic cells and cellular adhesion molecules (intercellular adhesion molecule 1, epithelial cell adhesion molecule 1) within the superficial perivascular infiltrate.⁸ There is no definitive therapy, but first-line interventions include emollients, topical steroids, and oral antihistamines. Nonpharmacologic management includes compression or support stockings, elevation of the lower extremities, and avoidance of offending medications (if identifiable).¹

Majocchi Purpura—Domenico Majocchi was a renowned Italian dermatologist who described an entity in 1898 that he called purpura annularis telangiectodes, now also known as Majocchi purpura.⁹ It is more common in females, young adults, and children. Majocchi purpura has rarely been reported in families with a possible autosomal-dominant inheritance.¹⁰ Typically, bluish-red annular macules with central atrophy surrounded by hyperpigmentation may be seen on the lower extremities, potentially extending to the upper extremities.¹ Treatment of Majocchi purpura remains a challenge but may respond to narrowband UVB phototherapy. Emollients and topical steroids also are used as first-line treatments. Biopsy demonstrates telangiectasia, pericapillary infiltration of mononuclear lymphocytes, and papillary dermal hemosiderin.¹¹

Gougerot-Blum Purpura—In 1925, French dermatologists Henri Gougerot and Paul Blum described a pigmented purpuric lichenoid dermatitis known as Gougerot-Blum purpura,¹² a rare PPD characterized by lichenoid papules that eventually coalesce into plaques of various colors, along with red-brown hyperpigmentation.⁴ As with other PPD variants, the legs are most involved, with rare extension to the trunk or thighs. The plaques may resemble and be mistaken for Kaposi sarcoma, cutaneous vasculitis, traumatic purpura, or mycosis fungoides. Dermoscopic examination reveals small, polygonal or round, red dots underlying brown scaly patches.¹³ Gougerot-Blum purpura is found more commonly in adult men and rarely affects children.⁴ Histologically, a lichenoid and superficial perivascular infiltrate composed of lymphocytes and macrophages is seen. Various therapies have been described, including topical steroids, antihistamines, psoralen plus UVA phototherapy, and cyclosporin A.¹⁴

Eczematoid Purpura of Doucas and Kapetanakis—In 1949, Greek dermatologists Christopher Doucas and John Kapetanakis observed several cases of purpuric dermatosis similar in form to the “pigmented purpuric lichenoid dermatitis” of Gougerot-Blum purpura¹² and to the “progressive pigmentary dermatitis” of Schamberg disease.³ After observing a gradual disappearance of the classic yellow color from hemosiderin deposition, Doucas and Kapetanakis described a new bright red eruption with lichenification.¹⁵ Eczematoid purpura of Doucas and Kapetanakis is rare and predominantly seen in middle-aged males. Hyperpigmented or dark brown macules may develop bilaterally on the legs, progressing to the thighs and upper extremities. Unlike the other types of PPD, DK is extensive and severely pruritic.⁴

Although most PPD can be drug induced, DK has shown the greatest tendency for pruritic erythematous plaques following drug usage including but not limited to amlodipine, aspirin, acetaminophen, thiamine, interferon alfa, chlordiazepoxide, and isotretinoin. Additionally, DK has been associated with a contact allergy to clothing dyes and rubber.⁴ On histology, epidermal spongiosis may be seen, correlating with the eczematoid clinical findings. Spontaneous remission also is more common compared to the other PPDs. Treatment consists of topical corticosteroids and antihistamines.¹⁶

Lichen Aureus—Lichen aureus was first observed by the dermatologist R.H. Martin in 1958.¹⁷ It is clinically characterized by closely aggregated purpuric papules with a distinctive golden-brown color more often localized to the lower extremities and sometimes in a dermatomal distribution. Lichen aureus affects males and females equally, and similar to Majocchi purpura can be seen in children.⁴ Histopathologic examination reveals a prominent lichenoid plus superficial and deep perivascular lymphocytic infiltrate, extravasated erythrocytes, papillary dermal edema, hemosiderophages, and an unaffected epidermis. In rare cases, perineural infiltrates may be seen. Topical steroids usually are ineffective in lichen aureus treatment, but responses to psoralen plus UVA therapy also have been noted.¹⁷

Differential Diagnosis

COVID-19–Related Cutaneous Changes—Because COVID-19–related pathology is now a common differential diagnosis for many cutaneous eruptions,one must be mindful of the possibility for patients to have PPD, cutaneous changes from underlying COVID-19, or both.¹⁸ The microvascular changes from COVID-19 infection can be variable.¹⁹ Besides the presence of erythema along a distal digit, manifestations can include reticulated dusky erythema mimicking livedoid vasculopathy or inflammatory purpura.¹⁹

Retiform Purpura—Retiform purpura may occur in the setting of microvascular occlusion and can represent the pattern of underlying dermal vasculature. It is nonblanching and typically stellate or branching.²⁰ The microvascular occlusion may be a result of hypercoagulability or may be secondary to cutaneous vasculitis, resulting in thrombosis and subsequent vascular occlusion.²¹ There are many reasons for hypercoagulability in retiform purpura, including disseminated intravascular coagulation in the setting of COVID-19 infection.²² The treatment of retiform purpura is aimed at alleviating the underlying cause and providing symptomatic relief. Conversely, the PPDs generally are benign and require minimal workup.

Leukocytoclastic Vasculitis—The hallmark of leukocytoclastic vasculitis is palpable purpura, often appearing as nonblanchable papules, typically in a dependent distribution such as the lower extremities (Figure 3). Although it primarily affects children, Henoch-Schönlein purpura is a type of leukocytoclastic vasculitis with lesions potentially similar in appearance to those of PPD.²³ Palpable purpura may be painful and may ulcerate but rarely is pruritic. Leukocytoclastic vasculitis represents perivascular infiltrates composed of neutrophils, lymphocytes, and occasionally eosinophils, along with karyorrhexis, luminal fibrin, and fibrinoid degeneration of blood vessel walls, often resulting from immune complex deposition. Leukocytoclastic vasculitis may affect blood vessels of any size and requires further clinical and laboratory evaluation for infection (including COVID-19), hypercoagulability, autoimmune disease, or medication-related reactions.²⁴

Stasis Dermatitis—Stasis dermatitis, a chronic inflammatory condition stemming from retrograde venous flow due to incompetent venous valves, mimics PPD. Stasis dermatitis initially appears as demarcated erythematous plaques, fissures, and scaling of the lower legs bilaterally, usually involving the medial malleolus.²⁵ With time, the affected region develops overlying brawny hyperpigmentation and fibrosis (Figure 4). Pruritus or pain are common features, while fissures and superficial erosions may heal and recur, leading to lichenification.

Although both commonly appear on the lower extremities, duplex ultrasonography may be helpful to distinguish PPDs from stasis dermatitis since the latter occurs in the context of chronic venous insufficiency, varicose veins, soft tissue edema, and lymphedema.²⁵ Additionally, pruritus, lichenification, and edema often are not seen in most PPD variants, although stasis dermatitis and PPD may occur in tandem. Conservative treatment involves elevation of the extremities, compression, and topical steroids for symptomatic relief.

Cellulitis—The key characteristics of cellulitis are redness, swelling, warmth, tenderness, fever, and leukocytosis. A history of trauma, such as a prior break in the skin, and pain in the affected area suggest cellulitis. Several skin conditions present similarly to cellulitis, including PPD, and thus approximately 30% of cases are misdiagnosed.²⁶ Cellulitis rarely presents in a bilateral or diffusely scattered pattern as seen in PPDs. Rather, it is unilateral with smooth indistinct borders. Variables suggestive of cellulitis include immunosuppression, rapid progression, and previous occurrences. Hyperpigmented plaques or thickening of the skin are more indicative of a chronic process such as stasis dermatitis or lipodermatosclerosis rather than acute cellulitis. Purpura is not a typical finding in most cases of soft tissue cellulitis. Treatment may be case specific depending on severity, presence or absence of sepsis, findings on blood cultures, or other pathologic evaluation. Antibiotics are directed to the causative organism, typically Streptococcus and Staphylococcus species, although coverage against various gram-negative organisms may be indicated.²⁷

Caution With Teledermatology

COVID-19 has established the value of telemedicine in providing access to health care services for at-risk or underserved individuals. The PPDs are benign, often asymptomatic, and potentially identifiable with teledermatology alone; however, they also can easily be mistaken for COVID-19–related eruptions, vasculitis, other types of purpura, stasis dermatitis, or other complications of lower extremity stasis and lymphedema, especially in an aging population. If tissue biopsy is required, as in the workup of vasculitis, the efficacy of telemedicine becomes more questionable. It is important to delineate the potentially confusing PPDs from other potentially dangerous or life-threatening inflammatory dermatoses.²⁸

ILLUSTRATION © IRYNA INSHYNA/SHUTTERSTOCK

Patient satisfaction questionnaires were developed in the 1980s as part of the movement to better understand the patient’s experience and their perspective of the quality of care. In 1985, the Press Ganey survey—now the most widely used method to assess patient satisfaction—was developed by 2 professors in anthropology and sociology-statistics at Notre Dame. Initially intended for inpatient admissions, the survey was validated based on a few thousand survey results.¹ Given the strong interest in improving patient satisfaction at the time, it became widely adopted and quickly expanded into outpatient encounters and ambulatory surgery settings.

Although other surveys have been developed,² the Press Ganey survey is the most commonly used assessment tool for patient satisfaction metrics in the United States, with approximately 50% of all hospitals and more than 41,000 health care organizations using its services.^3,4 The survey consists of 6 domains related to satisfaction with:

1. the care provider

2. the nurse or assistant

3. personal issues

4. overall assessment

5. access

6. moving through the visit. 

Survey items are scored using a 5-point Likert scale, with scores ranging from “very poor” (a score of 1) to “very good” (a score of 5). According to the company, because this format is balanced and parallel (unlike a “poor” to “excellent” format), responses can be quantified and used statistically without violating methodologic assumptions. Also, variability in patients’ responses with this format allows for the identification of opportunities to improve, unlike “yes/no” response formats.¹ There are limitations to this design, however, which can impact data quality,⁵ as we will see.

While the distribution process varies by institution, there is an algorithm laid out by Press Ganey for administering surveys to patients in their preferred language after outpatient visits. Based on recent research into Press Ganey response rates, the typical response rate is estimated to be 16% to 19%.⁶ Although this low response rate is typical of survey data, it inherently introduces the risk of responder bias—meaning results may be skewed by patients who represent the extremes of satisfaction or dissatisfaction.

Adoption of the survey as we move toward value-based care

More recently, patients’ satisfaction with their health care has received increased attention as we move to a patient-centered care model and as health care reimbursement models shift toward value-based care. Current trends in health care policy statements include the importance of raising the standard of care and shifting from a “fee-for-service” to a “pay-for-performance” reimbursement model.^7,8 As a result, hospitals are establishing systems to measure “performance” that are not nationally standardized or extensively studied with objective measures. The changing standard of health care expectations in the United States is a topic of much public debate.⁹ And as expectations and new standards are defined, the impact of implementing novel measures of performance should be evaluated prior to widespread adoption and utilization.

Patient satisfaction also has been identified as a driver for hospital finances through loyalty, described as the “likelihood to return to that system for future medical services.”^10,11 This measure has contributed to policy changes that reinforce prioritization of patient satisfaction. For example, the Affordable Care Act tied Medicare reimbursement and patient satisfaction together in the Hospital Value-Based Purchasing Program. This program uses measures of clinical processes, efficiency, outcomes, and patient experiences to calculate a total score that results in hospital reimbursement and incentives,¹² which creates a direct pathway from patient experience to reimbursement—underscoring hospitals’ desire for ongoing assessment of patient satisfaction.

Continue to: Gender, race, and age bias...

Gender, race, and age bias

Although the rationale behind gathering patient input is important, recent data suggest that patient satisfaction surveys are subject to inherent biases.^6,13,14 These biases tend to negatively impact women and non-White physicians, adding to the systemic discrimination against women and physicians of color that already exists in health care.

In a single-site retrospective study performed in 2018 by Rogo-Gupta et al, female gynecologists were found to be 47% less likely to receive top patient satisfaction scores than their male counterparts owing to their gender alone, suggesting that gender bias may impact the results of patient satisfaction questionnaires.¹³ The authors encouraged that the results of patient satisfaction surveys be interpreted with great caution until the impact on female physicians is better understood.

A multi-center study by the same group (Rogo-Gupta et al) assessed the same construct across 5 different geographically diverse institutions.¹⁵ This study confirmed that female gynecologists were less likely to receive a top satisfaction score from their patients (19% lower odds when compared with male gynecologists). They also studied the effects of other patient demographics, including age, race/ethnicity, and race concordance. Older patients (aged ≥63 years) had an over-3-fold increase in odds of providing a top satisfaction score than younger patients. Additionally, Asian physicians had significantly lower odds of receiving a top satisfaction score when compared with White physicians, while Asian patients had significantly lower odds of providing a top satisfaction score when compared with White patients. Lastly, in most cases, when underrepresented-in-medicine patients saw an underrepresented-in-medicine physician (race concordance), there was a significant increase in odds of receiving a top satisfaction score. Asian race concordance, however, actually resulted in a lower likelihood of receiving a top satisfaction score.¹⁵

Literature from other specialties supports these findings. These results are consistent with emerging data from other medical specialties that also suggest that Press Ganey survey data are subject to inherent biases. For example, data from emergency medicine literature have shown discrepancies between patient satisfaction for providers at tertiary inner-city institutions versus those in affluent suburban populations,¹⁶ and that worse mortality is actually correlated with better patient satisfaction scores, and vice versa.¹⁷

Another study by Sotto-Santiago in 2019 assessed patient satisfaction scores in multiple specialties at a single institution where quality-related financial incentives were offered based on this metric. They found a significant difference in patient satisfaction scores between underrepresented and White physicians, which suggests a potential bias among patients and institutional practices—ultimately leading to pay inequities through differences in financial incentives.¹⁸

Percentile differences reveal small gaps in satisfaction ratings

When examining the difference between raw Press Ganey patient satisfaction data and the percentiles associated with these scores, an interesting finding arises. Looking at the 2023 multicenter study by Rogo-Gupta et al, the difference in the top raw scores between male and female gynecologists appears to be small (3.3%).¹⁵ However, in 2020, the difference in top scores separating the top (75th) and bottom (25th) percentile quartiles of physicians was also small, at only 6.9%.

Considering the percentiles, if a provider who scores in the 25th percentile is compared with a colleague who scores in the 75th percentile, they may think the reported satisfaction score differences were quite large. This may potentially invoke feelings of decreased self-worth, negatively impact their professional identity or overall well-being, and they may seek (or be told to seek) improvement opportunities. Now imagine the provider in question realizes the difference between the 25th percentile and 75th percentile is actually only 6.9%. This information may completely change how the results are interpreted and acted upon by administrators. This is further changed with the understanding that 3.3% of the difference may be due to gender alone, narrowing the gap even further. Providers would become understandably frustrated if measures of success such as reimbursement, financial bonus or incentives, promotion, or advancement are linked to these results. It violates the value of fairness and does not offer an equitable starting point.

Evolution of the data distribution. Another consideration, as noted by Robert C. Lloyd, PhD, one of the statisticians who helped develop the percentile statistical analysis mapping in 1985, is that it was based on a classic bell-shaped distribution of patient satisfaction survey scores.¹⁹ Because hospitals, medical groups, and physicians have been working these past 20 years to achieve higher Press Ganey scores, the data no longer have a bell-shaped distribution. Rather, there are significant clusters of raw scores at the high end with a very narrow response range. When these data are mapped to the percentile spectrum, they are highly inaccurate.¹⁹

Impact of sample size. According to Press Ganey, a minimum of 30 survey responses collected over the designated time period is necessary to draw meaningful conclusions of the data for a specific individual, program, or hospital. Despite this requirement to achieve statistical significance, Sullivan and DeLucia found that the firm often provides comparative data about hospital departments and individual physicians based on a smaller sample size that may create an unacceptably large margin of error.²⁰ Sullivan, for example, said his department may only have 8 to 10 Press Ganey survey responses per month and yet still receives monthly reports from the company analyzing the data. Because of the small sample size, 1 month his department ranked in the 1st percentile and 2 months later it ranked in the 99th percentile.²⁰

The effect of a high ceiling rate. A psychometrics report for the Press Ganey survey is available from the vendor that provides vague assessments of reliability and validity based on 2,762 surveys from 12 practices across 10 states. This report describes a 12-question version of the survey with “no problems encountered” with missingness and response variability. The report further states that the Press Ganey survey demonstrates construct, convergent, divergent, and predictive validities, and high reliability; however, these data are not made available.¹

In response to this report, Presson et al analyzed more than 34,000 surveys from one institution to evaluate the reliability and validity of the Press Ganey survey.21 Overall, the survey demonstrated suitable psychometric properties for most metrics. However, Presson et al noted a significantly high ceiling rate of 29.3% for the total score, which ranged from 55.4% to 84.1% across items.²¹ (Ceiling rates are considered substantial if they occur more than 20% of the time.) Ultimately, a high ceiling rate reduces the power to discriminate between patients who have high satisfaction (everyone is “happy”) with those who are just slightly less than happy, but not dissatisfied. This data quality metric can impact the reliability and validity of a survey—and substantial ceiling rates can notably impact percentile rankings of scores within an institution, offering a possible explanation for the small percentage change between the top and bottom percentiles.

Continue to: Other issues with surveys...

Other issues with surveys

In addition to the limitations associated with percentile groupings, survey data are always subject to nonresponse bias, and small sample size can lead to nonsignificant results. Skewed responses also can make it difficult to identify true outlying providers who may need remediation or may be offering a superior patient experience. Satisfaction surveys also lack an assessment of objective data and instead assess how patients perceive and feel, which introduces subjectivity to the results.

Additionally, focusing on improving patient experience ratings can incentivize unnecessary or inappropriate care (ie, overprescribing of narcotics, prescribing antibiotics when not indicated, or ordering testing that may not change management). Some physicians even state that they are not getting the type of feedback that they are asking for and that the survey is not asking the right questions to elicit patient input that is meaningful to their practice. Lastly, the incorporation of trainees and advanced practice providers in the patient care experience leads to the assessment of an alternative provider being included in the ultimate score and may not be representative of that physician.

Patients’ perception and survey results. In some circumstances, the patient’s understanding of their medical situation may affect their responses. Some may argue that patients may mistake a physician’s confidence for competence, when in reality these two entities are mutually exclusive. In a randomized controlled trial, researchers from Mount Sinai School of Medicine and Columbia University Medical Center surveyed inner-city women with newly diagnosed and surgically treated early-stage breast cancer for their perceived quality of care and the process of getting care, including referrals, test results, and treatments. They compared the responses with patient records to determine the actual quality of care. Of the 374 women who received treatment for early-stage breast cancer, 55% said they received “excellent care,” but most—88%—actually got care that was in line with the best current treatment guidelines. Interestingly, the study found African American women were less likely to report excellent care than White or Hispanic women, less likely to trust their doctor, and more likely to say they experienced bias during the process. However, there was no difference in actual quality of care received in any group.²²

You can’t improve what you can’t control. Ultimately, while many providers think patient satisfaction survey results may help inform some aspects of their practice, they cannot improve what they cannot control. For example, the multicenter study by Rogo-Gupta et al found that older patients (≥63 years) have more than a 3-fold increase in odds of giving a top satisfaction score than younger patients (≤33 years), independent of other aspects of the care experience.15 Additionally, they found that older physicians (≥56 years) had a significant increase in odds of receiving a top satisfaction score when compared with physicians who were younger than 55 years old.¹⁵ Given that physicians clearly cannot control their own age or the age of their patients, the negative impacts of these biases need to be addressed and remedied at a systems level.

Why might these biases exist?

While we cannot completely understand all of the possible explanations for these biases, it is important to emphasize the long-standing prejudice and discrimination against women and people of color in our society and how this has impacted our behavior. While strides have been made, there clearly still seems to be a difference between what we say and how our biases impact our behavior. Women are still tougher on women in professional evaluations in other fields as well²³; it is not unique to medicine. While workplace improvements are slowly changing, women still face inequities. The more research we publish to describe it, the more we hope the conversation continues, allowing us to reduce the impact of bias on our sense of self-worth and identity related to our careers, narrow the pay gap, and see women advance at the same rate as male counterparts. Considerable transformation is crucial to prevent further workforce attrition.

With regard to the lower scores provided by Asian patients, studies suggest that cultural response bias, rather than true differences in quality of care, may account for these discrepancies. Previous literature has found that Asian patients are more likely to select midpoints, rather than extremes, when completing Likert-type studies²⁴ and are not more likely to change medical providers than other race/ethnicities, indicating that lower ratings may not necessarily imply greater dissatisfaction with care.²⁵

Far-reaching effects on finances, income, well-being, job satisfaction, etc.

Depending on how the results are distributed and used, the effects of patient satisfaction surveys can extend well beyond the original intentions. At some institutions, income for physicians is directly tied to their Press Ganey satisfaction scores, which could have profound implications for female and Asian physicians,^13,15 who would be paid less—resulting in a wider pay gap than already exists.¹⁸

When negative and not constructive, patient evaluations can contribute to physician burnout and a loss of productive members of the workforce.²⁶ This is especially important in obstetrics and gynecology, where physicians are most likely to experience burnout due to multiple factors such as high-risk medical conditions, pressures of the electronic medical record (EMR), the medicolegal environment, and difficulty balancing patient expectations for autonomy with professional judgement.²⁷ Burnout also disproportionately affects women and younger physicians, which is especially concerning given that, in 2017, approximately one-third of practicing obstetrician/gynecologists were women, while that same year more than 80% of trainees matching into the field were women.²⁸ In one survey sent to members of a prominent medical society, 20% of the medical professionals who responded said they have had their employment threatened by low patient satisfaction scores, 78% reported that patient satisfaction surveys moderately or severely affected their job satisfaction, and 28% stated they had considered quitting their job or leaving the medical profession.²⁹Another related effect is the association between malpractice proceedings and a lack of satisfaction with perceived quality of physician-patient communication.³⁰ This may be an important determinant of malpractice lawsuits, and ensuring high patient satisfaction may be a form of defensive medicine.

Continue to: Controlling the narrative for the future: Proposed strategies...

Controlling the narrative for the future: Proposed strategies

The rapid, widespread adoption of the Press Ganey survey across specialties, clinical care settings, and geographic areas may have been largely due to the ease and operational benefits for hospitals rather than after rigorous study and validation. For example, repeated use of a specific measurement tool may facilitate comparison across areas within a hospital but also across institutions, which can help assess performance at a national level. Hospitals also may have a financial incentive to work with a single third-party or vendor instead of using multiple options across multiple vendors. However, the impact of adoption of novel measures of performance should be evaluated prior to widespread adoption and utilization.

A similar example of an emergence of a technological advancement that has changed the field of medicine and how we provide care is the EMR. Epic is now the most commonly used medical record system and holds the market share of the industry, covering 78% of patients in the United States.³¹ While there are certainly many potential benefits of a common EMR, such as ease of information sharing and standardization of formatting, opportunities are identified in real time and require product adjustment. For example, modifications have been made to accurately represent gender outside of the previously used dichotomous options. Diagnoses such as cervical cancer screening can now be used even if the patient gender is listed as male.

Similarly, the Press Ganey and other patient satisfaction questionnaires should be evaluated and modified to address existing societal biases. The World Health Organization estimates that it will take 300 years to fix gender inequality,³² but we have an opportunity now to control the narrative and improve patient feedback.

Future research avenues

Ultimately, there is a need to further explore currently available methods of evaluating clinical encounters to better understand the inherent biases and limitations. We hope this review will encourage other physicians to examine their specialties and hospitals and require similar analyses from vendors of such satisfaction rating products prior to using them. At the very least, health systems should be willing to partner with vendors and physicians on an ongoing basis to better understand the biases involved in these survey results and make modifications as needed. Patients also obtain information from and contribute to self-reported, publicly available websites; therefore, additional exploration into a nationalized standard for assessing patient satisfaction also may serve as an opportunity to standardize the information patients evaluate.³³ Further assessment of the potential financial and emotional impact of using the currently available patient-reported surveys on female physicians, Asian physicians, young physicians, and physicians who see young patients is needed. It is time to put pressure on a broken patient satisfaction system and improve on a national level to avoid undue negative consequences on our physicians. Use of patient satisfaction survey data should be limited until we all understand and account for the biases that are evident. ●

ILLUSTRATION © IRYNA INSHYNA/SHUTTERSTOCK

Patient satisfaction questionnaires were developed in the 1980s as part of the movement to better understand the patient’s experience and their perspective of the quality of care. In 1985, the Press Ganey survey—now the most widely used method to assess patient satisfaction—was developed by 2 professors in anthropology and sociology-statistics at Notre Dame. Initially intended for inpatient admissions, the survey was validated based on a few thousand survey results.¹ Given the strong interest in improving patient satisfaction at the time, it became widely adopted and quickly expanded into outpatient encounters and ambulatory surgery settings.

Although other surveys have been developed,² the Press Ganey survey is the most commonly used assessment tool for patient satisfaction metrics in the United States, with approximately 50% of all hospitals and more than 41,000 health care organizations using its services.^3,4 The survey consists of 6 domains related to satisfaction with:

1. the care provider

2. the nurse or assistant

3. personal issues

4. overall assessment

5. access

6. moving through the visit. 

Survey items are scored using a 5-point Likert scale, with scores ranging from “very poor” (a score of 1) to “very good” (a score of 5). According to the company, because this format is balanced and parallel (unlike a “poor” to “excellent” format), responses can be quantified and used statistically without violating methodologic assumptions. Also, variability in patients’ responses with this format allows for the identification of opportunities to improve, unlike “yes/no” response formats.¹ There are limitations to this design, however, which can impact data quality,⁵ as we will see.

While the distribution process varies by institution, there is an algorithm laid out by Press Ganey for administering surveys to patients in their preferred language after outpatient visits. Based on recent research into Press Ganey response rates, the typical response rate is estimated to be 16% to 19%.⁶ Although this low response rate is typical of survey data, it inherently introduces the risk of responder bias—meaning results may be skewed by patients who represent the extremes of satisfaction or dissatisfaction.

Adoption of the survey as we move toward value-based care

More recently, patients’ satisfaction with their health care has received increased attention as we move to a patient-centered care model and as health care reimbursement models shift toward value-based care. Current trends in health care policy statements include the importance of raising the standard of care and shifting from a “fee-for-service” to a “pay-for-performance” reimbursement model.^7,8 As a result, hospitals are establishing systems to measure “performance” that are not nationally standardized or extensively studied with objective measures. The changing standard of health care expectations in the United States is a topic of much public debate.⁹ And as expectations and new standards are defined, the impact of implementing novel measures of performance should be evaluated prior to widespread adoption and utilization.

Patient satisfaction also has been identified as a driver for hospital finances through loyalty, described as the “likelihood to return to that system for future medical services.”^10,11 This measure has contributed to policy changes that reinforce prioritization of patient satisfaction. For example, the Affordable Care Act tied Medicare reimbursement and patient satisfaction together in the Hospital Value-Based Purchasing Program. This program uses measures of clinical processes, efficiency, outcomes, and patient experiences to calculate a total score that results in hospital reimbursement and incentives,¹² which creates a direct pathway from patient experience to reimbursement—underscoring hospitals’ desire for ongoing assessment of patient satisfaction.

Continue to: Gender, race, and age bias...

Gender, race, and age bias

Although the rationale behind gathering patient input is important, recent data suggest that patient satisfaction surveys are subject to inherent biases.^6,13,14 These biases tend to negatively impact women and non-White physicians, adding to the systemic discrimination against women and physicians of color that already exists in health care.

In a single-site retrospective study performed in 2018 by Rogo-Gupta et al, female gynecologists were found to be 47% less likely to receive top patient satisfaction scores than their male counterparts owing to their gender alone, suggesting that gender bias may impact the results of patient satisfaction questionnaires.¹³ The authors encouraged that the results of patient satisfaction surveys be interpreted with great caution until the impact on female physicians is better understood.

A multi-center study by the same group (Rogo-Gupta et al) assessed the same construct across 5 different geographically diverse institutions.¹⁵ This study confirmed that female gynecologists were less likely to receive a top satisfaction score from their patients (19% lower odds when compared with male gynecologists). They also studied the effects of other patient demographics, including age, race/ethnicity, and race concordance. Older patients (aged ≥63 years) had an over-3-fold increase in odds of providing a top satisfaction score than younger patients. Additionally, Asian physicians had significantly lower odds of receiving a top satisfaction score when compared with White physicians, while Asian patients had significantly lower odds of providing a top satisfaction score when compared with White patients. Lastly, in most cases, when underrepresented-in-medicine patients saw an underrepresented-in-medicine physician (race concordance), there was a significant increase in odds of receiving a top satisfaction score. Asian race concordance, however, actually resulted in a lower likelihood of receiving a top satisfaction score.¹⁵

Literature from other specialties supports these findings. These results are consistent with emerging data from other medical specialties that also suggest that Press Ganey survey data are subject to inherent biases. For example, data from emergency medicine literature have shown discrepancies between patient satisfaction for providers at tertiary inner-city institutions versus those in affluent suburban populations,¹⁶ and that worse mortality is actually correlated with better patient satisfaction scores, and vice versa.¹⁷

Another study by Sotto-Santiago in 2019 assessed patient satisfaction scores in multiple specialties at a single institution where quality-related financial incentives were offered based on this metric. They found a significant difference in patient satisfaction scores between underrepresented and White physicians, which suggests a potential bias among patients and institutional practices—ultimately leading to pay inequities through differences in financial incentives.¹⁸

Percentile differences reveal small gaps in satisfaction ratings

When examining the difference between raw Press Ganey patient satisfaction data and the percentiles associated with these scores, an interesting finding arises. Looking at the 2023 multicenter study by Rogo-Gupta et al, the difference in the top raw scores between male and female gynecologists appears to be small (3.3%).¹⁵ However, in 2020, the difference in top scores separating the top (75th) and bottom (25th) percentile quartiles of physicians was also small, at only 6.9%.

Considering the percentiles, if a provider who scores in the 25th percentile is compared with a colleague who scores in the 75th percentile, they may think the reported satisfaction score differences were quite large. This may potentially invoke feelings of decreased self-worth, negatively impact their professional identity or overall well-being, and they may seek (or be told to seek) improvement opportunities. Now imagine the provider in question realizes the difference between the 25th percentile and 75th percentile is actually only 6.9%. This information may completely change how the results are interpreted and acted upon by administrators. This is further changed with the understanding that 3.3% of the difference may be due to gender alone, narrowing the gap even further. Providers would become understandably frustrated if measures of success such as reimbursement, financial bonus or incentives, promotion, or advancement are linked to these results. It violates the value of fairness and does not offer an equitable starting point.

Evolution of the data distribution. Another consideration, as noted by Robert C. Lloyd, PhD, one of the statisticians who helped develop the percentile statistical analysis mapping in 1985, is that it was based on a classic bell-shaped distribution of patient satisfaction survey scores.¹⁹ Because hospitals, medical groups, and physicians have been working these past 20 years to achieve higher Press Ganey scores, the data no longer have a bell-shaped distribution. Rather, there are significant clusters of raw scores at the high end with a very narrow response range. When these data are mapped to the percentile spectrum, they are highly inaccurate.¹⁹

Impact of sample size. According to Press Ganey, a minimum of 30 survey responses collected over the designated time period is necessary to draw meaningful conclusions of the data for a specific individual, program, or hospital. Despite this requirement to achieve statistical significance, Sullivan and DeLucia found that the firm often provides comparative data about hospital departments and individual physicians based on a smaller sample size that may create an unacceptably large margin of error.²⁰ Sullivan, for example, said his department may only have 8 to 10 Press Ganey survey responses per month and yet still receives monthly reports from the company analyzing the data. Because of the small sample size, 1 month his department ranked in the 1st percentile and 2 months later it ranked in the 99th percentile.²⁰

The effect of a high ceiling rate. A psychometrics report for the Press Ganey survey is available from the vendor that provides vague assessments of reliability and validity based on 2,762 surveys from 12 practices across 10 states. This report describes a 12-question version of the survey with “no problems encountered” with missingness and response variability. The report further states that the Press Ganey survey demonstrates construct, convergent, divergent, and predictive validities, and high reliability; however, these data are not made available.¹

In response to this report, Presson et al analyzed more than 34,000 surveys from one institution to evaluate the reliability and validity of the Press Ganey survey.21 Overall, the survey demonstrated suitable psychometric properties for most metrics. However, Presson et al noted a significantly high ceiling rate of 29.3% for the total score, which ranged from 55.4% to 84.1% across items.²¹ (Ceiling rates are considered substantial if they occur more than 20% of the time.) Ultimately, a high ceiling rate reduces the power to discriminate between patients who have high satisfaction (everyone is “happy”) with those who are just slightly less than happy, but not dissatisfied. This data quality metric can impact the reliability and validity of a survey—and substantial ceiling rates can notably impact percentile rankings of scores within an institution, offering a possible explanation for the small percentage change between the top and bottom percentiles.

Continue to: Other issues with surveys...

Other issues with surveys

In addition to the limitations associated with percentile groupings, survey data are always subject to nonresponse bias, and small sample size can lead to nonsignificant results. Skewed responses also can make it difficult to identify true outlying providers who may need remediation or may be offering a superior patient experience. Satisfaction surveys also lack an assessment of objective data and instead assess how patients perceive and feel, which introduces subjectivity to the results.

Additionally, focusing on improving patient experience ratings can incentivize unnecessary or inappropriate care (ie, overprescribing of narcotics, prescribing antibiotics when not indicated, or ordering testing that may not change management). Some physicians even state that they are not getting the type of feedback that they are asking for and that the survey is not asking the right questions to elicit patient input that is meaningful to their practice. Lastly, the incorporation of trainees and advanced practice providers in the patient care experience leads to the assessment of an alternative provider being included in the ultimate score and may not be representative of that physician.

Patients’ perception and survey results. In some circumstances, the patient’s understanding of their medical situation may affect their responses. Some may argue that patients may mistake a physician’s confidence for competence, when in reality these two entities are mutually exclusive. In a randomized controlled trial, researchers from Mount Sinai School of Medicine and Columbia University Medical Center surveyed inner-city women with newly diagnosed and surgically treated early-stage breast cancer for their perceived quality of care and the process of getting care, including referrals, test results, and treatments. They compared the responses with patient records to determine the actual quality of care. Of the 374 women who received treatment for early-stage breast cancer, 55% said they received “excellent care,” but most—88%—actually got care that was in line with the best current treatment guidelines. Interestingly, the study found African American women were less likely to report excellent care than White or Hispanic women, less likely to trust their doctor, and more likely to say they experienced bias during the process. However, there was no difference in actual quality of care received in any group.²²

You can’t improve what you can’t control. Ultimately, while many providers think patient satisfaction survey results may help inform some aspects of their practice, they cannot improve what they cannot control. For example, the multicenter study by Rogo-Gupta et al found that older patients (≥63 years) have more than a 3-fold increase in odds of giving a top satisfaction score than younger patients (≤33 years), independent of other aspects of the care experience.15 Additionally, they found that older physicians (≥56 years) had a significant increase in odds of receiving a top satisfaction score when compared with physicians who were younger than 55 years old.¹⁵ Given that physicians clearly cannot control their own age or the age of their patients, the negative impacts of these biases need to be addressed and remedied at a systems level.

Why might these biases exist?

While we cannot completely understand all of the possible explanations for these biases, it is important to emphasize the long-standing prejudice and discrimination against women and people of color in our society and how this has impacted our behavior. While strides have been made, there clearly still seems to be a difference between what we say and how our biases impact our behavior. Women are still tougher on women in professional evaluations in other fields as well²³; it is not unique to medicine. While workplace improvements are slowly changing, women still face inequities. The more research we publish to describe it, the more we hope the conversation continues, allowing us to reduce the impact of bias on our sense of self-worth and identity related to our careers, narrow the pay gap, and see women advance at the same rate as male counterparts. Considerable transformation is crucial to prevent further workforce attrition.

With regard to the lower scores provided by Asian patients, studies suggest that cultural response bias, rather than true differences in quality of care, may account for these discrepancies. Previous literature has found that Asian patients are more likely to select midpoints, rather than extremes, when completing Likert-type studies²⁴ and are not more likely to change medical providers than other race/ethnicities, indicating that lower ratings may not necessarily imply greater dissatisfaction with care.²⁵

Far-reaching effects on finances, income, well-being, job satisfaction, etc.

Depending on how the results are distributed and used, the effects of patient satisfaction surveys can extend well beyond the original intentions. At some institutions, income for physicians is directly tied to their Press Ganey satisfaction scores, which could have profound implications for female and Asian physicians,^13,15 who would be paid less—resulting in a wider pay gap than already exists.¹⁸

When negative and not constructive, patient evaluations can contribute to physician burnout and a loss of productive members of the workforce.²⁶ This is especially important in obstetrics and gynecology, where physicians are most likely to experience burnout due to multiple factors such as high-risk medical conditions, pressures of the electronic medical record (EMR), the medicolegal environment, and difficulty balancing patient expectations for autonomy with professional judgement.²⁷ Burnout also disproportionately affects women and younger physicians, which is especially concerning given that, in 2017, approximately one-third of practicing obstetrician/gynecologists were women, while that same year more than 80% of trainees matching into the field were women.²⁸ In one survey sent to members of a prominent medical society, 20% of the medical professionals who responded said they have had their employment threatened by low patient satisfaction scores, 78% reported that patient satisfaction surveys moderately or severely affected their job satisfaction, and 28% stated they had considered quitting their job or leaving the medical profession.²⁹Another related effect is the association between malpractice proceedings and a lack of satisfaction with perceived quality of physician-patient communication.³⁰ This may be an important determinant of malpractice lawsuits, and ensuring high patient satisfaction may be a form of defensive medicine.

Continue to: Controlling the narrative for the future: Proposed strategies...

Controlling the narrative for the future: Proposed strategies

The rapid, widespread adoption of the Press Ganey survey across specialties, clinical care settings, and geographic areas may have been largely due to the ease and operational benefits for hospitals rather than after rigorous study and validation. For example, repeated use of a specific measurement tool may facilitate comparison across areas within a hospital but also across institutions, which can help assess performance at a national level. Hospitals also may have a financial incentive to work with a single third-party or vendor instead of using multiple options across multiple vendors. However, the impact of adoption of novel measures of performance should be evaluated prior to widespread adoption and utilization.

A similar example of an emergence of a technological advancement that has changed the field of medicine and how we provide care is the EMR. Epic is now the most commonly used medical record system and holds the market share of the industry, covering 78% of patients in the United States.³¹ While there are certainly many potential benefits of a common EMR, such as ease of information sharing and standardization of formatting, opportunities are identified in real time and require product adjustment. For example, modifications have been made to accurately represent gender outside of the previously used dichotomous options. Diagnoses such as cervical cancer screening can now be used even if the patient gender is listed as male.

Similarly, the Press Ganey and other patient satisfaction questionnaires should be evaluated and modified to address existing societal biases. The World Health Organization estimates that it will take 300 years to fix gender inequality,³² but we have an opportunity now to control the narrative and improve patient feedback.

Future research avenues

Ultimately, there is a need to further explore currently available methods of evaluating clinical encounters to better understand the inherent biases and limitations. We hope this review will encourage other physicians to examine their specialties and hospitals and require similar analyses from vendors of such satisfaction rating products prior to using them. At the very least, health systems should be willing to partner with vendors and physicians on an ongoing basis to better understand the biases involved in these survey results and make modifications as needed. Patients also obtain information from and contribute to self-reported, publicly available websites; therefore, additional exploration into a nationalized standard for assessing patient satisfaction also may serve as an opportunity to standardize the information patients evaluate.³³ Further assessment of the potential financial and emotional impact of using the currently available patient-reported surveys on female physicians, Asian physicians, young physicians, and physicians who see young patients is needed. It is time to put pressure on a broken patient satisfaction system and improve on a national level to avoid undue negative consequences on our physicians. Use of patient satisfaction survey data should be limited until we all understand and account for the biases that are evident. ●

ILLUSTRATION © IRYNA INSHYNA/SHUTTERSTOCK

Patient satisfaction questionnaires were developed in the 1980s as part of the movement to better understand the patient’s experience and their perspective of the quality of care. In 1985, the Press Ganey survey—now the most widely used method to assess patient satisfaction—was developed by 2 professors in anthropology and sociology-statistics at Notre Dame. Initially intended for inpatient admissions, the survey was validated based on a few thousand survey results.¹ Given the strong interest in improving patient satisfaction at the time, it became widely adopted and quickly expanded into outpatient encounters and ambulatory surgery settings.

Although other surveys have been developed,² the Press Ganey survey is the most commonly used assessment tool for patient satisfaction metrics in the United States, with approximately 50% of all hospitals and more than 41,000 health care organizations using its services.^3,4 The survey consists of 6 domains related to satisfaction with:

1. the care provider

2. the nurse or assistant

3. personal issues

4. overall assessment

5. access

6. moving through the visit. 

Survey items are scored using a 5-point Likert scale, with scores ranging from “very poor” (a score of 1) to “very good” (a score of 5). According to the company, because this format is balanced and parallel (unlike a “poor” to “excellent” format), responses can be quantified and used statistically without violating methodologic assumptions. Also, variability in patients’ responses with this format allows for the identification of opportunities to improve, unlike “yes/no” response formats.¹ There are limitations to this design, however, which can impact data quality,⁵ as we will see.

While the distribution process varies by institution, there is an algorithm laid out by Press Ganey for administering surveys to patients in their preferred language after outpatient visits. Based on recent research into Press Ganey response rates, the typical response rate is estimated to be 16% to 19%.⁶ Although this low response rate is typical of survey data, it inherently introduces the risk of responder bias—meaning results may be skewed by patients who represent the extremes of satisfaction or dissatisfaction.

Adoption of the survey as we move toward value-based care

More recently, patients’ satisfaction with their health care has received increased attention as we move to a patient-centered care model and as health care reimbursement models shift toward value-based care. Current trends in health care policy statements include the importance of raising the standard of care and shifting from a “fee-for-service” to a “pay-for-performance” reimbursement model.^7,8 As a result, hospitals are establishing systems to measure “performance” that are not nationally standardized or extensively studied with objective measures. The changing standard of health care expectations in the United States is a topic of much public debate.⁹ And as expectations and new standards are defined, the impact of implementing novel measures of performance should be evaluated prior to widespread adoption and utilization.

Patient satisfaction also has been identified as a driver for hospital finances through loyalty, described as the “likelihood to return to that system for future medical services.”^10,11 This measure has contributed to policy changes that reinforce prioritization of patient satisfaction. For example, the Affordable Care Act tied Medicare reimbursement and patient satisfaction together in the Hospital Value-Based Purchasing Program. This program uses measures of clinical processes, efficiency, outcomes, and patient experiences to calculate a total score that results in hospital reimbursement and incentives,¹² which creates a direct pathway from patient experience to reimbursement—underscoring hospitals’ desire for ongoing assessment of patient satisfaction.

Continue to: Gender, race, and age bias...

Gender, race, and age bias

Although the rationale behind gathering patient input is important, recent data suggest that patient satisfaction surveys are subject to inherent biases.^6,13,14 These biases tend to negatively impact women and non-White physicians, adding to the systemic discrimination against women and physicians of color that already exists in health care.

In a single-site retrospective study performed in 2018 by Rogo-Gupta et al, female gynecologists were found to be 47% less likely to receive top patient satisfaction scores than their male counterparts owing to their gender alone, suggesting that gender bias may impact the results of patient satisfaction questionnaires.¹³ The authors encouraged that the results of patient satisfaction surveys be interpreted with great caution until the impact on female physicians is better understood.

A multi-center study by the same group (Rogo-Gupta et al) assessed the same construct across 5 different geographically diverse institutions.¹⁵ This study confirmed that female gynecologists were less likely to receive a top satisfaction score from their patients (19% lower odds when compared with male gynecologists). They also studied the effects of other patient demographics, including age, race/ethnicity, and race concordance. Older patients (aged ≥63 years) had an over-3-fold increase in odds of providing a top satisfaction score than younger patients. Additionally, Asian physicians had significantly lower odds of receiving a top satisfaction score when compared with White physicians, while Asian patients had significantly lower odds of providing a top satisfaction score when compared with White patients. Lastly, in most cases, when underrepresented-in-medicine patients saw an underrepresented-in-medicine physician (race concordance), there was a significant increase in odds of receiving a top satisfaction score. Asian race concordance, however, actually resulted in a lower likelihood of receiving a top satisfaction score.¹⁵

Literature from other specialties supports these findings. These results are consistent with emerging data from other medical specialties that also suggest that Press Ganey survey data are subject to inherent biases. For example, data from emergency medicine literature have shown discrepancies between patient satisfaction for providers at tertiary inner-city institutions versus those in affluent suburban populations,¹⁶ and that worse mortality is actually correlated with better patient satisfaction scores, and vice versa.¹⁷

Another study by Sotto-Santiago in 2019 assessed patient satisfaction scores in multiple specialties at a single institution where quality-related financial incentives were offered based on this metric. They found a significant difference in patient satisfaction scores between underrepresented and White physicians, which suggests a potential bias among patients and institutional practices—ultimately leading to pay inequities through differences in financial incentives.¹⁸

Percentile differences reveal small gaps in satisfaction ratings

When examining the difference between raw Press Ganey patient satisfaction data and the percentiles associated with these scores, an interesting finding arises. Looking at the 2023 multicenter study by Rogo-Gupta et al, the difference in the top raw scores between male and female gynecologists appears to be small (3.3%).¹⁵ However, in 2020, the difference in top scores separating the top (75th) and bottom (25th) percentile quartiles of physicians was also small, at only 6.9%.

Considering the percentiles, if a provider who scores in the 25th percentile is compared with a colleague who scores in the 75th percentile, they may think the reported satisfaction score differences were quite large. This may potentially invoke feelings of decreased self-worth, negatively impact their professional identity or overall well-being, and they may seek (or be told to seek) improvement opportunities. Now imagine the provider in question realizes the difference between the 25th percentile and 75th percentile is actually only 6.9%. This information may completely change how the results are interpreted and acted upon by administrators. This is further changed with the understanding that 3.3% of the difference may be due to gender alone, narrowing the gap even further. Providers would become understandably frustrated if measures of success such as reimbursement, financial bonus or incentives, promotion, or advancement are linked to these results. It violates the value of fairness and does not offer an equitable starting point.

Evolution of the data distribution. Another consideration, as noted by Robert C. Lloyd, PhD, one of the statisticians who helped develop the percentile statistical analysis mapping in 1985, is that it was based on a classic bell-shaped distribution of patient satisfaction survey scores.¹⁹ Because hospitals, medical groups, and physicians have been working these past 20 years to achieve higher Press Ganey scores, the data no longer have a bell-shaped distribution. Rather, there are significant clusters of raw scores at the high end with a very narrow response range. When these data are mapped to the percentile spectrum, they are highly inaccurate.¹⁹

Impact of sample size. According to Press Ganey, a minimum of 30 survey responses collected over the designated time period is necessary to draw meaningful conclusions of the data for a specific individual, program, or hospital. Despite this requirement to achieve statistical significance, Sullivan and DeLucia found that the firm often provides comparative data about hospital departments and individual physicians based on a smaller sample size that may create an unacceptably large margin of error.²⁰ Sullivan, for example, said his department may only have 8 to 10 Press Ganey survey responses per month and yet still receives monthly reports from the company analyzing the data. Because of the small sample size, 1 month his department ranked in the 1st percentile and 2 months later it ranked in the 99th percentile.²⁰

The effect of a high ceiling rate. A psychometrics report for the Press Ganey survey is available from the vendor that provides vague assessments of reliability and validity based on 2,762 surveys from 12 practices across 10 states. This report describes a 12-question version of the survey with “no problems encountered” with missingness and response variability. The report further states that the Press Ganey survey demonstrates construct, convergent, divergent, and predictive validities, and high reliability; however, these data are not made available.¹

In response to this report, Presson et al analyzed more than 34,000 surveys from one institution to evaluate the reliability and validity of the Press Ganey survey.21 Overall, the survey demonstrated suitable psychometric properties for most metrics. However, Presson et al noted a significantly high ceiling rate of 29.3% for the total score, which ranged from 55.4% to 84.1% across items.²¹ (Ceiling rates are considered substantial if they occur more than 20% of the time.) Ultimately, a high ceiling rate reduces the power to discriminate between patients who have high satisfaction (everyone is “happy”) with those who are just slightly less than happy, but not dissatisfied. This data quality metric can impact the reliability and validity of a survey—and substantial ceiling rates can notably impact percentile rankings of scores within an institution, offering a possible explanation for the small percentage change between the top and bottom percentiles.

Continue to: Other issues with surveys...

Other issues with surveys

In addition to the limitations associated with percentile groupings, survey data are always subject to nonresponse bias, and small sample size can lead to nonsignificant results. Skewed responses also can make it difficult to identify true outlying providers who may need remediation or may be offering a superior patient experience. Satisfaction surveys also lack an assessment of objective data and instead assess how patients perceive and feel, which introduces subjectivity to the results.

Additionally, focusing on improving patient experience ratings can incentivize unnecessary or inappropriate care (ie, overprescribing of narcotics, prescribing antibiotics when not indicated, or ordering testing that may not change management). Some physicians even state that they are not getting the type of feedback that they are asking for and that the survey is not asking the right questions to elicit patient input that is meaningful to their practice. Lastly, the incorporation of trainees and advanced practice providers in the patient care experience leads to the assessment of an alternative provider being included in the ultimate score and may not be representative of that physician.

Patients’ perception and survey results. In some circumstances, the patient’s understanding of their medical situation may affect their responses. Some may argue that patients may mistake a physician’s confidence for competence, when in reality these two entities are mutually exclusive. In a randomized controlled trial, researchers from Mount Sinai School of Medicine and Columbia University Medical Center surveyed inner-city women with newly diagnosed and surgically treated early-stage breast cancer for their perceived quality of care and the process of getting care, including referrals, test results, and treatments. They compared the responses with patient records to determine the actual quality of care. Of the 374 women who received treatment for early-stage breast cancer, 55% said they received “excellent care,” but most—88%—actually got care that was in line with the best current treatment guidelines. Interestingly, the study found African American women were less likely to report excellent care than White or Hispanic women, less likely to trust their doctor, and more likely to say they experienced bias during the process. However, there was no difference in actual quality of care received in any group.²²

You can’t improve what you can’t control. Ultimately, while many providers think patient satisfaction survey results may help inform some aspects of their practice, they cannot improve what they cannot control. For example, the multicenter study by Rogo-Gupta et al found that older patients (≥63 years) have more than a 3-fold increase in odds of giving a top satisfaction score than younger patients (≤33 years), independent of other aspects of the care experience.15 Additionally, they found that older physicians (≥56 years) had a significant increase in odds of receiving a top satisfaction score when compared with physicians who were younger than 55 years old.¹⁵ Given that physicians clearly cannot control their own age or the age of their patients, the negative impacts of these biases need to be addressed and remedied at a systems level.

Why might these biases exist?

While we cannot completely understand all of the possible explanations for these biases, it is important to emphasize the long-standing prejudice and discrimination against women and people of color in our society and how this has impacted our behavior. While strides have been made, there clearly still seems to be a difference between what we say and how our biases impact our behavior. Women are still tougher on women in professional evaluations in other fields as well²³; it is not unique to medicine. While workplace improvements are slowly changing, women still face inequities. The more research we publish to describe it, the more we hope the conversation continues, allowing us to reduce the impact of bias on our sense of self-worth and identity related to our careers, narrow the pay gap, and see women advance at the same rate as male counterparts. Considerable transformation is crucial to prevent further workforce attrition.

With regard to the lower scores provided by Asian patients, studies suggest that cultural response bias, rather than true differences in quality of care, may account for these discrepancies. Previous literature has found that Asian patients are more likely to select midpoints, rather than extremes, when completing Likert-type studies²⁴ and are not more likely to change medical providers than other race/ethnicities, indicating that lower ratings may not necessarily imply greater dissatisfaction with care.²⁵

Far-reaching effects on finances, income, well-being, job satisfaction, etc.

Depending on how the results are distributed and used, the effects of patient satisfaction surveys can extend well beyond the original intentions. At some institutions, income for physicians is directly tied to their Press Ganey satisfaction scores, which could have profound implications for female and Asian physicians,^13,15 who would be paid less—resulting in a wider pay gap than already exists.¹⁸

When negative and not constructive, patient evaluations can contribute to physician burnout and a loss of productive members of the workforce.²⁶ This is especially important in obstetrics and gynecology, where physicians are most likely to experience burnout due to multiple factors such as high-risk medical conditions, pressures of the electronic medical record (EMR), the medicolegal environment, and difficulty balancing patient expectations for autonomy with professional judgement.²⁷ Burnout also disproportionately affects women and younger physicians, which is especially concerning given that, in 2017, approximately one-third of practicing obstetrician/gynecologists were women, while that same year more than 80% of trainees matching into the field were women.²⁸ In one survey sent to members of a prominent medical society, 20% of the medical professionals who responded said they have had their employment threatened by low patient satisfaction scores, 78% reported that patient satisfaction surveys moderately or severely affected their job satisfaction, and 28% stated they had considered quitting their job or leaving the medical profession.²⁹Another related effect is the association between malpractice proceedings and a lack of satisfaction with perceived quality of physician-patient communication.³⁰ This may be an important determinant of malpractice lawsuits, and ensuring high patient satisfaction may be a form of defensive medicine.

Continue to: Controlling the narrative for the future: Proposed strategies...

Controlling the narrative for the future: Proposed strategies

The rapid, widespread adoption of the Press Ganey survey across specialties, clinical care settings, and geographic areas may have been largely due to the ease and operational benefits for hospitals rather than after rigorous study and validation. For example, repeated use of a specific measurement tool may facilitate comparison across areas within a hospital but also across institutions, which can help assess performance at a national level. Hospitals also may have a financial incentive to work with a single third-party or vendor instead of using multiple options across multiple vendors. However, the impact of adoption of novel measures of performance should be evaluated prior to widespread adoption and utilization.

A similar example of an emergence of a technological advancement that has changed the field of medicine and how we provide care is the EMR. Epic is now the most commonly used medical record system and holds the market share of the industry, covering 78% of patients in the United States.³¹ While there are certainly many potential benefits of a common EMR, such as ease of information sharing and standardization of formatting, opportunities are identified in real time and require product adjustment. For example, modifications have been made to accurately represent gender outside of the previously used dichotomous options. Diagnoses such as cervical cancer screening can now be used even if the patient gender is listed as male.

Similarly, the Press Ganey and other patient satisfaction questionnaires should be evaluated and modified to address existing societal biases. The World Health Organization estimates that it will take 300 years to fix gender inequality,³² but we have an opportunity now to control the narrative and improve patient feedback.

Future research avenues

Ultimately, there is a need to further explore currently available methods of evaluating clinical encounters to better understand the inherent biases and limitations. We hope this review will encourage other physicians to examine their specialties and hospitals and require similar analyses from vendors of such satisfaction rating products prior to using them. At the very least, health systems should be willing to partner with vendors and physicians on an ongoing basis to better understand the biases involved in these survey results and make modifications as needed. Patients also obtain information from and contribute to self-reported, publicly available websites; therefore, additional exploration into a nationalized standard for assessing patient satisfaction also may serve as an opportunity to standardize the information patients evaluate.³³ Further assessment of the potential financial and emotional impact of using the currently available patient-reported surveys on female physicians, Asian physicians, young physicians, and physicians who see young patients is needed. It is time to put pressure on a broken patient satisfaction system and improve on a national level to avoid undue negative consequences on our physicians. Use of patient satisfaction survey data should be limited until we all understand and account for the biases that are evident. ●

This year’s menopause Update highlights a highly effective nonhormonal medication that recently received approval by the US Food and Drug Administration (FDA) for the treatment of bothersome menopausal vasomotor symptoms. In addition, the Update provides guidance regarding how ObGyns should respond when an endometrial biopsy for postmenopausal bleeding reveals proliferative changes.

Breakthrough in women’s health: A new nonhormone therapy for vasomotor symptoms

Johnson KA, Martin N, Nappi RE, et al. Efficacy and safety of fezolinetant in moderate-to-severe vasomotor symptoms associated with menopause: a phase 3 RCT. J Clin Endocrinol Metab. 2023;dgad058. doi:10.1210/clinem/dgad058.
 

Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023;401:1091-1102. doi:10.1016/S0140-6736(23)00085-5.

A new oral nonestrogen-containing medication for relief of moderate to severe hot flashes, fezolinetant (Veozah) 45 mg daily, has been approved by the FDA and was expected to be available by the end of May 2023. Fezolinetant is a selective neurokinin 3 (NK3) receptor antagonistthat offers a targeted nonhormonal approach to menopausal vasomotor symptoms (VMS), and it is the first in its class to make it to market.

The decline in estrogen at menopause appears to result in increased signaling at kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the thermoregulatory center within the hypothalamus with resultant increases in hot flashes.^1,2 Fezolinetant works by binding to and blocking the activities of the NK3 receptor.^3-5

Key study findings

Selective NK3 receptor antagonists, including fezolinetant, effectively reduce the frequency and severity of VMS comparable to that of hormone therapy (HT). Two phase 3 clinical trials, Skylight 1 and 2, confirmed the efficacy and safety of fezolinetant 45 mg in treating VMS,^6,7 and an additional 52-week placebo-controlled study, Skylight 4, confirmed long-term safety.⁸ Onset of action occurs within a week. Reported adverse events occurred in 1% to 2% of healthy menopausal women participating in clinical trials; these included headaches, abdominal pain, diarrhea, insomnia, back pain, hot flushes, and reversible elevated hepatic transaminase levels.^6-9

The published phase 2 trials⁹ and the international randomized controlled trial (RCT) 12-week studies, Skylight 1 and 2,^6,7 found that once-daily 30-mg and 45-mg doses of fezolinetant significantly reduced VMS frequency and severity at 12 weeks among women aged 40 to 60 years who reported an average of 7 moderate to severe VMS/day; the reduction in reported VMS was sustained at 40 weeks. Phase 3 data from Skylight 1 and 2 demonstrated fezolinetant’s efficacy in reducing the frequency and severity of VMS and provided information on the safety profile of fezolinetant compared with placebo over 12 weeks and a noncontrolled extension for an additional 40 weeks.^6,7

Oral fezolinetant was associated with improved quality of life, including reduced VMS-related interference with daily life.¹⁰ Johnson and colleagues, reporting for Skylight 2, found VMS frequency and severity improvement by week 1, which achieved statistical significance at weeks 4 and 12, with this improvement maintained through week 52.⁶ A 64.3% reduction in mean daily VMS from baseline was seen at 12 weeks for fezolinetant 45 mg compared with a 45.4% reduction for placebo. VMS severity significantly decreased compared with placebo at 4 and 12 weeks.⁶

Serious treatment-emergent adverse events were infrequent, reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo.⁶ Increases in levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) were noted and were described as asymptomatic, isolated, intermittent, or transient, and these levels returned to baseline during treatment or after discontinuation.⁶

Of the 5 participants taking fezolinetant in Skyline 1 with ALT or AST levels greater than 3 times the upper limit of normal in the 12-week randomized trial, levels returned to normal range while continuing treatment in 2 participants, with treatment interruption in 2, and with discontinuation in 1. No new safety signals were seen in the 40-week extension trial.⁶

Continue to: Endometrial and bone safety...

Endometrial and bone safety

Results from Skylight 4, a phase 3, randomized, double-blind, 52-week safety study, provided additional evidence that confirmed the longer-term safety of fezolinetant over a 52-week treatment period.⁸

Endometrial safety was assessed in postmenopausal women with normal baseline endometrium (n = 599).⁸ For fezolinetant 45 mg, 1 of 203 participants had endometrial hyperplasia (EH) (0.5%; upper limit of one-sided 95% confidence interval [CI], 2.3%); no cases of EH were noted in the placebo (0 of 186) or fezolinetant 30-mg (0 of 210) groups. The incidence of EH or malignancy in fezolinetant-treated participants was within prespecified limits, as assessed by blinded, centrally read endometrial biopsies. Endometrial malignancy occurred in 1 of 210 in the fezolinetant 30-mg group (0.5%; 95% CI, 2.2%) with no cases in the other groups, thus meeting FDA requirements for endometrial safety.⁸

In addition, no significant differences were noted in change from baseline endometrial thickness on transvaginal ultrasonography between fezolinetant-treated and placebo groups. Likewise, no loss of bone density was found on dual-energy x-ray absorptiometry (DEXA) scans or trabecular bone scores.⁸

Liver safety

Although no cases of severe liver injury were noted, elevations in serum transaminase concentrations greater than 3 times the upper limit of normal were observed in the clinical trials. In Skylight 4, liver enzyme elevations more than 3 times the upper limit of normal occurred in 6 of 583 participants taking placebo, 8 of 590 taking fezolinetant 30 mg, and 12 of 589 taking fezolinetant 45 mg.⁸

The prescribing information for fezolinetant includes a warning for elevated hepatic transaminases: Fezolinetant should not be started if baseline serum transaminase concentration is equal to or exceeds 2 times the upper limit of normal. Liver tests should be obtained at baseline and repeated every 3 months for the first 9 months and then if symptoms suggest liver injury.^11,12

Unmet need for nonhormone treatment of VMS

Vasomotor symptoms affect up to 80% of women, with approximately 25% bothersome enough to warrant treatment. Vasomotor symptoms persist for a median of 7 years, with duration and severity differing by race and ethnicity. Black, Hispanic, and possibly Native American women experience the highest burden of VMS.² Although VMS, including hot flashes, night sweats, and mood and sleep disturbances, often are considered an annoyance to those with mild symptoms, moderate to severe VMS impact women’s lives, including functioning at home or work, affecting relationships, and decreasing perceived quality of life, and they have been associated with workplace absenteeism and increased health care costs, both direct from medical care and testing and indirect costs from lost work.^13-15

Women with 7 or more daily moderate to severe VMS (defined as with sweating or affecting function) reported interference with sleep (94%), concentration (84%), mood (85%), energy (77%), and sexual activity (61%).¹⁶ Moderately to severely bothersome VMS have been associated with impaired psychological and general well-being, affecting work performance.¹⁷ Based on a Mayo Clinic workplace survey, Faubion and colleagues estimated an annual loss of $1.8 billion in the United States for menopause-related missed work and a $28 billion loss when medical expenses were added.¹⁵

Menopausal HT has been the primary treatment for VMS and has been shown to reduce the frequency and severity of hot flashes, with additional benefits on sleep, mood, fatigue, bone loss and reduction of fracture, and genitourinary syndrome of menopause (GSM), and with potential improvement in cardiovascular health with decreased type 2 diabetes.^18,19 For healthy women with early menopause and no contraindications, HT has been recommended until at least the age of natural menopause, as observational data suggest that HT prevents osteoporosis, cardiovascular disease, neurodegenerative changes, and sexual dysfunction for these women.^19,20 Similarly, for healthy women younger than age 60 or within 10 years of menopause, initiating HT has been shown to be safe and effective in treating bothersome VMS and preventing osteoporotic fractures and genitourinary changes.^19,21

Most systemic HT formulations are inexpensive (for example, available as generics), with multiple dosing and formulations available for use alone or combined as oral, transdermal, or vaginal therapies. Despite the fear that arose for clinicians and women from the initial 2002 findings of the Women’s Health Initiative regarding increased risk of breast cancer, stroke, venous thrombosis, cardiovascular disease, and dementia, major medical societies agree that when initiated at or soon after menopause, HT is a safe and effective therapy to relieve VMS, protect against bone loss, and treat genitourinary changes.^19,21

Many women, however, cannot take HT, including those with estrogen-sensitive cancers, such as breast or uterine cancers; prior cardiovascular disease, stroke, or venous thrombotic events; severe endometriosis; or migraine headaches with visual auras.² In addition, many symptomatic menopausal women without health contraindications choose not to take HT.² Until now, the only FDA-approved VMS nonhormone therapy has been a low-dose 7.5-mg paroxetine salt. Unfortunately, this formulation, along with the off-label use of other antidepressants (selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors), gabapentinoids, oxybutynin, and clonidine, are substantially less effective than HT in treating moderate to severe VMS.

Bottom line

A substantial unmet need remains for effective therapy for moderate to severe VMS for women who cannot or choose not to take menopausal HT to relieve VMS.^2,16 Effective, safe nonhormone treatment options such as the new NK3 receptor antagonist fezolinetant will address this clinically important need.

One concern is that the cost of developing and bringing to market the first of a new type of medication will be passed on to consumers, which may put it out of the price range for the many women who need it. However, the development and FDA approval of fezolinetant as the first NK3 receptor antagonist to treat menopausal VMS is potentially a practice changer. It provides a novel, effective, and safe FDA-approved nonhormonal treatment for menopausal women with moderate to severe VMS, particularly for women who cannot or will not take hormone therapy.

Continue to: When endometrial biopsy for postmenopausal bleeding reveals proliferative changes, how should we respond?...

Abraham C. Proliferative endometrium in menopause: to treat or not to treat? Obstet Gynecol. 2023;141:265-267. doi:10.1097/AOG.0000000000005054.

The following case represents a common scenario for ObGyns.

CASE Patient with proliferative endometrial changes

A menopausal patient with a body mass index (BMI) > 30 kg/m² presents with uterine bleeding. She does not use systemic menopausal hormone therapy. Endometrial biopsy indicates proliferative changes.

When endometrial biopsy performed for bleeding reveals proliferative changes in menopausal women, we traditionally have responded by reassuring the patient that the findings are benign and advising that she should let us know if future spotting or bleeding occurs.

However, a recent review by Abraham published in Obstetrics and Gynecology details the implications of proliferative endometrial changes in menopausal patients, advising that treatment, as well as monitoring, may be appropriate.²²

Endometrial changes and what they suggest

In premenopausal women, proliferative endometrial changes are physiologic and result from ovarian estrogen production early in each cycle, during what is called the proliferative (referring to the endometrium) or follicular (referring to the dominant follicle that synthesizes estrogen) phase. In menopausal women who are not using HT, however, proliferative endometrial changes, with orderly uniform glands seen on histologic evaluation, reflect aromatization of androgens by adipose and other tissues into estrogen.

The next step on the continuum to hyperplasia (benign or atypical) after proliferative endometrium is disordered proliferative endometrium. At this stage, histologic evaluation reveals scattered cystic and dilated glands that have a normal gland-to-stroma ratio with a low gland density overall and without any atypia. Randomly distributed glands may have tubal metaplasia or fibrin thrombi associated with microinfarcts, often presenting with irregular bleeding. This is a noncancerous change that occurs with excess estrogen (endogenous or exogenous).²³

Progestins reverse endometrial hyperplasia by activating progesterone receptors, which leads to stromal decidualization with thinning of the endometrium. They have a pronounced effect on the histologic appearance of the endometrium. By contrast, endometrial intraepithelial neoplasia (EIN, previously known as endometrial hyperplasiawith atypia) shows underlying molecular mutations and histologic alterations and represents a sharp transition to true neoplasia, which greatly increases the risk of endometrioid endometrial adenocarcinoma.²⁴

For decades, we have been aware that if women diagnosed with endometrial hyperplasia are not treated with progestational therapy, their future risk of endometrial cancer is elevated. More recently, we also recognize that menopausal women found to have proliferative endometrial changes, if not treated, have an increased risk of endometrial cancer.

In a retrospective cohort study of almost 300 menopausal women who were not treated after endometrial biopsy revealed proliferative changes, investigators followed participants for an average of 11 years.²⁵ These women had a mean BMI of 34 kg/m². During follow-up, almost 12% of these women were diagnosed with endometrial hyperplasia or cancer. This incidence of endometrial neoplasia was some 4 times higher than for women initially found to have atrophic endometrial changes.²⁵

Progestin treatment

Oral progestin therapy with follow-up endometrial biopsy constitutes traditional management for endometrial hyperplasia. Such therapy minimizes the likelihood that hyperplasia will progress to endometrial cancer.

We now recognize that the convenience, as well as the high endometrial progestin levels achieved, with levonorgestrel-releasing intrauterine devices (LNG-IUDs) have advantages over oral progestin therapy in treating endometrial hyperplasia. Indeed, a recent US report found that among women with EIN managed medically, use of progestin-releasing IUDs has grown from 7.7% in 2008 to 35.6% in 2020.²⁶

Although both oral and intrauterine progestin are highly effective in treating simple hyperplasia, progestin IUDs are substantially more effective than oral progestins in treating EIN.²⁷ Progestin concentrations in the endometrium have been shown to be 100-fold higher after LNG-IUD placement compared with oral progestin use.²² In addition, adverse effects, including bloating, unpleasant mood changes, and increased appetite, are more common with oral than intrauterine progestin therapy.²⁸

Unfortunately, data from randomized trials addressing progestational treatment of proliferative endometrium in menopausal women are not available to support the treatment of proliferative endometrium with either oral progestins or the LNG-IUD.²²

Role of ultrasonography

Another concern is relying on a finding of thin endometrial thickness on vaginal ultrasonography. In a simulated retrospective cohort study, use of transvaginal ultrasonography to determine the appropriateness of a biopsy was found not to be sufficiently accurate or racially equitable with regard to Black women.²⁹ In simulated data, transvaginal ultrasonography missed almost 5 times more cases of endometrial cancer among Black women compared with White women due to higher fibroid prevalence and nonendometrioid histologic type malignancies in Black women.²⁹

Assessing risk

If proliferative endometrium is found, Abraham suggests assessing risk using²²:

• age
• comorbidities (including obesity)
• endometrial echo thickness on vaginal ultrasonography.

Consider the patient’s risk and tolerance of recurrent bleeding as well as her tolerance for progestational adverse effects if medical therapy is chosen. Discussion about next steps should include reviewing the histologic findings with the patient and discussing the difference in risk of progression to endometrial cancer of a finding of proliferative endometrium compared with a histologic finding of endometrial hyperplasia.

Using this patient-centered approach, observation over time with follow-up endometrial biopsies remains a management option. Although some women may tolerate micronized progesterone over synthetic progestins, there is concern that it may be less effective in suppressing the endometrium than synthetic progestins.³⁰ Accordingly, synthetic progestins represent first-line options in this setting^.

In her review, Abraham suggests that when endometrial biopsy reveals proliferative changes in a menopausal woman, we should initiate progestin treatment and perform surveillance endometrial sampling every 3 to 6 months. If such sampling reveals benign but not proliferative endometrium, progestin therapy can be stopped and endometrial biopsy repeated if bleeding recurs.²² ●

This year’s menopause Update highlights a highly effective nonhormonal medication that recently received approval by the US Food and Drug Administration (FDA) for the treatment of bothersome menopausal vasomotor symptoms. In addition, the Update provides guidance regarding how ObGyns should respond when an endometrial biopsy for postmenopausal bleeding reveals proliferative changes.

Breakthrough in women’s health: A new nonhormone therapy for vasomotor symptoms

Johnson KA, Martin N, Nappi RE, et al. Efficacy and safety of fezolinetant in moderate-to-severe vasomotor symptoms associated with menopause: a phase 3 RCT. J Clin Endocrinol Metab. 2023;dgad058. doi:10.1210/clinem/dgad058.
 

Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023;401:1091-1102. doi:10.1016/S0140-6736(23)00085-5.

A new oral nonestrogen-containing medication for relief of moderate to severe hot flashes, fezolinetant (Veozah) 45 mg daily, has been approved by the FDA and was expected to be available by the end of May 2023. Fezolinetant is a selective neurokinin 3 (NK3) receptor antagonistthat offers a targeted nonhormonal approach to menopausal vasomotor symptoms (VMS), and it is the first in its class to make it to market.

The decline in estrogen at menopause appears to result in increased signaling at kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the thermoregulatory center within the hypothalamus with resultant increases in hot flashes.^1,2 Fezolinetant works by binding to and blocking the activities of the NK3 receptor.^3-5

Key study findings

Selective NK3 receptor antagonists, including fezolinetant, effectively reduce the frequency and severity of VMS comparable to that of hormone therapy (HT). Two phase 3 clinical trials, Skylight 1 and 2, confirmed the efficacy and safety of fezolinetant 45 mg in treating VMS,^6,7 and an additional 52-week placebo-controlled study, Skylight 4, confirmed long-term safety.⁸ Onset of action occurs within a week. Reported adverse events occurred in 1% to 2% of healthy menopausal women participating in clinical trials; these included headaches, abdominal pain, diarrhea, insomnia, back pain, hot flushes, and reversible elevated hepatic transaminase levels.^6-9

The published phase 2 trials⁹ and the international randomized controlled trial (RCT) 12-week studies, Skylight 1 and 2,^6,7 found that once-daily 30-mg and 45-mg doses of fezolinetant significantly reduced VMS frequency and severity at 12 weeks among women aged 40 to 60 years who reported an average of 7 moderate to severe VMS/day; the reduction in reported VMS was sustained at 40 weeks. Phase 3 data from Skylight 1 and 2 demonstrated fezolinetant’s efficacy in reducing the frequency and severity of VMS and provided information on the safety profile of fezolinetant compared with placebo over 12 weeks and a noncontrolled extension for an additional 40 weeks.^6,7

Oral fezolinetant was associated with improved quality of life, including reduced VMS-related interference with daily life.¹⁰ Johnson and colleagues, reporting for Skylight 2, found VMS frequency and severity improvement by week 1, which achieved statistical significance at weeks 4 and 12, with this improvement maintained through week 52.⁶ A 64.3% reduction in mean daily VMS from baseline was seen at 12 weeks for fezolinetant 45 mg compared with a 45.4% reduction for placebo. VMS severity significantly decreased compared with placebo at 4 and 12 weeks.⁶

Serious treatment-emergent adverse events were infrequent, reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo.⁶ Increases in levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) were noted and were described as asymptomatic, isolated, intermittent, or transient, and these levels returned to baseline during treatment or after discontinuation.⁶

Of the 5 participants taking fezolinetant in Skyline 1 with ALT or AST levels greater than 3 times the upper limit of normal in the 12-week randomized trial, levels returned to normal range while continuing treatment in 2 participants, with treatment interruption in 2, and with discontinuation in 1. No new safety signals were seen in the 40-week extension trial.⁶

Continue to: Endometrial and bone safety...

Endometrial and bone safety

Results from Skylight 4, a phase 3, randomized, double-blind, 52-week safety study, provided additional evidence that confirmed the longer-term safety of fezolinetant over a 52-week treatment period.⁸

Endometrial safety was assessed in postmenopausal women with normal baseline endometrium (n = 599).⁸ For fezolinetant 45 mg, 1 of 203 participants had endometrial hyperplasia (EH) (0.5%; upper limit of one-sided 95% confidence interval [CI], 2.3%); no cases of EH were noted in the placebo (0 of 186) or fezolinetant 30-mg (0 of 210) groups. The incidence of EH or malignancy in fezolinetant-treated participants was within prespecified limits, as assessed by blinded, centrally read endometrial biopsies. Endometrial malignancy occurred in 1 of 210 in the fezolinetant 30-mg group (0.5%; 95% CI, 2.2%) with no cases in the other groups, thus meeting FDA requirements for endometrial safety.⁸

In addition, no significant differences were noted in change from baseline endometrial thickness on transvaginal ultrasonography between fezolinetant-treated and placebo groups. Likewise, no loss of bone density was found on dual-energy x-ray absorptiometry (DEXA) scans or trabecular bone scores.⁸

Liver safety

Although no cases of severe liver injury were noted, elevations in serum transaminase concentrations greater than 3 times the upper limit of normal were observed in the clinical trials. In Skylight 4, liver enzyme elevations more than 3 times the upper limit of normal occurred in 6 of 583 participants taking placebo, 8 of 590 taking fezolinetant 30 mg, and 12 of 589 taking fezolinetant 45 mg.⁸

The prescribing information for fezolinetant includes a warning for elevated hepatic transaminases: Fezolinetant should not be started if baseline serum transaminase concentration is equal to or exceeds 2 times the upper limit of normal. Liver tests should be obtained at baseline and repeated every 3 months for the first 9 months and then if symptoms suggest liver injury.^11,12

Unmet need for nonhormone treatment of VMS

Vasomotor symptoms affect up to 80% of women, with approximately 25% bothersome enough to warrant treatment. Vasomotor symptoms persist for a median of 7 years, with duration and severity differing by race and ethnicity. Black, Hispanic, and possibly Native American women experience the highest burden of VMS.² Although VMS, including hot flashes, night sweats, and mood and sleep disturbances, often are considered an annoyance to those with mild symptoms, moderate to severe VMS impact women’s lives, including functioning at home or work, affecting relationships, and decreasing perceived quality of life, and they have been associated with workplace absenteeism and increased health care costs, both direct from medical care and testing and indirect costs from lost work.^13-15

Women with 7 or more daily moderate to severe VMS (defined as with sweating or affecting function) reported interference with sleep (94%), concentration (84%), mood (85%), energy (77%), and sexual activity (61%).¹⁶ Moderately to severely bothersome VMS have been associated with impaired psychological and general well-being, affecting work performance.¹⁷ Based on a Mayo Clinic workplace survey, Faubion and colleagues estimated an annual loss of $1.8 billion in the United States for menopause-related missed work and a $28 billion loss when medical expenses were added.¹⁵

Menopausal HT has been the primary treatment for VMS and has been shown to reduce the frequency and severity of hot flashes, with additional benefits on sleep, mood, fatigue, bone loss and reduction of fracture, and genitourinary syndrome of menopause (GSM), and with potential improvement in cardiovascular health with decreased type 2 diabetes.^18,19 For healthy women with early menopause and no contraindications, HT has been recommended until at least the age of natural menopause, as observational data suggest that HT prevents osteoporosis, cardiovascular disease, neurodegenerative changes, and sexual dysfunction for these women.^19,20 Similarly, for healthy women younger than age 60 or within 10 years of menopause, initiating HT has been shown to be safe and effective in treating bothersome VMS and preventing osteoporotic fractures and genitourinary changes.^19,21

Most systemic HT formulations are inexpensive (for example, available as generics), with multiple dosing and formulations available for use alone or combined as oral, transdermal, or vaginal therapies. Despite the fear that arose for clinicians and women from the initial 2002 findings of the Women’s Health Initiative regarding increased risk of breast cancer, stroke, venous thrombosis, cardiovascular disease, and dementia, major medical societies agree that when initiated at or soon after menopause, HT is a safe and effective therapy to relieve VMS, protect against bone loss, and treat genitourinary changes.^19,21

Many women, however, cannot take HT, including those with estrogen-sensitive cancers, such as breast or uterine cancers; prior cardiovascular disease, stroke, or venous thrombotic events; severe endometriosis; or migraine headaches with visual auras.² In addition, many symptomatic menopausal women without health contraindications choose not to take HT.² Until now, the only FDA-approved VMS nonhormone therapy has been a low-dose 7.5-mg paroxetine salt. Unfortunately, this formulation, along with the off-label use of other antidepressants (selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors), gabapentinoids, oxybutynin, and clonidine, are substantially less effective than HT in treating moderate to severe VMS.

Bottom line

A substantial unmet need remains for effective therapy for moderate to severe VMS for women who cannot or choose not to take menopausal HT to relieve VMS.^2,16 Effective, safe nonhormone treatment options such as the new NK3 receptor antagonist fezolinetant will address this clinically important need.

One concern is that the cost of developing and bringing to market the first of a new type of medication will be passed on to consumers, which may put it out of the price range for the many women who need it. However, the development and FDA approval of fezolinetant as the first NK3 receptor antagonist to treat menopausal VMS is potentially a practice changer. It provides a novel, effective, and safe FDA-approved nonhormonal treatment for menopausal women with moderate to severe VMS, particularly for women who cannot or will not take hormone therapy.

Continue to: When endometrial biopsy for postmenopausal bleeding reveals proliferative changes, how should we respond?...

Abraham C. Proliferative endometrium in menopause: to treat or not to treat? Obstet Gynecol. 2023;141:265-267. doi:10.1097/AOG.0000000000005054.

The following case represents a common scenario for ObGyns.

CASE Patient with proliferative endometrial changes

A menopausal patient with a body mass index (BMI) > 30 kg/m² presents with uterine bleeding. She does not use systemic menopausal hormone therapy. Endometrial biopsy indicates proliferative changes.

When endometrial biopsy performed for bleeding reveals proliferative changes in menopausal women, we traditionally have responded by reassuring the patient that the findings are benign and advising that she should let us know if future spotting or bleeding occurs.

However, a recent review by Abraham published in Obstetrics and Gynecology details the implications of proliferative endometrial changes in menopausal patients, advising that treatment, as well as monitoring, may be appropriate.²²

Endometrial changes and what they suggest

In premenopausal women, proliferative endometrial changes are physiologic and result from ovarian estrogen production early in each cycle, during what is called the proliferative (referring to the endometrium) or follicular (referring to the dominant follicle that synthesizes estrogen) phase. In menopausal women who are not using HT, however, proliferative endometrial changes, with orderly uniform glands seen on histologic evaluation, reflect aromatization of androgens by adipose and other tissues into estrogen.

The next step on the continuum to hyperplasia (benign or atypical) after proliferative endometrium is disordered proliferative endometrium. At this stage, histologic evaluation reveals scattered cystic and dilated glands that have a normal gland-to-stroma ratio with a low gland density overall and without any atypia. Randomly distributed glands may have tubal metaplasia or fibrin thrombi associated with microinfarcts, often presenting with irregular bleeding. This is a noncancerous change that occurs with excess estrogen (endogenous or exogenous).²³

Progestins reverse endometrial hyperplasia by activating progesterone receptors, which leads to stromal decidualization with thinning of the endometrium. They have a pronounced effect on the histologic appearance of the endometrium. By contrast, endometrial intraepithelial neoplasia (EIN, previously known as endometrial hyperplasiawith atypia) shows underlying molecular mutations and histologic alterations and represents a sharp transition to true neoplasia, which greatly increases the risk of endometrioid endometrial adenocarcinoma.²⁴

For decades, we have been aware that if women diagnosed with endometrial hyperplasia are not treated with progestational therapy, their future risk of endometrial cancer is elevated. More recently, we also recognize that menopausal women found to have proliferative endometrial changes, if not treated, have an increased risk of endometrial cancer.

In a retrospective cohort study of almost 300 menopausal women who were not treated after endometrial biopsy revealed proliferative changes, investigators followed participants for an average of 11 years.²⁵ These women had a mean BMI of 34 kg/m². During follow-up, almost 12% of these women were diagnosed with endometrial hyperplasia or cancer. This incidence of endometrial neoplasia was some 4 times higher than for women initially found to have atrophic endometrial changes.²⁵

Progestin treatment

Oral progestin therapy with follow-up endometrial biopsy constitutes traditional management for endometrial hyperplasia. Such therapy minimizes the likelihood that hyperplasia will progress to endometrial cancer.

We now recognize that the convenience, as well as the high endometrial progestin levels achieved, with levonorgestrel-releasing intrauterine devices (LNG-IUDs) have advantages over oral progestin therapy in treating endometrial hyperplasia. Indeed, a recent US report found that among women with EIN managed medically, use of progestin-releasing IUDs has grown from 7.7% in 2008 to 35.6% in 2020.²⁶

Although both oral and intrauterine progestin are highly effective in treating simple hyperplasia, progestin IUDs are substantially more effective than oral progestins in treating EIN.²⁷ Progestin concentrations in the endometrium have been shown to be 100-fold higher after LNG-IUD placement compared with oral progestin use.²² In addition, adverse effects, including bloating, unpleasant mood changes, and increased appetite, are more common with oral than intrauterine progestin therapy.²⁸

Unfortunately, data from randomized trials addressing progestational treatment of proliferative endometrium in menopausal women are not available to support the treatment of proliferative endometrium with either oral progestins or the LNG-IUD.²²

Role of ultrasonography

Another concern is relying on a finding of thin endometrial thickness on vaginal ultrasonography. In a simulated retrospective cohort study, use of transvaginal ultrasonography to determine the appropriateness of a biopsy was found not to be sufficiently accurate or racially equitable with regard to Black women.²⁹ In simulated data, transvaginal ultrasonography missed almost 5 times more cases of endometrial cancer among Black women compared with White women due to higher fibroid prevalence and nonendometrioid histologic type malignancies in Black women.²⁹

Assessing risk

If proliferative endometrium is found, Abraham suggests assessing risk using²²:

• age
• comorbidities (including obesity)
• endometrial echo thickness on vaginal ultrasonography.

Consider the patient’s risk and tolerance of recurrent bleeding as well as her tolerance for progestational adverse effects if medical therapy is chosen. Discussion about next steps should include reviewing the histologic findings with the patient and discussing the difference in risk of progression to endometrial cancer of a finding of proliferative endometrium compared with a histologic finding of endometrial hyperplasia.

Using this patient-centered approach, observation over time with follow-up endometrial biopsies remains a management option. Although some women may tolerate micronized progesterone over synthetic progestins, there is concern that it may be less effective in suppressing the endometrium than synthetic progestins.³⁰ Accordingly, synthetic progestins represent first-line options in this setting^.

In her review, Abraham suggests that when endometrial biopsy reveals proliferative changes in a menopausal woman, we should initiate progestin treatment and perform surveillance endometrial sampling every 3 to 6 months. If such sampling reveals benign but not proliferative endometrium, progestin therapy can be stopped and endometrial biopsy repeated if bleeding recurs.²² ●

This year’s menopause Update highlights a highly effective nonhormonal medication that recently received approval by the US Food and Drug Administration (FDA) for the treatment of bothersome menopausal vasomotor symptoms. In addition, the Update provides guidance regarding how ObGyns should respond when an endometrial biopsy for postmenopausal bleeding reveals proliferative changes.

Breakthrough in women’s health: A new nonhormone therapy for vasomotor symptoms

Johnson KA, Martin N, Nappi RE, et al. Efficacy and safety of fezolinetant in moderate-to-severe vasomotor symptoms associated with menopause: a phase 3 RCT. J Clin Endocrinol Metab. 2023;dgad058. doi:10.1210/clinem/dgad058.
 

Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023;401:1091-1102. doi:10.1016/S0140-6736(23)00085-5.

A new oral nonestrogen-containing medication for relief of moderate to severe hot flashes, fezolinetant (Veozah) 45 mg daily, has been approved by the FDA and was expected to be available by the end of May 2023. Fezolinetant is a selective neurokinin 3 (NK3) receptor antagonistthat offers a targeted nonhormonal approach to menopausal vasomotor symptoms (VMS), and it is the first in its class to make it to market.

The decline in estrogen at menopause appears to result in increased signaling at kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the thermoregulatory center within the hypothalamus with resultant increases in hot flashes.^1,2 Fezolinetant works by binding to and blocking the activities of the NK3 receptor.^3-5

Key study findings

Selective NK3 receptor antagonists, including fezolinetant, effectively reduce the frequency and severity of VMS comparable to that of hormone therapy (HT). Two phase 3 clinical trials, Skylight 1 and 2, confirmed the efficacy and safety of fezolinetant 45 mg in treating VMS,^6,7 and an additional 52-week placebo-controlled study, Skylight 4, confirmed long-term safety.⁸ Onset of action occurs within a week. Reported adverse events occurred in 1% to 2% of healthy menopausal women participating in clinical trials; these included headaches, abdominal pain, diarrhea, insomnia, back pain, hot flushes, and reversible elevated hepatic transaminase levels.^6-9

The published phase 2 trials⁹ and the international randomized controlled trial (RCT) 12-week studies, Skylight 1 and 2,^6,7 found that once-daily 30-mg and 45-mg doses of fezolinetant significantly reduced VMS frequency and severity at 12 weeks among women aged 40 to 60 years who reported an average of 7 moderate to severe VMS/day; the reduction in reported VMS was sustained at 40 weeks. Phase 3 data from Skylight 1 and 2 demonstrated fezolinetant’s efficacy in reducing the frequency and severity of VMS and provided information on the safety profile of fezolinetant compared with placebo over 12 weeks and a noncontrolled extension for an additional 40 weeks.^6,7

Oral fezolinetant was associated with improved quality of life, including reduced VMS-related interference with daily life.¹⁰ Johnson and colleagues, reporting for Skylight 2, found VMS frequency and severity improvement by week 1, which achieved statistical significance at weeks 4 and 12, with this improvement maintained through week 52.⁶ A 64.3% reduction in mean daily VMS from baseline was seen at 12 weeks for fezolinetant 45 mg compared with a 45.4% reduction for placebo. VMS severity significantly decreased compared with placebo at 4 and 12 weeks.⁶

Serious treatment-emergent adverse events were infrequent, reported by 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo.⁶ Increases in levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) were noted and were described as asymptomatic, isolated, intermittent, or transient, and these levels returned to baseline during treatment or after discontinuation.⁶

Of the 5 participants taking fezolinetant in Skyline 1 with ALT or AST levels greater than 3 times the upper limit of normal in the 12-week randomized trial, levels returned to normal range while continuing treatment in 2 participants, with treatment interruption in 2, and with discontinuation in 1. No new safety signals were seen in the 40-week extension trial.⁶

Continue to: Endometrial and bone safety...

Endometrial and bone safety

Results from Skylight 4, a phase 3, randomized, double-blind, 52-week safety study, provided additional evidence that confirmed the longer-term safety of fezolinetant over a 52-week treatment period.⁸

Endometrial safety was assessed in postmenopausal women with normal baseline endometrium (n = 599).⁸ For fezolinetant 45 mg, 1 of 203 participants had endometrial hyperplasia (EH) (0.5%; upper limit of one-sided 95% confidence interval [CI], 2.3%); no cases of EH were noted in the placebo (0 of 186) or fezolinetant 30-mg (0 of 210) groups. The incidence of EH or malignancy in fezolinetant-treated participants was within prespecified limits, as assessed by blinded, centrally read endometrial biopsies. Endometrial malignancy occurred in 1 of 210 in the fezolinetant 30-mg group (0.5%; 95% CI, 2.2%) with no cases in the other groups, thus meeting FDA requirements for endometrial safety.⁸

In addition, no significant differences were noted in change from baseline endometrial thickness on transvaginal ultrasonography between fezolinetant-treated and placebo groups. Likewise, no loss of bone density was found on dual-energy x-ray absorptiometry (DEXA) scans or trabecular bone scores.⁸

Liver safety

Although no cases of severe liver injury were noted, elevations in serum transaminase concentrations greater than 3 times the upper limit of normal were observed in the clinical trials. In Skylight 4, liver enzyme elevations more than 3 times the upper limit of normal occurred in 6 of 583 participants taking placebo, 8 of 590 taking fezolinetant 30 mg, and 12 of 589 taking fezolinetant 45 mg.⁸

The prescribing information for fezolinetant includes a warning for elevated hepatic transaminases: Fezolinetant should not be started if baseline serum transaminase concentration is equal to or exceeds 2 times the upper limit of normal. Liver tests should be obtained at baseline and repeated every 3 months for the first 9 months and then if symptoms suggest liver injury.^11,12

Unmet need for nonhormone treatment of VMS

Vasomotor symptoms affect up to 80% of women, with approximately 25% bothersome enough to warrant treatment. Vasomotor symptoms persist for a median of 7 years, with duration and severity differing by race and ethnicity. Black, Hispanic, and possibly Native American women experience the highest burden of VMS.² Although VMS, including hot flashes, night sweats, and mood and sleep disturbances, often are considered an annoyance to those with mild symptoms, moderate to severe VMS impact women’s lives, including functioning at home or work, affecting relationships, and decreasing perceived quality of life, and they have been associated with workplace absenteeism and increased health care costs, both direct from medical care and testing and indirect costs from lost work.^13-15

Women with 7 or more daily moderate to severe VMS (defined as with sweating or affecting function) reported interference with sleep (94%), concentration (84%), mood (85%), energy (77%), and sexual activity (61%).¹⁶ Moderately to severely bothersome VMS have been associated with impaired psychological and general well-being, affecting work performance.¹⁷ Based on a Mayo Clinic workplace survey, Faubion and colleagues estimated an annual loss of $1.8 billion in the United States for menopause-related missed work and a $28 billion loss when medical expenses were added.¹⁵

Menopausal HT has been the primary treatment for VMS and has been shown to reduce the frequency and severity of hot flashes, with additional benefits on sleep, mood, fatigue, bone loss and reduction of fracture, and genitourinary syndrome of menopause (GSM), and with potential improvement in cardiovascular health with decreased type 2 diabetes.^18,19 For healthy women with early menopause and no contraindications, HT has been recommended until at least the age of natural menopause, as observational data suggest that HT prevents osteoporosis, cardiovascular disease, neurodegenerative changes, and sexual dysfunction for these women.^19,20 Similarly, for healthy women younger than age 60 or within 10 years of menopause, initiating HT has been shown to be safe and effective in treating bothersome VMS and preventing osteoporotic fractures and genitourinary changes.^19,21

Most systemic HT formulations are inexpensive (for example, available as generics), with multiple dosing and formulations available for use alone or combined as oral, transdermal, or vaginal therapies. Despite the fear that arose for clinicians and women from the initial 2002 findings of the Women’s Health Initiative regarding increased risk of breast cancer, stroke, venous thrombosis, cardiovascular disease, and dementia, major medical societies agree that when initiated at or soon after menopause, HT is a safe and effective therapy to relieve VMS, protect against bone loss, and treat genitourinary changes.^19,21

Many women, however, cannot take HT, including those with estrogen-sensitive cancers, such as breast or uterine cancers; prior cardiovascular disease, stroke, or venous thrombotic events; severe endometriosis; or migraine headaches with visual auras.² In addition, many symptomatic menopausal women without health contraindications choose not to take HT.² Until now, the only FDA-approved VMS nonhormone therapy has been a low-dose 7.5-mg paroxetine salt. Unfortunately, this formulation, along with the off-label use of other antidepressants (selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors), gabapentinoids, oxybutynin, and clonidine, are substantially less effective than HT in treating moderate to severe VMS.

Bottom line

A substantial unmet need remains for effective therapy for moderate to severe VMS for women who cannot or choose not to take menopausal HT to relieve VMS.^2,16 Effective, safe nonhormone treatment options such as the new NK3 receptor antagonist fezolinetant will address this clinically important need.

One concern is that the cost of developing and bringing to market the first of a new type of medication will be passed on to consumers, which may put it out of the price range for the many women who need it. However, the development and FDA approval of fezolinetant as the first NK3 receptor antagonist to treat menopausal VMS is potentially a practice changer. It provides a novel, effective, and safe FDA-approved nonhormonal treatment for menopausal women with moderate to severe VMS, particularly for women who cannot or will not take hormone therapy.

Continue to: When endometrial biopsy for postmenopausal bleeding reveals proliferative changes, how should we respond?...

Abraham C. Proliferative endometrium in menopause: to treat or not to treat? Obstet Gynecol. 2023;141:265-267. doi:10.1097/AOG.0000000000005054.

The following case represents a common scenario for ObGyns.

CASE Patient with proliferative endometrial changes

A menopausal patient with a body mass index (BMI) > 30 kg/m² presents with uterine bleeding. She does not use systemic menopausal hormone therapy. Endometrial biopsy indicates proliferative changes.

When endometrial biopsy performed for bleeding reveals proliferative changes in menopausal women, we traditionally have responded by reassuring the patient that the findings are benign and advising that she should let us know if future spotting or bleeding occurs.

However, a recent review by Abraham published in Obstetrics and Gynecology details the implications of proliferative endometrial changes in menopausal patients, advising that treatment, as well as monitoring, may be appropriate.²²

Endometrial changes and what they suggest

In premenopausal women, proliferative endometrial changes are physiologic and result from ovarian estrogen production early in each cycle, during what is called the proliferative (referring to the endometrium) or follicular (referring to the dominant follicle that synthesizes estrogen) phase. In menopausal women who are not using HT, however, proliferative endometrial changes, with orderly uniform glands seen on histologic evaluation, reflect aromatization of androgens by adipose and other tissues into estrogen.

The next step on the continuum to hyperplasia (benign or atypical) after proliferative endometrium is disordered proliferative endometrium. At this stage, histologic evaluation reveals scattered cystic and dilated glands that have a normal gland-to-stroma ratio with a low gland density overall and without any atypia. Randomly distributed glands may have tubal metaplasia or fibrin thrombi associated with microinfarcts, often presenting with irregular bleeding. This is a noncancerous change that occurs with excess estrogen (endogenous or exogenous).²³

Progestins reverse endometrial hyperplasia by activating progesterone receptors, which leads to stromal decidualization with thinning of the endometrium. They have a pronounced effect on the histologic appearance of the endometrium. By contrast, endometrial intraepithelial neoplasia (EIN, previously known as endometrial hyperplasiawith atypia) shows underlying molecular mutations and histologic alterations and represents a sharp transition to true neoplasia, which greatly increases the risk of endometrioid endometrial adenocarcinoma.²⁴

For decades, we have been aware that if women diagnosed with endometrial hyperplasia are not treated with progestational therapy, their future risk of endometrial cancer is elevated. More recently, we also recognize that menopausal women found to have proliferative endometrial changes, if not treated, have an increased risk of endometrial cancer.

In a retrospective cohort study of almost 300 menopausal women who were not treated after endometrial biopsy revealed proliferative changes, investigators followed participants for an average of 11 years.²⁵ These women had a mean BMI of 34 kg/m². During follow-up, almost 12% of these women were diagnosed with endometrial hyperplasia or cancer. This incidence of endometrial neoplasia was some 4 times higher than for women initially found to have atrophic endometrial changes.²⁵

Progestin treatment

Oral progestin therapy with follow-up endometrial biopsy constitutes traditional management for endometrial hyperplasia. Such therapy minimizes the likelihood that hyperplasia will progress to endometrial cancer.

We now recognize that the convenience, as well as the high endometrial progestin levels achieved, with levonorgestrel-releasing intrauterine devices (LNG-IUDs) have advantages over oral progestin therapy in treating endometrial hyperplasia. Indeed, a recent US report found that among women with EIN managed medically, use of progestin-releasing IUDs has grown from 7.7% in 2008 to 35.6% in 2020.²⁶

Although both oral and intrauterine progestin are highly effective in treating simple hyperplasia, progestin IUDs are substantially more effective than oral progestins in treating EIN.²⁷ Progestin concentrations in the endometrium have been shown to be 100-fold higher after LNG-IUD placement compared with oral progestin use.²² In addition, adverse effects, including bloating, unpleasant mood changes, and increased appetite, are more common with oral than intrauterine progestin therapy.²⁸

Unfortunately, data from randomized trials addressing progestational treatment of proliferative endometrium in menopausal women are not available to support the treatment of proliferative endometrium with either oral progestins or the LNG-IUD.²²

Role of ultrasonography

Another concern is relying on a finding of thin endometrial thickness on vaginal ultrasonography. In a simulated retrospective cohort study, use of transvaginal ultrasonography to determine the appropriateness of a biopsy was found not to be sufficiently accurate or racially equitable with regard to Black women.²⁹ In simulated data, transvaginal ultrasonography missed almost 5 times more cases of endometrial cancer among Black women compared with White women due to higher fibroid prevalence and nonendometrioid histologic type malignancies in Black women.²⁹

Assessing risk

If proliferative endometrium is found, Abraham suggests assessing risk using²²:

• age
• comorbidities (including obesity)
• endometrial echo thickness on vaginal ultrasonography.

Consider the patient’s risk and tolerance of recurrent bleeding as well as her tolerance for progestational adverse effects if medical therapy is chosen. Discussion about next steps should include reviewing the histologic findings with the patient and discussing the difference in risk of progression to endometrial cancer of a finding of proliferative endometrium compared with a histologic finding of endometrial hyperplasia.

Using this patient-centered approach, observation over time with follow-up endometrial biopsies remains a management option. Although some women may tolerate micronized progesterone over synthetic progestins, there is concern that it may be less effective in suppressing the endometrium than synthetic progestins.³⁰ Accordingly, synthetic progestins represent first-line options in this setting^.

In her review, Abraham suggests that when endometrial biopsy reveals proliferative changes in a menopausal woman, we should initiate progestin treatment and perform surveillance endometrial sampling every 3 to 6 months. If such sampling reveals benign but not proliferative endometrium, progestin therapy can be stopped and endometrial biopsy repeated if bleeding recurs.²² ●

In 2022, the most significant advances in the treatment of gynecologic cancers were achieved for patients with ovarian cancer. While ovarian cancer continues to carry the worst prognosis of all gynecologic cancers, 5-year relative survival has gradually increased, from 34.4% in 1975 to 52.4% in 2014.¹

In this Update, we highlight the recent advances in our understanding of targeted therapy in ovarian cancer. We review SORAYA, a trial that demonstrated that mirvetuximab soravtansine, an antibody-drug conjugate, has promising efficacy in platinum-resistant ovarian cancers that overexpress folate receptor α. We also spotlight progress in the treatment of low-grade serous ovarian cancer, another notoriously chemotherapy-resistant disease, in GOG 281/LOGS, a phase 2 study of the MEK inhibitor trametinib. Finally, we discuss emerging long-term follow-up data on poly(ADP-ribose) polymerase (PARP) inhibitors, which are helping to refine the role of these groundbreaking drugs.

New drug approved for platinum-resistant epithelial ovarian cancer—the first since 2014

Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41:2436-2445. doi:10.1200/JCO.22.01900.

While most patients diagnosed with advanced ovarian cancer will respond to platinum-based chemotherapy, those whose disease recurs eventually develop resistance to platinum agents. Treatment options for platinum-resistant ovarian cancer are limited and prognosis is poor. Most regimens have a response rate of only 10%. Since the approval of bevacizumab combined with chemotherapy in 2014, no new agents have been approved by the US Food and Drug Administration (FDA) for use in platinum-resistant ovarian cancer.

Efficacy shown with mirvetuximab

Recently, Matulonis and colleagues published results of the SORAYA study, a single-arm,phase 2 trial, that examined the efficacy and safety of mirvetuximab soravtansine-gynx among women with platinum-resistant ovarian cancer.² Mirvetuximab is an antibody-drug conjugate composed of an antibody directed at the folate receptor α attached to a cytotoxic microtubule inhibitor.

The study included 106 patients with platinum-resistant ovarian cancer whose tumors expressed folate receptor α at a high level—a feature of approximately 50% of patients screened for the study. Twenty-nine patients experienced a partial response and 5 had a complete response, corresponding to a remarkable objective response rate of 32.4%. The median progression-free survival was 4.3 months.

Like other antibody-drug conjugates, ocular toxicities, including blurred vision (41%) and keratopathy (29%), were common. However, toxicity was manageable and rarely led to drug discontinuation.

Continue to: A novel agent for recurrent low-grade serous ovarian carcinoma...

A novel agent for recurrent low-grade serous ovarian carcinoma

Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022;399:541-553. doi:10.1016/S0140-6736(21)02175-9.

Low-grade serous carcinoma is a histologic subtype that makes up approximately 5% of all epithelial ovarian cancers.³ Patients with low-grade serous carcinoma are often younger and, because of the indolent nature of the histology, generally have a longer overall survival compared with patients with high-grade serous carcinoma. Unlike high-grade disease, however, low-grade serous carcinoma usually is resistant to chemotherapy, making treatment options limited for patients with advanced and recurrent disease.

Trametinib: A potential option

In an international, randomized, open-label trial (GOG 281/LOGS), Gershenson and colleagues investigated the efficacy of trametinib compared with standard-of-care chemotherapy in patients with recurrent low-grade serous ovarian cancer.⁴ Trametinib, a mitogen-activated protein kinase MEK inhibitor, is a targeted agent that is FDA approved for treatment in BRAF-mutated melanoma, lung, and thyroid cancers.

Patients with recurrent low-grade serous ovarian cancer were randomly assigned to trametinib (n = 130) or 1 of 5 standard-of-care treatment options (n = 130), including both chemotherapy and hormonal treatments. Those assigned to trametinib were significantly less likely to have disease progression (78% vs 89%), with a median progression-free survival of 13 months, compared with7.2 months in controls (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.36–0.64). Additionally, patients who had a radiographic response to trametinib experienced a longer duration of response compared with those who responded to standard-of-care treatment (13.6 months vs 5.9 months).

While there was no statistically significant difference in overall survival (HR, 0.76; 95% CI, 0.51–1.12), crossover to trametinib from the standard-of-care group was allowed and occurred among 68% of patients, which limits the study’s ability to measure differences in overall survival.

Trametinib was well tolerated by patients, but skin rash and anemia followed by hypertension were the most common adverse effects. In the standard-of-care group, the most common toxicities were abdominal pain, nausea, and anemia. A slightly higher proportion of patients in the trametinib group discontinued the drug due to toxicity compared with the standard-of-care group (36% vs 30%), but the there was no difference between the 2 groups in scores on quality-of-life assessments.

Continue to: PARP inhibitors benefit many women with ovarian cancer, but they may hurt others...

PARP inhibitors benefit many women with ovarian cancer, but they may hurt others

Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40:3952-3964. doi:10.1200/JCO.22.01003.

Poly(ADP-ribose) polymerase (PARP) inhibitors are a class of oral anticancer agents that target DNA repair. Since the initial FDA approval in 2014 of olaparib for the treatment of patients with recurrent BRCA-mutated ovarian cancer, PARP inhibitors have been approved for maintenance in both the frontline setting and after platinum-sensitive recurrence, and as single-agenttreatment for ovarian cancer with BRCA mutations or evidence of homologous repair deficiency (HRD), a BRCA-like molecular phenotype.⁵ The expanding role for PARP inhibitors in ovarian cancer seemed inexorable.

Restricted prescribing advised

In 2022, we learned that in certain settings, PARP inhibitors may be the wrong choice. Several “Dear Health Care Provider” letters were issued by AstraZeneca, Clovis, and GSK to advise physicians to restrict the prescribing of olaparib, rucaparib, and niraparib.^6,7

AstraZeneca and Clovis issued letters spurred by the final analysis of ARIEL4 and SOLO3 studies, 2 randomized trials that investigated, respectively, rucaparib and olaparib monotherapy compared with chemotherapy in recurrent ovarian cancer.^8,9 In both cases patients randomized to PARP inhibitors may have experienced an overall survival decrement compared with those who received chemotherapy.

At the FDA’s request, Clovis has withdrawn rucaparib as a treatment for patients with recurrent BRCA-mutant ovarian cancer who had received 2 or more lines of chemotherapy, and AstraZeneca withdrew olaparib monotherapy in germline BRCA-mutant patients with recurrent ovarian cancer. Shortly after these withdrawals, GSK also withdrew its indication for niraparib as a treatment for women with HRD, platinum-sensitive ovarian cancer who have received 3 or more prior chemotherapies. Furthermore, based on the final overall survival analysis of the NOVA study, GSK also restricted its indication for niraparib maintenance for recurrent ovarian cancer to patients with germline BRCA mutations, due to evidence of an overall survival detriment in this setting.¹⁰

Positive study results

Fortunately, 2022 was not all bad news for PARP inhibitors in ovarian cancer. In June 2022, the ATHENA-MONO trial, a phase 3 double-blind randomized controlled trial, demonstrated that rucaparib maintenance in patients with newly diagnosed epithelial ovarian cancer was associated with a significantly longer progression-free survival compared with placebo.¹¹ The effect was most pronounced in the BRCA-mutant/HRD population, with a median progression-free survival of 28.7 months in the rucaparib group compared with 11.3 months in the placebo group (HR, 0.47; 95% CI, 0.31–0.72). Thus, rucaparib was added to the list of PARP inhibitors approved for upfront maintenance therapy in epithelial ovarian cancer.

Similarly, the long-term overall survival analysis from the upfront trials SOLO-1 and PAOLA-1 showed an overall survival advantage of PARP inhibitor, compared with placebo, maintenance in patients with BRCA mutations or HRD tumors.^12,13 ●

In 2022, the most significant advances in the treatment of gynecologic cancers were achieved for patients with ovarian cancer. While ovarian cancer continues to carry the worst prognosis of all gynecologic cancers, 5-year relative survival has gradually increased, from 34.4% in 1975 to 52.4% in 2014.¹

In this Update, we highlight the recent advances in our understanding of targeted therapy in ovarian cancer. We review SORAYA, a trial that demonstrated that mirvetuximab soravtansine, an antibody-drug conjugate, has promising efficacy in platinum-resistant ovarian cancers that overexpress folate receptor α. We also spotlight progress in the treatment of low-grade serous ovarian cancer, another notoriously chemotherapy-resistant disease, in GOG 281/LOGS, a phase 2 study of the MEK inhibitor trametinib. Finally, we discuss emerging long-term follow-up data on poly(ADP-ribose) polymerase (PARP) inhibitors, which are helping to refine the role of these groundbreaking drugs.

New drug approved for platinum-resistant epithelial ovarian cancer—the first since 2014

Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41:2436-2445. doi:10.1200/JCO.22.01900.

While most patients diagnosed with advanced ovarian cancer will respond to platinum-based chemotherapy, those whose disease recurs eventually develop resistance to platinum agents. Treatment options for platinum-resistant ovarian cancer are limited and prognosis is poor. Most regimens have a response rate of only 10%. Since the approval of bevacizumab combined with chemotherapy in 2014, no new agents have been approved by the US Food and Drug Administration (FDA) for use in platinum-resistant ovarian cancer.

Efficacy shown with mirvetuximab

Recently, Matulonis and colleagues published results of the SORAYA study, a single-arm,phase 2 trial, that examined the efficacy and safety of mirvetuximab soravtansine-gynx among women with platinum-resistant ovarian cancer.² Mirvetuximab is an antibody-drug conjugate composed of an antibody directed at the folate receptor α attached to a cytotoxic microtubule inhibitor.

The study included 106 patients with platinum-resistant ovarian cancer whose tumors expressed folate receptor α at a high level—a feature of approximately 50% of patients screened for the study. Twenty-nine patients experienced a partial response and 5 had a complete response, corresponding to a remarkable objective response rate of 32.4%. The median progression-free survival was 4.3 months.

Like other antibody-drug conjugates, ocular toxicities, including blurred vision (41%) and keratopathy (29%), were common. However, toxicity was manageable and rarely led to drug discontinuation.

Continue to: A novel agent for recurrent low-grade serous ovarian carcinoma...

A novel agent for recurrent low-grade serous ovarian carcinoma

Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022;399:541-553. doi:10.1016/S0140-6736(21)02175-9.

Low-grade serous carcinoma is a histologic subtype that makes up approximately 5% of all epithelial ovarian cancers.³ Patients with low-grade serous carcinoma are often younger and, because of the indolent nature of the histology, generally have a longer overall survival compared with patients with high-grade serous carcinoma. Unlike high-grade disease, however, low-grade serous carcinoma usually is resistant to chemotherapy, making treatment options limited for patients with advanced and recurrent disease.

Trametinib: A potential option

In an international, randomized, open-label trial (GOG 281/LOGS), Gershenson and colleagues investigated the efficacy of trametinib compared with standard-of-care chemotherapy in patients with recurrent low-grade serous ovarian cancer.⁴ Trametinib, a mitogen-activated protein kinase MEK inhibitor, is a targeted agent that is FDA approved for treatment in BRAF-mutated melanoma, lung, and thyroid cancers.

Patients with recurrent low-grade serous ovarian cancer were randomly assigned to trametinib (n = 130) or 1 of 5 standard-of-care treatment options (n = 130), including both chemotherapy and hormonal treatments. Those assigned to trametinib were significantly less likely to have disease progression (78% vs 89%), with a median progression-free survival of 13 months, compared with7.2 months in controls (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.36–0.64). Additionally, patients who had a radiographic response to trametinib experienced a longer duration of response compared with those who responded to standard-of-care treatment (13.6 months vs 5.9 months).

While there was no statistically significant difference in overall survival (HR, 0.76; 95% CI, 0.51–1.12), crossover to trametinib from the standard-of-care group was allowed and occurred among 68% of patients, which limits the study’s ability to measure differences in overall survival.

Trametinib was well tolerated by patients, but skin rash and anemia followed by hypertension were the most common adverse effects. In the standard-of-care group, the most common toxicities were abdominal pain, nausea, and anemia. A slightly higher proportion of patients in the trametinib group discontinued the drug due to toxicity compared with the standard-of-care group (36% vs 30%), but the there was no difference between the 2 groups in scores on quality-of-life assessments.

Continue to: PARP inhibitors benefit many women with ovarian cancer, but they may hurt others...

PARP inhibitors benefit many women with ovarian cancer, but they may hurt others

Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40:3952-3964. doi:10.1200/JCO.22.01003.

Poly(ADP-ribose) polymerase (PARP) inhibitors are a class of oral anticancer agents that target DNA repair. Since the initial FDA approval in 2014 of olaparib for the treatment of patients with recurrent BRCA-mutated ovarian cancer, PARP inhibitors have been approved for maintenance in both the frontline setting and after platinum-sensitive recurrence, and as single-agenttreatment for ovarian cancer with BRCA mutations or evidence of homologous repair deficiency (HRD), a BRCA-like molecular phenotype.⁵ The expanding role for PARP inhibitors in ovarian cancer seemed inexorable.

Restricted prescribing advised

In 2022, we learned that in certain settings, PARP inhibitors may be the wrong choice. Several “Dear Health Care Provider” letters were issued by AstraZeneca, Clovis, and GSK to advise physicians to restrict the prescribing of olaparib, rucaparib, and niraparib.^6,7

AstraZeneca and Clovis issued letters spurred by the final analysis of ARIEL4 and SOLO3 studies, 2 randomized trials that investigated, respectively, rucaparib and olaparib monotherapy compared with chemotherapy in recurrent ovarian cancer.^8,9 In both cases patients randomized to PARP inhibitors may have experienced an overall survival decrement compared with those who received chemotherapy.

At the FDA’s request, Clovis has withdrawn rucaparib as a treatment for patients with recurrent BRCA-mutant ovarian cancer who had received 2 or more lines of chemotherapy, and AstraZeneca withdrew olaparib monotherapy in germline BRCA-mutant patients with recurrent ovarian cancer. Shortly after these withdrawals, GSK also withdrew its indication for niraparib as a treatment for women with HRD, platinum-sensitive ovarian cancer who have received 3 or more prior chemotherapies. Furthermore, based on the final overall survival analysis of the NOVA study, GSK also restricted its indication for niraparib maintenance for recurrent ovarian cancer to patients with germline BRCA mutations, due to evidence of an overall survival detriment in this setting.¹⁰

Positive study results

Fortunately, 2022 was not all bad news for PARP inhibitors in ovarian cancer. In June 2022, the ATHENA-MONO trial, a phase 3 double-blind randomized controlled trial, demonstrated that rucaparib maintenance in patients with newly diagnosed epithelial ovarian cancer was associated with a significantly longer progression-free survival compared with placebo.¹¹ The effect was most pronounced in the BRCA-mutant/HRD population, with a median progression-free survival of 28.7 months in the rucaparib group compared with 11.3 months in the placebo group (HR, 0.47; 95% CI, 0.31–0.72). Thus, rucaparib was added to the list of PARP inhibitors approved for upfront maintenance therapy in epithelial ovarian cancer.

Similarly, the long-term overall survival analysis from the upfront trials SOLO-1 and PAOLA-1 showed an overall survival advantage of PARP inhibitor, compared with placebo, maintenance in patients with BRCA mutations or HRD tumors.^12,13 ●

In 2022, the most significant advances in the treatment of gynecologic cancers were achieved for patients with ovarian cancer. While ovarian cancer continues to carry the worst prognosis of all gynecologic cancers, 5-year relative survival has gradually increased, from 34.4% in 1975 to 52.4% in 2014.¹

In this Update, we highlight the recent advances in our understanding of targeted therapy in ovarian cancer. We review SORAYA, a trial that demonstrated that mirvetuximab soravtansine, an antibody-drug conjugate, has promising efficacy in platinum-resistant ovarian cancers that overexpress folate receptor α. We also spotlight progress in the treatment of low-grade serous ovarian cancer, another notoriously chemotherapy-resistant disease, in GOG 281/LOGS, a phase 2 study of the MEK inhibitor trametinib. Finally, we discuss emerging long-term follow-up data on poly(ADP-ribose) polymerase (PARP) inhibitors, which are helping to refine the role of these groundbreaking drugs.

New drug approved for platinum-resistant epithelial ovarian cancer—the first since 2014

Matulonis UA, Lorusso D, Oaknin A, et al. Efficacy and safety of mirvetuximab soravtansine in patients with platinum-resistant ovarian cancer with high folate receptor alpha expression: results from the SORAYA study. J Clin Oncol. 2023;41:2436-2445. doi:10.1200/JCO.22.01900.

While most patients diagnosed with advanced ovarian cancer will respond to platinum-based chemotherapy, those whose disease recurs eventually develop resistance to platinum agents. Treatment options for platinum-resistant ovarian cancer are limited and prognosis is poor. Most regimens have a response rate of only 10%. Since the approval of bevacizumab combined with chemotherapy in 2014, no new agents have been approved by the US Food and Drug Administration (FDA) for use in platinum-resistant ovarian cancer.

Efficacy shown with mirvetuximab

Recently, Matulonis and colleagues published results of the SORAYA study, a single-arm,phase 2 trial, that examined the efficacy and safety of mirvetuximab soravtansine-gynx among women with platinum-resistant ovarian cancer.² Mirvetuximab is an antibody-drug conjugate composed of an antibody directed at the folate receptor α attached to a cytotoxic microtubule inhibitor.

The study included 106 patients with platinum-resistant ovarian cancer whose tumors expressed folate receptor α at a high level—a feature of approximately 50% of patients screened for the study. Twenty-nine patients experienced a partial response and 5 had a complete response, corresponding to a remarkable objective response rate of 32.4%. The median progression-free survival was 4.3 months.

Like other antibody-drug conjugates, ocular toxicities, including blurred vision (41%) and keratopathy (29%), were common. However, toxicity was manageable and rarely led to drug discontinuation.

Continue to: A novel agent for recurrent low-grade serous ovarian carcinoma...

A novel agent for recurrent low-grade serous ovarian carcinoma

Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022;399:541-553. doi:10.1016/S0140-6736(21)02175-9.

Low-grade serous carcinoma is a histologic subtype that makes up approximately 5% of all epithelial ovarian cancers.³ Patients with low-grade serous carcinoma are often younger and, because of the indolent nature of the histology, generally have a longer overall survival compared with patients with high-grade serous carcinoma. Unlike high-grade disease, however, low-grade serous carcinoma usually is resistant to chemotherapy, making treatment options limited for patients with advanced and recurrent disease.

Trametinib: A potential option

In an international, randomized, open-label trial (GOG 281/LOGS), Gershenson and colleagues investigated the efficacy of trametinib compared with standard-of-care chemotherapy in patients with recurrent low-grade serous ovarian cancer.⁴ Trametinib, a mitogen-activated protein kinase MEK inhibitor, is a targeted agent that is FDA approved for treatment in BRAF-mutated melanoma, lung, and thyroid cancers.

Patients with recurrent low-grade serous ovarian cancer were randomly assigned to trametinib (n = 130) or 1 of 5 standard-of-care treatment options (n = 130), including both chemotherapy and hormonal treatments. Those assigned to trametinib were significantly less likely to have disease progression (78% vs 89%), with a median progression-free survival of 13 months, compared with7.2 months in controls (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.36–0.64). Additionally, patients who had a radiographic response to trametinib experienced a longer duration of response compared with those who responded to standard-of-care treatment (13.6 months vs 5.9 months).

While there was no statistically significant difference in overall survival (HR, 0.76; 95% CI, 0.51–1.12), crossover to trametinib from the standard-of-care group was allowed and occurred among 68% of patients, which limits the study’s ability to measure differences in overall survival.

Trametinib was well tolerated by patients, but skin rash and anemia followed by hypertension were the most common adverse effects. In the standard-of-care group, the most common toxicities were abdominal pain, nausea, and anemia. A slightly higher proportion of patients in the trametinib group discontinued the drug due to toxicity compared with the standard-of-care group (36% vs 30%), but the there was no difference between the 2 groups in scores on quality-of-life assessments.

Continue to: PARP inhibitors benefit many women with ovarian cancer, but they may hurt others...

PARP inhibitors benefit many women with ovarian cancer, but they may hurt others

Monk BJ, Parkinson C, Lim MC, et al. A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40:3952-3964. doi:10.1200/JCO.22.01003.

Poly(ADP-ribose) polymerase (PARP) inhibitors are a class of oral anticancer agents that target DNA repair. Since the initial FDA approval in 2014 of olaparib for the treatment of patients with recurrent BRCA-mutated ovarian cancer, PARP inhibitors have been approved for maintenance in both the frontline setting and after platinum-sensitive recurrence, and as single-agenttreatment for ovarian cancer with BRCA mutations or evidence of homologous repair deficiency (HRD), a BRCA-like molecular phenotype.⁵ The expanding role for PARP inhibitors in ovarian cancer seemed inexorable.

Restricted prescribing advised

In 2022, we learned that in certain settings, PARP inhibitors may be the wrong choice. Several “Dear Health Care Provider” letters were issued by AstraZeneca, Clovis, and GSK to advise physicians to restrict the prescribing of olaparib, rucaparib, and niraparib.^6,7

AstraZeneca and Clovis issued letters spurred by the final analysis of ARIEL4 and SOLO3 studies, 2 randomized trials that investigated, respectively, rucaparib and olaparib monotherapy compared with chemotherapy in recurrent ovarian cancer.^8,9 In both cases patients randomized to PARP inhibitors may have experienced an overall survival decrement compared with those who received chemotherapy.

At the FDA’s request, Clovis has withdrawn rucaparib as a treatment for patients with recurrent BRCA-mutant ovarian cancer who had received 2 or more lines of chemotherapy, and AstraZeneca withdrew olaparib monotherapy in germline BRCA-mutant patients with recurrent ovarian cancer. Shortly after these withdrawals, GSK also withdrew its indication for niraparib as a treatment for women with HRD, platinum-sensitive ovarian cancer who have received 3 or more prior chemotherapies. Furthermore, based on the final overall survival analysis of the NOVA study, GSK also restricted its indication for niraparib maintenance for recurrent ovarian cancer to patients with germline BRCA mutations, due to evidence of an overall survival detriment in this setting.¹⁰

Positive study results

Fortunately, 2022 was not all bad news for PARP inhibitors in ovarian cancer. In June 2022, the ATHENA-MONO trial, a phase 3 double-blind randomized controlled trial, demonstrated that rucaparib maintenance in patients with newly diagnosed epithelial ovarian cancer was associated with a significantly longer progression-free survival compared with placebo.¹¹ The effect was most pronounced in the BRCA-mutant/HRD population, with a median progression-free survival of 28.7 months in the rucaparib group compared with 11.3 months in the placebo group (HR, 0.47; 95% CI, 0.31–0.72). Thus, rucaparib was added to the list of PARP inhibitors approved for upfront maintenance therapy in epithelial ovarian cancer.

Similarly, the long-term overall survival analysis from the upfront trials SOLO-1 and PAOLA-1 showed an overall survival advantage of PARP inhibitor, compared with placebo, maintenance in patients with BRCA mutations or HRD tumors.^12,13 ●

CASE 1 Multiparous female with short-interval pregnancies desires contraception

A 24-year-old woman (G4P3) presents for a routine prenatal visit in the third trimester. Her last 2 pregnancies have occurred within 3 months of her prior birth. She endorses feeling overwhelmed with having 4 children under the age of 5 years, and she specifies that she would like to avoid another pregnancy for several years. She plans to breast and bottle feed, and she notes that she tends to forget to take pills. When you look back at her prior charts, you note that she did not return for her last 2 postpartum visits. What can you offer her? What would be a safe contraceptive option for her?
 

Intrauterine devices (IUDs) are safe, effective, and reported by patients to be satisfactory methods of contraception precisely because they are prone to less user error. The Contraceptive Choice Project demonstrated that patients are more apt to choose them when barriers such as cost and access are removed and nondirective counseling is provided.¹ Given that unintended pregnancy rates hover around 48%, the American College of Obstetricians and Gynecologists (ACOG) recommends them as first-line methods for pregnancy prevention.^2,3

For repeat pregnancies, the postpartum period is an especially vulnerable time—non-breastfeeding women will ovulate as soon as 25 days after birth, and by 8 weeks 30% will have ovulated.⁴ Approximately 40% to 57% of women report having unprotected intercourse before 6 weeks postpartum, and nearly 70% of all pregnancies in the first year postpartum are unintended.^3,5 Furthermore, patients at highest risk for short-interval pregnancy, such as adolescents, are less likely to return for a postpartum visit.³

Short-interval pregnancies confer greater fetal risk, including risks of low-birth weight, preterm birth, small for gestational age and increased risk of neonatal intensive care unit admission.⁶ Additionally, maternal health may be compromised during a short-interval pregnancy, particularly in medically complex patients due to increased risks of adverse pregnancy outcomes, such as postpartum bleeding or uterine rupture and disease progression.⁷ A 2006 meta-analysis by Conde-Agudelo and colleagues found that waiting at least 18 months between pregnancies was optimal for reducing these risks.⁶

Thus, the immediate postpartum period is an optimal time for addressing contraceptive needs and for preventing short-interval and unintended pregnancy. This article aims to provide evidence supporting the use of immediate postpartum IUDs, as well as their associated risks and barriers to use.

IUD types and routes for immediate postpartum insertion

There are several randomized controlled trials (RCTs) that examine the immediate postpartum use of copper IUDs and levonorgestrel-releasing (LNG) IUDs.^8-11 In 2010, Chen and colleagues compared placement of the immediate postpartum IUD following vaginal delivery with interval placement at 6–8 weeks postpartum. Of 51 patients enrolled in each arm, 98% received an IUD immediately postpartum, and 90% received one during their postpartum visit. There were 12 expulsions (24%) in the immediate postpartum IUD group, compared with 2 (4.4%) in the interval group. Expelled IUDs were replaced, and at 6 months both groups had similar rates of IUD use.⁸

Whitaker and colleagues demonstrated similar findings after randomizing a small group of women who had a cesarean delivery (CD) to interval or immediate placement. There were significantly more expulsions in the post-placental group (20%) than the interval group (0%), but there were more users of the IUD in the post-placental group than in the interval group at 12 months.⁹

Two RCTs, by Lester and colleagues and Levi et al, demonstrated successful placement of the copper IUD or LNG-IUD following CD, with few expulsions (0% and 8%, respectively). Patients who were randomized to immediate postpartum IUD placement were more likely to receive an IUD than those who were randomized to interval insertion, mostly due to lack of postpartum follow up. Both studies followed patients out to 6 months, and rates of IUD continuation and satisfaction were higher at this time in the immediate postpartum IUD groups.^10,11

Continue to: Risks, contraindications, and breastfeeding impact...

What are the risks of immediate postpartum IUD placement? The highest risk of IUD placement in the immediate postpartum period appears to be expulsion (TABLE 1). In a meta-analysis conducted in 2022, which looked at 11 studies of immediate IUD insertion, the rates of expulsion were between 5% and 27%.^3,8,12,13 Results of a study by Cohen and colleagues demonstrated that most expulsions occurred within the first 12 weeks following delivery; of those expulsions that occurred, only 11% went unrecognized.¹³ Immediate postpartum IUD insertion does not increase the IUD-associated risks of perforation, infection, or immediate postpartum bleeding (although prolonged bleeding may be more common).¹²

Are there contraindications to placing an IUD immediately postpartum? The main contraindication to immediate postpartum IUD use is peripartum infection, including Triple I, endomyometritis, and puerperal sepsis. Other contraindications include retained placenta requiring manual or surgical removal, uterine anomalies, and other medical contraindications to IUD use as recommended by the US Medical Eligibility Criteria.¹⁴

Does immediate IUD placement affect breastfeeding? There is theoretical risk of decreased milk supply or difficulty breastfeeding with initiation of progestin-only methods of contraception in the immediate postpartum period, as the rapid fall in progesterone levels initiates lactogenesis. However, progestin-only methods appear to have limited effect on initiation and continuation of breastfeeding in the immediate postpartum period.¹⁵

There were 2 secondary analyses of a pair of RCTs comparing immediate and delayed postpartum IUD use. Results from Levi and colleagues demonstrated no difference between immediate and interval IUD placement groups in the proportion of women who were breastfeeding at 6, 12, and 24 weeks.¹⁶ Chen and colleagues’ study was smaller; researchers found that women with interval IUD placement were more likely to be exclusively breastfeeding and continuing to breastfeed at 6 months compared with the immediate postpartum group.¹⁷

To better characterize the impact of progestin implants, in a recent meta-analysis, authors examined the use of subcutaneous levonorgestrel rods and found no difference in breastfeeding initiation and continuation rates between women who had them placed immediately versus 6 ̶ 8 weeks postpartum.¹²

Benefits of immediate postpartum IUD placement

One benefit of immediate postpartum IUD insertion is a reduction in short-interval pregnancies. In a study by Cohen and colleagues¹³ of young women aged 13 to 22 years choosing immediate postpartum IUDs (82) or implants (162), the authors found that 61% of women retained their IUDs at 12 months postpartum. Because few requested IUD removal over that time frame, the discontinuation rate at 1 year was primarily due to expulsions. Pregnancy rates at 1 year were 7.6% in the IUD group and 1.5% in the implant group. However, the 7.6% rate in the IUD group was lower than in previously studied adolescent control groups: 18.6% of control adolescents (38 of 204) using a contraceptive form other than a postpartum etonogestrel implant had repeat pregnancy at 1 year.^13,18

Not only are patients who receive immediate postpartum IUDs more likely to receive them and continue their use, but they are also satisfied with the experience of receiving the IUD and with the method of contraception. A small mixed methods study of 66 patients demonstrated that women were interested in obtaining immediate postpartum contraception to avoid some of the logistical and financial challenges of returning for a postpartum visit. They also felt that the IUD placement was less painful than expected, and they didn’t feel that the insertion process imposed on their birth experience. Many described relief to know that they had a safe and effective contraceptive method upon leaving the hospital.¹⁹ Other studies have shown that even among women who expel an IUD following immediate postpartum placement, many choose to replace it in order to continue it as a contraceptive method.^8,9,13

Continue to: Instructions for placement...

1. Counsel appropriately. Thoroughly counsel patients regarding their options for postpartum contraception, with emphasis on the benefits, risks, and contraindications. Current recommendations to reduce the risk of expulsion are to place the IUD in the delivery room or operating room within 10 minutes of placental delivery.

2. Post ̶ vaginal delivery. Following vaginal delivery, remove the IUD from the inserter, cut the strings to 10 cm and, using either fingers to grasp the wings of the IUD or ring forceps, advance the IUD to the fundus. Ultrasound guidance may be used, but it does not appear to be helpful in preventing expulsion.²⁰

3. Post ̶ cesarean delivery. Once the placenta is delivered, place the IUD using the inserter or a ring forceps at the fundus and guide the strings into the cervix, then close the hysterotomy.

ACOG does recommend formal trainingbefore placing postpartum IUDs. One resource they provide is a free online webinar (https://www.acog.org/education-and-events/webinars/long-acting-reversible-contra ception-overview-and-hands-on-practice-for-residents).³

CASE 1 Resolved

The patient was counseled in the office about her options, and she was most interested in immediate postpartum LNG-IUD placement. She went on to deliver a healthy baby vaginally at 39 weeks. Within 10 minutes of placental delivery, she received an LNG-IUD. She returned to the office 3 months later for STI screening; her examination revealed correct placement and no evidence of expulsion. She expressed that she was happy with her IUD and thankful that she was able to receive it immediately after the birth of her baby.

CASE 2 Nulliparous woman desires IUD for postpartum contraception

A 33-year-old nulliparous woman presents in the third trimester for a routine prenatal visit. She had used the LNG-IUD prior to getting pregnant and reports that she was very happy with it. She knows she wants to wait at least 2 years before trying to get pregnant again, and she would like to resume contraception as soon as it is reasonably safe to do so. She has read that it is possible to get an IUD immediately postpartum and asks about it as a possible option.

What barriers will she face in obtaining an immediate postpartum IUD?

There are many barriers for patients who may be good candidates for immediate postpartum contraception (TABLE 2). Many patients are unaware that it is a safe option, and they often have concerns about such risks as infection, perforation, and effects on breastfeeding. Additionally, providers may not prioritize adequate counseling about postpartum contraception when they face time constraints and a need to counsel about other pregnancy-related topics during the prenatal visit schedule.^7,21

System, hospital, and clinician barriers to immediate postpartum IUD use

Hospital implementation of a successful postpartum IUD program requires pharmacy, intrapartum and postpartum nursing staff, physicians, administration, and billing to be aligned. Hospital administration and pharmacists must stock IUDs in the pharmacy. Hospital nursing staff attitudes toward and knowledge of postpartum contraception can have profound influence on how they discuss safe and effective methods of postpartum contraception with patients who may not have received counseling during prenatal care.²² In a survey of 108 ACOG fellows, nearly 75% of ObGyn physicians did not offer immediate postpartum IUDs; lack of provider training, lack of IUD availability, and concern about cost and payment were found to be common reasons why.²¹ Additionally, Catholic-affiliated and rural institutions are less likely to offer it, whereas more urban, teaching hospitals are more likely to have programs in place.²³ Prior to 2012, immediate postpartum IUD insertions and device costs were part of the global Medicaid obstetric fee in most states, and both hospital systems and individual providers were concerned about loss of revenue.²³

In 2015, Washington and colleagues published a decision analysis that examined the cost-effectiveness and cost savings associated with immediate postpartum IUD use. Accounting for expulsion rates, they found that immediate postpartum IUD placement can save $282,540 per 1,000 women over 2 years; additionally, immediate postpartum IUD use can prevent 88 unintended pregnancies per 1,000 women over 2 years.²⁴ Not only do immediate postpartum IUDs have great potential to prevent individual patients from undesired short-interval pregnancies (FIGURE 1), but they can also save the system substantial health care dollars (FIGURE 2).

Overcoming barriers

Immediate postpartum IUD implementation is attainable with practice, policy, and institutional changes. Education and training programs geared toward providers and nursing staff can improve understanding of the benefits and risks of immediate postpartum IUD placement. Additionally, clinicians must provide comprehensive, nondirective counseling during the antepartum period, informing patients of all safe and effective options. Expulsion risks should be disclosed, as well as the benefit of not needing to return for a separate postpartum contraception appointment.

Since 2012, many state Medicaid agencies have decoupled reimbursement for inpatient postpartum IUD insertion from the delivery fee. By 2018, more than half of states adopted this practice. Commercial insurers have followed suit in some cases, and as such, both Medicaid and commercially insured patients have had increased access to immediate postpartum IUDs.²³ This has translated into increased uptake of immediate postpartum IUDs among both Medicaid and commercially insured patients. Koch et al conducted a retrospective cohort study comparing IUD use in patients 1 year before and 1 year after the policy changes, and they found a 10-fold increase in use of immediate postpartum IUDs.²⁵

While education, counseling, access, and changes in reimbursement may increase access in many hospital systems, some barriers, such as religious affiliation of the hospital system, may be impossible to overcome. A viable alternative to immediate postpartum IUD placement may be early postpartum IUD placement, which could allow patients to coordinate this procedure with 1- or 2-week return routine postpartum visits for CD recovery, mental health screenings, and/or well-baby visits. More data are necessary before recommending this universally, but Averbach and colleagues published a promising meta-analysis that demonstrated no complete expulsions in studies in which IUDs were placed between 2 and 4 weeks postpartum, and only a pooled partial expulsion rate (of immediate postpartum, early inpatient, early outpatient, and interval placement) of 3.7%.⁴

CASE 2 Resolved

Although the patient was interested in receiving a postpartum LNG-IUD immediately after her vaginal birth, she had to wait until her 6-week postpartum visit. The hospital did not stock IUDs for immediate postpartum IUD use, and her provider, having not been trained on immediate postpartum insertion, did not feel comfortable trying to place it in the immediate postpartum time frame. ●

CASE 1 Multiparous female with short-interval pregnancies desires contraception

A 24-year-old woman (G4P3) presents for a routine prenatal visit in the third trimester. Her last 2 pregnancies have occurred within 3 months of her prior birth. She endorses feeling overwhelmed with having 4 children under the age of 5 years, and she specifies that she would like to avoid another pregnancy for several years. She plans to breast and bottle feed, and she notes that she tends to forget to take pills. When you look back at her prior charts, you note that she did not return for her last 2 postpartum visits. What can you offer her? What would be a safe contraceptive option for her?
 

Intrauterine devices (IUDs) are safe, effective, and reported by patients to be satisfactory methods of contraception precisely because they are prone to less user error. The Contraceptive Choice Project demonstrated that patients are more apt to choose them when barriers such as cost and access are removed and nondirective counseling is provided.¹ Given that unintended pregnancy rates hover around 48%, the American College of Obstetricians and Gynecologists (ACOG) recommends them as first-line methods for pregnancy prevention.^2,3

For repeat pregnancies, the postpartum period is an especially vulnerable time—non-breastfeeding women will ovulate as soon as 25 days after birth, and by 8 weeks 30% will have ovulated.⁴ Approximately 40% to 57% of women report having unprotected intercourse before 6 weeks postpartum, and nearly 70% of all pregnancies in the first year postpartum are unintended.^3,5 Furthermore, patients at highest risk for short-interval pregnancy, such as adolescents, are less likely to return for a postpartum visit.³

Short-interval pregnancies confer greater fetal risk, including risks of low-birth weight, preterm birth, small for gestational age and increased risk of neonatal intensive care unit admission.⁶ Additionally, maternal health may be compromised during a short-interval pregnancy, particularly in medically complex patients due to increased risks of adverse pregnancy outcomes, such as postpartum bleeding or uterine rupture and disease progression.⁷ A 2006 meta-analysis by Conde-Agudelo and colleagues found that waiting at least 18 months between pregnancies was optimal for reducing these risks.⁶

Thus, the immediate postpartum period is an optimal time for addressing contraceptive needs and for preventing short-interval and unintended pregnancy. This article aims to provide evidence supporting the use of immediate postpartum IUDs, as well as their associated risks and barriers to use.

IUD types and routes for immediate postpartum insertion

There are several randomized controlled trials (RCTs) that examine the immediate postpartum use of copper IUDs and levonorgestrel-releasing (LNG) IUDs.^8-11 In 2010, Chen and colleagues compared placement of the immediate postpartum IUD following vaginal delivery with interval placement at 6–8 weeks postpartum. Of 51 patients enrolled in each arm, 98% received an IUD immediately postpartum, and 90% received one during their postpartum visit. There were 12 expulsions (24%) in the immediate postpartum IUD group, compared with 2 (4.4%) in the interval group. Expelled IUDs were replaced, and at 6 months both groups had similar rates of IUD use.⁸

Whitaker and colleagues demonstrated similar findings after randomizing a small group of women who had a cesarean delivery (CD) to interval or immediate placement. There were significantly more expulsions in the post-placental group (20%) than the interval group (0%), but there were more users of the IUD in the post-placental group than in the interval group at 12 months.⁹

Two RCTs, by Lester and colleagues and Levi et al, demonstrated successful placement of the copper IUD or LNG-IUD following CD, with few expulsions (0% and 8%, respectively). Patients who were randomized to immediate postpartum IUD placement were more likely to receive an IUD than those who were randomized to interval insertion, mostly due to lack of postpartum follow up. Both studies followed patients out to 6 months, and rates of IUD continuation and satisfaction were higher at this time in the immediate postpartum IUD groups.^10,11

Continue to: Risks, contraindications, and breastfeeding impact...

What are the risks of immediate postpartum IUD placement? The highest risk of IUD placement in the immediate postpartum period appears to be expulsion (TABLE 1). In a meta-analysis conducted in 2022, which looked at 11 studies of immediate IUD insertion, the rates of expulsion were between 5% and 27%.^3,8,12,13 Results of a study by Cohen and colleagues demonstrated that most expulsions occurred within the first 12 weeks following delivery; of those expulsions that occurred, only 11% went unrecognized.¹³ Immediate postpartum IUD insertion does not increase the IUD-associated risks of perforation, infection, or immediate postpartum bleeding (although prolonged bleeding may be more common).¹²

Are there contraindications to placing an IUD immediately postpartum? The main contraindication to immediate postpartum IUD use is peripartum infection, including Triple I, endomyometritis, and puerperal sepsis. Other contraindications include retained placenta requiring manual or surgical removal, uterine anomalies, and other medical contraindications to IUD use as recommended by the US Medical Eligibility Criteria.¹⁴

Does immediate IUD placement affect breastfeeding? There is theoretical risk of decreased milk supply or difficulty breastfeeding with initiation of progestin-only methods of contraception in the immediate postpartum period, as the rapid fall in progesterone levels initiates lactogenesis. However, progestin-only methods appear to have limited effect on initiation and continuation of breastfeeding in the immediate postpartum period.¹⁵

There were 2 secondary analyses of a pair of RCTs comparing immediate and delayed postpartum IUD use. Results from Levi and colleagues demonstrated no difference between immediate and interval IUD placement groups in the proportion of women who were breastfeeding at 6, 12, and 24 weeks.¹⁶ Chen and colleagues’ study was smaller; researchers found that women with interval IUD placement were more likely to be exclusively breastfeeding and continuing to breastfeed at 6 months compared with the immediate postpartum group.¹⁷

To better characterize the impact of progestin implants, in a recent meta-analysis, authors examined the use of subcutaneous levonorgestrel rods and found no difference in breastfeeding initiation and continuation rates between women who had them placed immediately versus 6 ̶ 8 weeks postpartum.¹²

Benefits of immediate postpartum IUD placement

One benefit of immediate postpartum IUD insertion is a reduction in short-interval pregnancies. In a study by Cohen and colleagues¹³ of young women aged 13 to 22 years choosing immediate postpartum IUDs (82) or implants (162), the authors found that 61% of women retained their IUDs at 12 months postpartum. Because few requested IUD removal over that time frame, the discontinuation rate at 1 year was primarily due to expulsions. Pregnancy rates at 1 year were 7.6% in the IUD group and 1.5% in the implant group. However, the 7.6% rate in the IUD group was lower than in previously studied adolescent control groups: 18.6% of control adolescents (38 of 204) using a contraceptive form other than a postpartum etonogestrel implant had repeat pregnancy at 1 year.^13,18

Not only are patients who receive immediate postpartum IUDs more likely to receive them and continue their use, but they are also satisfied with the experience of receiving the IUD and with the method of contraception. A small mixed methods study of 66 patients demonstrated that women were interested in obtaining immediate postpartum contraception to avoid some of the logistical and financial challenges of returning for a postpartum visit. They also felt that the IUD placement was less painful than expected, and they didn’t feel that the insertion process imposed on their birth experience. Many described relief to know that they had a safe and effective contraceptive method upon leaving the hospital.¹⁹ Other studies have shown that even among women who expel an IUD following immediate postpartum placement, many choose to replace it in order to continue it as a contraceptive method.^8,9,13

Continue to: Instructions for placement...

1. Counsel appropriately. Thoroughly counsel patients regarding their options for postpartum contraception, with emphasis on the benefits, risks, and contraindications. Current recommendations to reduce the risk of expulsion are to place the IUD in the delivery room or operating room within 10 minutes of placental delivery.

2. Post ̶ vaginal delivery. Following vaginal delivery, remove the IUD from the inserter, cut the strings to 10 cm and, using either fingers to grasp the wings of the IUD or ring forceps, advance the IUD to the fundus. Ultrasound guidance may be used, but it does not appear to be helpful in preventing expulsion.²⁰

3. Post ̶ cesarean delivery. Once the placenta is delivered, place the IUD using the inserter or a ring forceps at the fundus and guide the strings into the cervix, then close the hysterotomy.

ACOG does recommend formal trainingbefore placing postpartum IUDs. One resource they provide is a free online webinar (https://www.acog.org/education-and-events/webinars/long-acting-reversible-contra ception-overview-and-hands-on-practice-for-residents).³

CASE 1 Resolved

The patient was counseled in the office about her options, and she was most interested in immediate postpartum LNG-IUD placement. She went on to deliver a healthy baby vaginally at 39 weeks. Within 10 minutes of placental delivery, she received an LNG-IUD. She returned to the office 3 months later for STI screening; her examination revealed correct placement and no evidence of expulsion. She expressed that she was happy with her IUD and thankful that she was able to receive it immediately after the birth of her baby.

CASE 2 Nulliparous woman desires IUD for postpartum contraception

A 33-year-old nulliparous woman presents in the third trimester for a routine prenatal visit. She had used the LNG-IUD prior to getting pregnant and reports that she was very happy with it. She knows she wants to wait at least 2 years before trying to get pregnant again, and she would like to resume contraception as soon as it is reasonably safe to do so. She has read that it is possible to get an IUD immediately postpartum and asks about it as a possible option.

What barriers will she face in obtaining an immediate postpartum IUD?

There are many barriers for patients who may be good candidates for immediate postpartum contraception (TABLE 2). Many patients are unaware that it is a safe option, and they often have concerns about such risks as infection, perforation, and effects on breastfeeding. Additionally, providers may not prioritize adequate counseling about postpartum contraception when they face time constraints and a need to counsel about other pregnancy-related topics during the prenatal visit schedule.^7,21

System, hospital, and clinician barriers to immediate postpartum IUD use

Hospital implementation of a successful postpartum IUD program requires pharmacy, intrapartum and postpartum nursing staff, physicians, administration, and billing to be aligned. Hospital administration and pharmacists must stock IUDs in the pharmacy. Hospital nursing staff attitudes toward and knowledge of postpartum contraception can have profound influence on how they discuss safe and effective methods of postpartum contraception with patients who may not have received counseling during prenatal care.²² In a survey of 108 ACOG fellows, nearly 75% of ObGyn physicians did not offer immediate postpartum IUDs; lack of provider training, lack of IUD availability, and concern about cost and payment were found to be common reasons why.²¹ Additionally, Catholic-affiliated and rural institutions are less likely to offer it, whereas more urban, teaching hospitals are more likely to have programs in place.²³ Prior to 2012, immediate postpartum IUD insertions and device costs were part of the global Medicaid obstetric fee in most states, and both hospital systems and individual providers were concerned about loss of revenue.²³

In 2015, Washington and colleagues published a decision analysis that examined the cost-effectiveness and cost savings associated with immediate postpartum IUD use. Accounting for expulsion rates, they found that immediate postpartum IUD placement can save $282,540 per 1,000 women over 2 years; additionally, immediate postpartum IUD use can prevent 88 unintended pregnancies per 1,000 women over 2 years.²⁴ Not only do immediate postpartum IUDs have great potential to prevent individual patients from undesired short-interval pregnancies (FIGURE 1), but they can also save the system substantial health care dollars (FIGURE 2).

Overcoming barriers

Immediate postpartum IUD implementation is attainable with practice, policy, and institutional changes. Education and training programs geared toward providers and nursing staff can improve understanding of the benefits and risks of immediate postpartum IUD placement. Additionally, clinicians must provide comprehensive, nondirective counseling during the antepartum period, informing patients of all safe and effective options. Expulsion risks should be disclosed, as well as the benefit of not needing to return for a separate postpartum contraception appointment.

Since 2012, many state Medicaid agencies have decoupled reimbursement for inpatient postpartum IUD insertion from the delivery fee. By 2018, more than half of states adopted this practice. Commercial insurers have followed suit in some cases, and as such, both Medicaid and commercially insured patients have had increased access to immediate postpartum IUDs.²³ This has translated into increased uptake of immediate postpartum IUDs among both Medicaid and commercially insured patients. Koch et al conducted a retrospective cohort study comparing IUD use in patients 1 year before and 1 year after the policy changes, and they found a 10-fold increase in use of immediate postpartum IUDs.²⁵

While education, counseling, access, and changes in reimbursement may increase access in many hospital systems, some barriers, such as religious affiliation of the hospital system, may be impossible to overcome. A viable alternative to immediate postpartum IUD placement may be early postpartum IUD placement, which could allow patients to coordinate this procedure with 1- or 2-week return routine postpartum visits for CD recovery, mental health screenings, and/or well-baby visits. More data are necessary before recommending this universally, but Averbach and colleagues published a promising meta-analysis that demonstrated no complete expulsions in studies in which IUDs were placed between 2 and 4 weeks postpartum, and only a pooled partial expulsion rate (of immediate postpartum, early inpatient, early outpatient, and interval placement) of 3.7%.⁴

CASE 2 Resolved

Although the patient was interested in receiving a postpartum LNG-IUD immediately after her vaginal birth, she had to wait until her 6-week postpartum visit. The hospital did not stock IUDs for immediate postpartum IUD use, and her provider, having not been trained on immediate postpartum insertion, did not feel comfortable trying to place it in the immediate postpartum time frame. ●

CASE 1 Multiparous female with short-interval pregnancies desires contraception

A 24-year-old woman (G4P3) presents for a routine prenatal visit in the third trimester. Her last 2 pregnancies have occurred within 3 months of her prior birth. She endorses feeling overwhelmed with having 4 children under the age of 5 years, and she specifies that she would like to avoid another pregnancy for several years. She plans to breast and bottle feed, and she notes that she tends to forget to take pills. When you look back at her prior charts, you note that she did not return for her last 2 postpartum visits. What can you offer her? What would be a safe contraceptive option for her?
 

Intrauterine devices (IUDs) are safe, effective, and reported by patients to be satisfactory methods of contraception precisely because they are prone to less user error. The Contraceptive Choice Project demonstrated that patients are more apt to choose them when barriers such as cost and access are removed and nondirective counseling is provided.¹ Given that unintended pregnancy rates hover around 48%, the American College of Obstetricians and Gynecologists (ACOG) recommends them as first-line methods for pregnancy prevention.^2,3

For repeat pregnancies, the postpartum period is an especially vulnerable time—non-breastfeeding women will ovulate as soon as 25 days after birth, and by 8 weeks 30% will have ovulated.⁴ Approximately 40% to 57% of women report having unprotected intercourse before 6 weeks postpartum, and nearly 70% of all pregnancies in the first year postpartum are unintended.^3,5 Furthermore, patients at highest risk for short-interval pregnancy, such as adolescents, are less likely to return for a postpartum visit.³

Short-interval pregnancies confer greater fetal risk, including risks of low-birth weight, preterm birth, small for gestational age and increased risk of neonatal intensive care unit admission.⁶ Additionally, maternal health may be compromised during a short-interval pregnancy, particularly in medically complex patients due to increased risks of adverse pregnancy outcomes, such as postpartum bleeding or uterine rupture and disease progression.⁷ A 2006 meta-analysis by Conde-Agudelo and colleagues found that waiting at least 18 months between pregnancies was optimal for reducing these risks.⁶

Thus, the immediate postpartum period is an optimal time for addressing contraceptive needs and for preventing short-interval and unintended pregnancy. This article aims to provide evidence supporting the use of immediate postpartum IUDs, as well as their associated risks and barriers to use.

IUD types and routes for immediate postpartum insertion

There are several randomized controlled trials (RCTs) that examine the immediate postpartum use of copper IUDs and levonorgestrel-releasing (LNG) IUDs.^8-11 In 2010, Chen and colleagues compared placement of the immediate postpartum IUD following vaginal delivery with interval placement at 6–8 weeks postpartum. Of 51 patients enrolled in each arm, 98% received an IUD immediately postpartum, and 90% received one during their postpartum visit. There were 12 expulsions (24%) in the immediate postpartum IUD group, compared with 2 (4.4%) in the interval group. Expelled IUDs were replaced, and at 6 months both groups had similar rates of IUD use.⁸

Whitaker and colleagues demonstrated similar findings after randomizing a small group of women who had a cesarean delivery (CD) to interval or immediate placement. There were significantly more expulsions in the post-placental group (20%) than the interval group (0%), but there were more users of the IUD in the post-placental group than in the interval group at 12 months.⁹

Two RCTs, by Lester and colleagues and Levi et al, demonstrated successful placement of the copper IUD or LNG-IUD following CD, with few expulsions (0% and 8%, respectively). Patients who were randomized to immediate postpartum IUD placement were more likely to receive an IUD than those who were randomized to interval insertion, mostly due to lack of postpartum follow up. Both studies followed patients out to 6 months, and rates of IUD continuation and satisfaction were higher at this time in the immediate postpartum IUD groups.^10,11

Continue to: Risks, contraindications, and breastfeeding impact...

What are the risks of immediate postpartum IUD placement? The highest risk of IUD placement in the immediate postpartum period appears to be expulsion (TABLE 1). In a meta-analysis conducted in 2022, which looked at 11 studies of immediate IUD insertion, the rates of expulsion were between 5% and 27%.^3,8,12,13 Results of a study by Cohen and colleagues demonstrated that most expulsions occurred within the first 12 weeks following delivery; of those expulsions that occurred, only 11% went unrecognized.¹³ Immediate postpartum IUD insertion does not increase the IUD-associated risks of perforation, infection, or immediate postpartum bleeding (although prolonged bleeding may be more common).¹²

Are there contraindications to placing an IUD immediately postpartum? The main contraindication to immediate postpartum IUD use is peripartum infection, including Triple I, endomyometritis, and puerperal sepsis. Other contraindications include retained placenta requiring manual or surgical removal, uterine anomalies, and other medical contraindications to IUD use as recommended by the US Medical Eligibility Criteria.¹⁴

Does immediate IUD placement affect breastfeeding? There is theoretical risk of decreased milk supply or difficulty breastfeeding with initiation of progestin-only methods of contraception in the immediate postpartum period, as the rapid fall in progesterone levels initiates lactogenesis. However, progestin-only methods appear to have limited effect on initiation and continuation of breastfeeding in the immediate postpartum period.¹⁵

There were 2 secondary analyses of a pair of RCTs comparing immediate and delayed postpartum IUD use. Results from Levi and colleagues demonstrated no difference between immediate and interval IUD placement groups in the proportion of women who were breastfeeding at 6, 12, and 24 weeks.¹⁶ Chen and colleagues’ study was smaller; researchers found that women with interval IUD placement were more likely to be exclusively breastfeeding and continuing to breastfeed at 6 months compared with the immediate postpartum group.¹⁷

To better characterize the impact of progestin implants, in a recent meta-analysis, authors examined the use of subcutaneous levonorgestrel rods and found no difference in breastfeeding initiation and continuation rates between women who had them placed immediately versus 6 ̶ 8 weeks postpartum.¹²

Benefits of immediate postpartum IUD placement

One benefit of immediate postpartum IUD insertion is a reduction in short-interval pregnancies. In a study by Cohen and colleagues¹³ of young women aged 13 to 22 years choosing immediate postpartum IUDs (82) or implants (162), the authors found that 61% of women retained their IUDs at 12 months postpartum. Because few requested IUD removal over that time frame, the discontinuation rate at 1 year was primarily due to expulsions. Pregnancy rates at 1 year were 7.6% in the IUD group and 1.5% in the implant group. However, the 7.6% rate in the IUD group was lower than in previously studied adolescent control groups: 18.6% of control adolescents (38 of 204) using a contraceptive form other than a postpartum etonogestrel implant had repeat pregnancy at 1 year.^13,18

Not only are patients who receive immediate postpartum IUDs more likely to receive them and continue their use, but they are also satisfied with the experience of receiving the IUD and with the method of contraception. A small mixed methods study of 66 patients demonstrated that women were interested in obtaining immediate postpartum contraception to avoid some of the logistical and financial challenges of returning for a postpartum visit. They also felt that the IUD placement was less painful than expected, and they didn’t feel that the insertion process imposed on their birth experience. Many described relief to know that they had a safe and effective contraceptive method upon leaving the hospital.¹⁹ Other studies have shown that even among women who expel an IUD following immediate postpartum placement, many choose to replace it in order to continue it as a contraceptive method.^8,9,13

Continue to: Instructions for placement...

1. Counsel appropriately. Thoroughly counsel patients regarding their options for postpartum contraception, with emphasis on the benefits, risks, and contraindications. Current recommendations to reduce the risk of expulsion are to place the IUD in the delivery room or operating room within 10 minutes of placental delivery.

2. Post ̶ vaginal delivery. Following vaginal delivery, remove the IUD from the inserter, cut the strings to 10 cm and, using either fingers to grasp the wings of the IUD or ring forceps, advance the IUD to the fundus. Ultrasound guidance may be used, but it does not appear to be helpful in preventing expulsion.²⁰

3. Post ̶ cesarean delivery. Once the placenta is delivered, place the IUD using the inserter or a ring forceps at the fundus and guide the strings into the cervix, then close the hysterotomy.

ACOG does recommend formal trainingbefore placing postpartum IUDs. One resource they provide is a free online webinar (https://www.acog.org/education-and-events/webinars/long-acting-reversible-contra ception-overview-and-hands-on-practice-for-residents).³

CASE 1 Resolved

The patient was counseled in the office about her options, and she was most interested in immediate postpartum LNG-IUD placement. She went on to deliver a healthy baby vaginally at 39 weeks. Within 10 minutes of placental delivery, she received an LNG-IUD. She returned to the office 3 months later for STI screening; her examination revealed correct placement and no evidence of expulsion. She expressed that she was happy with her IUD and thankful that she was able to receive it immediately after the birth of her baby.

CASE 2 Nulliparous woman desires IUD for postpartum contraception

A 33-year-old nulliparous woman presents in the third trimester for a routine prenatal visit. She had used the LNG-IUD prior to getting pregnant and reports that she was very happy with it. She knows she wants to wait at least 2 years before trying to get pregnant again, and she would like to resume contraception as soon as it is reasonably safe to do so. She has read that it is possible to get an IUD immediately postpartum and asks about it as a possible option.

What barriers will she face in obtaining an immediate postpartum IUD?

There are many barriers for patients who may be good candidates for immediate postpartum contraception (TABLE 2). Many patients are unaware that it is a safe option, and they often have concerns about such risks as infection, perforation, and effects on breastfeeding. Additionally, providers may not prioritize adequate counseling about postpartum contraception when they face time constraints and a need to counsel about other pregnancy-related topics during the prenatal visit schedule.^7,21

System, hospital, and clinician barriers to immediate postpartum IUD use

Hospital implementation of a successful postpartum IUD program requires pharmacy, intrapartum and postpartum nursing staff, physicians, administration, and billing to be aligned. Hospital administration and pharmacists must stock IUDs in the pharmacy. Hospital nursing staff attitudes toward and knowledge of postpartum contraception can have profound influence on how they discuss safe and effective methods of postpartum contraception with patients who may not have received counseling during prenatal care.²² In a survey of 108 ACOG fellows, nearly 75% of ObGyn physicians did not offer immediate postpartum IUDs; lack of provider training, lack of IUD availability, and concern about cost and payment were found to be common reasons why.²¹ Additionally, Catholic-affiliated and rural institutions are less likely to offer it, whereas more urban, teaching hospitals are more likely to have programs in place.²³ Prior to 2012, immediate postpartum IUD insertions and device costs were part of the global Medicaid obstetric fee in most states, and both hospital systems and individual providers were concerned about loss of revenue.²³

In 2015, Washington and colleagues published a decision analysis that examined the cost-effectiveness and cost savings associated with immediate postpartum IUD use. Accounting for expulsion rates, they found that immediate postpartum IUD placement can save $282,540 per 1,000 women over 2 years; additionally, immediate postpartum IUD use can prevent 88 unintended pregnancies per 1,000 women over 2 years.²⁴ Not only do immediate postpartum IUDs have great potential to prevent individual patients from undesired short-interval pregnancies (FIGURE 1), but they can also save the system substantial health care dollars (FIGURE 2).

Overcoming barriers

Immediate postpartum IUD implementation is attainable with practice, policy, and institutional changes. Education and training programs geared toward providers and nursing staff can improve understanding of the benefits and risks of immediate postpartum IUD placement. Additionally, clinicians must provide comprehensive, nondirective counseling during the antepartum period, informing patients of all safe and effective options. Expulsion risks should be disclosed, as well as the benefit of not needing to return for a separate postpartum contraception appointment.

Since 2012, many state Medicaid agencies have decoupled reimbursement for inpatient postpartum IUD insertion from the delivery fee. By 2018, more than half of states adopted this practice. Commercial insurers have followed suit in some cases, and as such, both Medicaid and commercially insured patients have had increased access to immediate postpartum IUDs.²³ This has translated into increased uptake of immediate postpartum IUDs among both Medicaid and commercially insured patients. Koch et al conducted a retrospective cohort study comparing IUD use in patients 1 year before and 1 year after the policy changes, and they found a 10-fold increase in use of immediate postpartum IUDs.²⁵

While education, counseling, access, and changes in reimbursement may increase access in many hospital systems, some barriers, such as religious affiliation of the hospital system, may be impossible to overcome. A viable alternative to immediate postpartum IUD placement may be early postpartum IUD placement, which could allow patients to coordinate this procedure with 1- or 2-week return routine postpartum visits for CD recovery, mental health screenings, and/or well-baby visits. More data are necessary before recommending this universally, but Averbach and colleagues published a promising meta-analysis that demonstrated no complete expulsions in studies in which IUDs were placed between 2 and 4 weeks postpartum, and only a pooled partial expulsion rate (of immediate postpartum, early inpatient, early outpatient, and interval placement) of 3.7%.⁴

CASE 2 Resolved

Although the patient was interested in receiving a postpartum LNG-IUD immediately after her vaginal birth, she had to wait until her 6-week postpartum visit. The hospital did not stock IUDs for immediate postpartum IUD use, and her provider, having not been trained on immediate postpartum insertion, did not feel comfortable trying to place it in the immediate postpartum time frame. ●

Advances in technology, including ubiquitous access to the internet and the capacity to transfer high-resolution representative images, have facilitated the adoption of telepathology by laboratories worldwide.^1-5 Telepathology includes the use of telecommunication links that enable transmission of digital pathology images for primary diagnosis, quality assurance (QA), education, research, or second opinion diagnoses.³ This improvement has culminated in approvals by the US Food and Drug Administration (FDA) of whole slide imaging (WSI) systems for surgical pathology slides: specifically, the Philips IntelliSite Digital Pathology Solution in 2017 and the Leica Aperio AT2 DX in 2020.^6-8 However, the approvals do not include telecytology due to lack of whole slide multiplanar scanning at different planes of focus or z-stacking capabilities.⁷

Long-term trends in pathology, specifically the slow reduction in the number of practicing pathologists available in the workforce compared with the total served population, along with the social distancing imperatives and disruptions brought about by the COVID-19 pandemic have made telepathology implementation pertinent to continue and improve pathology practice.^8-10

Description and Definitions

The primary modes of telepathology (static image telepathology, robotic telepathology, video microscopy, WSI, and multimodality telepathology) have been defined by the American Telemedicine Association (ATA).² WSI has been particularly suited for telepathology due to the ability to view digital slides in high resolution at various magnifications. These image files can also be viewed and shared with ease with other observers. Also, they take a shorter time to view compared with the use of a robotic microscope.³

Selection, Validation, and Implementation

WSI platforms vary in their characteristics and have several parameters, including but not limited to batch scanning vs continuous or random-access processing, throughput volume capacities, scan speed, cost, manual vs automatic loading of slides, image quality, slide capacity, flexibility for different slide sizes/features, telepathology capabilities once slide scanned, z-stacking, and regulatory approval status.⁸ Selection of the WSI device is dependent on need and cost considerations. For example, use for frozen section requires faster scanning speed and does not generally require a high throughput scanner.

Validation of telepathology by the testing site demonstrates that the new system performs as expected for its intended clinical use before being put into service and that the digital slides produced are acceptable for clinical diagnostic interpretation.¹¹ The College of American Pathologists (CAP) established WSI validation guidelines are part of the published laboratory standard of care.^11-13 An appropriate validation enables the benefits of telepathology while mitigating the risks.

There are 3 major CAP recommendations for validation. First, ≥ 60 cases should be included for each use case being validated with 20 additional cases for relevant ancillary applications not included in the 60 cases. Second, diagnostic concordance (ideally ≥ 95%) should be established between digital and glass slides for the same observer. Third, there should be a 2-week washout period between the viewing of digital and glass slides (Table 2).^12,13

Guidelines from the ATA establish that telepathology systems should be validated for clinical use, including non-WSI platforms.² Published validations of other non-WSI platforms (such as by robotic or multimodality telepathology) have followed the structure proposed in the guidelines by CAP for validating WSI.^14,15

Ensuring that all relevant responsibilities (clinical, facility, technical, training, documentation/archiving, quality management, and operations related) for the use of telepathology are met is another aspect of validation and implementation.² Clinical responsibilities include an agreement between the sending (referring) and receiving (consulting) parties on the information to accompany the digital material.² From ATA clinical guidelines, this includes identification information, provision to the consulting pathologist of all relevant clinical data, provision to retrieve for access any needed and/or relevant diagnostic material, and responsibility by referrer that the correct image/metadata was sent.² Involved parties should be trained to manage the materials being transmitted.²

Facility responsibilities include maintaining the standard of care defined by the facility and regulatory agencies.² The maintenance of accreditation, adherence to licensure requirements, and proper management of privileges to practice telepathology are also important.² Technical responsibilities include ensuring a proper validation that meets the standard of care and covers use cases.^2,11-13

All processes, training, and competencies should be followed and documented per standard facility operating procedures.² ATA recommends that telepathology should result in a formal report for diagnostic consultations, maintain logs of telepathology interactions or disclaimer statements, and have an appropriate retention policy.² The CAP recommends digital images used for primary diagnosis should be kept for 10 years if the original glass slides are not available.¹⁶ Once implemented, telepathology reports must be incorporated into the pathology and laboratory medicine department’s quality management plan for both the technical performance of the telepathology system and diagnostic performance of the pathologists using the system.² Operations responsibilities include ensuring that the telepathology system is maintained according to vendor recommendations and regulatory standards. Appropriate provisions for space and associated needs should be developed in conjunction with the information technology team of the facility to ensure appropriate security, privacy, and regulatory compliance.²

Applications and Uses

Telecytology. Rapid real-time telecytology has been documented to be useful in rapid on-site evaluations (ROSE) of the adequacy of fine needle aspirations (FNA).^17-21 Nevertheless, current Medicare reimbursement is limited given that ROSE is cost prohibitive, time consuming, and affects productivity in cytology laboratories.^17,22,23 Estimates of the time to provide ROSE for 1 procedure without telecytology range from 48.7 to 56.2 minutes.^17,23 The use of telecytology significantly reduces pathologist ROSE time without losing quality to about 12 minutes, of which only an average of 7.5 minutes was spent by the cytopathologist for the ROSE diagnosis.^17-21 ROSE also can be used for distant and remote locations to improve patient care.^17-21 Multiple vendors provide real-time telecytology service. Innovations using smartphone adapters, digital cameras that could work as their own IP addresses, and connection with high-speed dedicated connections with viewing platforms on high-sensitivity monitors can facilitate ROSE to improve patient management.^24,25 The successful accurate use of ROSE has been described; however, there are currently no FDA-approved telepathology ROSE platforms.^17-19,21-25

To date, the FDA has not approved any telecytology whole slide scanner due to a lack of z-stacking capability in submitted scanners.^7,21 Not all whole slide scanners offer z-stacking, though even in those that do offer it, the time necessary to scan the entire slide with adequate z-stacking takes too long to be clinically acceptable for many situations involving ROSE.²¹ WSI has also been used to develop international consensus for cytologic samples.²⁶ Published recommendations for the validation of these other modalities before usage follow the spirit of the CAP guidelines (as far as multiple cases with high concordance rates) for validation of WSI for diagnostic purposes but vary on the exact number of slides and acceptable concordance rate.^21,27 For ROSE with a robotic microscope without any on-site cytology personnel, documented standardized training of nonpathology staff members, such as the radiologist or other physician performing the FNA procedure, may be needed to enable the performance of ROSE telecytology and ensure compliance with regulations.^2,21 Besides ROSE, there are published validations for telecytology in primary diagnosis and QA, indicating a role for telecytology for diagnosis for laboratories that have properly validated and implemented the laboratory-developed test.^28-30

Frozen section. Telepathology has significant potential to improve access to frozen section consultation.^5,31-33 Benefits to improving access to frozen section include providing frozen section consultation at remote or off-site locations, increasing access to subspecialty consultation, improving workflow by eliminating the need to travel off-site to the frozen section case, cost savings in staff work time, and providing educational opportunities for pathology trainees.^5,31-33 In our experience, WSI with real-time viewing of frozen section allows for the assessment of transplant tissues, which is an evaluation that generally occurs at night. Discrepancies from frozen section telepathology using WSI to the final diagnosis may occur and those specific to WSI could result from slide or image quality, internet connectivity, and lack of training in using the telepathology system.³² Other issues that may lead to discrepancies between the frozen section diagnosis and the final diagnosis may occur with the review of glass slides by light microscopy.³⁴ Appropriate performance of validation, training, implementation, and quality control for telepathology can help in reaping the benefits while mitigating the risks.² In a large study comparing frozen section evaluation by telepathology with light microscopy, the sensitivity and specificity of frozen section were comparable between telepathology and light microscopy with a trend toward greater sensitivity by telepathology (0.92 and 0.99 for telepathology vs 0.90 and 0.99 by light microscopy alone, sensitivity and specificity, respectively).³³

Other applications. Evidence for efficacy in surgical pathology diagnosis led to FDA approval of the Philips IntelliSite Digital Pathology in 2017 and the Leica Aperio AT2 DX in 2020 WSI platforms.^6-8 The use of WSI in surgical pathology has been successfully validated or used in clinical practice at several pathology laboratory settings with documented benefits in the literature for primary and secondary diagnoses, QA, research, and education.^6-8,35-45 Benefits of telepathology include improved ergonomics and access to real-time pathologic services in remote areas or during on-site pathologist absence and expert second opinions. Telepathology also may reduce risk of slide loss during transport, shortened turnaround time, reduced costs of operation through workflow efficiencies, better load balancing, improve virtual collaboration, and digital storage of slides that may be irreplaceable.^3-8,35-45 Telepathology also has been shown to be useful for education, improving access to learning materials and increasing quality instructional materials at a lower cost.⁴⁵ The increased ease of collaboration with remote experts and access to slide material for other pathologists improves QA capabilities.^3-8,35-45 The availability of virtual slides is expected to promote further research in telepathology and pathology due to the increased availability of virtual material to researchers.^1,5,46

Telehematology. Published validations have shown effectiveness for hematopathology specimens, such as the peripheral smear. Telehematology also has demonstrated potential in a laboratory after proper validation and implementation as a laboratory-developed test.^37,47-49

Telemicrobiology and Computer-Assisted Pathologic Diagnosis. Telemicrobiology also has been successfully used for clinical, educational, and QA purposes.⁵⁰ The digitalization of slides involved with telepathology enables further innovation in machine learning for computer-assisted pathologic diagnosis (CAPD), which is already being used clinically for cervical Pap smears.²⁰ An artificial intelligence (AI)–based algorithm analyzes the slides to identify cells of interest, which are presented to the cytopathologist for confirmation.²⁰ However, the expansion of CAPD to include a variety of specimen types or diagnostic situations as well as safely and effectively take initiative in completing an accurate automated diagnosis requires additional development.^20,51,52 One of the key factors for machine learning to develop AI is the provision of a corpus of data.^51,52 Public, open-source data sources have been limited in size while private proprietary sources have highly restricted and expensive access; to address this, there is a current effort to build the world’s largest public open-source digital pathology corpus at Temple University Hospital, which may help enable innovations in the future.⁵²

Long-Term Trends/Applications

The COVID-19 pandemic has been unprecedented not only in its widespread morbidity and mortality, but also for the significant socioeconomic, health, lifestyle, societal, and workspace changes.^53-57 Specifically, the pandemic has introduced not only a need for social distancing and staff quarantines to prevent the spread of infection, but also a reduction in the workforce due to the stresses of COVID-19 (also known as the Great Resignation).⁵⁵ Before the pandemic, there was an existing downtrend in the number of pathologists in the US workforce.^9-10,58,59 From 2007 to 2017, the number of active pathologists in the US declined by 17.5% despite the increasing national population, resulting in not only an absolute decrease in the number of pathologists, but also an increasing population served per pathologist ratio.⁵⁹ Since 2017, this downtrend has continued; given the increasing loss of active pathologists from the workforce and the decreasing training of new pathologists, this decrease shows no signs of reversing even as the impact of the COVID-19 pandemic has begun to wane.^9,10,58-60

The advantages of telepathology in enabling social distancing and reducing travel to remote sites are known.^3-7,17 Given these advantages, some medical centers in the US have previously successfully validated and implemented telepathology operations earlier during the COVID-19 pandemic to ease workflow and ensure continued operations.^56,57 The use of telepathology also helps in balancing workload and continuing pathology operations even in light of the workforce reduction as cases no longer need to be signed out on site with glass slides but instead can be signed out at a remote laboratory. Although the impact of the COVID-19 pandemic on operations is decreasing, the capabilities for social distancing and reducing travel remain important to both improve operations and ensure resiliency in response to similar potential events.^3-7,17,60

Considering the long-term trends, the lessons of the COVID-19 pandemic, and the potential for future pandemics or other disasters, telepathology’s validation and implementation remains a reasonable choice for pathology practices looking to improve. A variety of practices not just in the general population, but also among US Department of Veterans Affairs medical centers (VAMCs) and the US Department of Defense Military Health System treating a veteran population can benefit from telepathology where it has previously been reported to have been reliable or successfully implemented.^61-63 Although the veteran population differs from the general population in several characteristics, such as the severity of disease, coexisting morbidities, and other history, given proper validation and implementation, telepathology’s usefulness extends across different pathology practice settings.^35-43,61-66

Limitations of Telepathology

In telepathology’s current state, there are limitations despite its immense promise.^6,35 These include initial capital costs, the additional training requirement, the additional time necessary to scan slides, technical challenges (ie, laboratory information system integration, color calibration, display artifacts, potential for small particle scanner omissions, and information technology dependence), the potential for slower evaluation per slide compared with optical microscopes, limitations of slide imaging (ie, z-stacking or lack of polarization on digital pathology), and occupational concerns regarding eye strain with increased computer monitor usage (ie, computer vision syndrome).^6,35 In addition, there are few telepathology scanners with FDA approval for WSI.^6-8

The improving technology of telepathology has made these limitations surmountable, including faster slide scanning and increasing digital storage capacity for large WSI files. Due to this improvement in technology, an increasing number of laboratory settings, have adopted telepathology as its advantages have begun to outweigh the limitations.^2-5 Additionally, the proper validation performed before implementing telepathology can help laboratories identify their unique challenges, troubleshoot, and resolve the limitations before use in clinical care.^11-13 Continuing QA during its use and implementation is important to ensure that telepathology performs as expected for clinical purposes despite its limitations.²

Conclusions

Telepathology is a promising technology that may improve pathology practice once properly validated and implemented.^1-8 Though there are barriers to this validation and implementation, particularly the capital costs and training, there are several potential benefits, including increased productivity, cost savings, improvement in the workflow, enhanced access to pathologic consultation, and adaptability of the pathology laboratory in an era of a decreased workforce and social distancing due to the COVID-19 pandemic.^1-8,55-56 This potential applies across the wide spectrum of potential telepathology uses from frozen section, telecytology (including ROSE) to primary and second opinion diagnoses.^1-8,17-33 The benefits also extends to QA, education, and research, as diagnoses can not only be rereviewed by specialty or second opinion consultation with ease, but also digital slides can be produced for educational and research purposes.^3-8,35-45 Settings that treat the general population and those focused on the care of veterans or members of the armed forces have reported similar reliability or successful implementation.^35-44,61-63 All in all, the use of telepathology represents an innovation that may transform the practice of pathology tomorrow.

Advances in technology, including ubiquitous access to the internet and the capacity to transfer high-resolution representative images, have facilitated the adoption of telepathology by laboratories worldwide.^1-5 Telepathology includes the use of telecommunication links that enable transmission of digital pathology images for primary diagnosis, quality assurance (QA), education, research, or second opinion diagnoses.³ This improvement has culminated in approvals by the US Food and Drug Administration (FDA) of whole slide imaging (WSI) systems for surgical pathology slides: specifically, the Philips IntelliSite Digital Pathology Solution in 2017 and the Leica Aperio AT2 DX in 2020.^6-8 However, the approvals do not include telecytology due to lack of whole slide multiplanar scanning at different planes of focus or z-stacking capabilities.⁷

Long-term trends in pathology, specifically the slow reduction in the number of practicing pathologists available in the workforce compared with the total served population, along with the social distancing imperatives and disruptions brought about by the COVID-19 pandemic have made telepathology implementation pertinent to continue and improve pathology practice.^8-10

Description and Definitions

The primary modes of telepathology (static image telepathology, robotic telepathology, video microscopy, WSI, and multimodality telepathology) have been defined by the American Telemedicine Association (ATA).² WSI has been particularly suited for telepathology due to the ability to view digital slides in high resolution at various magnifications. These image files can also be viewed and shared with ease with other observers. Also, they take a shorter time to view compared with the use of a robotic microscope.³

Selection, Validation, and Implementation

WSI platforms vary in their characteristics and have several parameters, including but not limited to batch scanning vs continuous or random-access processing, throughput volume capacities, scan speed, cost, manual vs automatic loading of slides, image quality, slide capacity, flexibility for different slide sizes/features, telepathology capabilities once slide scanned, z-stacking, and regulatory approval status.⁸ Selection of the WSI device is dependent on need and cost considerations. For example, use for frozen section requires faster scanning speed and does not generally require a high throughput scanner.

Validation of telepathology by the testing site demonstrates that the new system performs as expected for its intended clinical use before being put into service and that the digital slides produced are acceptable for clinical diagnostic interpretation.¹¹ The College of American Pathologists (CAP) established WSI validation guidelines are part of the published laboratory standard of care.^11-13 An appropriate validation enables the benefits of telepathology while mitigating the risks.

There are 3 major CAP recommendations for validation. First, ≥ 60 cases should be included for each use case being validated with 20 additional cases for relevant ancillary applications not included in the 60 cases. Second, diagnostic concordance (ideally ≥ 95%) should be established between digital and glass slides for the same observer. Third, there should be a 2-week washout period between the viewing of digital and glass slides (Table 2).^12,13

Guidelines from the ATA establish that telepathology systems should be validated for clinical use, including non-WSI platforms.² Published validations of other non-WSI platforms (such as by robotic or multimodality telepathology) have followed the structure proposed in the guidelines by CAP for validating WSI.^14,15

Ensuring that all relevant responsibilities (clinical, facility, technical, training, documentation/archiving, quality management, and operations related) for the use of telepathology are met is another aspect of validation and implementation.² Clinical responsibilities include an agreement between the sending (referring) and receiving (consulting) parties on the information to accompany the digital material.² From ATA clinical guidelines, this includes identification information, provision to the consulting pathologist of all relevant clinical data, provision to retrieve for access any needed and/or relevant diagnostic material, and responsibility by referrer that the correct image/metadata was sent.² Involved parties should be trained to manage the materials being transmitted.²

Facility responsibilities include maintaining the standard of care defined by the facility and regulatory agencies.² The maintenance of accreditation, adherence to licensure requirements, and proper management of privileges to practice telepathology are also important.² Technical responsibilities include ensuring a proper validation that meets the standard of care and covers use cases.^2,11-13

All processes, training, and competencies should be followed and documented per standard facility operating procedures.² ATA recommends that telepathology should result in a formal report for diagnostic consultations, maintain logs of telepathology interactions or disclaimer statements, and have an appropriate retention policy.² The CAP recommends digital images used for primary diagnosis should be kept for 10 years if the original glass slides are not available.¹⁶ Once implemented, telepathology reports must be incorporated into the pathology and laboratory medicine department’s quality management plan for both the technical performance of the telepathology system and diagnostic performance of the pathologists using the system.² Operations responsibilities include ensuring that the telepathology system is maintained according to vendor recommendations and regulatory standards. Appropriate provisions for space and associated needs should be developed in conjunction with the information technology team of the facility to ensure appropriate security, privacy, and regulatory compliance.²

Applications and Uses

Telecytology. Rapid real-time telecytology has been documented to be useful in rapid on-site evaluations (ROSE) of the adequacy of fine needle aspirations (FNA).^17-21 Nevertheless, current Medicare reimbursement is limited given that ROSE is cost prohibitive, time consuming, and affects productivity in cytology laboratories.^17,22,23 Estimates of the time to provide ROSE for 1 procedure without telecytology range from 48.7 to 56.2 minutes.^17,23 The use of telecytology significantly reduces pathologist ROSE time without losing quality to about 12 minutes, of which only an average of 7.5 minutes was spent by the cytopathologist for the ROSE diagnosis.^17-21 ROSE also can be used for distant and remote locations to improve patient care.^17-21 Multiple vendors provide real-time telecytology service. Innovations using smartphone adapters, digital cameras that could work as their own IP addresses, and connection with high-speed dedicated connections with viewing platforms on high-sensitivity monitors can facilitate ROSE to improve patient management.^24,25 The successful accurate use of ROSE has been described; however, there are currently no FDA-approved telepathology ROSE platforms.^17-19,21-25

To date, the FDA has not approved any telecytology whole slide scanner due to a lack of z-stacking capability in submitted scanners.^7,21 Not all whole slide scanners offer z-stacking, though even in those that do offer it, the time necessary to scan the entire slide with adequate z-stacking takes too long to be clinically acceptable for many situations involving ROSE.²¹ WSI has also been used to develop international consensus for cytologic samples.²⁶ Published recommendations for the validation of these other modalities before usage follow the spirit of the CAP guidelines (as far as multiple cases with high concordance rates) for validation of WSI for diagnostic purposes but vary on the exact number of slides and acceptable concordance rate.^21,27 For ROSE with a robotic microscope without any on-site cytology personnel, documented standardized training of nonpathology staff members, such as the radiologist or other physician performing the FNA procedure, may be needed to enable the performance of ROSE telecytology and ensure compliance with regulations.^2,21 Besides ROSE, there are published validations for telecytology in primary diagnosis and QA, indicating a role for telecytology for diagnosis for laboratories that have properly validated and implemented the laboratory-developed test.^28-30

Frozen section. Telepathology has significant potential to improve access to frozen section consultation.^5,31-33 Benefits to improving access to frozen section include providing frozen section consultation at remote or off-site locations, increasing access to subspecialty consultation, improving workflow by eliminating the need to travel off-site to the frozen section case, cost savings in staff work time, and providing educational opportunities for pathology trainees.^5,31-33 In our experience, WSI with real-time viewing of frozen section allows for the assessment of transplant tissues, which is an evaluation that generally occurs at night. Discrepancies from frozen section telepathology using WSI to the final diagnosis may occur and those specific to WSI could result from slide or image quality, internet connectivity, and lack of training in using the telepathology system.³² Other issues that may lead to discrepancies between the frozen section diagnosis and the final diagnosis may occur with the review of glass slides by light microscopy.³⁴ Appropriate performance of validation, training, implementation, and quality control for telepathology can help in reaping the benefits while mitigating the risks.² In a large study comparing frozen section evaluation by telepathology with light microscopy, the sensitivity and specificity of frozen section were comparable between telepathology and light microscopy with a trend toward greater sensitivity by telepathology (0.92 and 0.99 for telepathology vs 0.90 and 0.99 by light microscopy alone, sensitivity and specificity, respectively).³³

Other applications. Evidence for efficacy in surgical pathology diagnosis led to FDA approval of the Philips IntelliSite Digital Pathology in 2017 and the Leica Aperio AT2 DX in 2020 WSI platforms.^6-8 The use of WSI in surgical pathology has been successfully validated or used in clinical practice at several pathology laboratory settings with documented benefits in the literature for primary and secondary diagnoses, QA, research, and education.^6-8,35-45 Benefits of telepathology include improved ergonomics and access to real-time pathologic services in remote areas or during on-site pathologist absence and expert second opinions. Telepathology also may reduce risk of slide loss during transport, shortened turnaround time, reduced costs of operation through workflow efficiencies, better load balancing, improve virtual collaboration, and digital storage of slides that may be irreplaceable.^3-8,35-45 Telepathology also has been shown to be useful for education, improving access to learning materials and increasing quality instructional materials at a lower cost.⁴⁵ The increased ease of collaboration with remote experts and access to slide material for other pathologists improves QA capabilities.^3-8,35-45 The availability of virtual slides is expected to promote further research in telepathology and pathology due to the increased availability of virtual material to researchers.^1,5,46

Telehematology. Published validations have shown effectiveness for hematopathology specimens, such as the peripheral smear. Telehematology also has demonstrated potential in a laboratory after proper validation and implementation as a laboratory-developed test.^37,47-49

Telemicrobiology and Computer-Assisted Pathologic Diagnosis. Telemicrobiology also has been successfully used for clinical, educational, and QA purposes.⁵⁰ The digitalization of slides involved with telepathology enables further innovation in machine learning for computer-assisted pathologic diagnosis (CAPD), which is already being used clinically for cervical Pap smears.²⁰ An artificial intelligence (AI)–based algorithm analyzes the slides to identify cells of interest, which are presented to the cytopathologist for confirmation.²⁰ However, the expansion of CAPD to include a variety of specimen types or diagnostic situations as well as safely and effectively take initiative in completing an accurate automated diagnosis requires additional development.^20,51,52 One of the key factors for machine learning to develop AI is the provision of a corpus of data.^51,52 Public, open-source data sources have been limited in size while private proprietary sources have highly restricted and expensive access; to address this, there is a current effort to build the world’s largest public open-source digital pathology corpus at Temple University Hospital, which may help enable innovations in the future.⁵²

Long-Term Trends/Applications

The COVID-19 pandemic has been unprecedented not only in its widespread morbidity and mortality, but also for the significant socioeconomic, health, lifestyle, societal, and workspace changes.^53-57 Specifically, the pandemic has introduced not only a need for social distancing and staff quarantines to prevent the spread of infection, but also a reduction in the workforce due to the stresses of COVID-19 (also known as the Great Resignation).⁵⁵ Before the pandemic, there was an existing downtrend in the number of pathologists in the US workforce.^9-10,58,59 From 2007 to 2017, the number of active pathologists in the US declined by 17.5% despite the increasing national population, resulting in not only an absolute decrease in the number of pathologists, but also an increasing population served per pathologist ratio.⁵⁹ Since 2017, this downtrend has continued; given the increasing loss of active pathologists from the workforce and the decreasing training of new pathologists, this decrease shows no signs of reversing even as the impact of the COVID-19 pandemic has begun to wane.^9,10,58-60

The advantages of telepathology in enabling social distancing and reducing travel to remote sites are known.^3-7,17 Given these advantages, some medical centers in the US have previously successfully validated and implemented telepathology operations earlier during the COVID-19 pandemic to ease workflow and ensure continued operations.^56,57 The use of telepathology also helps in balancing workload and continuing pathology operations even in light of the workforce reduction as cases no longer need to be signed out on site with glass slides but instead can be signed out at a remote laboratory. Although the impact of the COVID-19 pandemic on operations is decreasing, the capabilities for social distancing and reducing travel remain important to both improve operations and ensure resiliency in response to similar potential events.^3-7,17,60

Considering the long-term trends, the lessons of the COVID-19 pandemic, and the potential for future pandemics or other disasters, telepathology’s validation and implementation remains a reasonable choice for pathology practices looking to improve. A variety of practices not just in the general population, but also among US Department of Veterans Affairs medical centers (VAMCs) and the US Department of Defense Military Health System treating a veteran population can benefit from telepathology where it has previously been reported to have been reliable or successfully implemented.^61-63 Although the veteran population differs from the general population in several characteristics, such as the severity of disease, coexisting morbidities, and other history, given proper validation and implementation, telepathology’s usefulness extends across different pathology practice settings.^35-43,61-66

Limitations of Telepathology

In telepathology’s current state, there are limitations despite its immense promise.^6,35 These include initial capital costs, the additional training requirement, the additional time necessary to scan slides, technical challenges (ie, laboratory information system integration, color calibration, display artifacts, potential for small particle scanner omissions, and information technology dependence), the potential for slower evaluation per slide compared with optical microscopes, limitations of slide imaging (ie, z-stacking or lack of polarization on digital pathology), and occupational concerns regarding eye strain with increased computer monitor usage (ie, computer vision syndrome).^6,35 In addition, there are few telepathology scanners with FDA approval for WSI.^6-8

The improving technology of telepathology has made these limitations surmountable, including faster slide scanning and increasing digital storage capacity for large WSI files. Due to this improvement in technology, an increasing number of laboratory settings, have adopted telepathology as its advantages have begun to outweigh the limitations.^2-5 Additionally, the proper validation performed before implementing telepathology can help laboratories identify their unique challenges, troubleshoot, and resolve the limitations before use in clinical care.^11-13 Continuing QA during its use and implementation is important to ensure that telepathology performs as expected for clinical purposes despite its limitations.²

Conclusions

Telepathology is a promising technology that may improve pathology practice once properly validated and implemented.^1-8 Though there are barriers to this validation and implementation, particularly the capital costs and training, there are several potential benefits, including increased productivity, cost savings, improvement in the workflow, enhanced access to pathologic consultation, and adaptability of the pathology laboratory in an era of a decreased workforce and social distancing due to the COVID-19 pandemic.^1-8,55-56 This potential applies across the wide spectrum of potential telepathology uses from frozen section, telecytology (including ROSE) to primary and second opinion diagnoses.^1-8,17-33 The benefits also extends to QA, education, and research, as diagnoses can not only be rereviewed by specialty or second opinion consultation with ease, but also digital slides can be produced for educational and research purposes.^3-8,35-45 Settings that treat the general population and those focused on the care of veterans or members of the armed forces have reported similar reliability or successful implementation.^35-44,61-63 All in all, the use of telepathology represents an innovation that may transform the practice of pathology tomorrow.

Advances in technology, including ubiquitous access to the internet and the capacity to transfer high-resolution representative images, have facilitated the adoption of telepathology by laboratories worldwide.^1-5 Telepathology includes the use of telecommunication links that enable transmission of digital pathology images for primary diagnosis, quality assurance (QA), education, research, or second opinion diagnoses.³ This improvement has culminated in approvals by the US Food and Drug Administration (FDA) of whole slide imaging (WSI) systems for surgical pathology slides: specifically, the Philips IntelliSite Digital Pathology Solution in 2017 and the Leica Aperio AT2 DX in 2020.^6-8 However, the approvals do not include telecytology due to lack of whole slide multiplanar scanning at different planes of focus or z-stacking capabilities.⁷

Long-term trends in pathology, specifically the slow reduction in the number of practicing pathologists available in the workforce compared with the total served population, along with the social distancing imperatives and disruptions brought about by the COVID-19 pandemic have made telepathology implementation pertinent to continue and improve pathology practice.^8-10

Description and Definitions

The primary modes of telepathology (static image telepathology, robotic telepathology, video microscopy, WSI, and multimodality telepathology) have been defined by the American Telemedicine Association (ATA).² WSI has been particularly suited for telepathology due to the ability to view digital slides in high resolution at various magnifications. These image files can also be viewed and shared with ease with other observers. Also, they take a shorter time to view compared with the use of a robotic microscope.³

Selection, Validation, and Implementation

WSI platforms vary in their characteristics and have several parameters, including but not limited to batch scanning vs continuous or random-access processing, throughput volume capacities, scan speed, cost, manual vs automatic loading of slides, image quality, slide capacity, flexibility for different slide sizes/features, telepathology capabilities once slide scanned, z-stacking, and regulatory approval status.⁸ Selection of the WSI device is dependent on need and cost considerations. For example, use for frozen section requires faster scanning speed and does not generally require a high throughput scanner.

Validation of telepathology by the testing site demonstrates that the new system performs as expected for its intended clinical use before being put into service and that the digital slides produced are acceptable for clinical diagnostic interpretation.¹¹ The College of American Pathologists (CAP) established WSI validation guidelines are part of the published laboratory standard of care.^11-13 An appropriate validation enables the benefits of telepathology while mitigating the risks.

There are 3 major CAP recommendations for validation. First, ≥ 60 cases should be included for each use case being validated with 20 additional cases for relevant ancillary applications not included in the 60 cases. Second, diagnostic concordance (ideally ≥ 95%) should be established between digital and glass slides for the same observer. Third, there should be a 2-week washout period between the viewing of digital and glass slides (Table 2).^12,13

Guidelines from the ATA establish that telepathology systems should be validated for clinical use, including non-WSI platforms.² Published validations of other non-WSI platforms (such as by robotic or multimodality telepathology) have followed the structure proposed in the guidelines by CAP for validating WSI.^14,15

Ensuring that all relevant responsibilities (clinical, facility, technical, training, documentation/archiving, quality management, and operations related) for the use of telepathology are met is another aspect of validation and implementation.² Clinical responsibilities include an agreement between the sending (referring) and receiving (consulting) parties on the information to accompany the digital material.² From ATA clinical guidelines, this includes identification information, provision to the consulting pathologist of all relevant clinical data, provision to retrieve for access any needed and/or relevant diagnostic material, and responsibility by referrer that the correct image/metadata was sent.² Involved parties should be trained to manage the materials being transmitted.²

Facility responsibilities include maintaining the standard of care defined by the facility and regulatory agencies.² The maintenance of accreditation, adherence to licensure requirements, and proper management of privileges to practice telepathology are also important.² Technical responsibilities include ensuring a proper validation that meets the standard of care and covers use cases.^2,11-13

All processes, training, and competencies should be followed and documented per standard facility operating procedures.² ATA recommends that telepathology should result in a formal report for diagnostic consultations, maintain logs of telepathology interactions or disclaimer statements, and have an appropriate retention policy.² The CAP recommends digital images used for primary diagnosis should be kept for 10 years if the original glass slides are not available.¹⁶ Once implemented, telepathology reports must be incorporated into the pathology and laboratory medicine department’s quality management plan for both the technical performance of the telepathology system and diagnostic performance of the pathologists using the system.² Operations responsibilities include ensuring that the telepathology system is maintained according to vendor recommendations and regulatory standards. Appropriate provisions for space and associated needs should be developed in conjunction with the information technology team of the facility to ensure appropriate security, privacy, and regulatory compliance.²

Applications and Uses

Telecytology. Rapid real-time telecytology has been documented to be useful in rapid on-site evaluations (ROSE) of the adequacy of fine needle aspirations (FNA).^17-21 Nevertheless, current Medicare reimbursement is limited given that ROSE is cost prohibitive, time consuming, and affects productivity in cytology laboratories.^17,22,23 Estimates of the time to provide ROSE for 1 procedure without telecytology range from 48.7 to 56.2 minutes.^17,23 The use of telecytology significantly reduces pathologist ROSE time without losing quality to about 12 minutes, of which only an average of 7.5 minutes was spent by the cytopathologist for the ROSE diagnosis.^17-21 ROSE also can be used for distant and remote locations to improve patient care.^17-21 Multiple vendors provide real-time telecytology service. Innovations using smartphone adapters, digital cameras that could work as their own IP addresses, and connection with high-speed dedicated connections with viewing platforms on high-sensitivity monitors can facilitate ROSE to improve patient management.^24,25 The successful accurate use of ROSE has been described; however, there are currently no FDA-approved telepathology ROSE platforms.^17-19,21-25

To date, the FDA has not approved any telecytology whole slide scanner due to a lack of z-stacking capability in submitted scanners.^7,21 Not all whole slide scanners offer z-stacking, though even in those that do offer it, the time necessary to scan the entire slide with adequate z-stacking takes too long to be clinically acceptable for many situations involving ROSE.²¹ WSI has also been used to develop international consensus for cytologic samples.²⁶ Published recommendations for the validation of these other modalities before usage follow the spirit of the CAP guidelines (as far as multiple cases with high concordance rates) for validation of WSI for diagnostic purposes but vary on the exact number of slides and acceptable concordance rate.^21,27 For ROSE with a robotic microscope without any on-site cytology personnel, documented standardized training of nonpathology staff members, such as the radiologist or other physician performing the FNA procedure, may be needed to enable the performance of ROSE telecytology and ensure compliance with regulations.^2,21 Besides ROSE, there are published validations for telecytology in primary diagnosis and QA, indicating a role for telecytology for diagnosis for laboratories that have properly validated and implemented the laboratory-developed test.^28-30

Frozen section. Telepathology has significant potential to improve access to frozen section consultation.^5,31-33 Benefits to improving access to frozen section include providing frozen section consultation at remote or off-site locations, increasing access to subspecialty consultation, improving workflow by eliminating the need to travel off-site to the frozen section case, cost savings in staff work time, and providing educational opportunities for pathology trainees.^5,31-33 In our experience, WSI with real-time viewing of frozen section allows for the assessment of transplant tissues, which is an evaluation that generally occurs at night. Discrepancies from frozen section telepathology using WSI to the final diagnosis may occur and those specific to WSI could result from slide or image quality, internet connectivity, and lack of training in using the telepathology system.³² Other issues that may lead to discrepancies between the frozen section diagnosis and the final diagnosis may occur with the review of glass slides by light microscopy.³⁴ Appropriate performance of validation, training, implementation, and quality control for telepathology can help in reaping the benefits while mitigating the risks.² In a large study comparing frozen section evaluation by telepathology with light microscopy, the sensitivity and specificity of frozen section were comparable between telepathology and light microscopy with a trend toward greater sensitivity by telepathology (0.92 and 0.99 for telepathology vs 0.90 and 0.99 by light microscopy alone, sensitivity and specificity, respectively).³³

Other applications. Evidence for efficacy in surgical pathology diagnosis led to FDA approval of the Philips IntelliSite Digital Pathology in 2017 and the Leica Aperio AT2 DX in 2020 WSI platforms.^6-8 The use of WSI in surgical pathology has been successfully validated or used in clinical practice at several pathology laboratory settings with documented benefits in the literature for primary and secondary diagnoses, QA, research, and education.^6-8,35-45 Benefits of telepathology include improved ergonomics and access to real-time pathologic services in remote areas or during on-site pathologist absence and expert second opinions. Telepathology also may reduce risk of slide loss during transport, shortened turnaround time, reduced costs of operation through workflow efficiencies, better load balancing, improve virtual collaboration, and digital storage of slides that may be irreplaceable.^3-8,35-45 Telepathology also has been shown to be useful for education, improving access to learning materials and increasing quality instructional materials at a lower cost.⁴⁵ The increased ease of collaboration with remote experts and access to slide material for other pathologists improves QA capabilities.^3-8,35-45 The availability of virtual slides is expected to promote further research in telepathology and pathology due to the increased availability of virtual material to researchers.^1,5,46

Telehematology. Published validations have shown effectiveness for hematopathology specimens, such as the peripheral smear. Telehematology also has demonstrated potential in a laboratory after proper validation and implementation as a laboratory-developed test.^37,47-49

Telemicrobiology and Computer-Assisted Pathologic Diagnosis. Telemicrobiology also has been successfully used for clinical, educational, and QA purposes.⁵⁰ The digitalization of slides involved with telepathology enables further innovation in machine learning for computer-assisted pathologic diagnosis (CAPD), which is already being used clinically for cervical Pap smears.²⁰ An artificial intelligence (AI)–based algorithm analyzes the slides to identify cells of interest, which are presented to the cytopathologist for confirmation.²⁰ However, the expansion of CAPD to include a variety of specimen types or diagnostic situations as well as safely and effectively take initiative in completing an accurate automated diagnosis requires additional development.^20,51,52 One of the key factors for machine learning to develop AI is the provision of a corpus of data.^51,52 Public, open-source data sources have been limited in size while private proprietary sources have highly restricted and expensive access; to address this, there is a current effort to build the world’s largest public open-source digital pathology corpus at Temple University Hospital, which may help enable innovations in the future.⁵²

Long-Term Trends/Applications

The COVID-19 pandemic has been unprecedented not only in its widespread morbidity and mortality, but also for the significant socioeconomic, health, lifestyle, societal, and workspace changes.^53-57 Specifically, the pandemic has introduced not only a need for social distancing and staff quarantines to prevent the spread of infection, but also a reduction in the workforce due to the stresses of COVID-19 (also known as the Great Resignation).⁵⁵ Before the pandemic, there was an existing downtrend in the number of pathologists in the US workforce.^9-10,58,59 From 2007 to 2017, the number of active pathologists in the US declined by 17.5% despite the increasing national population, resulting in not only an absolute decrease in the number of pathologists, but also an increasing population served per pathologist ratio.⁵⁹ Since 2017, this downtrend has continued; given the increasing loss of active pathologists from the workforce and the decreasing training of new pathologists, this decrease shows no signs of reversing even as the impact of the COVID-19 pandemic has begun to wane.^9,10,58-60

The advantages of telepathology in enabling social distancing and reducing travel to remote sites are known.^3-7,17 Given these advantages, some medical centers in the US have previously successfully validated and implemented telepathology operations earlier during the COVID-19 pandemic to ease workflow and ensure continued operations.^56,57 The use of telepathology also helps in balancing workload and continuing pathology operations even in light of the workforce reduction as cases no longer need to be signed out on site with glass slides but instead can be signed out at a remote laboratory. Although the impact of the COVID-19 pandemic on operations is decreasing, the capabilities for social distancing and reducing travel remain important to both improve operations and ensure resiliency in response to similar potential events.^3-7,17,60

Considering the long-term trends, the lessons of the COVID-19 pandemic, and the potential for future pandemics or other disasters, telepathology’s validation and implementation remains a reasonable choice for pathology practices looking to improve. A variety of practices not just in the general population, but also among US Department of Veterans Affairs medical centers (VAMCs) and the US Department of Defense Military Health System treating a veteran population can benefit from telepathology where it has previously been reported to have been reliable or successfully implemented.^61-63 Although the veteran population differs from the general population in several characteristics, such as the severity of disease, coexisting morbidities, and other history, given proper validation and implementation, telepathology’s usefulness extends across different pathology practice settings.^35-43,61-66

Limitations of Telepathology

In telepathology’s current state, there are limitations despite its immense promise.^6,35 These include initial capital costs, the additional training requirement, the additional time necessary to scan slides, technical challenges (ie, laboratory information system integration, color calibration, display artifacts, potential for small particle scanner omissions, and information technology dependence), the potential for slower evaluation per slide compared with optical microscopes, limitations of slide imaging (ie, z-stacking or lack of polarization on digital pathology), and occupational concerns regarding eye strain with increased computer monitor usage (ie, computer vision syndrome).^6,35 In addition, there are few telepathology scanners with FDA approval for WSI.^6-8

The improving technology of telepathology has made these limitations surmountable, including faster slide scanning and increasing digital storage capacity for large WSI files. Due to this improvement in technology, an increasing number of laboratory settings, have adopted telepathology as its advantages have begun to outweigh the limitations.^2-5 Additionally, the proper validation performed before implementing telepathology can help laboratories identify their unique challenges, troubleshoot, and resolve the limitations before use in clinical care.^11-13 Continuing QA during its use and implementation is important to ensure that telepathology performs as expected for clinical purposes despite its limitations.²

Conclusions

Telepathology is a promising technology that may improve pathology practice once properly validated and implemented.^1-8 Though there are barriers to this validation and implementation, particularly the capital costs and training, there are several potential benefits, including increased productivity, cost savings, improvement in the workflow, enhanced access to pathologic consultation, and adaptability of the pathology laboratory in an era of a decreased workforce and social distancing due to the COVID-19 pandemic.^1-8,55-56 This potential applies across the wide spectrum of potential telepathology uses from frozen section, telecytology (including ROSE) to primary and second opinion diagnoses.^1-8,17-33 The benefits also extends to QA, education, and research, as diagnoses can not only be rereviewed by specialty or second opinion consultation with ease, but also digital slides can be produced for educational and research purposes.^3-8,35-45 Settings that treat the general population and those focused on the care of veterans or members of the armed forces have reported similar reliability or successful implementation.^35-44,61-63 All in all, the use of telepathology represents an innovation that may transform the practice of pathology tomorrow.

Pain and pruritus are the most common complaints in patients who present to vulvar clinics.¹ These symptoms can be related to a variety of conditions, including vulvar lesions. There are both common and uncommon vulvar lesions. Vulvar lesions can be skin colored, yellow, and red. Certain lesions can be diagnosed with history and physical examination alone. Some more common lesions include acrochordons (skin tags), benign growths that are common in patients with diabetes, obesity, and pregnancy.^2,3 Other common vulvar lesions are papillomatosis, lichen simplex chronicus, and epidermoid cysts. Other lesions include low- and high-grade squamous intraepithelial lesions (HSIL).⁴ These lesions require biopsy for diagnosis as high-grade lesions require treatment. HSIL of the vulva is considered a premalignancy that necessitates treatment.⁵ Other lesions that can present with vulvar complaints are molluscum contagiosum, Bartholin gland duct cyst, intradermal melanocytic nevus, and squamous cell carcinoma. 

Rarely, other less common conditions can present as vulvar lesions. Syringomas are benign eccrine sweat gland neoplasms. They are more commonly found on the face, neck, or chest.⁶ On the vulva they are generally small subcutaneous skin-colored papules.⁷ They may be asymptomatic and noted only on routine examination. 

Vulvar syringomas also may present with symptoms. On the vulva, syringomas often present as pruritic papules that can be isolated or multifocal. Often on the labia majora they range in size from 2 to 20 mm.⁸

They can coalesce to form a larger lesion. They also may be described as painful. When  syringomas are pruritic, the overlying skin may appear thickened from rubbing or scratching, and excoriations may be present. 

Since vulvar syringomas are rare, there is no standard treatment. Biopsy is necessary for definitive diagnosis. For asymptomatic cases, expectant management is warranted. In symptomatic cases treatment can be considered. Treatment options include cryotherapy, laser ablation, and intralesional electrodissection.⁸ Intralesional electrodissection and curettage also has been described as treatment.⁹ Other treatment options include surgical excision of individual lesions or larger excisions if multifocal. 

The case study described in "Case letter: Vulvar syringoma" highlights the diagnostic and therapeutic challenges associated with rare lesions of the vulva. Referral to a specialty clinic may be warranted in these challenging cases. ●

Pain and pruritus are the most common complaints in patients who present to vulvar clinics.¹ These symptoms can be related to a variety of conditions, including vulvar lesions. There are both common and uncommon vulvar lesions. Vulvar lesions can be skin colored, yellow, and red. Certain lesions can be diagnosed with history and physical examination alone. Some more common lesions include acrochordons (skin tags), benign growths that are common in patients with diabetes, obesity, and pregnancy.^2,3 Other common vulvar lesions are papillomatosis, lichen simplex chronicus, and epidermoid cysts. Other lesions include low- and high-grade squamous intraepithelial lesions (HSIL).⁴ These lesions require biopsy for diagnosis as high-grade lesions require treatment. HSIL of the vulva is considered a premalignancy that necessitates treatment.⁵ Other lesions that can present with vulvar complaints are molluscum contagiosum, Bartholin gland duct cyst, intradermal melanocytic nevus, and squamous cell carcinoma. 

Rarely, other less common conditions can present as vulvar lesions. Syringomas are benign eccrine sweat gland neoplasms. They are more commonly found on the face, neck, or chest.⁶ On the vulva they are generally small subcutaneous skin-colored papules.⁷ They may be asymptomatic and noted only on routine examination. 

Vulvar syringomas also may present with symptoms. On the vulva, syringomas often present as pruritic papules that can be isolated or multifocal. Often on the labia majora they range in size from 2 to 20 mm.⁸

They can coalesce to form a larger lesion. They also may be described as painful. When  syringomas are pruritic, the overlying skin may appear thickened from rubbing or scratching, and excoriations may be present. 

Since vulvar syringomas are rare, there is no standard treatment. Biopsy is necessary for definitive diagnosis. For asymptomatic cases, expectant management is warranted. In symptomatic cases treatment can be considered. Treatment options include cryotherapy, laser ablation, and intralesional electrodissection.⁸ Intralesional electrodissection and curettage also has been described as treatment.⁹ Other treatment options include surgical excision of individual lesions or larger excisions if multifocal. 

The case study described in "Case letter: Vulvar syringoma" highlights the diagnostic and therapeutic challenges associated with rare lesions of the vulva. Referral to a specialty clinic may be warranted in these challenging cases. ●

Pain and pruritus are the most common complaints in patients who present to vulvar clinics.¹ These symptoms can be related to a variety of conditions, including vulvar lesions. There are both common and uncommon vulvar lesions. Vulvar lesions can be skin colored, yellow, and red. Certain lesions can be diagnosed with history and physical examination alone. Some more common lesions include acrochordons (skin tags), benign growths that are common in patients with diabetes, obesity, and pregnancy.^2,3 Other common vulvar lesions are papillomatosis, lichen simplex chronicus, and epidermoid cysts. Other lesions include low- and high-grade squamous intraepithelial lesions (HSIL).⁴ These lesions require biopsy for diagnosis as high-grade lesions require treatment. HSIL of the vulva is considered a premalignancy that necessitates treatment.⁵ Other lesions that can present with vulvar complaints are molluscum contagiosum, Bartholin gland duct cyst, intradermal melanocytic nevus, and squamous cell carcinoma. 

Rarely, other less common conditions can present as vulvar lesions. Syringomas are benign eccrine sweat gland neoplasms. They are more commonly found on the face, neck, or chest.⁶ On the vulva they are generally small subcutaneous skin-colored papules.⁷ They may be asymptomatic and noted only on routine examination. 

Vulvar syringomas also may present with symptoms. On the vulva, syringomas often present as pruritic papules that can be isolated or multifocal. Often on the labia majora they range in size from 2 to 20 mm.⁸

They can coalesce to form a larger lesion. They also may be described as painful. When  syringomas are pruritic, the overlying skin may appear thickened from rubbing or scratching, and excoriations may be present. 

Since vulvar syringomas are rare, there is no standard treatment. Biopsy is necessary for definitive diagnosis. For asymptomatic cases, expectant management is warranted. In symptomatic cases treatment can be considered. Treatment options include cryotherapy, laser ablation, and intralesional electrodissection.⁸ Intralesional electrodissection and curettage also has been described as treatment.⁹ Other treatment options include surgical excision of individual lesions or larger excisions if multifocal. 

The case study described in "Case letter: Vulvar syringoma" highlights the diagnostic and therapeutic challenges associated with rare lesions of the vulva. Referral to a specialty clinic may be warranted in these challenging cases. ●