Clinical Review

Multiple sclerosis (MS) is a complex, chronic immune-mediated disease of the central nervous system characterized by focal inflammation, demyelination, and neurodegeneration. Magnetic resonance imaging (MRI), first incorporated into the McDonald Criteria for the diagnosis of MS in 2001, is an integral tool in the diagnosis, prognosis, and therapeutic monitoring of people with MS (PwMS).¹

MRI research in MS is rapidly expanding and offers insights into the pathophysiology of MS with important implications for the routine clinical care of PwMS. At the Consortium of Multiple Sclerosis Centers 2024 Annual Meeting, the US Department of Veterans Affairs (VA) MS Centers of Excellence hosted an educational symposium highlighting MRI biomarkers in MS, including T2-lesions, chronic black holes (cBHs), brain atrophy, paramagnetic rim lesions (PRLs), and the central vein sign (CVS). The symposium also provided a brief overview of quantitative MRI techniques used to characterize MS lesion severity and research applications of these techniques. This clinical review summarizes the main points of that symposium with the goal of introducing key concepts to federal health care practitioners caring for PwMS.

MRI Biomarkers in MS

T2-lesions, Chronic Black Holes, and Brain Atrophy

Focal immune-mediated inflammation and demyelination in MS may be detected by MRI as hyperintense foci on T2-weighted (T2-w) imaging (eg, T2-w turbo spin echo or T2-w fluid attenuated inversion recovery sequences). These T2-lesions, critical for diagnosing MS, are typically ovoid and occur in the periventricular, juxtacortical, infratentorial spinal cord white matter (Figure 1A). T2-lesion number and volume show some association with disability and optic nerve.

Wattjes et al highlight 2 cases to demonstrate this point: a man aged 52 years with MS for 23 years and a woman aged 50 years with MS for 11 years. Despite having MS for a much shorter duration, the woman had worse disability due to a higher lesion number and volume.² T2-lesion volume also impacts disability progression in PwMS. Gauthier et al compared the probability of progression in 3 women, all of whom were aged 39 years and had MS for 6 years. The profile with highest probability of disability progression had the highest quartile of T2-lesion volume.³ T2-lesion volume over 2 years correlates with worse scores on disability metrics such as the MS functional composite, paced auditory serial addition task, and brain volume.⁴ A 2024 systematic review and meta-analysis demonstrated that T2-lesion volume is significantly correlated with clinical disability in PwMS.⁵

 

Select T2-lesions are also hypointense on T1-w spin echo images and are known as cBHs (Figure 1B). Histologically, T2-lesions with cBHs have more severe architectural disruption than those without cBHs.⁶ cBH number and volume are significantly correlated with disability, regardless of the degree of hypointensity on T1-w imaging.^5,7 A 10-year longitudinal study demonstrated that cBHs were associated with disease progression after 5 years while T2-lesion volume was not, indicating that cBHs may be a more accurate predictor of disability.⁸

Brain atrophy, another imaging biomarker of MS, affects both the cerebral white and gray matter. White matter fraction (the volume of white matter relative to the intracranial compartment volume) and gray matter fraction (the volume of gray matter relative to the intracranial compartment) are significantly lower among PwMS compared with healthy controls. In addition, gray matter fraction is lower among patients with primary and secondary progressive MS compared with those with relapsing-remitting MS, clinically isolated syndrome (CIS), and radiologically isolated syndrome (RIS). Gray matter fraction is also correlated with several motor and cognitive disability indices.⁹

Paramagnetic Rim Lesions

Neurologic worsening in PwMS occurs by 2 distinct mechanisms: relapse-associated worsening, a stepwise worsening of symptoms due to incomplete recovery following a relapse; and progression independent of relapse activity (PIRA), which is an irreversible neurologic deterioration in the absence of clinical or radiological relapses.¹⁰ PIRA is associated with neurodegeneration and predominates in both primary and secondary progressive MS. However, recent data demonstrated that PIRA may contribute to as much as 50% of disability worsening in relapsing MS and occurs early in the RMS disease course.^10,11 Current high-efficacy disease modifying therapy, such as ocrelizumab, are extraordinarily successful at preventing focal inflammation and relapses but are less effective for preventing the slow march of disability progression characterizing PIRA.^12,13 The prevention of PIRA is therefore an unmet treatment need.

Chronic active lesions (CALs) are an important driver of PIRA. When an acute gadolinium-enhancing lesion develops in PwMS, there are 3 possible fates of this lesion. The lesion may become chronically inactive, remyelinate, or transition to CALs.¹⁴ The histopathologic signature of CALs is compartmentalized, low-grade inflammation behind an intact blood-brain barrier with evidence of both active and chronic components.¹⁵ CALs may be found not only in cerebral white matter but also in the cerebral cortex and spinal cord.^16,17 Combined MRI and histopathological studies have shown that iron-laden microglia/macrophages can be detected by susceptibility-based MRI as a rim of paramagnetic signal surrounding select T2-lesions.¹⁹ These PRLs represent an in vivo imaging biomarker of CAL (Figure 1C). According to the North American Imaging in MS Cooperative (NAIMS) consensus criteria, a PRL must surround at least two-thirds of the outer edge of a T2-lesion, be visible in ≥ 2 consecutive MRI slices, and cannot be contrast enhancing.²⁰

PRLs can be visualized on multiple susceptibility-based imaging methods, including multiecho derived R2*/T2*, phase maps, susceptibility-weighted imaging, and quantitative susceptibility mapping.^21-23 Retrospective analyses have shown no significant differences in sensitivity across these imaging modalities.²⁴ Although first visualized with 7T MRI, PRLs may also be detected by 1.5T and 3T MRI with comparable sensitivities.^25-27 However, there remains a significant knowledge gap regarding the accuracy of each imaging modality. Systematic, prospectively designed studies are needed to ascertain the comparative value of each method.

The presence of PRL is a poor prognostic indicator. PwMS without PRLs have higher levels of disability, are more likely to progress, and demonstrate greater gray matter atrophy and cognitive dysfunction when compared with PwMS with PRLs.^27-29 Lesions with PRL tend to slowly expand, exhibit greater demyelination, and have diminished white matter integrity.^21,22,30

PRLs may also be used as a diagnostic tool. PRLs are highly specific for MS/CIS with a 99.7% specificity and 98.4% positive predictive value, although the sensitivity is limited to 24%.³¹ Taken together, these data indicate that the presence of a PRL substantially increases the likelihood of an MS/CIS diagnosis, whereas the absence of a PRL does not exclude these diagnoses. 

Several unanswered questions remain: Why do select acute MS lesions transition to CALs? How may investigators utilize PRLs as outcome measures in future clinical trials? How should PRLs be incorporated into the routine care of PwMS? As the role of this imaging biomarker is clarified both in the research and clinical settings, clinicians caring for PwMS can expect to increasingly encounter the topic of PRLs in the near future.

Central Vein Sign

A CVS is defined by the presence of a central vessel within a demyelinating plaque (Figure 1D). As early as the 1820s, MS plaques on gross pathology were noted to follow the course of a vessel. Early histological studies reported that up to 91% of MS plaques had a central vessel present.³² Lesion formation is dependent on the movement of lymphocytes and other inflammatory cells from the systemic circulation across the blood brain barrier into the perivascular space, a privileged site where immune cells interact with antigen presenting cells to launch an inflammatory cascade and eventual demyelinating lesion.³³

CVS can be visualized on 1.5T, 3T and 7T MRI. However, 7T MRI is superior to 3T in the detection of CVS, with 85% of MS lesions having CVS visible compared with 45% on 3T.³⁴ With advances in 7T MRI, fluid attenuated inversion recovery and T2* susceptibility, weighted sequences can be overlaid, allowing simultaneous visualization of the vessel and the demyelinating lesion. With higher density of parenchymal veins in the periventricular regions, the CVS is most seen in lesions of this territory but can also be present in juxtacortical, thalamic and infratentorial lesions with decreasing prevalence as these approach the cortex.³⁵

MS lesions are more likely to have CVS than T2 hyperintense white matter lesions of other causes, with a large study reporting 78% of MS lesions were CVS positive. Further, CVS positive lesions can be found across all MS phenotypes including relapsing remitting, primary progressive, and secondary progressive.³⁵ The CVS is also specific to MS lesions and is an effective tool for differentiating MS lesions from other common causes of T2 hyperintense lesions including chronic ischemic white matter disease,³⁶ migraines,³⁷ neuromyelitis optica spectrum disorders,^38,39 Susac syndrome,⁴⁰ and systemic autoimmune diseases (Behcet disease, systemic lupus erythematosus, and antiphospholipid syndrome).⁴¹

With CVS emerging as a promising radiographic biomarker for MS, NAIMS issued a consensus statement on necessary properties of a CVS. These criteria included appearance of a thin hypointense line or small dot, visualized in ≥ 2 perpendicular planes, with diameter < 2 mm, and running partially or entirely through the center of the lesion. They also clarified that lesions < 3 mm, confluent lesions, lesions with multiple vessels present or poorly visualized lesions were excluded.⁴²

A shared CVS definition was a necessary step toward routine use of CVS as a radiographic biomarker and its incorporation in the 2024 revised McDonald criteria.⁴³ Remaining limitations including 7T MRI is primarily available in research settings and the lack of consensus on a diagnostic threshold. There have been many proposed methods, including a 40% cut off,⁴⁴ 60% cut off,⁴⁵ and Select 3* or Select 6* methods.⁴⁶ The goal of each method is to optimize sensitivity and specificity while not compromising efficiency of MRI review for both neurologists and radiologists.

The CVS has significant potential as a radiographic biomarker for MS and may allow the early stages of MS to be differentiated from other common causes of white matter lesions on MRI. However, it remains unclear whether CVS holds prognostic value for patients, if CVS is suggestive of differing underlying pathology, or if the presence of a CVS is dynamic over time. Progress in these areas is anticipated as CVS is incorporated into routine clinical practice.

Quantitative MRI Techniques

In the research setting, several imaging modalities can be used to quantify the degree of microstructural injury in PwMS. The goal of these methods is to identify and quantify myelin and axonal damage, the major drivers of neurodegeneration. Among these methods, diffusion-based imaging is a measure of the amount of diffusion or fluid mobility across the tissues of the brain.⁴⁷ Diffusion-weighted imaging (DWI) yields several parametric maps including axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (Figure 2 A, B, and C). These parametric maps provide information on different directions of water molecules’ movements. Myelin surrounds the axons preventing water molecules diffusion perpendicular to axons (RD) while axonal content prevents water diffusion horizontal to the axons (AD).Thus, AD is considered more specific to axonal injury, whereas RD is specific to myelin content.⁴⁸ A higher value of any of these metrics is associated with a higher degree of tissue injury.

Although sensitive to axonal and myelin injury, AD and RD computed from single b-shell DWI experience several limitations including being affected by nonpathologic factors such as fiber orientation, distribution, and crossing, and by various nonmyelin specific pathologies including fluid accumulation during inflammation, myelin sheath thickness, and axonal intactness.⁴⁸ Several multi b-shell methods have been developed to overcome diffusion imaging limitations. For example, work at the Nashville VA MS Center of Excellence has focused on the use of the multicompartment diffusion MRI with spherical mean technique (SMT). This method removes the orientation dependency of the diffusion MRI signal, increasing the signal-to-noise ratio and reducing biases from fiber undulation, crossing, and dispersion.⁴⁹ SMT generates the apparent axonal volume fraction (V_ax), which is a direct measure of axonal integrity with lower values indicating lower axonal content and higher tissue destruction (Figure 2D). V_ax was previously validated in MS as a measure of axonal integrity.⁴⁹

In terms of myelin, several other specific measures have been developed. Magnetization transfer ratio (MTR) is another measure of tissue integrity that has been validated as a measure of tissue injury in MS (Figure 2E).^50,51 Zheng et al found that the percentage of lesions with low MTR was significantly higher among patients whose disease disability progressed compared with patients who did not.⁵²Selective inversion recovery with quantitative magnetization transfer (SIR-qMT) was developed to account for the limitations of MTR, including its sensitivity to edema and axonal density.⁵² Germane to myelin measurements, SIR-qMT generates the macromolecular to free size ratio (PSR). PSR represents the ratio of protons bound to macromolecules (myelin) to free protons (Figure 2F). PSR is considered a marker of myelin integrity, with lower values correlating with disability severity and indicating higher tissue damage and lower myelin content. Previous studies from the Nashville VA MS Center of Excellence validated the use of SIR-qMT among patients with MS, CIS, RIS, and healthy controls.⁵³

Quantitative MRI has several research applications in the field of MS. We demonstrated that PRL harbor a higher degree of myelin injury indicated by PSR compared with rimless lesions.⁵⁴ These MRI techniques are also helpful to investigate tissues surrounding the lesions, called normal appearing white matter (NAWM). Using quantitative MRI techniques such as MTR,⁵² PSR,⁵³ and V_ax,⁴⁹ investigators have demonstrated that NAWM is injured in PwMS, and proximal NAWM may have higher degree of tissue damage compared with distant NAWM.⁵⁵

Anticipated Innovations and Challenges

In the field of quantitative MRI, several new techniques are being adopted. Researchers are developing techniques such as myelin water fraction which evaluates the interaction between water and protons to measure myelin content. This is considered an advancement as it takes into account edema resulting from MS injury.⁵⁶ Another example is multicompartment diffusion imaging, such as standard model imaging,⁵⁷ and neurite orientation dispersion and density imaging,⁵⁸ which considers water as an additional compartment compared with the SMT derived V_ax. For PRL identification, more advanced methodologic techniques are developing such quantitative susceptibility mapping (QSM), which can detect iron deposits that surround the lesions with relatively high sensitivity and specificity of identifying PRL.⁵⁹

Despite these innovations, several challenges remain before possible incorporation into the clinical setting. These limitations include longer scan time, familiarity of clinicians in using these maps, higher financial cost, and the necessity of advanced imaging processing skills. Artificial intelligence is a promising tool that may overcome these challenges through creating automated processing pipelines and developing synthetic maps without the need for additional acquisition.⁶⁰

Conclusions

MRI is the most important tool for diagnosing and treating PwMS. Imaging biomarkers such as T2-lesions, cBHs, brain atrophy, PRLs, and CVS provide insight into the disease’s pathogenesis and are invaluable for the accurate diagnosis and prognostication of MS. Quantitative MRI techniques, while not available in the clinical setting, are important tools for translational research that may help direct the development of future therapeutics. In the near future, clinicians caring for PwMS should expect to encounter these imaging biomarkers more frequently in the clinical setting, especially with the inclusion of PRLs and CVS in the next iteration of the McDonald diagnostic criteria.

Multiple sclerosis (MS) is a complex, chronic immune-mediated disease of the central nervous system characterized by focal inflammation, demyelination, and neurodegeneration. Magnetic resonance imaging (MRI), first incorporated into the McDonald Criteria for the diagnosis of MS in 2001, is an integral tool in the diagnosis, prognosis, and therapeutic monitoring of people with MS (PwMS).¹

MRI research in MS is rapidly expanding and offers insights into the pathophysiology of MS with important implications for the routine clinical care of PwMS. At the Consortium of Multiple Sclerosis Centers 2024 Annual Meeting, the US Department of Veterans Affairs (VA) MS Centers of Excellence hosted an educational symposium highlighting MRI biomarkers in MS, including T2-lesions, chronic black holes (cBHs), brain atrophy, paramagnetic rim lesions (PRLs), and the central vein sign (CVS). The symposium also provided a brief overview of quantitative MRI techniques used to characterize MS lesion severity and research applications of these techniques. This clinical review summarizes the main points of that symposium with the goal of introducing key concepts to federal health care practitioners caring for PwMS.

MRI Biomarkers in MS

T2-lesions, Chronic Black Holes, and Brain Atrophy

Focal immune-mediated inflammation and demyelination in MS may be detected by MRI as hyperintense foci on T2-weighted (T2-w) imaging (eg, T2-w turbo spin echo or T2-w fluid attenuated inversion recovery sequences). These T2-lesions, critical for diagnosing MS, are typically ovoid and occur in the periventricular, juxtacortical, infratentorial spinal cord white matter (Figure 1A). T2-lesion number and volume show some association with disability and optic nerve.

Wattjes et al highlight 2 cases to demonstrate this point: a man aged 52 years with MS for 23 years and a woman aged 50 years with MS for 11 years. Despite having MS for a much shorter duration, the woman had worse disability due to a higher lesion number and volume.² T2-lesion volume also impacts disability progression in PwMS. Gauthier et al compared the probability of progression in 3 women, all of whom were aged 39 years and had MS for 6 years. The profile with highest probability of disability progression had the highest quartile of T2-lesion volume.³ T2-lesion volume over 2 years correlates with worse scores on disability metrics such as the MS functional composite, paced auditory serial addition task, and brain volume.⁴ A 2024 systematic review and meta-analysis demonstrated that T2-lesion volume is significantly correlated with clinical disability in PwMS.⁵

 

Select T2-lesions are also hypointense on T1-w spin echo images and are known as cBHs (Figure 1B). Histologically, T2-lesions with cBHs have more severe architectural disruption than those without cBHs.⁶ cBH number and volume are significantly correlated with disability, regardless of the degree of hypointensity on T1-w imaging.^5,7 A 10-year longitudinal study demonstrated that cBHs were associated with disease progression after 5 years while T2-lesion volume was not, indicating that cBHs may be a more accurate predictor of disability.⁸

Brain atrophy, another imaging biomarker of MS, affects both the cerebral white and gray matter. White matter fraction (the volume of white matter relative to the intracranial compartment volume) and gray matter fraction (the volume of gray matter relative to the intracranial compartment) are significantly lower among PwMS compared with healthy controls. In addition, gray matter fraction is lower among patients with primary and secondary progressive MS compared with those with relapsing-remitting MS, clinically isolated syndrome (CIS), and radiologically isolated syndrome (RIS). Gray matter fraction is also correlated with several motor and cognitive disability indices.⁹

Paramagnetic Rim Lesions

Neurologic worsening in PwMS occurs by 2 distinct mechanisms: relapse-associated worsening, a stepwise worsening of symptoms due to incomplete recovery following a relapse; and progression independent of relapse activity (PIRA), which is an irreversible neurologic deterioration in the absence of clinical or radiological relapses.¹⁰ PIRA is associated with neurodegeneration and predominates in both primary and secondary progressive MS. However, recent data demonstrated that PIRA may contribute to as much as 50% of disability worsening in relapsing MS and occurs early in the RMS disease course.^10,11 Current high-efficacy disease modifying therapy, such as ocrelizumab, are extraordinarily successful at preventing focal inflammation and relapses but are less effective for preventing the slow march of disability progression characterizing PIRA.^12,13 The prevention of PIRA is therefore an unmet treatment need.

Chronic active lesions (CALs) are an important driver of PIRA. When an acute gadolinium-enhancing lesion develops in PwMS, there are 3 possible fates of this lesion. The lesion may become chronically inactive, remyelinate, or transition to CALs.¹⁴ The histopathologic signature of CALs is compartmentalized, low-grade inflammation behind an intact blood-brain barrier with evidence of both active and chronic components.¹⁵ CALs may be found not only in cerebral white matter but also in the cerebral cortex and spinal cord.^16,17 Combined MRI and histopathological studies have shown that iron-laden microglia/macrophages can be detected by susceptibility-based MRI as a rim of paramagnetic signal surrounding select T2-lesions.¹⁹ These PRLs represent an in vivo imaging biomarker of CAL (Figure 1C). According to the North American Imaging in MS Cooperative (NAIMS) consensus criteria, a PRL must surround at least two-thirds of the outer edge of a T2-lesion, be visible in ≥ 2 consecutive MRI slices, and cannot be contrast enhancing.²⁰

PRLs can be visualized on multiple susceptibility-based imaging methods, including multiecho derived R2*/T2*, phase maps, susceptibility-weighted imaging, and quantitative susceptibility mapping.^21-23 Retrospective analyses have shown no significant differences in sensitivity across these imaging modalities.²⁴ Although first visualized with 7T MRI, PRLs may also be detected by 1.5T and 3T MRI with comparable sensitivities.^25-27 However, there remains a significant knowledge gap regarding the accuracy of each imaging modality. Systematic, prospectively designed studies are needed to ascertain the comparative value of each method.

The presence of PRL is a poor prognostic indicator. PwMS without PRLs have higher levels of disability, are more likely to progress, and demonstrate greater gray matter atrophy and cognitive dysfunction when compared with PwMS with PRLs.^27-29 Lesions with PRL tend to slowly expand, exhibit greater demyelination, and have diminished white matter integrity.^21,22,30

PRLs may also be used as a diagnostic tool. PRLs are highly specific for MS/CIS with a 99.7% specificity and 98.4% positive predictive value, although the sensitivity is limited to 24%.³¹ Taken together, these data indicate that the presence of a PRL substantially increases the likelihood of an MS/CIS diagnosis, whereas the absence of a PRL does not exclude these diagnoses. 

Several unanswered questions remain: Why do select acute MS lesions transition to CALs? How may investigators utilize PRLs as outcome measures in future clinical trials? How should PRLs be incorporated into the routine care of PwMS? As the role of this imaging biomarker is clarified both in the research and clinical settings, clinicians caring for PwMS can expect to increasingly encounter the topic of PRLs in the near future.

Central Vein Sign

A CVS is defined by the presence of a central vessel within a demyelinating plaque (Figure 1D). As early as the 1820s, MS plaques on gross pathology were noted to follow the course of a vessel. Early histological studies reported that up to 91% of MS plaques had a central vessel present.³² Lesion formation is dependent on the movement of lymphocytes and other inflammatory cells from the systemic circulation across the blood brain barrier into the perivascular space, a privileged site where immune cells interact with antigen presenting cells to launch an inflammatory cascade and eventual demyelinating lesion.³³

CVS can be visualized on 1.5T, 3T and 7T MRI. However, 7T MRI is superior to 3T in the detection of CVS, with 85% of MS lesions having CVS visible compared with 45% on 3T.³⁴ With advances in 7T MRI, fluid attenuated inversion recovery and T2* susceptibility, weighted sequences can be overlaid, allowing simultaneous visualization of the vessel and the demyelinating lesion. With higher density of parenchymal veins in the periventricular regions, the CVS is most seen in lesions of this territory but can also be present in juxtacortical, thalamic and infratentorial lesions with decreasing prevalence as these approach the cortex.³⁵

MS lesions are more likely to have CVS than T2 hyperintense white matter lesions of other causes, with a large study reporting 78% of MS lesions were CVS positive. Further, CVS positive lesions can be found across all MS phenotypes including relapsing remitting, primary progressive, and secondary progressive.³⁵ The CVS is also specific to MS lesions and is an effective tool for differentiating MS lesions from other common causes of T2 hyperintense lesions including chronic ischemic white matter disease,³⁶ migraines,³⁷ neuromyelitis optica spectrum disorders,^38,39 Susac syndrome,⁴⁰ and systemic autoimmune diseases (Behcet disease, systemic lupus erythematosus, and antiphospholipid syndrome).⁴¹

With CVS emerging as a promising radiographic biomarker for MS, NAIMS issued a consensus statement on necessary properties of a CVS. These criteria included appearance of a thin hypointense line or small dot, visualized in ≥ 2 perpendicular planes, with diameter < 2 mm, and running partially or entirely through the center of the lesion. They also clarified that lesions < 3 mm, confluent lesions, lesions with multiple vessels present or poorly visualized lesions were excluded.⁴²

A shared CVS definition was a necessary step toward routine use of CVS as a radiographic biomarker and its incorporation in the 2024 revised McDonald criteria.⁴³ Remaining limitations including 7T MRI is primarily available in research settings and the lack of consensus on a diagnostic threshold. There have been many proposed methods, including a 40% cut off,⁴⁴ 60% cut off,⁴⁵ and Select 3* or Select 6* methods.⁴⁶ The goal of each method is to optimize sensitivity and specificity while not compromising efficiency of MRI review for both neurologists and radiologists.

The CVS has significant potential as a radiographic biomarker for MS and may allow the early stages of MS to be differentiated from other common causes of white matter lesions on MRI. However, it remains unclear whether CVS holds prognostic value for patients, if CVS is suggestive of differing underlying pathology, or if the presence of a CVS is dynamic over time. Progress in these areas is anticipated as CVS is incorporated into routine clinical practice.

Quantitative MRI Techniques

In the research setting, several imaging modalities can be used to quantify the degree of microstructural injury in PwMS. The goal of these methods is to identify and quantify myelin and axonal damage, the major drivers of neurodegeneration. Among these methods, diffusion-based imaging is a measure of the amount of diffusion or fluid mobility across the tissues of the brain.⁴⁷ Diffusion-weighted imaging (DWI) yields several parametric maps including axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (Figure 2 A, B, and C). These parametric maps provide information on different directions of water molecules’ movements. Myelin surrounds the axons preventing water molecules diffusion perpendicular to axons (RD) while axonal content prevents water diffusion horizontal to the axons (AD).Thus, AD is considered more specific to axonal injury, whereas RD is specific to myelin content.⁴⁸ A higher value of any of these metrics is associated with a higher degree of tissue injury.

Although sensitive to axonal and myelin injury, AD and RD computed from single b-shell DWI experience several limitations including being affected by nonpathologic factors such as fiber orientation, distribution, and crossing, and by various nonmyelin specific pathologies including fluid accumulation during inflammation, myelin sheath thickness, and axonal intactness.⁴⁸ Several multi b-shell methods have been developed to overcome diffusion imaging limitations. For example, work at the Nashville VA MS Center of Excellence has focused on the use of the multicompartment diffusion MRI with spherical mean technique (SMT). This method removes the orientation dependency of the diffusion MRI signal, increasing the signal-to-noise ratio and reducing biases from fiber undulation, crossing, and dispersion.⁴⁹ SMT generates the apparent axonal volume fraction (V_ax), which is a direct measure of axonal integrity with lower values indicating lower axonal content and higher tissue destruction (Figure 2D). V_ax was previously validated in MS as a measure of axonal integrity.⁴⁹

In terms of myelin, several other specific measures have been developed. Magnetization transfer ratio (MTR) is another measure of tissue integrity that has been validated as a measure of tissue injury in MS (Figure 2E).^50,51 Zheng et al found that the percentage of lesions with low MTR was significantly higher among patients whose disease disability progressed compared with patients who did not.⁵²Selective inversion recovery with quantitative magnetization transfer (SIR-qMT) was developed to account for the limitations of MTR, including its sensitivity to edema and axonal density.⁵² Germane to myelin measurements, SIR-qMT generates the macromolecular to free size ratio (PSR). PSR represents the ratio of protons bound to macromolecules (myelin) to free protons (Figure 2F). PSR is considered a marker of myelin integrity, with lower values correlating with disability severity and indicating higher tissue damage and lower myelin content. Previous studies from the Nashville VA MS Center of Excellence validated the use of SIR-qMT among patients with MS, CIS, RIS, and healthy controls.⁵³

Quantitative MRI has several research applications in the field of MS. We demonstrated that PRL harbor a higher degree of myelin injury indicated by PSR compared with rimless lesions.⁵⁴ These MRI techniques are also helpful to investigate tissues surrounding the lesions, called normal appearing white matter (NAWM). Using quantitative MRI techniques such as MTR,⁵² PSR,⁵³ and V_ax,⁴⁹ investigators have demonstrated that NAWM is injured in PwMS, and proximal NAWM may have higher degree of tissue damage compared with distant NAWM.⁵⁵

Anticipated Innovations and Challenges

In the field of quantitative MRI, several new techniques are being adopted. Researchers are developing techniques such as myelin water fraction which evaluates the interaction between water and protons to measure myelin content. This is considered an advancement as it takes into account edema resulting from MS injury.⁵⁶ Another example is multicompartment diffusion imaging, such as standard model imaging,⁵⁷ and neurite orientation dispersion and density imaging,⁵⁸ which considers water as an additional compartment compared with the SMT derived V_ax. For PRL identification, more advanced methodologic techniques are developing such quantitative susceptibility mapping (QSM), which can detect iron deposits that surround the lesions with relatively high sensitivity and specificity of identifying PRL.⁵⁹

Despite these innovations, several challenges remain before possible incorporation into the clinical setting. These limitations include longer scan time, familiarity of clinicians in using these maps, higher financial cost, and the necessity of advanced imaging processing skills. Artificial intelligence is a promising tool that may overcome these challenges through creating automated processing pipelines and developing synthetic maps without the need for additional acquisition.⁶⁰

Conclusions

MRI is the most important tool for diagnosing and treating PwMS. Imaging biomarkers such as T2-lesions, cBHs, brain atrophy, PRLs, and CVS provide insight into the disease’s pathogenesis and are invaluable for the accurate diagnosis and prognostication of MS. Quantitative MRI techniques, while not available in the clinical setting, are important tools for translational research that may help direct the development of future therapeutics. In the near future, clinicians caring for PwMS should expect to encounter these imaging biomarkers more frequently in the clinical setting, especially with the inclusion of PRLs and CVS in the next iteration of the McDonald diagnostic criteria.

Multiple sclerosis (MS) is a complex, chronic immune-mediated disease of the central nervous system characterized by focal inflammation, demyelination, and neurodegeneration. Magnetic resonance imaging (MRI), first incorporated into the McDonald Criteria for the diagnosis of MS in 2001, is an integral tool in the diagnosis, prognosis, and therapeutic monitoring of people with MS (PwMS).¹

MRI research in MS is rapidly expanding and offers insights into the pathophysiology of MS with important implications for the routine clinical care of PwMS. At the Consortium of Multiple Sclerosis Centers 2024 Annual Meeting, the US Department of Veterans Affairs (VA) MS Centers of Excellence hosted an educational symposium highlighting MRI biomarkers in MS, including T2-lesions, chronic black holes (cBHs), brain atrophy, paramagnetic rim lesions (PRLs), and the central vein sign (CVS). The symposium also provided a brief overview of quantitative MRI techniques used to characterize MS lesion severity and research applications of these techniques. This clinical review summarizes the main points of that symposium with the goal of introducing key concepts to federal health care practitioners caring for PwMS.

MRI Biomarkers in MS

T2-lesions, Chronic Black Holes, and Brain Atrophy

Focal immune-mediated inflammation and demyelination in MS may be detected by MRI as hyperintense foci on T2-weighted (T2-w) imaging (eg, T2-w turbo spin echo or T2-w fluid attenuated inversion recovery sequences). These T2-lesions, critical for diagnosing MS, are typically ovoid and occur in the periventricular, juxtacortical, infratentorial spinal cord white matter (Figure 1A). T2-lesion number and volume show some association with disability and optic nerve.

Wattjes et al highlight 2 cases to demonstrate this point: a man aged 52 years with MS for 23 years and a woman aged 50 years with MS for 11 years. Despite having MS for a much shorter duration, the woman had worse disability due to a higher lesion number and volume.² T2-lesion volume also impacts disability progression in PwMS. Gauthier et al compared the probability of progression in 3 women, all of whom were aged 39 years and had MS for 6 years. The profile with highest probability of disability progression had the highest quartile of T2-lesion volume.³ T2-lesion volume over 2 years correlates with worse scores on disability metrics such as the MS functional composite, paced auditory serial addition task, and brain volume.⁴ A 2024 systematic review and meta-analysis demonstrated that T2-lesion volume is significantly correlated with clinical disability in PwMS.⁵

 

Select T2-lesions are also hypointense on T1-w spin echo images and are known as cBHs (Figure 1B). Histologically, T2-lesions with cBHs have more severe architectural disruption than those without cBHs.⁶ cBH number and volume are significantly correlated with disability, regardless of the degree of hypointensity on T1-w imaging.^5,7 A 10-year longitudinal study demonstrated that cBHs were associated with disease progression after 5 years while T2-lesion volume was not, indicating that cBHs may be a more accurate predictor of disability.⁸

Brain atrophy, another imaging biomarker of MS, affects both the cerebral white and gray matter. White matter fraction (the volume of white matter relative to the intracranial compartment volume) and gray matter fraction (the volume of gray matter relative to the intracranial compartment) are significantly lower among PwMS compared with healthy controls. In addition, gray matter fraction is lower among patients with primary and secondary progressive MS compared with those with relapsing-remitting MS, clinically isolated syndrome (CIS), and radiologically isolated syndrome (RIS). Gray matter fraction is also correlated with several motor and cognitive disability indices.⁹

Paramagnetic Rim Lesions

Neurologic worsening in PwMS occurs by 2 distinct mechanisms: relapse-associated worsening, a stepwise worsening of symptoms due to incomplete recovery following a relapse; and progression independent of relapse activity (PIRA), which is an irreversible neurologic deterioration in the absence of clinical or radiological relapses.¹⁰ PIRA is associated with neurodegeneration and predominates in both primary and secondary progressive MS. However, recent data demonstrated that PIRA may contribute to as much as 50% of disability worsening in relapsing MS and occurs early in the RMS disease course.^10,11 Current high-efficacy disease modifying therapy, such as ocrelizumab, are extraordinarily successful at preventing focal inflammation and relapses but are less effective for preventing the slow march of disability progression characterizing PIRA.^12,13 The prevention of PIRA is therefore an unmet treatment need.

Chronic active lesions (CALs) are an important driver of PIRA. When an acute gadolinium-enhancing lesion develops in PwMS, there are 3 possible fates of this lesion. The lesion may become chronically inactive, remyelinate, or transition to CALs.¹⁴ The histopathologic signature of CALs is compartmentalized, low-grade inflammation behind an intact blood-brain barrier with evidence of both active and chronic components.¹⁵ CALs may be found not only in cerebral white matter but also in the cerebral cortex and spinal cord.^16,17 Combined MRI and histopathological studies have shown that iron-laden microglia/macrophages can be detected by susceptibility-based MRI as a rim of paramagnetic signal surrounding select T2-lesions.¹⁹ These PRLs represent an in vivo imaging biomarker of CAL (Figure 1C). According to the North American Imaging in MS Cooperative (NAIMS) consensus criteria, a PRL must surround at least two-thirds of the outer edge of a T2-lesion, be visible in ≥ 2 consecutive MRI slices, and cannot be contrast enhancing.²⁰

PRLs can be visualized on multiple susceptibility-based imaging methods, including multiecho derived R2*/T2*, phase maps, susceptibility-weighted imaging, and quantitative susceptibility mapping.^21-23 Retrospective analyses have shown no significant differences in sensitivity across these imaging modalities.²⁴ Although first visualized with 7T MRI, PRLs may also be detected by 1.5T and 3T MRI with comparable sensitivities.^25-27 However, there remains a significant knowledge gap regarding the accuracy of each imaging modality. Systematic, prospectively designed studies are needed to ascertain the comparative value of each method.

The presence of PRL is a poor prognostic indicator. PwMS without PRLs have higher levels of disability, are more likely to progress, and demonstrate greater gray matter atrophy and cognitive dysfunction when compared with PwMS with PRLs.^27-29 Lesions with PRL tend to slowly expand, exhibit greater demyelination, and have diminished white matter integrity.^21,22,30

PRLs may also be used as a diagnostic tool. PRLs are highly specific for MS/CIS with a 99.7% specificity and 98.4% positive predictive value, although the sensitivity is limited to 24%.³¹ Taken together, these data indicate that the presence of a PRL substantially increases the likelihood of an MS/CIS diagnosis, whereas the absence of a PRL does not exclude these diagnoses. 

Several unanswered questions remain: Why do select acute MS lesions transition to CALs? How may investigators utilize PRLs as outcome measures in future clinical trials? How should PRLs be incorporated into the routine care of PwMS? As the role of this imaging biomarker is clarified both in the research and clinical settings, clinicians caring for PwMS can expect to increasingly encounter the topic of PRLs in the near future.

Central Vein Sign

A CVS is defined by the presence of a central vessel within a demyelinating plaque (Figure 1D). As early as the 1820s, MS plaques on gross pathology were noted to follow the course of a vessel. Early histological studies reported that up to 91% of MS plaques had a central vessel present.³² Lesion formation is dependent on the movement of lymphocytes and other inflammatory cells from the systemic circulation across the blood brain barrier into the perivascular space, a privileged site where immune cells interact with antigen presenting cells to launch an inflammatory cascade and eventual demyelinating lesion.³³

CVS can be visualized on 1.5T, 3T and 7T MRI. However, 7T MRI is superior to 3T in the detection of CVS, with 85% of MS lesions having CVS visible compared with 45% on 3T.³⁴ With advances in 7T MRI, fluid attenuated inversion recovery and T2* susceptibility, weighted sequences can be overlaid, allowing simultaneous visualization of the vessel and the demyelinating lesion. With higher density of parenchymal veins in the periventricular regions, the CVS is most seen in lesions of this territory but can also be present in juxtacortical, thalamic and infratentorial lesions with decreasing prevalence as these approach the cortex.³⁵

MS lesions are more likely to have CVS than T2 hyperintense white matter lesions of other causes, with a large study reporting 78% of MS lesions were CVS positive. Further, CVS positive lesions can be found across all MS phenotypes including relapsing remitting, primary progressive, and secondary progressive.³⁵ The CVS is also specific to MS lesions and is an effective tool for differentiating MS lesions from other common causes of T2 hyperintense lesions including chronic ischemic white matter disease,³⁶ migraines,³⁷ neuromyelitis optica spectrum disorders,^38,39 Susac syndrome,⁴⁰ and systemic autoimmune diseases (Behcet disease, systemic lupus erythematosus, and antiphospholipid syndrome).⁴¹

With CVS emerging as a promising radiographic biomarker for MS, NAIMS issued a consensus statement on necessary properties of a CVS. These criteria included appearance of a thin hypointense line or small dot, visualized in ≥ 2 perpendicular planes, with diameter < 2 mm, and running partially or entirely through the center of the lesion. They also clarified that lesions < 3 mm, confluent lesions, lesions with multiple vessels present or poorly visualized lesions were excluded.⁴²

A shared CVS definition was a necessary step toward routine use of CVS as a radiographic biomarker and its incorporation in the 2024 revised McDonald criteria.⁴³ Remaining limitations including 7T MRI is primarily available in research settings and the lack of consensus on a diagnostic threshold. There have been many proposed methods, including a 40% cut off,⁴⁴ 60% cut off,⁴⁵ and Select 3* or Select 6* methods.⁴⁶ The goal of each method is to optimize sensitivity and specificity while not compromising efficiency of MRI review for both neurologists and radiologists.

The CVS has significant potential as a radiographic biomarker for MS and may allow the early stages of MS to be differentiated from other common causes of white matter lesions on MRI. However, it remains unclear whether CVS holds prognostic value for patients, if CVS is suggestive of differing underlying pathology, or if the presence of a CVS is dynamic over time. Progress in these areas is anticipated as CVS is incorporated into routine clinical practice.

Quantitative MRI Techniques

In the research setting, several imaging modalities can be used to quantify the degree of microstructural injury in PwMS. The goal of these methods is to identify and quantify myelin and axonal damage, the major drivers of neurodegeneration. Among these methods, diffusion-based imaging is a measure of the amount of diffusion or fluid mobility across the tissues of the brain.⁴⁷ Diffusion-weighted imaging (DWI) yields several parametric maps including axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (Figure 2 A, B, and C). These parametric maps provide information on different directions of water molecules’ movements. Myelin surrounds the axons preventing water molecules diffusion perpendicular to axons (RD) while axonal content prevents water diffusion horizontal to the axons (AD).Thus, AD is considered more specific to axonal injury, whereas RD is specific to myelin content.⁴⁸ A higher value of any of these metrics is associated with a higher degree of tissue injury.

Although sensitive to axonal and myelin injury, AD and RD computed from single b-shell DWI experience several limitations including being affected by nonpathologic factors such as fiber orientation, distribution, and crossing, and by various nonmyelin specific pathologies including fluid accumulation during inflammation, myelin sheath thickness, and axonal intactness.⁴⁸ Several multi b-shell methods have been developed to overcome diffusion imaging limitations. For example, work at the Nashville VA MS Center of Excellence has focused on the use of the multicompartment diffusion MRI with spherical mean technique (SMT). This method removes the orientation dependency of the diffusion MRI signal, increasing the signal-to-noise ratio and reducing biases from fiber undulation, crossing, and dispersion.⁴⁹ SMT generates the apparent axonal volume fraction (V_ax), which is a direct measure of axonal integrity with lower values indicating lower axonal content and higher tissue destruction (Figure 2D). V_ax was previously validated in MS as a measure of axonal integrity.⁴⁹

In terms of myelin, several other specific measures have been developed. Magnetization transfer ratio (MTR) is another measure of tissue integrity that has been validated as a measure of tissue injury in MS (Figure 2E).^50,51 Zheng et al found that the percentage of lesions with low MTR was significantly higher among patients whose disease disability progressed compared with patients who did not.⁵²Selective inversion recovery with quantitative magnetization transfer (SIR-qMT) was developed to account for the limitations of MTR, including its sensitivity to edema and axonal density.⁵² Germane to myelin measurements, SIR-qMT generates the macromolecular to free size ratio (PSR). PSR represents the ratio of protons bound to macromolecules (myelin) to free protons (Figure 2F). PSR is considered a marker of myelin integrity, with lower values correlating with disability severity and indicating higher tissue damage and lower myelin content. Previous studies from the Nashville VA MS Center of Excellence validated the use of SIR-qMT among patients with MS, CIS, RIS, and healthy controls.⁵³

Quantitative MRI has several research applications in the field of MS. We demonstrated that PRL harbor a higher degree of myelin injury indicated by PSR compared with rimless lesions.⁵⁴ These MRI techniques are also helpful to investigate tissues surrounding the lesions, called normal appearing white matter (NAWM). Using quantitative MRI techniques such as MTR,⁵² PSR,⁵³ and V_ax,⁴⁹ investigators have demonstrated that NAWM is injured in PwMS, and proximal NAWM may have higher degree of tissue damage compared with distant NAWM.⁵⁵

Anticipated Innovations and Challenges

In the field of quantitative MRI, several new techniques are being adopted. Researchers are developing techniques such as myelin water fraction which evaluates the interaction between water and protons to measure myelin content. This is considered an advancement as it takes into account edema resulting from MS injury.⁵⁶ Another example is multicompartment diffusion imaging, such as standard model imaging,⁵⁷ and neurite orientation dispersion and density imaging,⁵⁸ which considers water as an additional compartment compared with the SMT derived V_ax. For PRL identification, more advanced methodologic techniques are developing such quantitative susceptibility mapping (QSM), which can detect iron deposits that surround the lesions with relatively high sensitivity and specificity of identifying PRL.⁵⁹

Despite these innovations, several challenges remain before possible incorporation into the clinical setting. These limitations include longer scan time, familiarity of clinicians in using these maps, higher financial cost, and the necessity of advanced imaging processing skills. Artificial intelligence is a promising tool that may overcome these challenges through creating automated processing pipelines and developing synthetic maps without the need for additional acquisition.⁶⁰

Conclusions

MRI is the most important tool for diagnosing and treating PwMS. Imaging biomarkers such as T2-lesions, cBHs, brain atrophy, PRLs, and CVS provide insight into the disease’s pathogenesis and are invaluable for the accurate diagnosis and prognostication of MS. Quantitative MRI techniques, while not available in the clinical setting, are important tools for translational research that may help direct the development of future therapeutics. In the near future, clinicians caring for PwMS should expect to encounter these imaging biomarkers more frequently in the clinical setting, especially with the inclusion of PRLs and CVS in the next iteration of the McDonald diagnostic criteria.

The introduction of extended reality (XR) to the operating room (OR) has proved promising for enhancing surgical precision and improving patient outcomes. In the field of orthopedic surgery, precise alignment of implants is integral to maintaining functional range of motion and preventing impingement of adjacent neurovascular structures. XR systems have shown promise in arthroplasty including by improving precision and streamlining surgery by allowing surgeons to create 3D preoperative plans that are accessible intraoperatively. This article explores the current applications of XR in arthroplasty, highlights recent advancements and benefits, and describes limitations in comparison to traditional techniques.

Methods

A literature search identified studies involving the use of XR in arthroplasty and current US Food and Drug Administration (FDA)-approved XR systems. Multiple electronic databases were used, including PubMed, Google Scholar, and IEEE Xplore. Search terms included: extended reality, augmented reality, virtual reality, arthroplasty, joint replacement, total knee arthroplasty, total shoulder arthroplasty, and total hip arthroplasty. The study design, intervention details, outcomes, and comparisons with traditional surgical techniques were thematically analyzed, with identification of common ideas associated with XR use in arthroplasty. This narrative report highlights the integration of XR in arthroplasty.

Extended Reality Fundamentals

XR encompasses augmented reality (AR), virtual reality (VR), and mixed reality (MR). AR involves superimposing digitally rendered information and images onto the surgeon’s view of the real world, typically through the use of a headset and smart glasses.¹ AR allows the surgeon to move and interact freely within the OR, removing the need for additional screens or devices to display patient information or imaging. VR is a fully immersive simulation using a headset that obstructs the view of the real world but allows the user to move freely within this virtual setting, often with audio or other sensory stimuli. MR combines AR and VR to create a digital model that allows for real-world interaction, with the advantage of adapting information and models in real time.² Whereas in AR the surgeon can view the data projected from the headset, MR provides the ability to interact with and manipulate the digital content (Figure). Both AR and MR have been adapted for use in the OR, while VR has been adapted for use in surgical planning and training.

Extended Reality Use in Orthopedics

The HipNav system was introduced in 1995 to create preoperative plans that assist surgeons in accurately implanting the acetabular cup during total hip arthroplasty (THA).³ Although not commercially successful, this system spurred surgeons to experiment with XR to improve the accuracy and alignment of orthopedic implants. Systems capable of displaying the desired intraoperative implant placement have flourished, with applications in fracture reduction, arthroplasty, solid tumor resection, and hardware placement.^4-7 Accurate alignment has been linked to improvements in patient outcomes.^8-10 XR has great potential within the field of arthroplasty, with multiple new systems approved by the FDA and currently available in the US (Table).

Hip Arthroplasty

Orientation of the acetabular cup is a technically challenging part of THA. Accuracy in the anteversion and inclination angles of the acetabular cup is required to maintain implant stability, preserve functional range of motion (ROM), and prevent precocious wear.^11,12 Despite preoperative planning, surgeons often overestimate the inclination angle and underestimate anteversion.¹³ Improper implantation of the acetabular cup can lead to joint instability caused by aseptic loosening, increasing the risk of dislocation and the need for revision surgery.^14,15 Dislocations typically present to the emergency department, but primary care practitioners may encounter patients with pain or diminished sensation due to impingement or instability.¹⁶

The introduction of XR into the OR has provided the opportunity for real-time navigation and adjustment of the acetabular cup to maximize anteversion and inclination angles. Currently, 2 FDA-approved systems are available for THA: the Zimmer and Surgical Planning Associates HipInsight system, and the Insight Augmented Reality Visualization and Information System (ARVIS). The HipInsight system consists of a hologram projection using the Microsoft HoloLens2 device and optimizes preoperative planning, producing accuracy of anteversion and inclination angles within 3°.¹⁷ ARVIS employs existing surgical helmets and 2 mounted tracking cameras to provide navigation intraoperatively. ARVIS has also been approved for use in total knee arthroplasty (TKA) and unicompartmental knee arthroplasty.¹⁸

HipInsight has shown utility in increasing the accuracy of acetabular cup placement along with the use of biplanar radiographic scans.¹⁹ However, there are no studies validating the efficacy of ARVIS and HipInsight and assessing long-term disease-oriented or patient-oriented outcomes.

Knee Arthroplasty

In the setting of TKA, XR is most effective in ensuring accurate resection of the tibial and femoral components. Achieving the planned femoral coronal, axial, and sagittal angles allows the prosthesis to be on the femoral axis of rotation, improving functional outcomes. XR systems for TKA have been shown to increase the accuracy of distal femoral resection with a limited increase in surgery duration.^20,21 For TKA in particular, patients are often less satisfied with the result than surgeons expect.²² Accurate alignment can improve patient satisfaction and reduce return-to-clinic rates for postoperative pain management, a factor that primary care practitioners should consider when recommending a patient for TKA.²³

Along with ARVIS, 3 additional XR systems are FDA-approved for use in TKA. The Pixee Medical Knee+ system uses smart glasses and trackers to aid in the positioning of instruments for improved accuracy while allowing real-time navigation.²⁴ The Medacta NextAR Knee’s single-use tracking system allows for intraoperative navigation with the use of AR glasses.²⁵ The Polaris STELLAR Knee uses MR and avoids the need for preoperative imaging by capturing real-time anatomic data.²⁶

The Pixee Medical Knee+ system was commercially available in Europe for several years prior to FDA approval, so more research exists on its efficacy. One study found that the Pixee Medical Knee+ system initially demonstrated an inferior clinical outcome, attributed to the learning curve associated with using the system.²⁷ However, more recent studies have shown its utility in improving alignment, regardless of implant specifications.^28,29 The Medacta NextAR Knee system has been shown to improve accuracy of tibial rotation and soft tissue balance and even increase OR efficiency.^30,31 The Polaris STELLAR Knee system received FDA approval in 2023; no published research exists on its accuracy and outcomes.²⁶

Shoulder Arthroplasty

Minimally invasive techniques are favored in total shoulder arthroplasty (TSA) due to the vitality of maintaining the surrounding soft tissue to maximize preservation of motility and strength.³² However, this complicates the procedure by decreasing the ability to effectively access and visualize key structures of the shoulder. Accordingly, issues with implant positioning and alignment are more common with TSA than other joint arthroplasties, making XR particularly promising.³³ Some studies report that up to 67% of patients experience glenohumeral instability, which can clinically present as weakness, decreased range of motion, and persistent shoulder pain.^34,35 The use of preoperative computed tomography to improve understanding of glenoid anatomy and glenohumeral subluxation is becoming increasingly common, and it can be combined with XR to improve accuracy.^36,37

Two FDA-approved systems are available. The Stryker Blueprint MR system is used for intraoperative guidance and integration for patient imaging used for preoperative planning. The Medacta NextAR Shoulder system is a parallel of the company’s TKA system. The Stryker Blueprint MR system combines the Microsoft HoloLens 2 headset to display preoperative plans with a secondary display for coordination with the rest of the surgical team.³⁸ Similar to the Medacta NextAR Knee, the Medacta NextAR Shoulder system uses the same single-use tracking system and AR glasses for intraoperative guidance.³⁹

Data on the long-term outcomes of using these systems are still limited, but the Stryker Blueprint MR system has not been shown to accurately predict postoperative ROM.⁴⁰ Cadaveric studies have demonstrated that the Medacta NextAR Shoulder system can provide accurate inclination, retroversion, entry point, depth, and rotation values based on the preoperative planned values.^41,42 However, this accuracy has yet to be confirmed in vivo, and the impact of using XR in TSA on long-term outcomes is still unknown.

Challenges and Limitations

Though XR has proven to be promising in arthroplasty, several limitations regarding widespread implementation exist. In particular, there is a steep learning curve associated with the use of XR systems, which can cause increased operative time and even initial inferior outcomes, as demonstrated with the Pixee Medical Knee+ system. The need for extensive practice and training prior to use could delay widespread adoption and may cause discrepancies in surgical outcomes. Unfamiliarity with the system and technological difficulties that may require troubleshooting can also increase operative time, particularly for surgeons new to using the XR system. Though intraoperative navigation is expected to improve accuracy of implant alignment, its added complexity may also result in longer surgeries.

In addition to the steep learning curve and increased operative time, there is a high upfront cost associated with XR systems. Exact costs of XR systems are not typically disclosed, but available estimates suggest an average sales price of about $1000 per case. Given the proprietary nature of these technologies, publicly available cost data are limited, making it challenging to fully assess the financial burden on health care institutions. Though some systems, such as ARVIS, can be integrated with existing surgical helmets, many require the purchase of AR glasses and secondary displays. This can cause further variation in the total expense for each system. In low-resource settings, this represents a significant challenge to widespread implementation. To justify this cost, additional research on long-term patient outcomes is needed to ensure the benefits of XR systems outweigh the cost. 

Although early studies on XR systems in arthroplasty have shown improvements in precision and short-term outcomes, long-term data regarding effectiveness remains. Even systems such as ARVIS and HipInsight have limited long-term follow-up, making it difficult to assess whether the improved accuracy with these XR systems translates into improved patient outcomes compared with traditional arthroplasty.

CONCLUSIONS

XR technologies have shown significant potential in enhancing precision and patient outcomes. Through the integration of XR in the OR, surgeons can visualize preoperative plans and even make intraoperative changes, with the benefit of improving implant alignment.

There are some disadvantages to its use, however, including high cost and increased operative time. Despite this, the integration of XR into surgical practice can deliver more precise implant alignment and address other challenges faced with conventional techniques. As these technologies evolve and studies on long-term outcomes validate their utility, XR has the potential to transform the field of arthroplasty.

The introduction of extended reality (XR) to the operating room (OR) has proved promising for enhancing surgical precision and improving patient outcomes. In the field of orthopedic surgery, precise alignment of implants is integral to maintaining functional range of motion and preventing impingement of adjacent neurovascular structures. XR systems have shown promise in arthroplasty including by improving precision and streamlining surgery by allowing surgeons to create 3D preoperative plans that are accessible intraoperatively. This article explores the current applications of XR in arthroplasty, highlights recent advancements and benefits, and describes limitations in comparison to traditional techniques.

Methods

A literature search identified studies involving the use of XR in arthroplasty and current US Food and Drug Administration (FDA)-approved XR systems. Multiple electronic databases were used, including PubMed, Google Scholar, and IEEE Xplore. Search terms included: extended reality, augmented reality, virtual reality, arthroplasty, joint replacement, total knee arthroplasty, total shoulder arthroplasty, and total hip arthroplasty. The study design, intervention details, outcomes, and comparisons with traditional surgical techniques were thematically analyzed, with identification of common ideas associated with XR use in arthroplasty. This narrative report highlights the integration of XR in arthroplasty.

Extended Reality Fundamentals

XR encompasses augmented reality (AR), virtual reality (VR), and mixed reality (MR). AR involves superimposing digitally rendered information and images onto the surgeon’s view of the real world, typically through the use of a headset and smart glasses.¹ AR allows the surgeon to move and interact freely within the OR, removing the need for additional screens or devices to display patient information or imaging. VR is a fully immersive simulation using a headset that obstructs the view of the real world but allows the user to move freely within this virtual setting, often with audio or other sensory stimuli. MR combines AR and VR to create a digital model that allows for real-world interaction, with the advantage of adapting information and models in real time.² Whereas in AR the surgeon can view the data projected from the headset, MR provides the ability to interact with and manipulate the digital content (Figure). Both AR and MR have been adapted for use in the OR, while VR has been adapted for use in surgical planning and training.

Extended Reality Use in Orthopedics

The HipNav system was introduced in 1995 to create preoperative plans that assist surgeons in accurately implanting the acetabular cup during total hip arthroplasty (THA).³ Although not commercially successful, this system spurred surgeons to experiment with XR to improve the accuracy and alignment of orthopedic implants. Systems capable of displaying the desired intraoperative implant placement have flourished, with applications in fracture reduction, arthroplasty, solid tumor resection, and hardware placement.^4-7 Accurate alignment has been linked to improvements in patient outcomes.^8-10 XR has great potential within the field of arthroplasty, with multiple new systems approved by the FDA and currently available in the US (Table).

Hip Arthroplasty

Orientation of the acetabular cup is a technically challenging part of THA. Accuracy in the anteversion and inclination angles of the acetabular cup is required to maintain implant stability, preserve functional range of motion (ROM), and prevent precocious wear.^11,12 Despite preoperative planning, surgeons often overestimate the inclination angle and underestimate anteversion.¹³ Improper implantation of the acetabular cup can lead to joint instability caused by aseptic loosening, increasing the risk of dislocation and the need for revision surgery.^14,15 Dislocations typically present to the emergency department, but primary care practitioners may encounter patients with pain or diminished sensation due to impingement or instability.¹⁶

The introduction of XR into the OR has provided the opportunity for real-time navigation and adjustment of the acetabular cup to maximize anteversion and inclination angles. Currently, 2 FDA-approved systems are available for THA: the Zimmer and Surgical Planning Associates HipInsight system, and the Insight Augmented Reality Visualization and Information System (ARVIS). The HipInsight system consists of a hologram projection using the Microsoft HoloLens2 device and optimizes preoperative planning, producing accuracy of anteversion and inclination angles within 3°.¹⁷ ARVIS employs existing surgical helmets and 2 mounted tracking cameras to provide navigation intraoperatively. ARVIS has also been approved for use in total knee arthroplasty (TKA) and unicompartmental knee arthroplasty.¹⁸

HipInsight has shown utility in increasing the accuracy of acetabular cup placement along with the use of biplanar radiographic scans.¹⁹ However, there are no studies validating the efficacy of ARVIS and HipInsight and assessing long-term disease-oriented or patient-oriented outcomes.

Knee Arthroplasty

In the setting of TKA, XR is most effective in ensuring accurate resection of the tibial and femoral components. Achieving the planned femoral coronal, axial, and sagittal angles allows the prosthesis to be on the femoral axis of rotation, improving functional outcomes. XR systems for TKA have been shown to increase the accuracy of distal femoral resection with a limited increase in surgery duration.^20,21 For TKA in particular, patients are often less satisfied with the result than surgeons expect.²² Accurate alignment can improve patient satisfaction and reduce return-to-clinic rates for postoperative pain management, a factor that primary care practitioners should consider when recommending a patient for TKA.²³

Along with ARVIS, 3 additional XR systems are FDA-approved for use in TKA. The Pixee Medical Knee+ system uses smart glasses and trackers to aid in the positioning of instruments for improved accuracy while allowing real-time navigation.²⁴ The Medacta NextAR Knee’s single-use tracking system allows for intraoperative navigation with the use of AR glasses.²⁵ The Polaris STELLAR Knee uses MR and avoids the need for preoperative imaging by capturing real-time anatomic data.²⁶

The Pixee Medical Knee+ system was commercially available in Europe for several years prior to FDA approval, so more research exists on its efficacy. One study found that the Pixee Medical Knee+ system initially demonstrated an inferior clinical outcome, attributed to the learning curve associated with using the system.²⁷ However, more recent studies have shown its utility in improving alignment, regardless of implant specifications.^28,29 The Medacta NextAR Knee system has been shown to improve accuracy of tibial rotation and soft tissue balance and even increase OR efficiency.^30,31 The Polaris STELLAR Knee system received FDA approval in 2023; no published research exists on its accuracy and outcomes.²⁶

Shoulder Arthroplasty

Minimally invasive techniques are favored in total shoulder arthroplasty (TSA) due to the vitality of maintaining the surrounding soft tissue to maximize preservation of motility and strength.³² However, this complicates the procedure by decreasing the ability to effectively access and visualize key structures of the shoulder. Accordingly, issues with implant positioning and alignment are more common with TSA than other joint arthroplasties, making XR particularly promising.³³ Some studies report that up to 67% of patients experience glenohumeral instability, which can clinically present as weakness, decreased range of motion, and persistent shoulder pain.^34,35 The use of preoperative computed tomography to improve understanding of glenoid anatomy and glenohumeral subluxation is becoming increasingly common, and it can be combined with XR to improve accuracy.^36,37

Two FDA-approved systems are available. The Stryker Blueprint MR system is used for intraoperative guidance and integration for patient imaging used for preoperative planning. The Medacta NextAR Shoulder system is a parallel of the company’s TKA system. The Stryker Blueprint MR system combines the Microsoft HoloLens 2 headset to display preoperative plans with a secondary display for coordination with the rest of the surgical team.³⁸ Similar to the Medacta NextAR Knee, the Medacta NextAR Shoulder system uses the same single-use tracking system and AR glasses for intraoperative guidance.³⁹

Data on the long-term outcomes of using these systems are still limited, but the Stryker Blueprint MR system has not been shown to accurately predict postoperative ROM.⁴⁰ Cadaveric studies have demonstrated that the Medacta NextAR Shoulder system can provide accurate inclination, retroversion, entry point, depth, and rotation values based on the preoperative planned values.^41,42 However, this accuracy has yet to be confirmed in vivo, and the impact of using XR in TSA on long-term outcomes is still unknown.

Challenges and Limitations

Though XR has proven to be promising in arthroplasty, several limitations regarding widespread implementation exist. In particular, there is a steep learning curve associated with the use of XR systems, which can cause increased operative time and even initial inferior outcomes, as demonstrated with the Pixee Medical Knee+ system. The need for extensive practice and training prior to use could delay widespread adoption and may cause discrepancies in surgical outcomes. Unfamiliarity with the system and technological difficulties that may require troubleshooting can also increase operative time, particularly for surgeons new to using the XR system. Though intraoperative navigation is expected to improve accuracy of implant alignment, its added complexity may also result in longer surgeries.

In addition to the steep learning curve and increased operative time, there is a high upfront cost associated with XR systems. Exact costs of XR systems are not typically disclosed, but available estimates suggest an average sales price of about $1000 per case. Given the proprietary nature of these technologies, publicly available cost data are limited, making it challenging to fully assess the financial burden on health care institutions. Though some systems, such as ARVIS, can be integrated with existing surgical helmets, many require the purchase of AR glasses and secondary displays. This can cause further variation in the total expense for each system. In low-resource settings, this represents a significant challenge to widespread implementation. To justify this cost, additional research on long-term patient outcomes is needed to ensure the benefits of XR systems outweigh the cost. 

Although early studies on XR systems in arthroplasty have shown improvements in precision and short-term outcomes, long-term data regarding effectiveness remains. Even systems such as ARVIS and HipInsight have limited long-term follow-up, making it difficult to assess whether the improved accuracy with these XR systems translates into improved patient outcomes compared with traditional arthroplasty.

CONCLUSIONS

XR technologies have shown significant potential in enhancing precision and patient outcomes. Through the integration of XR in the OR, surgeons can visualize preoperative plans and even make intraoperative changes, with the benefit of improving implant alignment.

There are some disadvantages to its use, however, including high cost and increased operative time. Despite this, the integration of XR into surgical practice can deliver more precise implant alignment and address other challenges faced with conventional techniques. As these technologies evolve and studies on long-term outcomes validate their utility, XR has the potential to transform the field of arthroplasty.

The introduction of extended reality (XR) to the operating room (OR) has proved promising for enhancing surgical precision and improving patient outcomes. In the field of orthopedic surgery, precise alignment of implants is integral to maintaining functional range of motion and preventing impingement of adjacent neurovascular structures. XR systems have shown promise in arthroplasty including by improving precision and streamlining surgery by allowing surgeons to create 3D preoperative plans that are accessible intraoperatively. This article explores the current applications of XR in arthroplasty, highlights recent advancements and benefits, and describes limitations in comparison to traditional techniques.

Methods

A literature search identified studies involving the use of XR in arthroplasty and current US Food and Drug Administration (FDA)-approved XR systems. Multiple electronic databases were used, including PubMed, Google Scholar, and IEEE Xplore. Search terms included: extended reality, augmented reality, virtual reality, arthroplasty, joint replacement, total knee arthroplasty, total shoulder arthroplasty, and total hip arthroplasty. The study design, intervention details, outcomes, and comparisons with traditional surgical techniques were thematically analyzed, with identification of common ideas associated with XR use in arthroplasty. This narrative report highlights the integration of XR in arthroplasty.

Extended Reality Fundamentals

XR encompasses augmented reality (AR), virtual reality (VR), and mixed reality (MR). AR involves superimposing digitally rendered information and images onto the surgeon’s view of the real world, typically through the use of a headset and smart glasses.¹ AR allows the surgeon to move and interact freely within the OR, removing the need for additional screens or devices to display patient information or imaging. VR is a fully immersive simulation using a headset that obstructs the view of the real world but allows the user to move freely within this virtual setting, often with audio or other sensory stimuli. MR combines AR and VR to create a digital model that allows for real-world interaction, with the advantage of adapting information and models in real time.² Whereas in AR the surgeon can view the data projected from the headset, MR provides the ability to interact with and manipulate the digital content (Figure). Both AR and MR have been adapted for use in the OR, while VR has been adapted for use in surgical planning and training.

Extended Reality Use in Orthopedics

The HipNav system was introduced in 1995 to create preoperative plans that assist surgeons in accurately implanting the acetabular cup during total hip arthroplasty (THA).³ Although not commercially successful, this system spurred surgeons to experiment with XR to improve the accuracy and alignment of orthopedic implants. Systems capable of displaying the desired intraoperative implant placement have flourished, with applications in fracture reduction, arthroplasty, solid tumor resection, and hardware placement.^4-7 Accurate alignment has been linked to improvements in patient outcomes.^8-10 XR has great potential within the field of arthroplasty, with multiple new systems approved by the FDA and currently available in the US (Table).

Hip Arthroplasty

Orientation of the acetabular cup is a technically challenging part of THA. Accuracy in the anteversion and inclination angles of the acetabular cup is required to maintain implant stability, preserve functional range of motion (ROM), and prevent precocious wear.^11,12 Despite preoperative planning, surgeons often overestimate the inclination angle and underestimate anteversion.¹³ Improper implantation of the acetabular cup can lead to joint instability caused by aseptic loosening, increasing the risk of dislocation and the need for revision surgery.^14,15 Dislocations typically present to the emergency department, but primary care practitioners may encounter patients with pain or diminished sensation due to impingement or instability.¹⁶

The introduction of XR into the OR has provided the opportunity for real-time navigation and adjustment of the acetabular cup to maximize anteversion and inclination angles. Currently, 2 FDA-approved systems are available for THA: the Zimmer and Surgical Planning Associates HipInsight system, and the Insight Augmented Reality Visualization and Information System (ARVIS). The HipInsight system consists of a hologram projection using the Microsoft HoloLens2 device and optimizes preoperative planning, producing accuracy of anteversion and inclination angles within 3°.¹⁷ ARVIS employs existing surgical helmets and 2 mounted tracking cameras to provide navigation intraoperatively. ARVIS has also been approved for use in total knee arthroplasty (TKA) and unicompartmental knee arthroplasty.¹⁸

HipInsight has shown utility in increasing the accuracy of acetabular cup placement along with the use of biplanar radiographic scans.¹⁹ However, there are no studies validating the efficacy of ARVIS and HipInsight and assessing long-term disease-oriented or patient-oriented outcomes.

Knee Arthroplasty

In the setting of TKA, XR is most effective in ensuring accurate resection of the tibial and femoral components. Achieving the planned femoral coronal, axial, and sagittal angles allows the prosthesis to be on the femoral axis of rotation, improving functional outcomes. XR systems for TKA have been shown to increase the accuracy of distal femoral resection with a limited increase in surgery duration.^20,21 For TKA in particular, patients are often less satisfied with the result than surgeons expect.²² Accurate alignment can improve patient satisfaction and reduce return-to-clinic rates for postoperative pain management, a factor that primary care practitioners should consider when recommending a patient for TKA.²³

Along with ARVIS, 3 additional XR systems are FDA-approved for use in TKA. The Pixee Medical Knee+ system uses smart glasses and trackers to aid in the positioning of instruments for improved accuracy while allowing real-time navigation.²⁴ The Medacta NextAR Knee’s single-use tracking system allows for intraoperative navigation with the use of AR glasses.²⁵ The Polaris STELLAR Knee uses MR and avoids the need for preoperative imaging by capturing real-time anatomic data.²⁶

The Pixee Medical Knee+ system was commercially available in Europe for several years prior to FDA approval, so more research exists on its efficacy. One study found that the Pixee Medical Knee+ system initially demonstrated an inferior clinical outcome, attributed to the learning curve associated with using the system.²⁷ However, more recent studies have shown its utility in improving alignment, regardless of implant specifications.^28,29 The Medacta NextAR Knee system has been shown to improve accuracy of tibial rotation and soft tissue balance and even increase OR efficiency.^30,31 The Polaris STELLAR Knee system received FDA approval in 2023; no published research exists on its accuracy and outcomes.²⁶

Shoulder Arthroplasty

Minimally invasive techniques are favored in total shoulder arthroplasty (TSA) due to the vitality of maintaining the surrounding soft tissue to maximize preservation of motility and strength.³² However, this complicates the procedure by decreasing the ability to effectively access and visualize key structures of the shoulder. Accordingly, issues with implant positioning and alignment are more common with TSA than other joint arthroplasties, making XR particularly promising.³³ Some studies report that up to 67% of patients experience glenohumeral instability, which can clinically present as weakness, decreased range of motion, and persistent shoulder pain.^34,35 The use of preoperative computed tomography to improve understanding of glenoid anatomy and glenohumeral subluxation is becoming increasingly common, and it can be combined with XR to improve accuracy.^36,37

Two FDA-approved systems are available. The Stryker Blueprint MR system is used for intraoperative guidance and integration for patient imaging used for preoperative planning. The Medacta NextAR Shoulder system is a parallel of the company’s TKA system. The Stryker Blueprint MR system combines the Microsoft HoloLens 2 headset to display preoperative plans with a secondary display for coordination with the rest of the surgical team.³⁸ Similar to the Medacta NextAR Knee, the Medacta NextAR Shoulder system uses the same single-use tracking system and AR glasses for intraoperative guidance.³⁹

Data on the long-term outcomes of using these systems are still limited, but the Stryker Blueprint MR system has not been shown to accurately predict postoperative ROM.⁴⁰ Cadaveric studies have demonstrated that the Medacta NextAR Shoulder system can provide accurate inclination, retroversion, entry point, depth, and rotation values based on the preoperative planned values.^41,42 However, this accuracy has yet to be confirmed in vivo, and the impact of using XR in TSA on long-term outcomes is still unknown.

Challenges and Limitations

Though XR has proven to be promising in arthroplasty, several limitations regarding widespread implementation exist. In particular, there is a steep learning curve associated with the use of XR systems, which can cause increased operative time and even initial inferior outcomes, as demonstrated with the Pixee Medical Knee+ system. The need for extensive practice and training prior to use could delay widespread adoption and may cause discrepancies in surgical outcomes. Unfamiliarity with the system and technological difficulties that may require troubleshooting can also increase operative time, particularly for surgeons new to using the XR system. Though intraoperative navigation is expected to improve accuracy of implant alignment, its added complexity may also result in longer surgeries.

In addition to the steep learning curve and increased operative time, there is a high upfront cost associated with XR systems. Exact costs of XR systems are not typically disclosed, but available estimates suggest an average sales price of about $1000 per case. Given the proprietary nature of these technologies, publicly available cost data are limited, making it challenging to fully assess the financial burden on health care institutions. Though some systems, such as ARVIS, can be integrated with existing surgical helmets, many require the purchase of AR glasses and secondary displays. This can cause further variation in the total expense for each system. In low-resource settings, this represents a significant challenge to widespread implementation. To justify this cost, additional research on long-term patient outcomes is needed to ensure the benefits of XR systems outweigh the cost. 

Although early studies on XR systems in arthroplasty have shown improvements in precision and short-term outcomes, long-term data regarding effectiveness remains. Even systems such as ARVIS and HipInsight have limited long-term follow-up, making it difficult to assess whether the improved accuracy with these XR systems translates into improved patient outcomes compared with traditional arthroplasty.

CONCLUSIONS

XR technologies have shown significant potential in enhancing precision and patient outcomes. Through the integration of XR in the OR, surgeons can visualize preoperative plans and even make intraoperative changes, with the benefit of improving implant alignment.

There are some disadvantages to its use, however, including high cost and increased operative time. Despite this, the integration of XR into surgical practice can deliver more precise implant alignment and address other challenges faced with conventional techniques. As these technologies evolve and studies on long-term outcomes validate their utility, XR has the potential to transform the field of arthroplasty.

Steatocystomas are small sebum-filled cysts that typically manifest in the dermis and originate from sebaceous follicles. Although commonly asymptomatic, these lesions can manifest with pruritus or become infected, predisposing patients to further complications.¹ Steatocystomas can manifest as single (steatocystoma simplex [SS]) or numerous (steatocystoma multiplex [SM]) lesions; the lesions also can spontaneously rupture with characteristics that resemble hidradenitis suppurativa (HS)(steatocystoma multiplex suppurativa [SMS]).^1,2

Steatocystomas are relatively rare, and there is limited consensus in the published literature on the etiology and management of this condition. In this article, we present a comprehensive review of steatocystomas in the current literature. We highlight important features to consider when making the diagnosis and also offer recommendations for best-practice treatment.

Historical Background

Although not explicitly identified by name, the first documentation of steatocystomas is a case report published in 1873. In this account, the author described a patient who presented with approximately 250 flesh-colored dermal cysts across the body that varied in size.³ In 1899, the term steatocystoma multiple—derived from Greek roots meaning “fatty bag”—was first used.⁴

In 1982, almost a century later, Brownstein⁵ reported some of the earliest cases of SS. This solitary subtype is identical to SM on a microscopic level; however, unlike SM, this variant occurs as a single lesion that typically forms in adulthood and in the absence of family history. Other benign adnexal tumors (eg, pilomatricomas, pilar cysts, and sebaceous hyperplasias) also can manifest as either solitary or multiple lesions.

In 1976, McDonald and Reed⁶ reported the first known cases of patients with both SM and HS. At the time, the co-occurrence of these conditions was viewed as coincidental, but there were postulations of a shared inflammatory process and hereditary link⁶; it was not until 1982 that the term steatocystoma multiplex suppurativum was coined to describe this variant.⁷ Although rare, there have been multiple documented instances of SMS since. It has been suggested that the convergence of these conditions may indicate a shared follicular proliferation defect.⁸ Ongoing investigation is warranted to explain the underlying pathogenesis of this unique variant.

Epidemiology

The available epidemiologic data primarily relate to SM, the most common steatocystoma variant. Nevertheless, SM is a relatively rare condition, and the exact incidence and prevalence remain unknown.^8,9 Steatocystomas typically manifest in the first and second decades of life and have been observed in patients of both sexes, with studies demonstrating no notable sex bias.^4,9

Etiology and Pathophysiology

Steatocystomas can occur sporadically or may be inherited as an autosomal-dominant condition.⁴ Typically, SS tends to manifest as an isolated occurrence without any inherent genetic predisposition.⁵ Alternatively, SM may develop sporadically or be associated with a mutation in the keratin 17 gene (KRT17).⁴ Steatocystoma multiplex also has been associated with at least 4 different missense mutations, including N92H, R94H, and R94C, located on the long (q) arm of chromosome 17.^4,10-12

The keratin 17 gene is responsible for encoding the keratin 17 protein, a type I intermediate filament predominantly synthesized in the basal cells of epithelial tissue. This fibrous structural protein can regulate many processes, including inflammation and cell proliferation, and is found in regions such as the sebaceous glands, hair follicles, and eccrine sweat glands. Overexpression of KRT17 has been suggested in other cutaneous conditions, most notably psoriasis.¹² Despite KRT17’s many roles, it remains unclear why SM typically manifests with a myriad of sebum-containing cysts as the primary symptom.¹² Continued investigation into the genetic underpinnings of SM and the keratin 17 protein is necessary to further elucidate a more comprehensive understanding of this condition.

Hormonal influences have been suggested as a potential trigger for steatocystoma growth.^4,13 This condition is associated with dysfunction of the sebaceous glands, and, correspondingly, the incidence of disease is highest in pubertal patients, in whom androgen levels and sebum production are elevated.^4,13,14 Two cases of transgender men taking testosterone therapy presenting with steatocystomas provide additional clinical support for this association.¹⁵

Additionally, the use of immunomodulatory agents, such as ustekinumab (anti–interleukin 12/interleukin 23), has been shown to trigger SM. It is predicted that the reduced expression of certain interferons and interleukins may lead to downstream consequences in the keratin 17 pathway and lead to SM lesion formation in genetically susceptible individuals.¹⁶ Targeting these potential causes in the future may prove efficacious in the secondary prevention of familial SM manifestation or exacerbations.

Mutations in the KRT17 gene also have been implicated in pachyonychia congenita type 2 (PC-2).⁴ Marked by extensive systemic hyperkeratosis, PC-2 has been observed to coincide with SM in certain patients.^4,5 Interestingly, the location of the KRT17 mutations are identical in both PC-2 and SM.⁴ Although most individuals with hereditary SM do not exhibit the characteristic features of PC-2, mild nail and dental abnormalities have been observed in some SM cases.^4,10 This relationship suggests that SM may be a less severe variant of PC-2 or part of a complex polygenetic spectrum of disease.¹⁰ Further research is imperative to determine the exact nature and extent of the relationship between these conditions.

Clinical Manifestations

Steatocystomas are flesh-colored subcutaneous cysts that range in size from less than 3 mm to larger than 3 cm in diameter (Figure). They form within a single pilosebaceous unit and typically display firm attachment due to their origination in the dermis.^2,7,17 Steatocystomas generally contain lipid material, and less frequently, keratin and hair shafts, distinguishing them as the only “true” sebaceous cysts.¹⁸ Their color can range from flesh-toned to yellow, with reports of occasional dark-blue shades and calcifications.^19,20 Steatocystomas can persist indefinitely, and they usually are asymptomatic.

Diagnosis of steatocystoma is confirmed by biopsy.⁴ Steatocystomas are characterized by a dermal cyst lined by stratified squamous cell epithelium (eFigures 1 and 2).²¹ Classically they feature flattened sebaceous lobules, multinucleated giant cells, and abortive hair follicles. The lining of these cysts is marked by lymphocytic infiltrate and a dense, wrinkled, eosinophilic keratin cuticle that replaces the granular layer.²² The cyst maintains an epidermal connection through a follicular infundibulum characterized by clumps of keratinocytes, sebocytes, corneocytes, and/or hair follicles.⁷ Aspirated contents reveal crystalline structures and anucleate squamous cells upon microscopic analysis. That being said, variable histologic findings of steatocystomas have been described.²³

Steatocystoma simplex, as the name implies, classifies a single isolated steatocystoma. This subtype exhibits similar histopathologic and clinical features to the other subtypes of steatocystomas. Notably, SS is not associated with a genetic mutation and is not an inherited condition within families.⁵ Steatocystoma multiplex manifests with many steatocystomas, often distributed widely across the body.^3,4 The chest, axillae, and groin are the most common locations; however, these cysts can manifest on the face, back, abdomen, and extremities.^4,18-22 Rare occurrences of SM limited to the face, scalp, and distal extremities have been documented.^18,21,24,25 Due to the possibility of an autosomal-dominant inheritance, it is advisable to take a comprehensive family history in patients for whom SM is in the differential.¹⁷

Steatocystoma multiplex—especially familial variants—has been shown to develop in conjunction with other dermatologic conditions, including eruptive vellus hair (EVH) cysts, persistent infantile milia, and epidermoid/dermoid cysts.²⁶ While some investigators regard these as separate entities due to their varied genetic etiology, it has been suggested that these conditions may be related and that the diagnosis is determined by the location of cyst origin along the sebaceous ducts.^26,27 Other dermatologic conditions and lesions that frequently manifest comorbidly with SM include hidrocystomas, syringomas, pilonidal cysts, lichen planus, nodulocystic acne, trichotillomania, trichoblastomas, trichoepithelioma, HS, keratoacanthomas, acrokeratosis verruciformis of Hopf, and embryonal hair formation. Steatocystoma multiplex, manifesting comorbidly with dental and orofacial malformations (eg, partial noneruption of secondary teeth, natal and defective teeth, and bilateral preauricular sinuses) has been classified as SM natal teeth syndrome.⁶

Steatocystoma multiplex suppurativa is a rare and serious variant of SM characterized by inflammation, cyst rupture, sinus tract formation, and scarring.²⁴ Patients with SMS typically have multiple intact SM cysts, which can aid in differentiation from HS.^2,24 Steatocystoma multiplex suppurativa is associated with more complications than SS and SM, including cyst perforation, development of purulent and/or foul-smelling discharge, infection, scarring, pain, and overall discomfort.²

Given its rarity and the potential manifestations that overlap with other conditions, steatocystomas easily can be misdiagnosed. In some clinical instances, EVHs may share similar characteristics with SM; however, certain distinguishing features exist, including a central tuft of protruding hairs and different expressed contents, such as the vellus hair shafts, from the cyst’s lumen.²⁸ Furthermore, histologic examination of EVHs reveals epidermoid keratinization of the lining as well as a lack of sebaceous glands within the wall.^28,29 Other similar conditions include epidermoid cysts, pilar cysts, lipomas, epidermal inclusion cysts, dermoid cysts, sebaceous hyperplasia, folliculitis, xanthomas, neurofibromatosis, and syringomas.³⁰ Occasionally, SMS can be mistaken for HS or acne conglobata, and SM lesions with a facial distribution can mimic acne vulgaris.^1,31 These conditions should be excluded before a diagnosis of SS, SM, or SMS is made. 

Importantly, SM is visually indistinguishable from subcutaneous metastasis on physical examination, and there are reports of oncologic conditions (eg, pulmonary adenocarcinoma metastasized to the skin) being mistaken for SS or SM.³² Therefore, a thorough clinical examination, histopathologic analysis, and potential use of other imaging modalities such as ultrasonography (US) are needed to ensure an accurate diagnosis.

Ultrasonography has demonstrated utility in diagnosing steatocystomas.^33-35 Steatocystomas have incidentally been found on routine mammograms and can demonstrate well-defined circular nodules with radiolucent characteristics and a thin radiodense outline.^33,36 Homogeneous hypoechoic nodules within the dermis without posterior acoustic features generally are observed (eFigure 3).^33,37 In patients declining biopsy, US may be useful in further characterization of an unknown lesion. Color Doppler US can be used to distinguish SMS from HS. Specifically, SM typically exhibits an absence of Doppler signaling due to a lack of vascularity, providing a helpful diagnostic clue for the SMS variant.³³

Management and Treatment Options

There is no established standard treatment for steatocystomas; therefore, the approach to management is contingent on clinical presentation and patient preferences. Various medical, surgical, and laser management options are available, each with its own advantages and limitations. Treatment of SM is difficult due to the large number of lesions.³⁸ In many cases, continued observation is a viable treatment option, as most SS and SM lesions are asymptomatic; however, cosmetic concerns can be debilitating for patients with SM and may warrant intervention.³⁹ More extensive medical and surgical management often are necessary in SMS due to associated morbidity. Discussing options and goals as well as setting realistic expectations with the patient are essential in determining the optimal approach.

Medical Management—In medical literature, oral isotretinoin (13-cis-retinoic acid) has been the mainstay of therapy for steatocystoma, as its effect on the size and activity of sebaceous glands is hypothesized to decrease disease activity.^38,40 Interventional studies and case reports have exhibited varying degrees of effectiveness.^1,38-41 Some reports depict a reduction in the formation of new lesions and a decrease in the size of pre-existing lesions, some show mild delayed therapeutic efficacy, and others suggest exacerbation of the condition.^1,38-41 This outcome variability is attributed to isotretinoin’s preferential efficacy in treating inflammatory lesions.^40,42

Tetracycline derivatives and intralesional steroid injections also have been employed with some efficacy in patients with focal inflammatory SM and SMS.⁴³ There is limited evidence on the long-term outcomes of these interventions, and intralesional injections often are not recommended in conditions such as SM, in which there are many lesions present.

Surgical Management—Minimally invasive surgical procedures including drainage and resections have been used with varying efficacy in SS and SM. Typically, a 2- to 3-mm incision or sharp-tipped cautery is employed to puncture the cyst. Alternatively, radiofrequency probes with a 2.4-MHz frequency setting have been used to minimize incision size.⁴⁴ The contents then are expressed with manual pressure or forceps, and the cyst sac is extracted using forceps and/or a vein hook (eFigure 4).^44,45 The specific surgical techniques and their respective advantages and limitations are summarized in the eTable. Reported advantages and limitations of surgical techniques are derived from information provided by the authors of steatocystoma case reports, which are based on observations of a very limited sample size.

Laser Treatment—Various laser modalities have been used in the management of steatocystomas, including carbon dioxide lasers, erbium-doped yttrium aluminum garnet lasers, 1450-nm diode plus 1550-nm fractionated erbium-doped fiber lasers, and 1927-nm diode lasers.^54,55-57 These lasers are used to perforate the cyst before extirpation and have displayed advantages in minimizing scar length.⁵⁸ The super-pulse mode of carbon dioxide lasers demonstrates efficacy with minimal scarring and recurrence, and this mode is preferred to minimize thermal damage.^54,59 Furthermore, this modality can be especially useful in patients whose condition is refractory to other noninvasive options.⁵⁹ Similarly, the erbium-doped yttrium aluminum garnet laser was well tolerated with no complications noted.⁵⁵ The 1927-nm diode laser also displayed good outcomes as well as no recurrence.⁵⁷ With laser use, it is important to note that multiple treatments are needed to see optimal outcomes.⁵⁴ Moreover, laser settings must be carefully considered, especially in patients with Fitzpatrick skin type III or higher, and topical anti-inflammatory agents should be considered posttreatment to minimize complications.^54,59,60

Recommendations

For management of SS, we recommend conservative therapy of watchful observation, as scarring or postinflammatory pigment change may be brought on by medical or surgical therapy; however, if SS is cosmetically bothersome, laser or surgical excision can be done (eFigure 4).^4,43-53 It is important to counsel the patient on risks/benefits. For SM, watchful observation also is indicated; however, systemic therapies aimed at prevention may be the most efficacious by limiting disease progression, and oral tetracycline or isotretinoin may be tried.⁴ Tetracyclines have the risk for photosensitivity and are teratogenic, while isotretinoin is extremely teratogenic, requires laboratory monitoring and regular pregnancy tests in women, and often causes substantial mucosal dryness. If lesions are bothersome or refractory to these therapies, intralesional steroids or surgical/laser procedures can be tried throughout multiple visits.^43-53 For SMS, systemic therapies frequently are recommended. The risks of systemic tetracycline and isotretinoin therapies must be discussed. Patients with treatment-refractory SMS may require surgical excision or deroofing of sinus tracts.^43-53 This management is similar to that of HS and must be tailored to the patient.

Conclusion

Overall, steatocystomas are a relatively rare pathology, with a limited consensus on their etiology and management. This review summarizes the current knowledge on the condition to support clinicians in diagnosis and management, ranging from watchful waiting to surgical removal. By individualizing treatment plans, clinicians ultimately can optimize outcomes in patients with steatocystomas.

Steatocystomas are small sebum-filled cysts that typically manifest in the dermis and originate from sebaceous follicles. Although commonly asymptomatic, these lesions can manifest with pruritus or become infected, predisposing patients to further complications.¹ Steatocystomas can manifest as single (steatocystoma simplex [SS]) or numerous (steatocystoma multiplex [SM]) lesions; the lesions also can spontaneously rupture with characteristics that resemble hidradenitis suppurativa (HS)(steatocystoma multiplex suppurativa [SMS]).^1,2

Steatocystomas are relatively rare, and there is limited consensus in the published literature on the etiology and management of this condition. In this article, we present a comprehensive review of steatocystomas in the current literature. We highlight important features to consider when making the diagnosis and also offer recommendations for best-practice treatment.

Historical Background

Although not explicitly identified by name, the first documentation of steatocystomas is a case report published in 1873. In this account, the author described a patient who presented with approximately 250 flesh-colored dermal cysts across the body that varied in size.³ In 1899, the term steatocystoma multiple—derived from Greek roots meaning “fatty bag”—was first used.⁴

In 1982, almost a century later, Brownstein⁵ reported some of the earliest cases of SS. This solitary subtype is identical to SM on a microscopic level; however, unlike SM, this variant occurs as a single lesion that typically forms in adulthood and in the absence of family history. Other benign adnexal tumors (eg, pilomatricomas, pilar cysts, and sebaceous hyperplasias) also can manifest as either solitary or multiple lesions.

In 1976, McDonald and Reed⁶ reported the first known cases of patients with both SM and HS. At the time, the co-occurrence of these conditions was viewed as coincidental, but there were postulations of a shared inflammatory process and hereditary link⁶; it was not until 1982 that the term steatocystoma multiplex suppurativum was coined to describe this variant.⁷ Although rare, there have been multiple documented instances of SMS since. It has been suggested that the convergence of these conditions may indicate a shared follicular proliferation defect.⁸ Ongoing investigation is warranted to explain the underlying pathogenesis of this unique variant.

Epidemiology

The available epidemiologic data primarily relate to SM, the most common steatocystoma variant. Nevertheless, SM is a relatively rare condition, and the exact incidence and prevalence remain unknown.^8,9 Steatocystomas typically manifest in the first and second decades of life and have been observed in patients of both sexes, with studies demonstrating no notable sex bias.^4,9

Etiology and Pathophysiology

Steatocystomas can occur sporadically or may be inherited as an autosomal-dominant condition.⁴ Typically, SS tends to manifest as an isolated occurrence without any inherent genetic predisposition.⁵ Alternatively, SM may develop sporadically or be associated with a mutation in the keratin 17 gene (KRT17).⁴ Steatocystoma multiplex also has been associated with at least 4 different missense mutations, including N92H, R94H, and R94C, located on the long (q) arm of chromosome 17.^4,10-12

The keratin 17 gene is responsible for encoding the keratin 17 protein, a type I intermediate filament predominantly synthesized in the basal cells of epithelial tissue. This fibrous structural protein can regulate many processes, including inflammation and cell proliferation, and is found in regions such as the sebaceous glands, hair follicles, and eccrine sweat glands. Overexpression of KRT17 has been suggested in other cutaneous conditions, most notably psoriasis.¹² Despite KRT17’s many roles, it remains unclear why SM typically manifests with a myriad of sebum-containing cysts as the primary symptom.¹² Continued investigation into the genetic underpinnings of SM and the keratin 17 protein is necessary to further elucidate a more comprehensive understanding of this condition.

Hormonal influences have been suggested as a potential trigger for steatocystoma growth.^4,13 This condition is associated with dysfunction of the sebaceous glands, and, correspondingly, the incidence of disease is highest in pubertal patients, in whom androgen levels and sebum production are elevated.^4,13,14 Two cases of transgender men taking testosterone therapy presenting with steatocystomas provide additional clinical support for this association.¹⁵

Additionally, the use of immunomodulatory agents, such as ustekinumab (anti–interleukin 12/interleukin 23), has been shown to trigger SM. It is predicted that the reduced expression of certain interferons and interleukins may lead to downstream consequences in the keratin 17 pathway and lead to SM lesion formation in genetically susceptible individuals.¹⁶ Targeting these potential causes in the future may prove efficacious in the secondary prevention of familial SM manifestation or exacerbations.

Mutations in the KRT17 gene also have been implicated in pachyonychia congenita type 2 (PC-2).⁴ Marked by extensive systemic hyperkeratosis, PC-2 has been observed to coincide with SM in certain patients.^4,5 Interestingly, the location of the KRT17 mutations are identical in both PC-2 and SM.⁴ Although most individuals with hereditary SM do not exhibit the characteristic features of PC-2, mild nail and dental abnormalities have been observed in some SM cases.^4,10 This relationship suggests that SM may be a less severe variant of PC-2 or part of a complex polygenetic spectrum of disease.¹⁰ Further research is imperative to determine the exact nature and extent of the relationship between these conditions.

Clinical Manifestations

Steatocystomas are flesh-colored subcutaneous cysts that range in size from less than 3 mm to larger than 3 cm in diameter (Figure). They form within a single pilosebaceous unit and typically display firm attachment due to their origination in the dermis.^2,7,17 Steatocystomas generally contain lipid material, and less frequently, keratin and hair shafts, distinguishing them as the only “true” sebaceous cysts.¹⁸ Their color can range from flesh-toned to yellow, with reports of occasional dark-blue shades and calcifications.^19,20 Steatocystomas can persist indefinitely, and they usually are asymptomatic.

Diagnosis of steatocystoma is confirmed by biopsy.⁴ Steatocystomas are characterized by a dermal cyst lined by stratified squamous cell epithelium (eFigures 1 and 2).²¹ Classically they feature flattened sebaceous lobules, multinucleated giant cells, and abortive hair follicles. The lining of these cysts is marked by lymphocytic infiltrate and a dense, wrinkled, eosinophilic keratin cuticle that replaces the granular layer.²² The cyst maintains an epidermal connection through a follicular infundibulum characterized by clumps of keratinocytes, sebocytes, corneocytes, and/or hair follicles.⁷ Aspirated contents reveal crystalline structures and anucleate squamous cells upon microscopic analysis. That being said, variable histologic findings of steatocystomas have been described.²³

Steatocystoma simplex, as the name implies, classifies a single isolated steatocystoma. This subtype exhibits similar histopathologic and clinical features to the other subtypes of steatocystomas. Notably, SS is not associated with a genetic mutation and is not an inherited condition within families.⁵ Steatocystoma multiplex manifests with many steatocystomas, often distributed widely across the body.^3,4 The chest, axillae, and groin are the most common locations; however, these cysts can manifest on the face, back, abdomen, and extremities.^4,18-22 Rare occurrences of SM limited to the face, scalp, and distal extremities have been documented.^18,21,24,25 Due to the possibility of an autosomal-dominant inheritance, it is advisable to take a comprehensive family history in patients for whom SM is in the differential.¹⁷

Steatocystoma multiplex—especially familial variants—has been shown to develop in conjunction with other dermatologic conditions, including eruptive vellus hair (EVH) cysts, persistent infantile milia, and epidermoid/dermoid cysts.²⁶ While some investigators regard these as separate entities due to their varied genetic etiology, it has been suggested that these conditions may be related and that the diagnosis is determined by the location of cyst origin along the sebaceous ducts.^26,27 Other dermatologic conditions and lesions that frequently manifest comorbidly with SM include hidrocystomas, syringomas, pilonidal cysts, lichen planus, nodulocystic acne, trichotillomania, trichoblastomas, trichoepithelioma, HS, keratoacanthomas, acrokeratosis verruciformis of Hopf, and embryonal hair formation. Steatocystoma multiplex, manifesting comorbidly with dental and orofacial malformations (eg, partial noneruption of secondary teeth, natal and defective teeth, and bilateral preauricular sinuses) has been classified as SM natal teeth syndrome.⁶

Steatocystoma multiplex suppurativa is a rare and serious variant of SM characterized by inflammation, cyst rupture, sinus tract formation, and scarring.²⁴ Patients with SMS typically have multiple intact SM cysts, which can aid in differentiation from HS.^2,24 Steatocystoma multiplex suppurativa is associated with more complications than SS and SM, including cyst perforation, development of purulent and/or foul-smelling discharge, infection, scarring, pain, and overall discomfort.²

Given its rarity and the potential manifestations that overlap with other conditions, steatocystomas easily can be misdiagnosed. In some clinical instances, EVHs may share similar characteristics with SM; however, certain distinguishing features exist, including a central tuft of protruding hairs and different expressed contents, such as the vellus hair shafts, from the cyst’s lumen.²⁸ Furthermore, histologic examination of EVHs reveals epidermoid keratinization of the lining as well as a lack of sebaceous glands within the wall.^28,29 Other similar conditions include epidermoid cysts, pilar cysts, lipomas, epidermal inclusion cysts, dermoid cysts, sebaceous hyperplasia, folliculitis, xanthomas, neurofibromatosis, and syringomas.³⁰ Occasionally, SMS can be mistaken for HS or acne conglobata, and SM lesions with a facial distribution can mimic acne vulgaris.^1,31 These conditions should be excluded before a diagnosis of SS, SM, or SMS is made. 

Importantly, SM is visually indistinguishable from subcutaneous metastasis on physical examination, and there are reports of oncologic conditions (eg, pulmonary adenocarcinoma metastasized to the skin) being mistaken for SS or SM.³² Therefore, a thorough clinical examination, histopathologic analysis, and potential use of other imaging modalities such as ultrasonography (US) are needed to ensure an accurate diagnosis.

Ultrasonography has demonstrated utility in diagnosing steatocystomas.^33-35 Steatocystomas have incidentally been found on routine mammograms and can demonstrate well-defined circular nodules with radiolucent characteristics and a thin radiodense outline.^33,36 Homogeneous hypoechoic nodules within the dermis without posterior acoustic features generally are observed (eFigure 3).^33,37 In patients declining biopsy, US may be useful in further characterization of an unknown lesion. Color Doppler US can be used to distinguish SMS from HS. Specifically, SM typically exhibits an absence of Doppler signaling due to a lack of vascularity, providing a helpful diagnostic clue for the SMS variant.³³

Management and Treatment Options

There is no established standard treatment for steatocystomas; therefore, the approach to management is contingent on clinical presentation and patient preferences. Various medical, surgical, and laser management options are available, each with its own advantages and limitations. Treatment of SM is difficult due to the large number of lesions.³⁸ In many cases, continued observation is a viable treatment option, as most SS and SM lesions are asymptomatic; however, cosmetic concerns can be debilitating for patients with SM and may warrant intervention.³⁹ More extensive medical and surgical management often are necessary in SMS due to associated morbidity. Discussing options and goals as well as setting realistic expectations with the patient are essential in determining the optimal approach.

Medical Management—In medical literature, oral isotretinoin (13-cis-retinoic acid) has been the mainstay of therapy for steatocystoma, as its effect on the size and activity of sebaceous glands is hypothesized to decrease disease activity.^38,40 Interventional studies and case reports have exhibited varying degrees of effectiveness.^1,38-41 Some reports depict a reduction in the formation of new lesions and a decrease in the size of pre-existing lesions, some show mild delayed therapeutic efficacy, and others suggest exacerbation of the condition.^1,38-41 This outcome variability is attributed to isotretinoin’s preferential efficacy in treating inflammatory lesions.^40,42

Tetracycline derivatives and intralesional steroid injections also have been employed with some efficacy in patients with focal inflammatory SM and SMS.⁴³ There is limited evidence on the long-term outcomes of these interventions, and intralesional injections often are not recommended in conditions such as SM, in which there are many lesions present.

Surgical Management—Minimally invasive surgical procedures including drainage and resections have been used with varying efficacy in SS and SM. Typically, a 2- to 3-mm incision or sharp-tipped cautery is employed to puncture the cyst. Alternatively, radiofrequency probes with a 2.4-MHz frequency setting have been used to minimize incision size.⁴⁴ The contents then are expressed with manual pressure or forceps, and the cyst sac is extracted using forceps and/or a vein hook (eFigure 4).^44,45 The specific surgical techniques and their respective advantages and limitations are summarized in the eTable. Reported advantages and limitations of surgical techniques are derived from information provided by the authors of steatocystoma case reports, which are based on observations of a very limited sample size.

Laser Treatment—Various laser modalities have been used in the management of steatocystomas, including carbon dioxide lasers, erbium-doped yttrium aluminum garnet lasers, 1450-nm diode plus 1550-nm fractionated erbium-doped fiber lasers, and 1927-nm diode lasers.^54,55-57 These lasers are used to perforate the cyst before extirpation and have displayed advantages in minimizing scar length.⁵⁸ The super-pulse mode of carbon dioxide lasers demonstrates efficacy with minimal scarring and recurrence, and this mode is preferred to minimize thermal damage.^54,59 Furthermore, this modality can be especially useful in patients whose condition is refractory to other noninvasive options.⁵⁹ Similarly, the erbium-doped yttrium aluminum garnet laser was well tolerated with no complications noted.⁵⁵ The 1927-nm diode laser also displayed good outcomes as well as no recurrence.⁵⁷ With laser use, it is important to note that multiple treatments are needed to see optimal outcomes.⁵⁴ Moreover, laser settings must be carefully considered, especially in patients with Fitzpatrick skin type III or higher, and topical anti-inflammatory agents should be considered posttreatment to minimize complications.^54,59,60

Recommendations

For management of SS, we recommend conservative therapy of watchful observation, as scarring or postinflammatory pigment change may be brought on by medical or surgical therapy; however, if SS is cosmetically bothersome, laser or surgical excision can be done (eFigure 4).^4,43-53 It is important to counsel the patient on risks/benefits. For SM, watchful observation also is indicated; however, systemic therapies aimed at prevention may be the most efficacious by limiting disease progression, and oral tetracycline or isotretinoin may be tried.⁴ Tetracyclines have the risk for photosensitivity and are teratogenic, while isotretinoin is extremely teratogenic, requires laboratory monitoring and regular pregnancy tests in women, and often causes substantial mucosal dryness. If lesions are bothersome or refractory to these therapies, intralesional steroids or surgical/laser procedures can be tried throughout multiple visits.^43-53 For SMS, systemic therapies frequently are recommended. The risks of systemic tetracycline and isotretinoin therapies must be discussed. Patients with treatment-refractory SMS may require surgical excision or deroofing of sinus tracts.^43-53 This management is similar to that of HS and must be tailored to the patient.

Conclusion

Overall, steatocystomas are a relatively rare pathology, with a limited consensus on their etiology and management. This review summarizes the current knowledge on the condition to support clinicians in diagnosis and management, ranging from watchful waiting to surgical removal. By individualizing treatment plans, clinicians ultimately can optimize outcomes in patients with steatocystomas.

Steatocystomas are small sebum-filled cysts that typically manifest in the dermis and originate from sebaceous follicles. Although commonly asymptomatic, these lesions can manifest with pruritus or become infected, predisposing patients to further complications.¹ Steatocystomas can manifest as single (steatocystoma simplex [SS]) or numerous (steatocystoma multiplex [SM]) lesions; the lesions also can spontaneously rupture with characteristics that resemble hidradenitis suppurativa (HS)(steatocystoma multiplex suppurativa [SMS]).^1,2

Steatocystomas are relatively rare, and there is limited consensus in the published literature on the etiology and management of this condition. In this article, we present a comprehensive review of steatocystomas in the current literature. We highlight important features to consider when making the diagnosis and also offer recommendations for best-practice treatment.

Historical Background

Although not explicitly identified by name, the first documentation of steatocystomas is a case report published in 1873. In this account, the author described a patient who presented with approximately 250 flesh-colored dermal cysts across the body that varied in size.³ In 1899, the term steatocystoma multiple—derived from Greek roots meaning “fatty bag”—was first used.⁴

In 1982, almost a century later, Brownstein⁵ reported some of the earliest cases of SS. This solitary subtype is identical to SM on a microscopic level; however, unlike SM, this variant occurs as a single lesion that typically forms in adulthood and in the absence of family history. Other benign adnexal tumors (eg, pilomatricomas, pilar cysts, and sebaceous hyperplasias) also can manifest as either solitary or multiple lesions.

In 1976, McDonald and Reed⁶ reported the first known cases of patients with both SM and HS. At the time, the co-occurrence of these conditions was viewed as coincidental, but there were postulations of a shared inflammatory process and hereditary link⁶; it was not until 1982 that the term steatocystoma multiplex suppurativum was coined to describe this variant.⁷ Although rare, there have been multiple documented instances of SMS since. It has been suggested that the convergence of these conditions may indicate a shared follicular proliferation defect.⁸ Ongoing investigation is warranted to explain the underlying pathogenesis of this unique variant.

Epidemiology

The available epidemiologic data primarily relate to SM, the most common steatocystoma variant. Nevertheless, SM is a relatively rare condition, and the exact incidence and prevalence remain unknown.^8,9 Steatocystomas typically manifest in the first and second decades of life and have been observed in patients of both sexes, with studies demonstrating no notable sex bias.^4,9

Etiology and Pathophysiology

Steatocystomas can occur sporadically or may be inherited as an autosomal-dominant condition.⁴ Typically, SS tends to manifest as an isolated occurrence without any inherent genetic predisposition.⁵ Alternatively, SM may develop sporadically or be associated with a mutation in the keratin 17 gene (KRT17).⁴ Steatocystoma multiplex also has been associated with at least 4 different missense mutations, including N92H, R94H, and R94C, located on the long (q) arm of chromosome 17.^4,10-12

The keratin 17 gene is responsible for encoding the keratin 17 protein, a type I intermediate filament predominantly synthesized in the basal cells of epithelial tissue. This fibrous structural protein can regulate many processes, including inflammation and cell proliferation, and is found in regions such as the sebaceous glands, hair follicles, and eccrine sweat glands. Overexpression of KRT17 has been suggested in other cutaneous conditions, most notably psoriasis.¹² Despite KRT17’s many roles, it remains unclear why SM typically manifests with a myriad of sebum-containing cysts as the primary symptom.¹² Continued investigation into the genetic underpinnings of SM and the keratin 17 protein is necessary to further elucidate a more comprehensive understanding of this condition.

Hormonal influences have been suggested as a potential trigger for steatocystoma growth.^4,13 This condition is associated with dysfunction of the sebaceous glands, and, correspondingly, the incidence of disease is highest in pubertal patients, in whom androgen levels and sebum production are elevated.^4,13,14 Two cases of transgender men taking testosterone therapy presenting with steatocystomas provide additional clinical support for this association.¹⁵

Additionally, the use of immunomodulatory agents, such as ustekinumab (anti–interleukin 12/interleukin 23), has been shown to trigger SM. It is predicted that the reduced expression of certain interferons and interleukins may lead to downstream consequences in the keratin 17 pathway and lead to SM lesion formation in genetically susceptible individuals.¹⁶ Targeting these potential causes in the future may prove efficacious in the secondary prevention of familial SM manifestation or exacerbations.

Mutations in the KRT17 gene also have been implicated in pachyonychia congenita type 2 (PC-2).⁴ Marked by extensive systemic hyperkeratosis, PC-2 has been observed to coincide with SM in certain patients.^4,5 Interestingly, the location of the KRT17 mutations are identical in both PC-2 and SM.⁴ Although most individuals with hereditary SM do not exhibit the characteristic features of PC-2, mild nail and dental abnormalities have been observed in some SM cases.^4,10 This relationship suggests that SM may be a less severe variant of PC-2 or part of a complex polygenetic spectrum of disease.¹⁰ Further research is imperative to determine the exact nature and extent of the relationship between these conditions.

Clinical Manifestations

Steatocystomas are flesh-colored subcutaneous cysts that range in size from less than 3 mm to larger than 3 cm in diameter (Figure). They form within a single pilosebaceous unit and typically display firm attachment due to their origination in the dermis.^2,7,17 Steatocystomas generally contain lipid material, and less frequently, keratin and hair shafts, distinguishing them as the only “true” sebaceous cysts.¹⁸ Their color can range from flesh-toned to yellow, with reports of occasional dark-blue shades and calcifications.^19,20 Steatocystomas can persist indefinitely, and they usually are asymptomatic.

Diagnosis of steatocystoma is confirmed by biopsy.⁴ Steatocystomas are characterized by a dermal cyst lined by stratified squamous cell epithelium (eFigures 1 and 2).²¹ Classically they feature flattened sebaceous lobules, multinucleated giant cells, and abortive hair follicles. The lining of these cysts is marked by lymphocytic infiltrate and a dense, wrinkled, eosinophilic keratin cuticle that replaces the granular layer.²² The cyst maintains an epidermal connection through a follicular infundibulum characterized by clumps of keratinocytes, sebocytes, corneocytes, and/or hair follicles.⁷ Aspirated contents reveal crystalline structures and anucleate squamous cells upon microscopic analysis. That being said, variable histologic findings of steatocystomas have been described.²³

Steatocystoma simplex, as the name implies, classifies a single isolated steatocystoma. This subtype exhibits similar histopathologic and clinical features to the other subtypes of steatocystomas. Notably, SS is not associated with a genetic mutation and is not an inherited condition within families.⁵ Steatocystoma multiplex manifests with many steatocystomas, often distributed widely across the body.^3,4 The chest, axillae, and groin are the most common locations; however, these cysts can manifest on the face, back, abdomen, and extremities.^4,18-22 Rare occurrences of SM limited to the face, scalp, and distal extremities have been documented.^18,21,24,25 Due to the possibility of an autosomal-dominant inheritance, it is advisable to take a comprehensive family history in patients for whom SM is in the differential.¹⁷

Steatocystoma multiplex—especially familial variants—has been shown to develop in conjunction with other dermatologic conditions, including eruptive vellus hair (EVH) cysts, persistent infantile milia, and epidermoid/dermoid cysts.²⁶ While some investigators regard these as separate entities due to their varied genetic etiology, it has been suggested that these conditions may be related and that the diagnosis is determined by the location of cyst origin along the sebaceous ducts.^26,27 Other dermatologic conditions and lesions that frequently manifest comorbidly with SM include hidrocystomas, syringomas, pilonidal cysts, lichen planus, nodulocystic acne, trichotillomania, trichoblastomas, trichoepithelioma, HS, keratoacanthomas, acrokeratosis verruciformis of Hopf, and embryonal hair formation. Steatocystoma multiplex, manifesting comorbidly with dental and orofacial malformations (eg, partial noneruption of secondary teeth, natal and defective teeth, and bilateral preauricular sinuses) has been classified as SM natal teeth syndrome.⁶

Steatocystoma multiplex suppurativa is a rare and serious variant of SM characterized by inflammation, cyst rupture, sinus tract formation, and scarring.²⁴ Patients with SMS typically have multiple intact SM cysts, which can aid in differentiation from HS.^2,24 Steatocystoma multiplex suppurativa is associated with more complications than SS and SM, including cyst perforation, development of purulent and/or foul-smelling discharge, infection, scarring, pain, and overall discomfort.²

Given its rarity and the potential manifestations that overlap with other conditions, steatocystomas easily can be misdiagnosed. In some clinical instances, EVHs may share similar characteristics with SM; however, certain distinguishing features exist, including a central tuft of protruding hairs and different expressed contents, such as the vellus hair shafts, from the cyst’s lumen.²⁸ Furthermore, histologic examination of EVHs reveals epidermoid keratinization of the lining as well as a lack of sebaceous glands within the wall.^28,29 Other similar conditions include epidermoid cysts, pilar cysts, lipomas, epidermal inclusion cysts, dermoid cysts, sebaceous hyperplasia, folliculitis, xanthomas, neurofibromatosis, and syringomas.³⁰ Occasionally, SMS can be mistaken for HS or acne conglobata, and SM lesions with a facial distribution can mimic acne vulgaris.^1,31 These conditions should be excluded before a diagnosis of SS, SM, or SMS is made. 

Importantly, SM is visually indistinguishable from subcutaneous metastasis on physical examination, and there are reports of oncologic conditions (eg, pulmonary adenocarcinoma metastasized to the skin) being mistaken for SS or SM.³² Therefore, a thorough clinical examination, histopathologic analysis, and potential use of other imaging modalities such as ultrasonography (US) are needed to ensure an accurate diagnosis.

Ultrasonography has demonstrated utility in diagnosing steatocystomas.^33-35 Steatocystomas have incidentally been found on routine mammograms and can demonstrate well-defined circular nodules with radiolucent characteristics and a thin radiodense outline.^33,36 Homogeneous hypoechoic nodules within the dermis without posterior acoustic features generally are observed (eFigure 3).^33,37 In patients declining biopsy, US may be useful in further characterization of an unknown lesion. Color Doppler US can be used to distinguish SMS from HS. Specifically, SM typically exhibits an absence of Doppler signaling due to a lack of vascularity, providing a helpful diagnostic clue for the SMS variant.³³

Management and Treatment Options

There is no established standard treatment for steatocystomas; therefore, the approach to management is contingent on clinical presentation and patient preferences. Various medical, surgical, and laser management options are available, each with its own advantages and limitations. Treatment of SM is difficult due to the large number of lesions.³⁸ In many cases, continued observation is a viable treatment option, as most SS and SM lesions are asymptomatic; however, cosmetic concerns can be debilitating for patients with SM and may warrant intervention.³⁹ More extensive medical and surgical management often are necessary in SMS due to associated morbidity. Discussing options and goals as well as setting realistic expectations with the patient are essential in determining the optimal approach.

Medical Management—In medical literature, oral isotretinoin (13-cis-retinoic acid) has been the mainstay of therapy for steatocystoma, as its effect on the size and activity of sebaceous glands is hypothesized to decrease disease activity.^38,40 Interventional studies and case reports have exhibited varying degrees of effectiveness.^1,38-41 Some reports depict a reduction in the formation of new lesions and a decrease in the size of pre-existing lesions, some show mild delayed therapeutic efficacy, and others suggest exacerbation of the condition.^1,38-41 This outcome variability is attributed to isotretinoin’s preferential efficacy in treating inflammatory lesions.^40,42

Tetracycline derivatives and intralesional steroid injections also have been employed with some efficacy in patients with focal inflammatory SM and SMS.⁴³ There is limited evidence on the long-term outcomes of these interventions, and intralesional injections often are not recommended in conditions such as SM, in which there are many lesions present.

Surgical Management—Minimally invasive surgical procedures including drainage and resections have been used with varying efficacy in SS and SM. Typically, a 2- to 3-mm incision or sharp-tipped cautery is employed to puncture the cyst. Alternatively, radiofrequency probes with a 2.4-MHz frequency setting have been used to minimize incision size.⁴⁴ The contents then are expressed with manual pressure or forceps, and the cyst sac is extracted using forceps and/or a vein hook (eFigure 4).^44,45 The specific surgical techniques and their respective advantages and limitations are summarized in the eTable. Reported advantages and limitations of surgical techniques are derived from information provided by the authors of steatocystoma case reports, which are based on observations of a very limited sample size.

Laser Treatment—Various laser modalities have been used in the management of steatocystomas, including carbon dioxide lasers, erbium-doped yttrium aluminum garnet lasers, 1450-nm diode plus 1550-nm fractionated erbium-doped fiber lasers, and 1927-nm diode lasers.^54,55-57 These lasers are used to perforate the cyst before extirpation and have displayed advantages in minimizing scar length.⁵⁸ The super-pulse mode of carbon dioxide lasers demonstrates efficacy with minimal scarring and recurrence, and this mode is preferred to minimize thermal damage.^54,59 Furthermore, this modality can be especially useful in patients whose condition is refractory to other noninvasive options.⁵⁹ Similarly, the erbium-doped yttrium aluminum garnet laser was well tolerated with no complications noted.⁵⁵ The 1927-nm diode laser also displayed good outcomes as well as no recurrence.⁵⁷ With laser use, it is important to note that multiple treatments are needed to see optimal outcomes.⁵⁴ Moreover, laser settings must be carefully considered, especially in patients with Fitzpatrick skin type III or higher, and topical anti-inflammatory agents should be considered posttreatment to minimize complications.^54,59,60

Recommendations

For management of SS, we recommend conservative therapy of watchful observation, as scarring or postinflammatory pigment change may be brought on by medical or surgical therapy; however, if SS is cosmetically bothersome, laser or surgical excision can be done (eFigure 4).^4,43-53 It is important to counsel the patient on risks/benefits. For SM, watchful observation also is indicated; however, systemic therapies aimed at prevention may be the most efficacious by limiting disease progression, and oral tetracycline or isotretinoin may be tried.⁴ Tetracyclines have the risk for photosensitivity and are teratogenic, while isotretinoin is extremely teratogenic, requires laboratory monitoring and regular pregnancy tests in women, and often causes substantial mucosal dryness. If lesions are bothersome or refractory to these therapies, intralesional steroids or surgical/laser procedures can be tried throughout multiple visits.^43-53 For SMS, systemic therapies frequently are recommended. The risks of systemic tetracycline and isotretinoin therapies must be discussed. Patients with treatment-refractory SMS may require surgical excision or deroofing of sinus tracts.^43-53 This management is similar to that of HS and must be tailored to the patient.

Conclusion

Overall, steatocystomas are a relatively rare pathology, with a limited consensus on their etiology and management. This review summarizes the current knowledge on the condition to support clinicians in diagnosis and management, ranging from watchful waiting to surgical removal. By individualizing treatment plans, clinicians ultimately can optimize outcomes in patients with steatocystomas.

There are 3 uncommon types of mechanobullous skin diseases caused by relative reduction or complete loss of functional type VII collagen, which is the main component of anchoring fibrils in the lamina densa of the basement membrane zone (BMZ) of the skin and mucous membrane epithelium.¹ The function of the anchoring fibrils is to maintain adherence of the basement membrane of the epithelium to the connective tissue of the papillary dermis and submucosa.¹ The mechanism of action of the loss of type VII collagen function is via autoimmunity in epidermolysis bullosa acquisita (EBA)² and bullous systemic lupus erythematosus (BSLE).³ In the heritable family of 4 epidermolysis bullosa (EB) variants, only one of the subtypes—dystrophic EB (DEB)—is caused by various recessive and dominant mutations of the type VII collagen gene (COL7A1).⁴ The other 3 diseases in the family—EB simplex, junctional EB, and Kindler syndrome—are caused by diverse mutations that corrupt the integrity of keratinocytes and the BMZ.^5,6 This article provides an overview of these 3 subtypes to help differentiate them from DEB.

Epidermolysis Bullosa

Epidermolysis bullosa consists of a heterogeneous family of 4 major genetic mechanobullous diseases that affect the skin and mucous membranes with more than 30 subtypes.¹ Dystrophic EB is caused by mutations in the COL7A1 gene, which encodes for the α-1 chain of collagen type VII. Classically, EB is divided into 4 main variants based on the location of the cleavage plane or split occurring in the epithelium, which in turn helps to predict the severity of the illness.

Epidermolysis bullosa may be inherited in an ­autosomal-dominant or autosomal-recessive fashion, or it may occur as a spontaneous mutation. All sexes and races are affected equally. Patients present at birth or in early childhood with fragile skin and mucous membranes that may develop blisters, erosions, and ulcerations after minor trauma.⁷ These lesions are marked by slow healing and scar formation and often are associated with itching and pain.

Dystrophic Epidermolysis Bullosa

Dystrophic EB accounts for approximately 25%⁶ of all EB cases in the United States and may be inherited as either a dominant or recessive trait. Hundreds of different pathogenic mutations have been discovered in the COL7A1 gene in the subtypes of DEB.^4,8 Dominant DEB tends to cause milder disease because the patients retain one normal COL7A1 allele and produce some type VII collagen (Figure 1), whereas patients with recessive DEB lack type VII collagen completely.⁹ The cleavage plane is between the lamina densa and the superficial dermis or submucosa. Severity is variable and ranges from ­localization to the hands and feet to severe generalized blistering and painful ulcerations depending on which of the many possible gene mutations have been inherited. Sequelae include mitten deformities, malalignment and tooth decay, and the development of early aggressive squamous cell carcinomas, which may be fatal. The most severe cases of recessive DEB also may have internal organ involvement.

Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex is the most common variant, comprising approximately 70%of EB cases in the United States.⁶ Epidermolysis bullosa simplex usually is inherited as autosomal-dominant mutations in the keratin 5 or keratin 14 genes,¹⁰ not COL7A1. Skin blistering results from cleavage within the basal cell layer where the keratin genes are primarily expressed. Blisters tend to occur in acral areas such as hands and feet and may heal without scarring in the localized form of epidermolysis bullosa simplex (Figure 2).

Junctional Epidermolysis Bullosa and Kindler Syndrome

Junctional epidermolysis bullosa (JEB) and Kindler syndrome¹¹ are the rarest of the autosomal-recessive EB ­variants.⁶ The plane of cleavage in JEB is through the lamina lucida of the BMZ. Junctional epidermolysis bullosa is caused by mutations of the genes that encode for the 3 chains of laminin 332 protein and type XVII collagen,^5,12 not to be confused with type VII collagen. As with DEB, there is a wide range of severity in JEB, from localized effects on the eyes, oral cavity, and tooth enamel to widespread blistering and skin cancers. In JEB cases involving newborns, nonhealing wounds on the face, buttocks, fingers, and toes may be seen, with devastating complications in the oral cavity, esophagus, and larynx. Life expectancy is limited to 2 years or less.⁶ There have only been approximately 40,013 cases of Kindler syndrome reported worldwide⁶ and there is clinical overlap with DEB. Patients also may demonstrate poikiloderma and photosensitivity. Kindler syndrome is caused by mutations in the FERMT1 gene which encodes for kindlin-1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix.^5,11 Loss of function produces variable cleavage planes around the dermoepidermal junction.

Clinical management of all EB variants, especially the severe recessive types, traditionally has been limited to the prevention of trauma to the skin and mucous membranes and supportive care, including dressing changes to erosions and ulcerations, antibiotic ointments as needed, and amelioration of pain and pruritus. Bone marrow and pluripotential stem cell transplants have been attempted.¹² Complications of EB, such as deformities of the hands and feet caused by excessive scarring, esophageal strictures, poor dentition, and squamous cell carcinomas, must be addressed by a multidisciplinary team of specialists, including plastic surgery, gastroenterology, dentistry/oral surgery, ophthalmology, and dermatology/Mohs surgery. 

Until recently, there were no medications approved by the US Food and Drug Administration (FDA) specifically indicated for EB. In 2023, topical gene therapy was approved by the FDA for both recessive and dominant forms of DEB. Normal COL7A1 sequences are delivered by an attenuated herpes simplex virus 1 vector (beremagene geperpavec) in a gel applied directly to the wounds of patients with DEB. In a clinical trial, matching wounds on 31 patients (62 wounds total) were treated with the active agent or placebo gel. After 6 months, complete wound closure was observed in 67% (21/31) of those treated with the active agent and 22% (7/31) of those treated with placebo (P=.002).¹⁴ In a single case report, a patient with recessive DEB and cicatrizing conjunctivitis (Figure 3) was given ophthalmic beremagene geperpavec after surgery and had improved visual acuity.¹⁵ A topical gel consisting of birch triterpenes to promote healing of partial-thickness wounds also was approved for patients with DEB and JEB by the FDA and the European Commission. In a study of 223 patients, 41% of those using active gel and 29% of those using placebo gel achieved the primary end point of percentage of target wounds that had first complete closure at 45 days.¹⁶ 

The most recent FDA approval for DEB involves transferring the functional COL7A1 gene to the patient’s skin cells, then expanding the gene-corrected cells into sheets of keratinocytes that can be surgically applied to the chronic wound sites. In a phase 3 trial of prademagene zamikeracel (pz-cel), 11 patients with 86 matched wounds were randomized to receive pz-cel (50%) or standard wound care (50%). After 24 weeks, 35 wounds treated with pz-cel were at least 50% healed compared to 7 control wounds.¹⁷ The results for healing and reduction of pain were statistically significant (P<.0001 and P<.0002, respectively).¹⁷ Recombinant collagen VII as replacement therapy also is under study to be given by intravenous infusion to increase tissue collagen VII where it is lacking. This treatment has shown early biologic and therapeutic effects.^9,18 Larger long-term follow-up studies are necessary to confirm persistence of the gene-corrected skin cells, the functionality of the replacement collagen VII, and the potential risk for the development of autoantibodies to type VII collagen.

Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita is a rare autoimmune subepithelial bullous disease that primarily affects middle-aged adults but also has been reported in children.¹⁹ Epidermolysis bullosa acquisita is caused by circulating pathogenic IgG autoantibodies that target and bind to type VII collagen in the anchoring fibrils,^20-22 thereby disrupting the attachment of the epithelium to its underlying connective tissue.

The 2 major clinical manifestations of EBA include a mechanobullous disease resembling inherited forms of DEB (Figure 4) and an inflammatory bullous pemphigoid (BP)–like disease,²³ as well as a combination of both types of skin lesions (Figure 5). The skin and mucous membranes of the oral cavity, esophagus, eyes, and urogenital areas are affected in both types; scarring may cause functional disabilities. In the mechanobullous type of EBA, it is common for blisters and erosions to develop in trauma-prone areas such as the hands, feet, elbows, and knees. The blisters tend to heal with scarring and milia formation as might be seen in porphyria cutanea tarda or cicatricial pemphigoid, which are in the differential diagnosis. Dystrophy of the fingernails or complete nail loss may be observed, resembling DEB. In the BP-like presentation, tense blisters arise upon inflamed or urticarial skin and mucous membranes, which may then become generalized. 

Histopathology in both forms of EBA demonstrates subepithelial separation as clefts or blisters. The mechanobullous type shows a sparse inflammatory infiltrate compared to large collections of neutrophils and eosinophils in the blister cavity and in the superficial dermis in the BP-like cases. The final diagnosis rests on the results of immunopathology testing.²⁴ Direct immunofluorescence of perilesional skin and mucosa shows a linear-granular band of IgG and C3 and other conjugates along the BMZ. Deposits of IgA alone in EBA occur in only about 2.4% of cases and are observed more often when there is mucous membrane involvement.² Indirect immunofluorescence of sera against salt-split skin substrates detects immunoreactants in the floor of the blister rather than in the roof, as would be seen in BP. Highly specific and sensitive enzyme-linked immunosorbent assay (ELISA) kits now are commercially available and can detect autoantibodies against the N-terminal domain of type VII collagen in more than 90% of cases of EBA.²⁵ 

Inflammatory bowel disease (IBD), particularly Crohn disease (CD), precedes the onset of EBA in approximately 25% of cases.^26,27 Ulcerative colitis is much less common. Type VII collagen is normally present in the basement membrane of intestinal epithelium. In a survey of patients with IBD, 68% of those with CD and 13% of those with ulcerative colitis had circulating anti–type VII collagen antibodies detected by ELISA without having symptoms of EBA.²⁸ A case report of a patient with both well-proven EBA and CD highlighted the clinical difficulty of controlling EBA: treatment with prednisolone and sulfasalazine improved the CD but had little effect on the skin blisters.²⁹ A variety of malignancies have been reported in association with EBA, including cancers of the uterine cervix,³⁰ thyroid, and pancreas,³¹ lymphoma, and chronic lymphatic leukemia. Some of these cases have met the criteria for classification as paraneoplastic, whereas others may have been coincidental. 

Treatment for chronic EBA generally has been limited.^2,24 Putative antineutrophil drugs such as dapsone and colchicine combined with systemic corticosteroids may be useful in milder or juvenile cases, which tend to have a better prognosis than adult cases.¹⁹ In more severe EBA, systemic corticosteroids and/or immunosuppressive drugs such as azathioprine,²³ cyclophosphamide,²³ mycophenolate mofetil,³¹ methotrexate,²³ cyclosporine,³³ and infliximab²³ have been used. More recently, rituximab infusion monotherapy³³ and rituximab combined with intravenous immunoglobulin or adjuvant immunoadsorption of the pathogenic autoantibodies have induced remission of refractory EBA.³² Adjuvant immunoadsorption therapy is not widely available. Multispecialty care often is required, especially ophthalmology for conjunctival involvement and gastroenterology for potential esophageal stenosis and the early detection and treatment of IBD.

Bullous Systemic Lupus Erythematosus

Bullous systemic lupus erythematosus is a rare and specific autoimmune skin complication that mostly is seen in patients with an established diagnosis of systemic lupus erythematosus (SLE) who are experiencing a disease flare. Although more common in women, it has been reported in all sexes and races as well as in children. Vesicles and bullae may arise on sun-exposed (Figure 6) and sun-protected areas of skin.

Histopathology shows subepidermal separation with collections of neutrophils and nuclear fragments in the blister cavity. The differential diagnosis of BSLE includes EBA, BP, dermatitis herpetiformis, and linear IgA bullous dermatosis. Direct immunofluorescence testing shows linear-granular deposits of IgG and/or IgM and IgA along the BMZ.³⁴ When utilizing the indirect immunofluorescence split-skin assay, the autoantibody to type VII collagen would be detected in the floor of the blister if the serum titer was sufficiently high.³ Proposed criteria for the diagnosis of BSLE have been published: 1) diagnosis of SLE now based on the 2019 European League Against Rheumatism/American College of Rheumatology classification³⁵; 2) vesicles and bullae arising upon but not limited to sun-exposed skin; 3) histopathology featuring neutrophil-rich subepithelial bullae; 4) positive indirect immunofluorescence for circulating BMZ antibodies using separated human skin as substrate; 5) and direct immunofluorescence showing IgG and/or IgM and often IgA at the BMZ.³⁶ Using ELISA to detect circulating antibodies against type VII collagen²⁴ should now be added to the criteria. The new criteria for SLE³⁴ do not include BSLE, perhaps because it occurs in less than 1% of patients with SLE.³⁷ 

Further investigation by Gammon et al³ confirmed that the autoantibodies in BSLE are identical to those found in EBA (ie, directed against type VII collagen in the lamina densa). Bullous systemic lupus erythematosus is not considered to be the coexistence of EBA with SLE but rather a specific entity wherein type VII collagen autoantibodies are expressed in the autoimmune spectrum of SLE. It is especially important to make the diagnosis of BSLE because it is predictive of more serious systemic complications of SLE (eg, hematologic and renal disease is found in up to 90% of cases).³⁸ 

The natural course of BSLE is variable. Treatments include systemic corticosteroids, dapsone, and immunosuppressive drugs such as azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide, especially in cases with nephritis.³⁷ There may be spontaneous resolution of the rash as the inflammatory activity of SLE subsides. Rituximab has been used effectively in several refractory cases of BSLE that failed to respond to all other conventional treatments.³⁹

Conclusion

Anchoring fibrils are composed primarily of type VII collagen. Their role is to maintain the attachment of epithelium to the upper dermis and submucosa. The reduction or complete loss of type VII collagen caused by mutations of the COL7A1 gene results in dominant DEB or recessive DEB, respectively. Two distinct non-heritable immunobullous diseases, EBA and BSLE, are caused by autoantibodies that target type VII collagen. A comparison of the 4 type VII collagen disorders can be found in the Table.

There are 3 uncommon types of mechanobullous skin diseases caused by relative reduction or complete loss of functional type VII collagen, which is the main component of anchoring fibrils in the lamina densa of the basement membrane zone (BMZ) of the skin and mucous membrane epithelium.¹ The function of the anchoring fibrils is to maintain adherence of the basement membrane of the epithelium to the connective tissue of the papillary dermis and submucosa.¹ The mechanism of action of the loss of type VII collagen function is via autoimmunity in epidermolysis bullosa acquisita (EBA)² and bullous systemic lupus erythematosus (BSLE).³ In the heritable family of 4 epidermolysis bullosa (EB) variants, only one of the subtypes—dystrophic EB (DEB)—is caused by various recessive and dominant mutations of the type VII collagen gene (COL7A1).⁴ The other 3 diseases in the family—EB simplex, junctional EB, and Kindler syndrome—are caused by diverse mutations that corrupt the integrity of keratinocytes and the BMZ.^5,6 This article provides an overview of these 3 subtypes to help differentiate them from DEB.

Epidermolysis Bullosa

Epidermolysis bullosa consists of a heterogeneous family of 4 major genetic mechanobullous diseases that affect the skin and mucous membranes with more than 30 subtypes.¹ Dystrophic EB is caused by mutations in the COL7A1 gene, which encodes for the α-1 chain of collagen type VII. Classically, EB is divided into 4 main variants based on the location of the cleavage plane or split occurring in the epithelium, which in turn helps to predict the severity of the illness.

Epidermolysis bullosa may be inherited in an ­autosomal-dominant or autosomal-recessive fashion, or it may occur as a spontaneous mutation. All sexes and races are affected equally. Patients present at birth or in early childhood with fragile skin and mucous membranes that may develop blisters, erosions, and ulcerations after minor trauma.⁷ These lesions are marked by slow healing and scar formation and often are associated with itching and pain.

Dystrophic Epidermolysis Bullosa

Dystrophic EB accounts for approximately 25%⁶ of all EB cases in the United States and may be inherited as either a dominant or recessive trait. Hundreds of different pathogenic mutations have been discovered in the COL7A1 gene in the subtypes of DEB.^4,8 Dominant DEB tends to cause milder disease because the patients retain one normal COL7A1 allele and produce some type VII collagen (Figure 1), whereas patients with recessive DEB lack type VII collagen completely.⁹ The cleavage plane is between the lamina densa and the superficial dermis or submucosa. Severity is variable and ranges from ­localization to the hands and feet to severe generalized blistering and painful ulcerations depending on which of the many possible gene mutations have been inherited. Sequelae include mitten deformities, malalignment and tooth decay, and the development of early aggressive squamous cell carcinomas, which may be fatal. The most severe cases of recessive DEB also may have internal organ involvement.

Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex is the most common variant, comprising approximately 70%of EB cases in the United States.⁶ Epidermolysis bullosa simplex usually is inherited as autosomal-dominant mutations in the keratin 5 or keratin 14 genes,¹⁰ not COL7A1. Skin blistering results from cleavage within the basal cell layer where the keratin genes are primarily expressed. Blisters tend to occur in acral areas such as hands and feet and may heal without scarring in the localized form of epidermolysis bullosa simplex (Figure 2).

Junctional Epidermolysis Bullosa and Kindler Syndrome

Junctional epidermolysis bullosa (JEB) and Kindler syndrome¹¹ are the rarest of the autosomal-recessive EB ­variants.⁶ The plane of cleavage in JEB is through the lamina lucida of the BMZ. Junctional epidermolysis bullosa is caused by mutations of the genes that encode for the 3 chains of laminin 332 protein and type XVII collagen,^5,12 not to be confused with type VII collagen. As with DEB, there is a wide range of severity in JEB, from localized effects on the eyes, oral cavity, and tooth enamel to widespread blistering and skin cancers. In JEB cases involving newborns, nonhealing wounds on the face, buttocks, fingers, and toes may be seen, with devastating complications in the oral cavity, esophagus, and larynx. Life expectancy is limited to 2 years or less.⁶ There have only been approximately 40,013 cases of Kindler syndrome reported worldwide⁶ and there is clinical overlap with DEB. Patients also may demonstrate poikiloderma and photosensitivity. Kindler syndrome is caused by mutations in the FERMT1 gene which encodes for kindlin-1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix.^5,11 Loss of function produces variable cleavage planes around the dermoepidermal junction.

Clinical management of all EB variants, especially the severe recessive types, traditionally has been limited to the prevention of trauma to the skin and mucous membranes and supportive care, including dressing changes to erosions and ulcerations, antibiotic ointments as needed, and amelioration of pain and pruritus. Bone marrow and pluripotential stem cell transplants have been attempted.¹² Complications of EB, such as deformities of the hands and feet caused by excessive scarring, esophageal strictures, poor dentition, and squamous cell carcinomas, must be addressed by a multidisciplinary team of specialists, including plastic surgery, gastroenterology, dentistry/oral surgery, ophthalmology, and dermatology/Mohs surgery. 

Until recently, there were no medications approved by the US Food and Drug Administration (FDA) specifically indicated for EB. In 2023, topical gene therapy was approved by the FDA for both recessive and dominant forms of DEB. Normal COL7A1 sequences are delivered by an attenuated herpes simplex virus 1 vector (beremagene geperpavec) in a gel applied directly to the wounds of patients with DEB. In a clinical trial, matching wounds on 31 patients (62 wounds total) were treated with the active agent or placebo gel. After 6 months, complete wound closure was observed in 67% (21/31) of those treated with the active agent and 22% (7/31) of those treated with placebo (P=.002).¹⁴ In a single case report, a patient with recessive DEB and cicatrizing conjunctivitis (Figure 3) was given ophthalmic beremagene geperpavec after surgery and had improved visual acuity.¹⁵ A topical gel consisting of birch triterpenes to promote healing of partial-thickness wounds also was approved for patients with DEB and JEB by the FDA and the European Commission. In a study of 223 patients, 41% of those using active gel and 29% of those using placebo gel achieved the primary end point of percentage of target wounds that had first complete closure at 45 days.¹⁶ 

The most recent FDA approval for DEB involves transferring the functional COL7A1 gene to the patient’s skin cells, then expanding the gene-corrected cells into sheets of keratinocytes that can be surgically applied to the chronic wound sites. In a phase 3 trial of prademagene zamikeracel (pz-cel), 11 patients with 86 matched wounds were randomized to receive pz-cel (50%) or standard wound care (50%). After 24 weeks, 35 wounds treated with pz-cel were at least 50% healed compared to 7 control wounds.¹⁷ The results for healing and reduction of pain were statistically significant (P<.0001 and P<.0002, respectively).¹⁷ Recombinant collagen VII as replacement therapy also is under study to be given by intravenous infusion to increase tissue collagen VII where it is lacking. This treatment has shown early biologic and therapeutic effects.^9,18 Larger long-term follow-up studies are necessary to confirm persistence of the gene-corrected skin cells, the functionality of the replacement collagen VII, and the potential risk for the development of autoantibodies to type VII collagen.

Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita is a rare autoimmune subepithelial bullous disease that primarily affects middle-aged adults but also has been reported in children.¹⁹ Epidermolysis bullosa acquisita is caused by circulating pathogenic IgG autoantibodies that target and bind to type VII collagen in the anchoring fibrils,^20-22 thereby disrupting the attachment of the epithelium to its underlying connective tissue.

The 2 major clinical manifestations of EBA include a mechanobullous disease resembling inherited forms of DEB (Figure 4) and an inflammatory bullous pemphigoid (BP)–like disease,²³ as well as a combination of both types of skin lesions (Figure 5). The skin and mucous membranes of the oral cavity, esophagus, eyes, and urogenital areas are affected in both types; scarring may cause functional disabilities. In the mechanobullous type of EBA, it is common for blisters and erosions to develop in trauma-prone areas such as the hands, feet, elbows, and knees. The blisters tend to heal with scarring and milia formation as might be seen in porphyria cutanea tarda or cicatricial pemphigoid, which are in the differential diagnosis. Dystrophy of the fingernails or complete nail loss may be observed, resembling DEB. In the BP-like presentation, tense blisters arise upon inflamed or urticarial skin and mucous membranes, which may then become generalized. 

Histopathology in both forms of EBA demonstrates subepithelial separation as clefts or blisters. The mechanobullous type shows a sparse inflammatory infiltrate compared to large collections of neutrophils and eosinophils in the blister cavity and in the superficial dermis in the BP-like cases. The final diagnosis rests on the results of immunopathology testing.²⁴ Direct immunofluorescence of perilesional skin and mucosa shows a linear-granular band of IgG and C3 and other conjugates along the BMZ. Deposits of IgA alone in EBA occur in only about 2.4% of cases and are observed more often when there is mucous membrane involvement.² Indirect immunofluorescence of sera against salt-split skin substrates detects immunoreactants in the floor of the blister rather than in the roof, as would be seen in BP. Highly specific and sensitive enzyme-linked immunosorbent assay (ELISA) kits now are commercially available and can detect autoantibodies against the N-terminal domain of type VII collagen in more than 90% of cases of EBA.²⁵ 

Inflammatory bowel disease (IBD), particularly Crohn disease (CD), precedes the onset of EBA in approximately 25% of cases.^26,27 Ulcerative colitis is much less common. Type VII collagen is normally present in the basement membrane of intestinal epithelium. In a survey of patients with IBD, 68% of those with CD and 13% of those with ulcerative colitis had circulating anti–type VII collagen antibodies detected by ELISA without having symptoms of EBA.²⁸ A case report of a patient with both well-proven EBA and CD highlighted the clinical difficulty of controlling EBA: treatment with prednisolone and sulfasalazine improved the CD but had little effect on the skin blisters.²⁹ A variety of malignancies have been reported in association with EBA, including cancers of the uterine cervix,³⁰ thyroid, and pancreas,³¹ lymphoma, and chronic lymphatic leukemia. Some of these cases have met the criteria for classification as paraneoplastic, whereas others may have been coincidental. 

Treatment for chronic EBA generally has been limited.^2,24 Putative antineutrophil drugs such as dapsone and colchicine combined with systemic corticosteroids may be useful in milder or juvenile cases, which tend to have a better prognosis than adult cases.¹⁹ In more severe EBA, systemic corticosteroids and/or immunosuppressive drugs such as azathioprine,²³ cyclophosphamide,²³ mycophenolate mofetil,³¹ methotrexate,²³ cyclosporine,³³ and infliximab²³ have been used. More recently, rituximab infusion monotherapy³³ and rituximab combined with intravenous immunoglobulin or adjuvant immunoadsorption of the pathogenic autoantibodies have induced remission of refractory EBA.³² Adjuvant immunoadsorption therapy is not widely available. Multispecialty care often is required, especially ophthalmology for conjunctival involvement and gastroenterology for potential esophageal stenosis and the early detection and treatment of IBD.

Bullous Systemic Lupus Erythematosus

Bullous systemic lupus erythematosus is a rare and specific autoimmune skin complication that mostly is seen in patients with an established diagnosis of systemic lupus erythematosus (SLE) who are experiencing a disease flare. Although more common in women, it has been reported in all sexes and races as well as in children. Vesicles and bullae may arise on sun-exposed (Figure 6) and sun-protected areas of skin.

Histopathology shows subepidermal separation with collections of neutrophils and nuclear fragments in the blister cavity. The differential diagnosis of BSLE includes EBA, BP, dermatitis herpetiformis, and linear IgA bullous dermatosis. Direct immunofluorescence testing shows linear-granular deposits of IgG and/or IgM and IgA along the BMZ.³⁴ When utilizing the indirect immunofluorescence split-skin assay, the autoantibody to type VII collagen would be detected in the floor of the blister if the serum titer was sufficiently high.³ Proposed criteria for the diagnosis of BSLE have been published: 1) diagnosis of SLE now based on the 2019 European League Against Rheumatism/American College of Rheumatology classification³⁵; 2) vesicles and bullae arising upon but not limited to sun-exposed skin; 3) histopathology featuring neutrophil-rich subepithelial bullae; 4) positive indirect immunofluorescence for circulating BMZ antibodies using separated human skin as substrate; 5) and direct immunofluorescence showing IgG and/or IgM and often IgA at the BMZ.³⁶ Using ELISA to detect circulating antibodies against type VII collagen²⁴ should now be added to the criteria. The new criteria for SLE³⁴ do not include BSLE, perhaps because it occurs in less than 1% of patients with SLE.³⁷ 

Further investigation by Gammon et al³ confirmed that the autoantibodies in BSLE are identical to those found in EBA (ie, directed against type VII collagen in the lamina densa). Bullous systemic lupus erythematosus is not considered to be the coexistence of EBA with SLE but rather a specific entity wherein type VII collagen autoantibodies are expressed in the autoimmune spectrum of SLE. It is especially important to make the diagnosis of BSLE because it is predictive of more serious systemic complications of SLE (eg, hematologic and renal disease is found in up to 90% of cases).³⁸ 

The natural course of BSLE is variable. Treatments include systemic corticosteroids, dapsone, and immunosuppressive drugs such as azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide, especially in cases with nephritis.³⁷ There may be spontaneous resolution of the rash as the inflammatory activity of SLE subsides. Rituximab has been used effectively in several refractory cases of BSLE that failed to respond to all other conventional treatments.³⁹

Conclusion

Anchoring fibrils are composed primarily of type VII collagen. Their role is to maintain the attachment of epithelium to the upper dermis and submucosa. The reduction or complete loss of type VII collagen caused by mutations of the COL7A1 gene results in dominant DEB or recessive DEB, respectively. Two distinct non-heritable immunobullous diseases, EBA and BSLE, are caused by autoantibodies that target type VII collagen. A comparison of the 4 type VII collagen disorders can be found in the Table.

There are 3 uncommon types of mechanobullous skin diseases caused by relative reduction or complete loss of functional type VII collagen, which is the main component of anchoring fibrils in the lamina densa of the basement membrane zone (BMZ) of the skin and mucous membrane epithelium.¹ The function of the anchoring fibrils is to maintain adherence of the basement membrane of the epithelium to the connective tissue of the papillary dermis and submucosa.¹ The mechanism of action of the loss of type VII collagen function is via autoimmunity in epidermolysis bullosa acquisita (EBA)² and bullous systemic lupus erythematosus (BSLE).³ In the heritable family of 4 epidermolysis bullosa (EB) variants, only one of the subtypes—dystrophic EB (DEB)—is caused by various recessive and dominant mutations of the type VII collagen gene (COL7A1).⁴ The other 3 diseases in the family—EB simplex, junctional EB, and Kindler syndrome—are caused by diverse mutations that corrupt the integrity of keratinocytes and the BMZ.^5,6 This article provides an overview of these 3 subtypes to help differentiate them from DEB.

Epidermolysis Bullosa

Epidermolysis bullosa consists of a heterogeneous family of 4 major genetic mechanobullous diseases that affect the skin and mucous membranes with more than 30 subtypes.¹ Dystrophic EB is caused by mutations in the COL7A1 gene, which encodes for the α-1 chain of collagen type VII. Classically, EB is divided into 4 main variants based on the location of the cleavage plane or split occurring in the epithelium, which in turn helps to predict the severity of the illness.

Epidermolysis bullosa may be inherited in an ­autosomal-dominant or autosomal-recessive fashion, or it may occur as a spontaneous mutation. All sexes and races are affected equally. Patients present at birth or in early childhood with fragile skin and mucous membranes that may develop blisters, erosions, and ulcerations after minor trauma.⁷ These lesions are marked by slow healing and scar formation and often are associated with itching and pain.

Dystrophic Epidermolysis Bullosa

Dystrophic EB accounts for approximately 25%⁶ of all EB cases in the United States and may be inherited as either a dominant or recessive trait. Hundreds of different pathogenic mutations have been discovered in the COL7A1 gene in the subtypes of DEB.^4,8 Dominant DEB tends to cause milder disease because the patients retain one normal COL7A1 allele and produce some type VII collagen (Figure 1), whereas patients with recessive DEB lack type VII collagen completely.⁹ The cleavage plane is between the lamina densa and the superficial dermis or submucosa. Severity is variable and ranges from ­localization to the hands and feet to severe generalized blistering and painful ulcerations depending on which of the many possible gene mutations have been inherited. Sequelae include mitten deformities, malalignment and tooth decay, and the development of early aggressive squamous cell carcinomas, which may be fatal. The most severe cases of recessive DEB also may have internal organ involvement.

Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex is the most common variant, comprising approximately 70%of EB cases in the United States.⁶ Epidermolysis bullosa simplex usually is inherited as autosomal-dominant mutations in the keratin 5 or keratin 14 genes,¹⁰ not COL7A1. Skin blistering results from cleavage within the basal cell layer where the keratin genes are primarily expressed. Blisters tend to occur in acral areas such as hands and feet and may heal without scarring in the localized form of epidermolysis bullosa simplex (Figure 2).

Junctional Epidermolysis Bullosa and Kindler Syndrome

Junctional epidermolysis bullosa (JEB) and Kindler syndrome¹¹ are the rarest of the autosomal-recessive EB ­variants.⁶ The plane of cleavage in JEB is through the lamina lucida of the BMZ. Junctional epidermolysis bullosa is caused by mutations of the genes that encode for the 3 chains of laminin 332 protein and type XVII collagen,^5,12 not to be confused with type VII collagen. As with DEB, there is a wide range of severity in JEB, from localized effects on the eyes, oral cavity, and tooth enamel to widespread blistering and skin cancers. In JEB cases involving newborns, nonhealing wounds on the face, buttocks, fingers, and toes may be seen, with devastating complications in the oral cavity, esophagus, and larynx. Life expectancy is limited to 2 years or less.⁶ There have only been approximately 40,013 cases of Kindler syndrome reported worldwide⁶ and there is clinical overlap with DEB. Patients also may demonstrate poikiloderma and photosensitivity. Kindler syndrome is caused by mutations in the FERMT1 gene which encodes for kindlin-1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix.^5,11 Loss of function produces variable cleavage planes around the dermoepidermal junction.

Clinical management of all EB variants, especially the severe recessive types, traditionally has been limited to the prevention of trauma to the skin and mucous membranes and supportive care, including dressing changes to erosions and ulcerations, antibiotic ointments as needed, and amelioration of pain and pruritus. Bone marrow and pluripotential stem cell transplants have been attempted.¹² Complications of EB, such as deformities of the hands and feet caused by excessive scarring, esophageal strictures, poor dentition, and squamous cell carcinomas, must be addressed by a multidisciplinary team of specialists, including plastic surgery, gastroenterology, dentistry/oral surgery, ophthalmology, and dermatology/Mohs surgery. 

Until recently, there were no medications approved by the US Food and Drug Administration (FDA) specifically indicated for EB. In 2023, topical gene therapy was approved by the FDA for both recessive and dominant forms of DEB. Normal COL7A1 sequences are delivered by an attenuated herpes simplex virus 1 vector (beremagene geperpavec) in a gel applied directly to the wounds of patients with DEB. In a clinical trial, matching wounds on 31 patients (62 wounds total) were treated with the active agent or placebo gel. After 6 months, complete wound closure was observed in 67% (21/31) of those treated with the active agent and 22% (7/31) of those treated with placebo (P=.002).¹⁴ In a single case report, a patient with recessive DEB and cicatrizing conjunctivitis (Figure 3) was given ophthalmic beremagene geperpavec after surgery and had improved visual acuity.¹⁵ A topical gel consisting of birch triterpenes to promote healing of partial-thickness wounds also was approved for patients with DEB and JEB by the FDA and the European Commission. In a study of 223 patients, 41% of those using active gel and 29% of those using placebo gel achieved the primary end point of percentage of target wounds that had first complete closure at 45 days.¹⁶ 

The most recent FDA approval for DEB involves transferring the functional COL7A1 gene to the patient’s skin cells, then expanding the gene-corrected cells into sheets of keratinocytes that can be surgically applied to the chronic wound sites. In a phase 3 trial of prademagene zamikeracel (pz-cel), 11 patients with 86 matched wounds were randomized to receive pz-cel (50%) or standard wound care (50%). After 24 weeks, 35 wounds treated with pz-cel were at least 50% healed compared to 7 control wounds.¹⁷ The results for healing and reduction of pain were statistically significant (P<.0001 and P<.0002, respectively).¹⁷ Recombinant collagen VII as replacement therapy also is under study to be given by intravenous infusion to increase tissue collagen VII where it is lacking. This treatment has shown early biologic and therapeutic effects.^9,18 Larger long-term follow-up studies are necessary to confirm persistence of the gene-corrected skin cells, the functionality of the replacement collagen VII, and the potential risk for the development of autoantibodies to type VII collagen.

Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita is a rare autoimmune subepithelial bullous disease that primarily affects middle-aged adults but also has been reported in children.¹⁹ Epidermolysis bullosa acquisita is caused by circulating pathogenic IgG autoantibodies that target and bind to type VII collagen in the anchoring fibrils,^20-22 thereby disrupting the attachment of the epithelium to its underlying connective tissue.

The 2 major clinical manifestations of EBA include a mechanobullous disease resembling inherited forms of DEB (Figure 4) and an inflammatory bullous pemphigoid (BP)–like disease,²³ as well as a combination of both types of skin lesions (Figure 5). The skin and mucous membranes of the oral cavity, esophagus, eyes, and urogenital areas are affected in both types; scarring may cause functional disabilities. In the mechanobullous type of EBA, it is common for blisters and erosions to develop in trauma-prone areas such as the hands, feet, elbows, and knees. The blisters tend to heal with scarring and milia formation as might be seen in porphyria cutanea tarda or cicatricial pemphigoid, which are in the differential diagnosis. Dystrophy of the fingernails or complete nail loss may be observed, resembling DEB. In the BP-like presentation, tense blisters arise upon inflamed or urticarial skin and mucous membranes, which may then become generalized. 

Histopathology in both forms of EBA demonstrates subepithelial separation as clefts or blisters. The mechanobullous type shows a sparse inflammatory infiltrate compared to large collections of neutrophils and eosinophils in the blister cavity and in the superficial dermis in the BP-like cases. The final diagnosis rests on the results of immunopathology testing.²⁴ Direct immunofluorescence of perilesional skin and mucosa shows a linear-granular band of IgG and C3 and other conjugates along the BMZ. Deposits of IgA alone in EBA occur in only about 2.4% of cases and are observed more often when there is mucous membrane involvement.² Indirect immunofluorescence of sera against salt-split skin substrates detects immunoreactants in the floor of the blister rather than in the roof, as would be seen in BP. Highly specific and sensitive enzyme-linked immunosorbent assay (ELISA) kits now are commercially available and can detect autoantibodies against the N-terminal domain of type VII collagen in more than 90% of cases of EBA.²⁵ 

Inflammatory bowel disease (IBD), particularly Crohn disease (CD), precedes the onset of EBA in approximately 25% of cases.^26,27 Ulcerative colitis is much less common. Type VII collagen is normally present in the basement membrane of intestinal epithelium. In a survey of patients with IBD, 68% of those with CD and 13% of those with ulcerative colitis had circulating anti–type VII collagen antibodies detected by ELISA without having symptoms of EBA.²⁸ A case report of a patient with both well-proven EBA and CD highlighted the clinical difficulty of controlling EBA: treatment with prednisolone and sulfasalazine improved the CD but had little effect on the skin blisters.²⁹ A variety of malignancies have been reported in association with EBA, including cancers of the uterine cervix,³⁰ thyroid, and pancreas,³¹ lymphoma, and chronic lymphatic leukemia. Some of these cases have met the criteria for classification as paraneoplastic, whereas others may have been coincidental. 

Treatment for chronic EBA generally has been limited.^2,24 Putative antineutrophil drugs such as dapsone and colchicine combined with systemic corticosteroids may be useful in milder or juvenile cases, which tend to have a better prognosis than adult cases.¹⁹ In more severe EBA, systemic corticosteroids and/or immunosuppressive drugs such as azathioprine,²³ cyclophosphamide,²³ mycophenolate mofetil,³¹ methotrexate,²³ cyclosporine,³³ and infliximab²³ have been used. More recently, rituximab infusion monotherapy³³ and rituximab combined with intravenous immunoglobulin or adjuvant immunoadsorption of the pathogenic autoantibodies have induced remission of refractory EBA.³² Adjuvant immunoadsorption therapy is not widely available. Multispecialty care often is required, especially ophthalmology for conjunctival involvement and gastroenterology for potential esophageal stenosis and the early detection and treatment of IBD.

Bullous Systemic Lupus Erythematosus

Bullous systemic lupus erythematosus is a rare and specific autoimmune skin complication that mostly is seen in patients with an established diagnosis of systemic lupus erythematosus (SLE) who are experiencing a disease flare. Although more common in women, it has been reported in all sexes and races as well as in children. Vesicles and bullae may arise on sun-exposed (Figure 6) and sun-protected areas of skin.

Histopathology shows subepidermal separation with collections of neutrophils and nuclear fragments in the blister cavity. The differential diagnosis of BSLE includes EBA, BP, dermatitis herpetiformis, and linear IgA bullous dermatosis. Direct immunofluorescence testing shows linear-granular deposits of IgG and/or IgM and IgA along the BMZ.³⁴ When utilizing the indirect immunofluorescence split-skin assay, the autoantibody to type VII collagen would be detected in the floor of the blister if the serum titer was sufficiently high.³ Proposed criteria for the diagnosis of BSLE have been published: 1) diagnosis of SLE now based on the 2019 European League Against Rheumatism/American College of Rheumatology classification³⁵; 2) vesicles and bullae arising upon but not limited to sun-exposed skin; 3) histopathology featuring neutrophil-rich subepithelial bullae; 4) positive indirect immunofluorescence for circulating BMZ antibodies using separated human skin as substrate; 5) and direct immunofluorescence showing IgG and/or IgM and often IgA at the BMZ.³⁶ Using ELISA to detect circulating antibodies against type VII collagen²⁴ should now be added to the criteria. The new criteria for SLE³⁴ do not include BSLE, perhaps because it occurs in less than 1% of patients with SLE.³⁷ 

Further investigation by Gammon et al³ confirmed that the autoantibodies in BSLE are identical to those found in EBA (ie, directed against type VII collagen in the lamina densa). Bullous systemic lupus erythematosus is not considered to be the coexistence of EBA with SLE but rather a specific entity wherein type VII collagen autoantibodies are expressed in the autoimmune spectrum of SLE. It is especially important to make the diagnosis of BSLE because it is predictive of more serious systemic complications of SLE (eg, hematologic and renal disease is found in up to 90% of cases).³⁸ 

The natural course of BSLE is variable. Treatments include systemic corticosteroids, dapsone, and immunosuppressive drugs such as azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide, especially in cases with nephritis.³⁷ There may be spontaneous resolution of the rash as the inflammatory activity of SLE subsides. Rituximab has been used effectively in several refractory cases of BSLE that failed to respond to all other conventional treatments.³⁹

Conclusion

Anchoring fibrils are composed primarily of type VII collagen. Their role is to maintain the attachment of epithelium to the upper dermis and submucosa. The reduction or complete loss of type VII collagen caused by mutations of the COL7A1 gene results in dominant DEB or recessive DEB, respectively. Two distinct non-heritable immunobullous diseases, EBA and BSLE, are caused by autoantibodies that target type VII collagen. A comparison of the 4 type VII collagen disorders can be found in the Table.

Humans possess the ability to recognize and distinguish a large range of odors that can be utilized in a wide range of applications. For example, sommeliers can classify more than 88 smells specific to the roughly 800 volatile organic compounds (VOCs) in wine. Thorough physical examination is essential in dermatology, and although sight and touch play the most important diagnostic roles, the sense of smell often is overlooked. Dermatologists are rigorously trained on the many visual aspects of skin disease and have a plethora of terms to describe these features while there is minimal characterization of odors. Research on odors and the role of olfaction in dermatologic practice is limited.^1,2 We conducted a literature review of PubMed and Google Scholar for peer-reviewed articles discussing the role of odors in dermatologic diseases. Keywords included odor + dermatology, smell + dermatology, cutaneous odor, odor + diagnosis, and disease odor. Relevant studies were identified by screening their abstracts, followed by a full-text review. A total of 38 articles written in English that presented information on the odor associated with dermatologic diseases were included. Articles that were unrelated to the topic or written in a language other than English were excluded.

Common Skin Odors

The human body emits odorants—small VOCs—in various forms (skin/sweat, breath, urine, reproductive fluids). Human odor originates from the oxidation and bacterial metabolism of sweat and sebum on the skin.³ While many odors are physiologic and not cause for concern, others can signal underlying dermatologic pathologies.⁴ Odor-producing conditions can be categorized broadly into infectious diseases, disorders of keratinization and acantholysis, metabolic disorders, and organ dysfunction (Table). Infectious causes include bacterial infections and chronic wounds, which commonly emit characteristic offensive odors. For example, coryneform infections produce methanethiol, causing a cheesy odor of putrid fruit, and pseudomonal pyoderma infections emit a grape juice–like or mousy odor.

Bacterial and Fungal Infections

Bacterial and fungal infections often have distinct smells. Coryneform infections emit an odor of sweaty feet, pseudomonal infections emit a grape juice–like or mousy odor, and trichomycosis infections (caused by Corynebacterium tenuis) present with malodor.⁵ Pseudomonas can infect pyoderma gangrenosum lesions, producing a characteristic malodor.⁵ These smells can be clues for infectious etiology and guide further workup.

Pitted keratolysis, a malodorous pitted rash characterized by infection of the stratum corneum by Kytococcus sedentarius, Dermatophilus congolensis, or Corynebacterium species, is associated with a rotten smell. Its pungent odor, clinical location, and characteristic appearance often are enough to make a diagnosis. The amount of bacteria maintained in the stratum corneum is correlated with the extent of the lesion. Controlling excessive moisture in footwear, aluminum chloride, and topical microbial agents work together to eliminate the skin eruption.⁶ 

Hidradenitis suppurativa, a chronic inflammatory disease of apocrine gland–containing skin, can manifest with abscesses, draining sinuses, and nodules that produce a foul-smelling, purulent discharge. The disease can be debilitating, largely impacting patients’ quality of life, making early diagnosis and treatment critical.^7,8 Therapy is dependent on disease severity and includes topical antibiotics, systemic therapies, and biologics.⁸ 

Patients with atopic dermatitis often experience bacterial superinfection with Staphylococcus aureus. A case report described a patient who developed a fishy odor in this setting that resolved with antibiotic treatment, implicating S aureus in the etiology of the smell.⁹ 

A seminal fluid odor has been reported in cases of Pasteurella wound infection. In such cases, Pasteurella multocida subspecies septica was identified in the wounds caused by a dog scratch and a cat bite. The seminal fluid–like odor was apparent hours after the inciting incident and resolved after treatment with antibiotics.¹⁰ 

Fungal infections frequently emit musty or moldy odors. Tinea pedis (athlete’s foot) is the most prevalent cutaneous fungal infection. The presence of tinea pedis is associated with an intense foul-smelling odor, itching, fissuring, scaling, or maceration of the interdigital regions. The rash and odor resolve with use of topical antifungal agents.^11,12 Seborrheic dermatitis, a prevalent and chronic dermatosis, is characterized by yellow greasy scaling on an erythematous base. In severe cases, a greasy crust with an offensive odor can cover the entire scalp.¹³ The specific cause of this odor is unclear, but it is thought that sebum production and the immunological response to specific Malassezia yeast species may play a role.¹⁴

Genetic and Metabolic Disorders

An array of disorders of keratinization and acantholysis can manifest with distinctive smells that dermatologists frequently encounter. For example, Darier disease, characterized by keratotic papules progressing to crusted plaques, has a signature foul-smelling odor associated with cutaneous bacterial colonization.¹⁵ Similarly, Hailey-Hailey disease, an autosomal-dominant disorder with crusted erosions in skinfold areas, produces a distinct foul smell.¹⁶ Disorders such as pemphigus vulgaris and pemphigus foliaceus emit a peculiar fishy odor that can be helpful in making a diagnosis.¹⁷ Additionally, bullous ichthyosiform erythroderma, keratitis-ichthyosis-deafness syndrome, mal de Meleda, and Papillon-Lefèvre syndrome are all associated with malodor.⁵

Certain metabolic disorders can manifest and present initially with identifiable odors. Trimethylaminuria is a psychologically disabling disease known for its rotting fishy smell due to high amounts of trimethylamine appearing in affected individuals’ sweat, urine, and breath. Previously considered to be very rare, Messenger et al¹⁸ reported the disorder is likely underdiagnosed in those with idiopathic malodor production. Detection and treatment can greatly improve patient quality of life.

Phenylketonuria is an autosomal-recessive inborn error of phenylalanine metabolism that produces a musty body and urine odor as well as other neurologic and dermatologic symptoms.^19,20 Patients can present with eczematous rashes, fair skin, and blue eyes. Phenylacetic acid produces the characteristic odor in the bodily fluids, and the disease is treated with a phenylalanine-free diet.²¹ 

Maple syrup urine disease is a disorder of the oxidative decarboxylation of valine, leucine, and isoleucine (branched-chain amino acids) characterized by urine that smells sweet, resembling maple syrup, in afflicted individuals. The odor also can be present in other bodily secretions, such as sweat. Patients present early in infancy with poor feeding and vomiting as well as neurologic symptoms, eventually leading to intellectual disability. These individuals must avoid the branched-chain amino acids in their diets.²¹ 

Other metabolic storage disorders linked with specific odors are methionine adenosyltransferase deficiency (boiled cabbage), hypermethioninemia (fishy, boiled cabbage), isovaleric acidemia (sweaty feet), methionine malabsorption syndrome (pungent malodor), and dimethylglycine dehydrogenase deficiency (fishy).^5,21,22

In diabetic ketoacidosis, a life-threatening complication of diabetes, the excess of ketone bodies produced causes patients to have a distinct fruity breath and urine odor, as well as fatigue, polyuria, polydipsia, nausea, and vomiting.²² Although patients with type 1 diabetes typically comprise the cohort of patients presenting with diabetic ketoacidosis, patients with type 2 diabetes can exhibit cutaneous manifestations such as infection, xerosis, and inflammatory skin diseases.^23,24 

Organ Dysfunction

A peculiar body odor can be a sign of organ dysfunction. Renal dysfunction may present with both an odor and dermatologic manifestations. Patients with end-stage renal disease can have an ammonialike uremic breath odor as the result of excessive nitrogenous waste products and increased concentrations of urea in their saliva.^4,22 These patients also can exhibit pruritus, xerosis, pigmentation changes, nail changes, other dermatoses, and rarely uremic frost with white urate crystals present on the skin.^25,26 

Liver failure has been associated with an ammonialike musty breath odor termed fetor hepaticus. Shimamoto et al²⁷ reported notably higher levels of breath ammonia levels in patients with hepatic encephalopathy, indicating that excess ammonia is responsible for the odor. Fetor hepaticus has unique characteristics that can permit a diagnosis of liver disease, though it has been reported in cases in which a liver injury could not be identified.²⁸ 

Aging patients typically have a distinctive smell. Haze et al²⁹ analyzed the body odor of patients aged 26 to 75 years and discovered the compound 2-nonenal—an unsaturated aldehyde with a smell described as greasy and grassy—was found only in patients older than 40 years. The researchers’ analysis of skin-surface lipids also revealed that the presence of ω7 unsaturated fatty acids and lipid peroxides increased with age. They concluded that 2-nonenal is generated from the oxidative degradation of ω7 unsaturated fatty acids by lipid peroxides, suggesting that 2-nonenal may be a cause of the odor of old age.²⁹

Cutaneous Malignancies 

Research shows that the profiles of the body’s continuously released VOCs change in the presence of malignancy. Some studies suggest that melanoma may have a unique odor. Willis et al³⁰ reported that after a 13-month training period, a dog was able to correctly identify melanoma and distinguish it from basal cell carcinoma, benign nevi, and healthy skin based on olfaction alone. Additional cases have been reported in which dogs have been able to identify melanoma based on smell, suggesting that canine olfactory detection of melanoma could possibly aid in the diagnosis of skin cancer, which warrants further investigation.^31,32 There is limited evidence on the specific odors of other cutaneous malignancies, such as basal cell carcinoma and squamous cell carcinoma. 

Bacterial superinfection of cutaneous malignancy can secrete pungent odors. An offensive rotting odor has been associated with necrotic malignant ulcers of the vagina. This malodor likely is a result of the formation of putrescine, cadaverine, short-chain fatty acids (isovaleric and butyric acids) and sulfur-containing compounds by bacteria.³³ Recognition of similar smells may aid in management of these infections.

Diagnostic Techniques

Evaluating human skin odor is challenging, as the components of VOCs are complicated and typically found at trace levels. Studies indicate that gas chromatography–mass spectrometry is the most effective way to analyze human odor. This method separates, quantifies, and analyzes VOCs from samples containing odors.³⁴ Gas chromatography–mass spectrometry, however, has limitations, as the time for analysis is lengthy, the equipment is large, and the process is expensive.³ Research supports the usefulness and validity of quantitative gas chromatography–olfactometry to detect odorants and evaluate odor activity of VOCs in various samples.³⁵ With this technique, human assessors act in place of more conventional detectors, such as mass spectrometers. This method has been used to evaluate odorants in human urine with the goal of increasing understanding of metabolization and excretion processes.³⁶ However, gas chromatography–olfactometry typically is used in the analysis of food and drink, and future research should be aimed at applying this method to medicine. 

Zheng et al³ proposed a wearable electronic nose as a tool to identify human odor to emulate the odor recognition of a canine’s nose. They developed a sensor array based on the composites of carbon nanotubes and polymers able to examine and identify odors in the air. Study participants wore the electronic nose on the arm with the sensory array facing the armpits while they walked on a treadmill. Although many issues regarding odor measurement were not addressed in this study, the research suggests further studies are warranted to improve analysis of odor.³

Clinical Cases

Patient 1—Arseculeratne et al³⁷ described a 41-year-old man who presented with a fishy odor that others had noticed since the age of 13 years but that the patient could not smell himself. Based on his presentation, he was worked up for trimethylaminuria and found to have elevated levels of urinary trimethylamine (TMA) with a raised TMA/TMA-oxidase ratio. These findings were consistent with a diagnosis of primary trimethylaminuria, and the patient was referred to a dietician for counseling on foods that contain low amounts of choline and lecithin. Initially his urinary TMA level fell but then rose again, indicating possible relaxation of his diet. He then took a 10-day course of metronidazole, which helped reduce some of the malodor. The authors reported that the most impactful therapy for the patient was being able to discuss the disorder with his friends and family members.³⁷ This case highlighted the importance of confirming the diagnosis and early initiation of dietary and pharmacologic interventions in patients with trimethylaminuria. In patients reporting a persistent fishy body odor, trimethylaminuria should be on the differential.

Patient 2—In 1999, Schissel et al⁶ described a 20-year-old active-duty soldier who presented to the dermatology department with smelly trench foot and tinea pedis. The soldier reported having this malodorous pitted rash for more than 10 years. He also reported occasional interdigital burning and itching and noted no improvement despite using various topical antifungals. Physical examination revealed an “overpowering pungent odor” when the patient removed his shoes. He had many tender, white, and wet plaques with scalloped borders coalescing into shallow pits on the plantar surface of the feet and great toes. Potassium hydroxide preparation of the great toe plaques and interdigital web spaces were positive for fungal elements, and bacterial cultures isolated moderate coagulase-negative staphylococcal and Corynebacterium species. Additionally, fungal cultures identified Acremonium species. The patient was started on clotrimazole cream twice daily, clindamycin solution twice daily, and topical ammonium chloride nightly. Two weeks later, the patient reported resolution of symptoms, including the malodor.⁶ In pitted keratolysis, warm and wet environments within boots or shoes allow for the growth of bacteria and fungi. The extent of the lesions is related to the amount of bacteria within the stratum corneum. The diagnosis often is made based on odor, location, and appearance of the rash alone. The most common organisms implicated as causal agents in the condition are Kytococcus sedentarius, Dermatophilus congolensis, and species of Corynebacterium and Actinomyces. It is thought that these organisms release proteolytic enzymes that degrade the horny layer, releasing a mixture of thiols, thioesters, and sulfides, which cause the pungent odor. Familiarity with the characteristic odor aids in prompt diagnosis and treatment, which will ultimately heal the skin eruption. 

Patient 3—Srivastava et al³² described a 43-year-old woman who presented with a nevus on the back since childhood. She noticed that it had changed and grown over the past few years and reported that her dog would often sniff the lesion and try to scratch and bite the lesion. This reaction from her dog led the patient to seek out evaluation from a dermatologist. The patient had no personal history of skin cancer, bad sunburns, tanning bed use, or use of immunosuppressants. She reported that her father had a history of basal cell carcinoma. Physical examination revealed a 1.2×1.5-cm brown patch with an ulcerated nodule located on the lower aspect of the lesion. The patient underwent a wide local excision and sentinel lymph node biopsy with pathology showing a 4-mm-thick melanoma with positive lymph nodes. She then underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. Following the surgery, the patient’s dog would sniff the back and calmly rest his head in her lap. She has not had a recurrence and credits her dog for saving her life.³² Canine olfaction may play a role in detecting skin cancers, as evidenced by this case. Patients and dermatologists should pay attention to the behavior of dogs toward skin lesions. Harnessing this sense into a method to noninvasively screen for melanoma in humans should be further investigated.

Patient 4—Matthews et al³⁸ described a 32-year-old woman who presented to an emergency eye clinic with a white “lump” on the left upper eyelid of 6 months’ duration. Physical examination revealed 3 nodular and cystic lesions oozing a thick yellow-white discharge. Cultures were taken, and the patient was started on chloramphenicol ointment once daily to the skin. At follow-up, the lesions had not changed, and the cultures were negative. The patient reported an intermittent malodorous discharge and noted multiple similar lesions on her body. Excisional biopsy demonstrated histologic findings including dyskeratosis, papillomatosis, and suprabasal acantholysis associated with focal underlying chronic inflammatory infiltrate. She was referred to a dermatologist and was diagnosed with Darier disease. She was started on clobetasone butyrate when necessary and adapalene nocte. Understanding the smell associated with Darier disease in conjunction with the cutaneous findings may aid in earlier diagnosis, improving outcomes for affected patients.³⁸ 

Conclusion

The sense of smell may be an overlooked diagnostic tool that dermatologists innately possess. Odors detected when examining patients should be considered, as these odors may help guide a diagnosis. Early diagnosis and treatment are important in many dermatologic diseases, so it is imperative to consider all diagnostic clues. Although physician olfaction may aid in diagnosis, its utility remains challenging, as there is a lack of consensus and terminology regarding odor in disease. A limitation of training to identify disease-specific odors is the requirement of engaging in often unpleasant odors. Methods to objectively measure odor are expensive and still in the early stages of development. Further research and exploration of olfactory-based diagnostic techniques is warranted to potentially improve dermatologic diagnosis. 

Humans possess the ability to recognize and distinguish a large range of odors that can be utilized in a wide range of applications. For example, sommeliers can classify more than 88 smells specific to the roughly 800 volatile organic compounds (VOCs) in wine. Thorough physical examination is essential in dermatology, and although sight and touch play the most important diagnostic roles, the sense of smell often is overlooked. Dermatologists are rigorously trained on the many visual aspects of skin disease and have a plethora of terms to describe these features while there is minimal characterization of odors. Research on odors and the role of olfaction in dermatologic practice is limited.^1,2 We conducted a literature review of PubMed and Google Scholar for peer-reviewed articles discussing the role of odors in dermatologic diseases. Keywords included odor + dermatology, smell + dermatology, cutaneous odor, odor + diagnosis, and disease odor. Relevant studies were identified by screening their abstracts, followed by a full-text review. A total of 38 articles written in English that presented information on the odor associated with dermatologic diseases were included. Articles that were unrelated to the topic or written in a language other than English were excluded.

Common Skin Odors

The human body emits odorants—small VOCs—in various forms (skin/sweat, breath, urine, reproductive fluids). Human odor originates from the oxidation and bacterial metabolism of sweat and sebum on the skin.³ While many odors are physiologic and not cause for concern, others can signal underlying dermatologic pathologies.⁴ Odor-producing conditions can be categorized broadly into infectious diseases, disorders of keratinization and acantholysis, metabolic disorders, and organ dysfunction (Table). Infectious causes include bacterial infections and chronic wounds, which commonly emit characteristic offensive odors. For example, coryneform infections produce methanethiol, causing a cheesy odor of putrid fruit, and pseudomonal pyoderma infections emit a grape juice–like or mousy odor.

Bacterial and Fungal Infections

Bacterial and fungal infections often have distinct smells. Coryneform infections emit an odor of sweaty feet, pseudomonal infections emit a grape juice–like or mousy odor, and trichomycosis infections (caused by Corynebacterium tenuis) present with malodor.⁵ Pseudomonas can infect pyoderma gangrenosum lesions, producing a characteristic malodor.⁵ These smells can be clues for infectious etiology and guide further workup.

Pitted keratolysis, a malodorous pitted rash characterized by infection of the stratum corneum by Kytococcus sedentarius, Dermatophilus congolensis, or Corynebacterium species, is associated with a rotten smell. Its pungent odor, clinical location, and characteristic appearance often are enough to make a diagnosis. The amount of bacteria maintained in the stratum corneum is correlated with the extent of the lesion. Controlling excessive moisture in footwear, aluminum chloride, and topical microbial agents work together to eliminate the skin eruption.⁶ 

Hidradenitis suppurativa, a chronic inflammatory disease of apocrine gland–containing skin, can manifest with abscesses, draining sinuses, and nodules that produce a foul-smelling, purulent discharge. The disease can be debilitating, largely impacting patients’ quality of life, making early diagnosis and treatment critical.^7,8 Therapy is dependent on disease severity and includes topical antibiotics, systemic therapies, and biologics.⁸ 

Patients with atopic dermatitis often experience bacterial superinfection with Staphylococcus aureus. A case report described a patient who developed a fishy odor in this setting that resolved with antibiotic treatment, implicating S aureus in the etiology of the smell.⁹ 

A seminal fluid odor has been reported in cases of Pasteurella wound infection. In such cases, Pasteurella multocida subspecies septica was identified in the wounds caused by a dog scratch and a cat bite. The seminal fluid–like odor was apparent hours after the inciting incident and resolved after treatment with antibiotics.¹⁰ 

Fungal infections frequently emit musty or moldy odors. Tinea pedis (athlete’s foot) is the most prevalent cutaneous fungal infection. The presence of tinea pedis is associated with an intense foul-smelling odor, itching, fissuring, scaling, or maceration of the interdigital regions. The rash and odor resolve with use of topical antifungal agents.^11,12 Seborrheic dermatitis, a prevalent and chronic dermatosis, is characterized by yellow greasy scaling on an erythematous base. In severe cases, a greasy crust with an offensive odor can cover the entire scalp.¹³ The specific cause of this odor is unclear, but it is thought that sebum production and the immunological response to specific Malassezia yeast species may play a role.¹⁴

Genetic and Metabolic Disorders

An array of disorders of keratinization and acantholysis can manifest with distinctive smells that dermatologists frequently encounter. For example, Darier disease, characterized by keratotic papules progressing to crusted plaques, has a signature foul-smelling odor associated with cutaneous bacterial colonization.¹⁵ Similarly, Hailey-Hailey disease, an autosomal-dominant disorder with crusted erosions in skinfold areas, produces a distinct foul smell.¹⁶ Disorders such as pemphigus vulgaris and pemphigus foliaceus emit a peculiar fishy odor that can be helpful in making a diagnosis.¹⁷ Additionally, bullous ichthyosiform erythroderma, keratitis-ichthyosis-deafness syndrome, mal de Meleda, and Papillon-Lefèvre syndrome are all associated with malodor.⁵

Certain metabolic disorders can manifest and present initially with identifiable odors. Trimethylaminuria is a psychologically disabling disease known for its rotting fishy smell due to high amounts of trimethylamine appearing in affected individuals’ sweat, urine, and breath. Previously considered to be very rare, Messenger et al¹⁸ reported the disorder is likely underdiagnosed in those with idiopathic malodor production. Detection and treatment can greatly improve patient quality of life.

Phenylketonuria is an autosomal-recessive inborn error of phenylalanine metabolism that produces a musty body and urine odor as well as other neurologic and dermatologic symptoms.^19,20 Patients can present with eczematous rashes, fair skin, and blue eyes. Phenylacetic acid produces the characteristic odor in the bodily fluids, and the disease is treated with a phenylalanine-free diet.²¹ 

Maple syrup urine disease is a disorder of the oxidative decarboxylation of valine, leucine, and isoleucine (branched-chain amino acids) characterized by urine that smells sweet, resembling maple syrup, in afflicted individuals. The odor also can be present in other bodily secretions, such as sweat. Patients present early in infancy with poor feeding and vomiting as well as neurologic symptoms, eventually leading to intellectual disability. These individuals must avoid the branched-chain amino acids in their diets.²¹ 

Other metabolic storage disorders linked with specific odors are methionine adenosyltransferase deficiency (boiled cabbage), hypermethioninemia (fishy, boiled cabbage), isovaleric acidemia (sweaty feet), methionine malabsorption syndrome (pungent malodor), and dimethylglycine dehydrogenase deficiency (fishy).^5,21,22

In diabetic ketoacidosis, a life-threatening complication of diabetes, the excess of ketone bodies produced causes patients to have a distinct fruity breath and urine odor, as well as fatigue, polyuria, polydipsia, nausea, and vomiting.²² Although patients with type 1 diabetes typically comprise the cohort of patients presenting with diabetic ketoacidosis, patients with type 2 diabetes can exhibit cutaneous manifestations such as infection, xerosis, and inflammatory skin diseases.^23,24 

Organ Dysfunction

A peculiar body odor can be a sign of organ dysfunction. Renal dysfunction may present with both an odor and dermatologic manifestations. Patients with end-stage renal disease can have an ammonialike uremic breath odor as the result of excessive nitrogenous waste products and increased concentrations of urea in their saliva.^4,22 These patients also can exhibit pruritus, xerosis, pigmentation changes, nail changes, other dermatoses, and rarely uremic frost with white urate crystals present on the skin.^25,26 

Liver failure has been associated with an ammonialike musty breath odor termed fetor hepaticus. Shimamoto et al²⁷ reported notably higher levels of breath ammonia levels in patients with hepatic encephalopathy, indicating that excess ammonia is responsible for the odor. Fetor hepaticus has unique characteristics that can permit a diagnosis of liver disease, though it has been reported in cases in which a liver injury could not be identified.²⁸ 

Aging patients typically have a distinctive smell. Haze et al²⁹ analyzed the body odor of patients aged 26 to 75 years and discovered the compound 2-nonenal—an unsaturated aldehyde with a smell described as greasy and grassy—was found only in patients older than 40 years. The researchers’ analysis of skin-surface lipids also revealed that the presence of ω7 unsaturated fatty acids and lipid peroxides increased with age. They concluded that 2-nonenal is generated from the oxidative degradation of ω7 unsaturated fatty acids by lipid peroxides, suggesting that 2-nonenal may be a cause of the odor of old age.²⁹

Cutaneous Malignancies 

Research shows that the profiles of the body’s continuously released VOCs change in the presence of malignancy. Some studies suggest that melanoma may have a unique odor. Willis et al³⁰ reported that after a 13-month training period, a dog was able to correctly identify melanoma and distinguish it from basal cell carcinoma, benign nevi, and healthy skin based on olfaction alone. Additional cases have been reported in which dogs have been able to identify melanoma based on smell, suggesting that canine olfactory detection of melanoma could possibly aid in the diagnosis of skin cancer, which warrants further investigation.^31,32 There is limited evidence on the specific odors of other cutaneous malignancies, such as basal cell carcinoma and squamous cell carcinoma. 

Bacterial superinfection of cutaneous malignancy can secrete pungent odors. An offensive rotting odor has been associated with necrotic malignant ulcers of the vagina. This malodor likely is a result of the formation of putrescine, cadaverine, short-chain fatty acids (isovaleric and butyric acids) and sulfur-containing compounds by bacteria.³³ Recognition of similar smells may aid in management of these infections.

Diagnostic Techniques

Evaluating human skin odor is challenging, as the components of VOCs are complicated and typically found at trace levels. Studies indicate that gas chromatography–mass spectrometry is the most effective way to analyze human odor. This method separates, quantifies, and analyzes VOCs from samples containing odors.³⁴ Gas chromatography–mass spectrometry, however, has limitations, as the time for analysis is lengthy, the equipment is large, and the process is expensive.³ Research supports the usefulness and validity of quantitative gas chromatography–olfactometry to detect odorants and evaluate odor activity of VOCs in various samples.³⁵ With this technique, human assessors act in place of more conventional detectors, such as mass spectrometers. This method has been used to evaluate odorants in human urine with the goal of increasing understanding of metabolization and excretion processes.³⁶ However, gas chromatography–olfactometry typically is used in the analysis of food and drink, and future research should be aimed at applying this method to medicine. 

Zheng et al³ proposed a wearable electronic nose as a tool to identify human odor to emulate the odor recognition of a canine’s nose. They developed a sensor array based on the composites of carbon nanotubes and polymers able to examine and identify odors in the air. Study participants wore the electronic nose on the arm with the sensory array facing the armpits while they walked on a treadmill. Although many issues regarding odor measurement were not addressed in this study, the research suggests further studies are warranted to improve analysis of odor.³

Clinical Cases

Patient 1—Arseculeratne et al³⁷ described a 41-year-old man who presented with a fishy odor that others had noticed since the age of 13 years but that the patient could not smell himself. Based on his presentation, he was worked up for trimethylaminuria and found to have elevated levels of urinary trimethylamine (TMA) with a raised TMA/TMA-oxidase ratio. These findings were consistent with a diagnosis of primary trimethylaminuria, and the patient was referred to a dietician for counseling on foods that contain low amounts of choline and lecithin. Initially his urinary TMA level fell but then rose again, indicating possible relaxation of his diet. He then took a 10-day course of metronidazole, which helped reduce some of the malodor. The authors reported that the most impactful therapy for the patient was being able to discuss the disorder with his friends and family members.³⁷ This case highlighted the importance of confirming the diagnosis and early initiation of dietary and pharmacologic interventions in patients with trimethylaminuria. In patients reporting a persistent fishy body odor, trimethylaminuria should be on the differential.

Patient 2—In 1999, Schissel et al⁶ described a 20-year-old active-duty soldier who presented to the dermatology department with smelly trench foot and tinea pedis. The soldier reported having this malodorous pitted rash for more than 10 years. He also reported occasional interdigital burning and itching and noted no improvement despite using various topical antifungals. Physical examination revealed an “overpowering pungent odor” when the patient removed his shoes. He had many tender, white, and wet plaques with scalloped borders coalescing into shallow pits on the plantar surface of the feet and great toes. Potassium hydroxide preparation of the great toe plaques and interdigital web spaces were positive for fungal elements, and bacterial cultures isolated moderate coagulase-negative staphylococcal and Corynebacterium species. Additionally, fungal cultures identified Acremonium species. The patient was started on clotrimazole cream twice daily, clindamycin solution twice daily, and topical ammonium chloride nightly. Two weeks later, the patient reported resolution of symptoms, including the malodor.⁶ In pitted keratolysis, warm and wet environments within boots or shoes allow for the growth of bacteria and fungi. The extent of the lesions is related to the amount of bacteria within the stratum corneum. The diagnosis often is made based on odor, location, and appearance of the rash alone. The most common organisms implicated as causal agents in the condition are Kytococcus sedentarius, Dermatophilus congolensis, and species of Corynebacterium and Actinomyces. It is thought that these organisms release proteolytic enzymes that degrade the horny layer, releasing a mixture of thiols, thioesters, and sulfides, which cause the pungent odor. Familiarity with the characteristic odor aids in prompt diagnosis and treatment, which will ultimately heal the skin eruption. 

Patient 3—Srivastava et al³² described a 43-year-old woman who presented with a nevus on the back since childhood. She noticed that it had changed and grown over the past few years and reported that her dog would often sniff the lesion and try to scratch and bite the lesion. This reaction from her dog led the patient to seek out evaluation from a dermatologist. The patient had no personal history of skin cancer, bad sunburns, tanning bed use, or use of immunosuppressants. She reported that her father had a history of basal cell carcinoma. Physical examination revealed a 1.2×1.5-cm brown patch with an ulcerated nodule located on the lower aspect of the lesion. The patient underwent a wide local excision and sentinel lymph node biopsy with pathology showing a 4-mm-thick melanoma with positive lymph nodes. She then underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. Following the surgery, the patient’s dog would sniff the back and calmly rest his head in her lap. She has not had a recurrence and credits her dog for saving her life.³² Canine olfaction may play a role in detecting skin cancers, as evidenced by this case. Patients and dermatologists should pay attention to the behavior of dogs toward skin lesions. Harnessing this sense into a method to noninvasively screen for melanoma in humans should be further investigated.

Patient 4—Matthews et al³⁸ described a 32-year-old woman who presented to an emergency eye clinic with a white “lump” on the left upper eyelid of 6 months’ duration. Physical examination revealed 3 nodular and cystic lesions oozing a thick yellow-white discharge. Cultures were taken, and the patient was started on chloramphenicol ointment once daily to the skin. At follow-up, the lesions had not changed, and the cultures were negative. The patient reported an intermittent malodorous discharge and noted multiple similar lesions on her body. Excisional biopsy demonstrated histologic findings including dyskeratosis, papillomatosis, and suprabasal acantholysis associated with focal underlying chronic inflammatory infiltrate. She was referred to a dermatologist and was diagnosed with Darier disease. She was started on clobetasone butyrate when necessary and adapalene nocte. Understanding the smell associated with Darier disease in conjunction with the cutaneous findings may aid in earlier diagnosis, improving outcomes for affected patients.³⁸ 

Conclusion

The sense of smell may be an overlooked diagnostic tool that dermatologists innately possess. Odors detected when examining patients should be considered, as these odors may help guide a diagnosis. Early diagnosis and treatment are important in many dermatologic diseases, so it is imperative to consider all diagnostic clues. Although physician olfaction may aid in diagnosis, its utility remains challenging, as there is a lack of consensus and terminology regarding odor in disease. A limitation of training to identify disease-specific odors is the requirement of engaging in often unpleasant odors. Methods to objectively measure odor are expensive and still in the early stages of development. Further research and exploration of olfactory-based diagnostic techniques is warranted to potentially improve dermatologic diagnosis. 

Humans possess the ability to recognize and distinguish a large range of odors that can be utilized in a wide range of applications. For example, sommeliers can classify more than 88 smells specific to the roughly 800 volatile organic compounds (VOCs) in wine. Thorough physical examination is essential in dermatology, and although sight and touch play the most important diagnostic roles, the sense of smell often is overlooked. Dermatologists are rigorously trained on the many visual aspects of skin disease and have a plethora of terms to describe these features while there is minimal characterization of odors. Research on odors and the role of olfaction in dermatologic practice is limited.^1,2 We conducted a literature review of PubMed and Google Scholar for peer-reviewed articles discussing the role of odors in dermatologic diseases. Keywords included odor + dermatology, smell + dermatology, cutaneous odor, odor + diagnosis, and disease odor. Relevant studies were identified by screening their abstracts, followed by a full-text review. A total of 38 articles written in English that presented information on the odor associated with dermatologic diseases were included. Articles that were unrelated to the topic or written in a language other than English were excluded.

Common Skin Odors

The human body emits odorants—small VOCs—in various forms (skin/sweat, breath, urine, reproductive fluids). Human odor originates from the oxidation and bacterial metabolism of sweat and sebum on the skin.³ While many odors are physiologic and not cause for concern, others can signal underlying dermatologic pathologies.⁴ Odor-producing conditions can be categorized broadly into infectious diseases, disorders of keratinization and acantholysis, metabolic disorders, and organ dysfunction (Table). Infectious causes include bacterial infections and chronic wounds, which commonly emit characteristic offensive odors. For example, coryneform infections produce methanethiol, causing a cheesy odor of putrid fruit, and pseudomonal pyoderma infections emit a grape juice–like or mousy odor.

Bacterial and Fungal Infections

Bacterial and fungal infections often have distinct smells. Coryneform infections emit an odor of sweaty feet, pseudomonal infections emit a grape juice–like or mousy odor, and trichomycosis infections (caused by Corynebacterium tenuis) present with malodor.⁵ Pseudomonas can infect pyoderma gangrenosum lesions, producing a characteristic malodor.⁵ These smells can be clues for infectious etiology and guide further workup.

Pitted keratolysis, a malodorous pitted rash characterized by infection of the stratum corneum by Kytococcus sedentarius, Dermatophilus congolensis, or Corynebacterium species, is associated with a rotten smell. Its pungent odor, clinical location, and characteristic appearance often are enough to make a diagnosis. The amount of bacteria maintained in the stratum corneum is correlated with the extent of the lesion. Controlling excessive moisture in footwear, aluminum chloride, and topical microbial agents work together to eliminate the skin eruption.⁶ 

Hidradenitis suppurativa, a chronic inflammatory disease of apocrine gland–containing skin, can manifest with abscesses, draining sinuses, and nodules that produce a foul-smelling, purulent discharge. The disease can be debilitating, largely impacting patients’ quality of life, making early diagnosis and treatment critical.^7,8 Therapy is dependent on disease severity and includes topical antibiotics, systemic therapies, and biologics.⁸ 

Patients with atopic dermatitis often experience bacterial superinfection with Staphylococcus aureus. A case report described a patient who developed a fishy odor in this setting that resolved with antibiotic treatment, implicating S aureus in the etiology of the smell.⁹ 

A seminal fluid odor has been reported in cases of Pasteurella wound infection. In such cases, Pasteurella multocida subspecies septica was identified in the wounds caused by a dog scratch and a cat bite. The seminal fluid–like odor was apparent hours after the inciting incident and resolved after treatment with antibiotics.¹⁰ 

Fungal infections frequently emit musty or moldy odors. Tinea pedis (athlete’s foot) is the most prevalent cutaneous fungal infection. The presence of tinea pedis is associated with an intense foul-smelling odor, itching, fissuring, scaling, or maceration of the interdigital regions. The rash and odor resolve with use of topical antifungal agents.^11,12 Seborrheic dermatitis, a prevalent and chronic dermatosis, is characterized by yellow greasy scaling on an erythematous base. In severe cases, a greasy crust with an offensive odor can cover the entire scalp.¹³ The specific cause of this odor is unclear, but it is thought that sebum production and the immunological response to specific Malassezia yeast species may play a role.¹⁴

Genetic and Metabolic Disorders

An array of disorders of keratinization and acantholysis can manifest with distinctive smells that dermatologists frequently encounter. For example, Darier disease, characterized by keratotic papules progressing to crusted plaques, has a signature foul-smelling odor associated with cutaneous bacterial colonization.¹⁵ Similarly, Hailey-Hailey disease, an autosomal-dominant disorder with crusted erosions in skinfold areas, produces a distinct foul smell.¹⁶ Disorders such as pemphigus vulgaris and pemphigus foliaceus emit a peculiar fishy odor that can be helpful in making a diagnosis.¹⁷ Additionally, bullous ichthyosiform erythroderma, keratitis-ichthyosis-deafness syndrome, mal de Meleda, and Papillon-Lefèvre syndrome are all associated with malodor.⁵

Certain metabolic disorders can manifest and present initially with identifiable odors. Trimethylaminuria is a psychologically disabling disease known for its rotting fishy smell due to high amounts of trimethylamine appearing in affected individuals’ sweat, urine, and breath. Previously considered to be very rare, Messenger et al¹⁸ reported the disorder is likely underdiagnosed in those with idiopathic malodor production. Detection and treatment can greatly improve patient quality of life.

Phenylketonuria is an autosomal-recessive inborn error of phenylalanine metabolism that produces a musty body and urine odor as well as other neurologic and dermatologic symptoms.^19,20 Patients can present with eczematous rashes, fair skin, and blue eyes. Phenylacetic acid produces the characteristic odor in the bodily fluids, and the disease is treated with a phenylalanine-free diet.²¹ 

Maple syrup urine disease is a disorder of the oxidative decarboxylation of valine, leucine, and isoleucine (branched-chain amino acids) characterized by urine that smells sweet, resembling maple syrup, in afflicted individuals. The odor also can be present in other bodily secretions, such as sweat. Patients present early in infancy with poor feeding and vomiting as well as neurologic symptoms, eventually leading to intellectual disability. These individuals must avoid the branched-chain amino acids in their diets.²¹ 

Other metabolic storage disorders linked with specific odors are methionine adenosyltransferase deficiency (boiled cabbage), hypermethioninemia (fishy, boiled cabbage), isovaleric acidemia (sweaty feet), methionine malabsorption syndrome (pungent malodor), and dimethylglycine dehydrogenase deficiency (fishy).^5,21,22

In diabetic ketoacidosis, a life-threatening complication of diabetes, the excess of ketone bodies produced causes patients to have a distinct fruity breath and urine odor, as well as fatigue, polyuria, polydipsia, nausea, and vomiting.²² Although patients with type 1 diabetes typically comprise the cohort of patients presenting with diabetic ketoacidosis, patients with type 2 diabetes can exhibit cutaneous manifestations such as infection, xerosis, and inflammatory skin diseases.^23,24 

Organ Dysfunction

A peculiar body odor can be a sign of organ dysfunction. Renal dysfunction may present with both an odor and dermatologic manifestations. Patients with end-stage renal disease can have an ammonialike uremic breath odor as the result of excessive nitrogenous waste products and increased concentrations of urea in their saliva.^4,22 These patients also can exhibit pruritus, xerosis, pigmentation changes, nail changes, other dermatoses, and rarely uremic frost with white urate crystals present on the skin.^25,26 

Liver failure has been associated with an ammonialike musty breath odor termed fetor hepaticus. Shimamoto et al²⁷ reported notably higher levels of breath ammonia levels in patients with hepatic encephalopathy, indicating that excess ammonia is responsible for the odor. Fetor hepaticus has unique characteristics that can permit a diagnosis of liver disease, though it has been reported in cases in which a liver injury could not be identified.²⁸ 

Aging patients typically have a distinctive smell. Haze et al²⁹ analyzed the body odor of patients aged 26 to 75 years and discovered the compound 2-nonenal—an unsaturated aldehyde with a smell described as greasy and grassy—was found only in patients older than 40 years. The researchers’ analysis of skin-surface lipids also revealed that the presence of ω7 unsaturated fatty acids and lipid peroxides increased with age. They concluded that 2-nonenal is generated from the oxidative degradation of ω7 unsaturated fatty acids by lipid peroxides, suggesting that 2-nonenal may be a cause of the odor of old age.²⁹

Cutaneous Malignancies 

Research shows that the profiles of the body’s continuously released VOCs change in the presence of malignancy. Some studies suggest that melanoma may have a unique odor. Willis et al³⁰ reported that after a 13-month training period, a dog was able to correctly identify melanoma and distinguish it from basal cell carcinoma, benign nevi, and healthy skin based on olfaction alone. Additional cases have been reported in which dogs have been able to identify melanoma based on smell, suggesting that canine olfactory detection of melanoma could possibly aid in the diagnosis of skin cancer, which warrants further investigation.^31,32 There is limited evidence on the specific odors of other cutaneous malignancies, such as basal cell carcinoma and squamous cell carcinoma. 

Bacterial superinfection of cutaneous malignancy can secrete pungent odors. An offensive rotting odor has been associated with necrotic malignant ulcers of the vagina. This malodor likely is a result of the formation of putrescine, cadaverine, short-chain fatty acids (isovaleric and butyric acids) and sulfur-containing compounds by bacteria.³³ Recognition of similar smells may aid in management of these infections.

Diagnostic Techniques

Evaluating human skin odor is challenging, as the components of VOCs are complicated and typically found at trace levels. Studies indicate that gas chromatography–mass spectrometry is the most effective way to analyze human odor. This method separates, quantifies, and analyzes VOCs from samples containing odors.³⁴ Gas chromatography–mass spectrometry, however, has limitations, as the time for analysis is lengthy, the equipment is large, and the process is expensive.³ Research supports the usefulness and validity of quantitative gas chromatography–olfactometry to detect odorants and evaluate odor activity of VOCs in various samples.³⁵ With this technique, human assessors act in place of more conventional detectors, such as mass spectrometers. This method has been used to evaluate odorants in human urine with the goal of increasing understanding of metabolization and excretion processes.³⁶ However, gas chromatography–olfactometry typically is used in the analysis of food and drink, and future research should be aimed at applying this method to medicine. 

Zheng et al³ proposed a wearable electronic nose as a tool to identify human odor to emulate the odor recognition of a canine’s nose. They developed a sensor array based on the composites of carbon nanotubes and polymers able to examine and identify odors in the air. Study participants wore the electronic nose on the arm with the sensory array facing the armpits while they walked on a treadmill. Although many issues regarding odor measurement were not addressed in this study, the research suggests further studies are warranted to improve analysis of odor.³

Clinical Cases

Patient 1—Arseculeratne et al³⁷ described a 41-year-old man who presented with a fishy odor that others had noticed since the age of 13 years but that the patient could not smell himself. Based on his presentation, he was worked up for trimethylaminuria and found to have elevated levels of urinary trimethylamine (TMA) with a raised TMA/TMA-oxidase ratio. These findings were consistent with a diagnosis of primary trimethylaminuria, and the patient was referred to a dietician for counseling on foods that contain low amounts of choline and lecithin. Initially his urinary TMA level fell but then rose again, indicating possible relaxation of his diet. He then took a 10-day course of metronidazole, which helped reduce some of the malodor. The authors reported that the most impactful therapy for the patient was being able to discuss the disorder with his friends and family members.³⁷ This case highlighted the importance of confirming the diagnosis and early initiation of dietary and pharmacologic interventions in patients with trimethylaminuria. In patients reporting a persistent fishy body odor, trimethylaminuria should be on the differential.

Patient 2—In 1999, Schissel et al⁶ described a 20-year-old active-duty soldier who presented to the dermatology department with smelly trench foot and tinea pedis. The soldier reported having this malodorous pitted rash for more than 10 years. He also reported occasional interdigital burning and itching and noted no improvement despite using various topical antifungals. Physical examination revealed an “overpowering pungent odor” when the patient removed his shoes. He had many tender, white, and wet plaques with scalloped borders coalescing into shallow pits on the plantar surface of the feet and great toes. Potassium hydroxide preparation of the great toe plaques and interdigital web spaces were positive for fungal elements, and bacterial cultures isolated moderate coagulase-negative staphylococcal and Corynebacterium species. Additionally, fungal cultures identified Acremonium species. The patient was started on clotrimazole cream twice daily, clindamycin solution twice daily, and topical ammonium chloride nightly. Two weeks later, the patient reported resolution of symptoms, including the malodor.⁶ In pitted keratolysis, warm and wet environments within boots or shoes allow for the growth of bacteria and fungi. The extent of the lesions is related to the amount of bacteria within the stratum corneum. The diagnosis often is made based on odor, location, and appearance of the rash alone. The most common organisms implicated as causal agents in the condition are Kytococcus sedentarius, Dermatophilus congolensis, and species of Corynebacterium and Actinomyces. It is thought that these organisms release proteolytic enzymes that degrade the horny layer, releasing a mixture of thiols, thioesters, and sulfides, which cause the pungent odor. Familiarity with the characteristic odor aids in prompt diagnosis and treatment, which will ultimately heal the skin eruption. 

Patient 3—Srivastava et al³² described a 43-year-old woman who presented with a nevus on the back since childhood. She noticed that it had changed and grown over the past few years and reported that her dog would often sniff the lesion and try to scratch and bite the lesion. This reaction from her dog led the patient to seek out evaluation from a dermatologist. The patient had no personal history of skin cancer, bad sunburns, tanning bed use, or use of immunosuppressants. She reported that her father had a history of basal cell carcinoma. Physical examination revealed a 1.2×1.5-cm brown patch with an ulcerated nodule located on the lower aspect of the lesion. The patient underwent a wide local excision and sentinel lymph node biopsy with pathology showing a 4-mm-thick melanoma with positive lymph nodes. She then underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. Following the surgery, the patient’s dog would sniff the back and calmly rest his head in her lap. She has not had a recurrence and credits her dog for saving her life.³² Canine olfaction may play a role in detecting skin cancers, as evidenced by this case. Patients and dermatologists should pay attention to the behavior of dogs toward skin lesions. Harnessing this sense into a method to noninvasively screen for melanoma in humans should be further investigated.

Patient 4—Matthews et al³⁸ described a 32-year-old woman who presented to an emergency eye clinic with a white “lump” on the left upper eyelid of 6 months’ duration. Physical examination revealed 3 nodular and cystic lesions oozing a thick yellow-white discharge. Cultures were taken, and the patient was started on chloramphenicol ointment once daily to the skin. At follow-up, the lesions had not changed, and the cultures were negative. The patient reported an intermittent malodorous discharge and noted multiple similar lesions on her body. Excisional biopsy demonstrated histologic findings including dyskeratosis, papillomatosis, and suprabasal acantholysis associated with focal underlying chronic inflammatory infiltrate. She was referred to a dermatologist and was diagnosed with Darier disease. She was started on clobetasone butyrate when necessary and adapalene nocte. Understanding the smell associated with Darier disease in conjunction with the cutaneous findings may aid in earlier diagnosis, improving outcomes for affected patients.³⁸ 

Conclusion

The sense of smell may be an overlooked diagnostic tool that dermatologists innately possess. Odors detected when examining patients should be considered, as these odors may help guide a diagnosis. Early diagnosis and treatment are important in many dermatologic diseases, so it is imperative to consider all diagnostic clues. Although physician olfaction may aid in diagnosis, its utility remains challenging, as there is a lack of consensus and terminology regarding odor in disease. A limitation of training to identify disease-specific odors is the requirement of engaging in often unpleasant odors. Methods to objectively measure odor are expensive and still in the early stages of development. Further research and exploration of olfactory-based diagnostic techniques is warranted to potentially improve dermatologic diagnosis. 

Fluoroscopy is an imaging technique that allows for real-time visualization of internal structures in the body using continuous radiography beams. More than 1 million fluoroscopy-guided procedures are performed annually in the United States.¹ Utilization of these procedures continues to increase, and so does the probability of related complications, as prolonged exposure to ionizing radiation can cause skin injuries.² Fortunately, the incidence of radiation-induced skin injuries compared with the total number of fluoroscopic procedures performed remains small,² although one study suggested the incidence may be as high as 8.9% in at-risk populations.³

Radiation dermatitis is well recognized in dermatology as a complication of oncologic management; however, radiation dermatitis as a complication of fluoroscopic procedures is underrecognized.⁴ Fluoroscopy-induced radiation dermatitis can be categorized as acute, subacute, or chronic.⁵ Common fluoroscopic procedures that have been associated with fluoroscopy-induced radiation dermatitis include interventional cardiac procedures, neurovascular procedures, transjugular intrahepatic portosystemic shunt procedures, and endovascular abdominal aortic aneurysm repairs.^6,7

Patients with fluoroscopy-induced radiation dermatitis, particularly fluoroscopy-induced chronic radiation dermatitis (FICRD), can present to dermatology up to several years after the initial fluoroscopy procedure with no awareness of the association between the procedure and their skin findings. This presents a diagnostic challenge, and FICRD often is overlooked.^5,8-10

We conducted a literature search of PubMed articles indexed for MEDLINE using the search terms ­fluoroscopy and dermatitis. In this reappraisal, we will provide a comprehensive overview of fluoroscopy-induced ­radiation dermatitis with an emphasis on FICRD, covering its clinical manifestations, pathophysiology, risk factors, ­differential diagnosis, histology, and management. The aim of this review is to highlight the salient features and mimickers of FICRD and inform readers how to approach suspected cases, leading to accurate diagnosis and ­effective management.

Pathophysiology 

Fluoroscopy-induced radiation dermatitis is the result of dose-dependent radiation-induced tissue damage. As the peak skin dosage (PSD) of radiation increases over the course of a procedure or multiple procedures, the severity of skin injury predictably increases. During fluoroscopic procedures, the standard irradiation dosage ranges from 0.02 Gy/min to 0.05 Gy/min.¹¹ Transient skin changes may start to be seen around 2 Gy of cumulative exposure. Fluoroscopic procedures typically range in duration from 60 to 120 minutes; however, complex cases may exceed that. Additionally, multiple procedures performed within shorter intervals can result in greater PSD accumulation. Shorter intervals between procedures do not allow enough time for damage repair from the previous ­procedure and can result in further severe damage when the skin is re-exposed to radiation.² The American College of Radiology recommends medical follow-up after 10 Gy of cumulative exposure, while cumulative exposure above 15 Gy within a 6- to 12-month period is defined as a sentinel event, according to The Joint Commission.^12-14

Depending on the patient’s total radiation dosage during one or more procedures, the result of the tissue damage manifests differently at varying times: early skin changes are categorized as fluoroscopy-induced acute radiation dermatitis, and late skin changes are categorized as FICRD (Table 1).

Clinical Manifestations

Acute radiation dermatitis from fluoroscopic procedures manifests within hours to days up to 90 days following radiation exposure and can be characterized by erythema with blistering, desquamation, epilation, pigmentation changes, and even necrosis if the accumulated dosage exceeds 15 Gy.¹⁵ Chronic radiation dermatitis (which as related to fluoroscopic procedures is termed FICRD) has a longer onset of weeks to years and is clinically characterized by telangiectasias, permanent erythema, dermal atrophy, or ulcerations. Clinically, subacute radiation dermatitis shares features of both acute and chronic radiation dermatitis; therefore, it is differentiated based on its histologic features.^5,16

Although fluoroscopy-induced acute radiation dermatitis (Table 1) may precede FICRD, acute manifestations of fluoroscopy-related dermatitis can be subtle and often manifest in areas not easily visualized. Because referrals to dermatologists for full-skin examinations after fluoroscopy procedures are not standard, patients may not be aware of the association between these procedures and the development of skin lesions. Nonetheless, some patients may report a history of skin changes such as redness days or weeks after a fluoroscopic procedure with accompanying pain and pruritus limited to the fluoroscopy-exposed region, which tend to self-resolve.¹⁷ The risk for FICRD is thought to increase if a history of fluoroscopy-induced acute radiation dermatitis is present.¹⁸

The location of the skin findings correlates to the area exposed to prolonged radiation during the procedure(s). The most common areas include the scapular and subscapular regions, the right lateral trunk inferior to the axilla, the mid back, and the right anterolateral chest.^16,19,20 These regions are associated with more complex (eg, cardiac) procedures that have been reported to lead to prolonged radiation exposure. The skin findings in FICRD are described as geometric, corresponding to the squarish or rectangular radiography beam that is directed at the patient. Additionally, radiography beams spread outward as they travel in space; therefore, skin injuries are common at the region more distal to the path of origination of the beam.^21-23 Subsequently, a geometric, dyspigmented, indurated or atrophic plaque with telangiectasias and erosions or ulcerations with progressive worsening is a common manifestation of FICRD.^5,16,23 Patients also commonly present with pruritus or severe pain associated with the lesion.^24,25  

Dermatologic Manifestations of FICRD

Skin responses seen weeks to years after a fluoroscopic procedure and typically after cumulative radiation exposure of 10 Gy or greater are categorized as FICRD (Table 2). These changes also can be clinically graded based on the Radiation Therapy Oncology Group classification of radiation dermatitis (Tables 3 and 4).²⁶ Chronic changes in the skin largely result from remodeling of the vasculature and the subcutaneous tissue over time. Unlike acute changes, chronic changes typically persist and continue to worsen.²⁷

Telangiectasias—Anywhere from months to 1 year after exposure to 10 Gy of radiation, proliferation of atypical superficial vessels in the dermis can be seen, typically manifesting as telangiectasias on physical examination. Telangiectasias can increase with time and can even exhibit a dose-dependent relationship to the radiation exposure.²⁸

Atrophy—Atrophic-appearing skin after radiation exposure is the result of direct injury to both the epidermis and fibroblasts in the dermis. The destruction of keratinocytes leads to a thin epidermis, and destruction of dermal fibroblasts causes insufficient collagen production.²⁹ Clinically, this process manifests as an atrophic plaque that can be seen 12 weeks to 1 year after the procedure. 

Fibrosis—Approximately 1 year after the exposure, the initial damage can lead to disruption of molecular pathways, causing fibrosis. Transforming growth factor (TGF) β1 is the main factor involved.²⁹ Damage to the endothelial cells results in increased TGF-β1 levels, which causes increased stimulation of remaining atypical fibroblasts and thus increased irregular collagen deposition.³⁰ Further adding to this knowledge, Wei et al³¹ recently proposed that damage to the epidermal keratinocytes leads to disruption of yes-associated protein 1, which is a protective factor released from keratinocytes that regulates the dermal fibroblasts. However, extensive damage to the keratinocytes can lead to lower yes-associated protein 1 levels and its downstream activity, leading to increased levels of TGF-β1 and fibroblast activity.³¹ Clinically, this fibrotic stage is seen as indurated plaques in patients. 

Necrosis—There are 2 forms of necrosis that can be seen. Ischemic dermal necrosis typically occurs in the acute phase after 10 weeks and approximately 18 Gy of cumulative exposure. It results from substantial skin damage, including microvascular damage and reduction in dermal capillaries, leading to ischemia of the tissue.² Late dermal necrosis is the process seen in the chronic stage of FICRD and radiation dermatitis not related to ­fluoroscopy. It results from the inability of the fibrotic dermis to vascularly support the epidermis above it.² It can be seen anywhere from 1 to 4 years after the procedure. This stage clinically manifests as worsening ulcerations with major pain and increased risk for secondary infections.¹⁶ 

Dyspigmentation—Dyspigmentation at the site of the radiation exposure can be seen acutely and chronically. Dosage above 15 to 18 Gy can lead to destruction of melanocytes, which can cause hypopigmentation in exposed areas. However, melanocytes are relatively resistant to radiation; therefore, dosages below the threshold of destruction of 15 to 18 Gy can cause melanocytic hyperactivity leading to hyperpigmentation.³² Hence, pigmentary changes can vary greatly. Classically, a central area of hypopigmentation with surrounding hyperpigmentation is seen.

Histology 

Histologic appearance of radiation dermatitis varies depending on its stage. Acute radiation dermatitis primarily demonstrates superficial dermal edema, damage to the basal cell layer, small vessel dilation with thrombi, and hemorrhage along with a sparse inflammatory cell infiltrate.³³ Histology typically is the only way to characterize subacute radiation dermatitis.⁵ Lichenoid tissue reaction is its characteristic feature. Mononuclear cells are found adjected to necrotic keratinocytes along with prominent vacuolization of the basal cell layer.³³

The key histologic features of chronic radiation dermatitis include epidermal atrophy, hyperkeratosis, telangiectasias, loss of adnexal structures, and dermal fibrosis along with sparse atypical stellate fibroblasts.³⁴ However, clinical context of fluoroscopic exposure is required for the dermatopathologist to differentiate chronic radiation dermatitis from its histologic differential of morphea and lichen sclerosus. In a cross-sectional study, only 1 of 6 cases (16.7%) was correctly diagnosed as chronic radiation dermatitis in the absence of correlating clinical history.³⁵ 

Risk Factors for FICRD 

Since the diagnosis of FICRD can be a clinical challenge, understanding the risk factors can be helpful. The general likelihood of developing FICRD is related to the duration, frequency, interval, intensity, and area of radiation exposure. Procedures exceeding the normal duration of 60 to 120 minutes have been well documented as a substantial risk factor for radiation dermatitis and FICRD.^36-38 The risk tends to be higher in longer procedures because they result in more radiation exposure and higher accumulated PSD. Obesity (ie, body mass index >26) is the major risk factor that has been associated with longer procedure times, as higher radiation dosages are necessary to penetrate the body of a larger patient and a larger skin surface area is exposed.^37-39

Other risk factors associated with FICRD relate to how prone a patient is to radiation-induced DNA damage. Older patients are at higher risk due to lower intrinsic ability of the tissue to repair itself.¹¹ Patients with a history of connective tissue diseases—particularly lupus, scleroderma, and mixed connective tissue disease—are at an increased risk.⁴⁰ Furthermore, patients with genetic disorders that impair DNA repair are more susceptible to radiation-induced DNA damage; therefore, patients with ataxia-telangiectasia, xeroderma pigmentosum, Fanconi anemia, and hereditary nevoid basal cell carcinoma are at higher risk for FICRD.³⁹ Similarly, medications that can affect DNA repair also have been shown to be risk factors. These medications include chemotherapeutic agents such as actinomycin D, cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil.^2,39 Diabetes, hyperthyroidism, and tobacco use also have been shown to increase a patient’s risk for FICRD.³⁹ It also is reasonable to believe that patients with defects in fibroblasts or with elastin or collagen disorders (eg, Ehlers-Danlos syndrome) would be at higher risk, but there are no known studies highlighting the association in the literature.

Differential Diagnosis of FICRD 

Acute allergic or irritant contact dermatitis manifests with a localized area of erythematous skin accompanied by pruritus.⁴¹ Patients with FICRD can present with a localized area of erythema and hyperpigmentation with minimal atrophy. The lesion may accompany substantial pruritus, which can favor the more common diagnosis of contact dermatitis.^35,42,43

Fixed-drug eruption manifests as a well-defined, hyperpigmented plaque in a fixed location that occurs upon ingestion of a drug.⁴⁴ Fluoroscopy-induced chronic radiation dermatitis lesions are well demarcated and geometrically shaped and therefore can mimic lesions seen in fixed-drug eruptions.⁴⁵ Additionally, the patient population undergoing fluoroscopic procedures tends to have major comorbidities requiring multiple medications.⁴

Decubitus ulcers are a result of vascular compromise to an area of skin due to constant pressure and are most commonly seen in the sacral region of patients with ­obesity.⁴⁶ Ulcerated FICRD lesions can manifest on the lower midback. These lesions can be seen after endovascular repair of abdominal aortic aneurysm or prostatic artery embolization.^20,21 The location of these lesions can mimic decubitus ulcers if fluoroscopic history is unknown. As mentioned, obesity also increases the risk for FICRD. 

Morphea can manifest as a localized area of induration and hyperpigmentation of the skin.⁴⁷ When FICRD has progressed to dermal fibrosis, patients can present with indurated plaques without ulcerations, which can be hard to differentiate from morphea.^16,48 However, the presence of ulcerations or hyperkeratosis can differentiate morphea from FICRD.¹⁶

Ultimately, it is the location of FICRD lesions that remains the biggest diagnostic clue. Any suspicious lesion present on the scapular or subscapular areas, anterolateral chest, and/or mid back should prompt an investigation into recent or remote history of fluoroscopic procedures. 

Management of FICRD

Diagnosis of FICRD should be made clinically based on the history and physical examination whenever possible, since a biopsy is not recommended.³⁵ Wound healing in FICRD is delayed, and biopsies can lead to ulcerations or secondary infections.¹⁷ Therefore, it is important to remain suspicious for FICRD. Management of FICRD should correspond to the clinical findings outlined by a recent Delphi consensus survey.⁴⁹ Regardless, the core of FICRD management framework should always include good hygiene, maintenance of skin hydration to improve epithelialization, and sufficient photoprotection.^49,50

Among the first signs of FICRD are telangiectasias. Although asymptomatic, their appearance can be distressing for patients. Pulsed dye laser therapy is a first-line option that has been studied and has shown clinical efficacy for treatment of telangiectasias and vascular changes in patients with FICRD.^49,51

If patients develop fibrotic changes, treatment options are limited. Fibrosis is hard to reverse, and the management approach is limited to symptomatic relief. Mechanical and deep-friction massages have been shown to be effective at reducing skin induration in patients.⁵² Fractional ablative lasers also may be utilized for skin contractures, especially if range of motion is affected.^53,54 Although it comes with its own challenges, autologous fat grafting has shown promise in reducing postradiation fibrosis and inducing angiogenesis in tissue.⁵⁵ Oral pentoxifylline also has shown mild efficacy, as it may be able to suppress TGF-β1 levels.⁵³ However, prevention of fibrotic changes may be the most important. Wei et al³¹ suggested that low-dose oral prednisolone at 5 mg twice daily for 3 weeks might be an option to prevent the progression of skin changes and even reverse fibrosis to an extent; however, further evidence regarding its efficacy still is necessary. Additionally, no evidence was identified to support the use of topical corticosteroids for fibrotic changes seen in FICRD.⁵⁶

Patients with FICRD or even acute radiation dermatitis after fluoroscopy tend to develop superficial ulcerations from minor traumas. Good wound hygiene, antiseptic care, and absorbent dressings, such as hydrogel and hydrocolloid, may be sufficient for treating these wounds, as seen in the Figure.^42,48 However, once patients develop refractory ulcerations or necrosis, treatment options are then limited to surgical removal with a flap or graft.^5,33,42,45
 

Risk for basal cell carcinomas and squamous cell carcinomas is higher in patients with radiation exposure; however, the exact risk from fluoroscopic procedures is unknown. One study demonstrated an increased risk of 6.9% in development of skin cancer after a median radiation exposure of 15.5 Gy and a mean latency period of 38.3 years,⁵⁷ and in another retrospective study, the risk was higher in Fitzpatrick skin types I and II.⁵⁸ Unlike the development of radiodermatitis itself, which shows a dose-dependent response, development of skin cancers follows a stochastic pattern (not dose dependent).⁵⁹ Therefore, it is important to identify these high-risk patients and establish follow-up.

Conclusion

Fluoroscopy-induced chronic radiation dermatitis can be a diagnostic challenge, as skin changes may not be readily associated with the procedure by patients. Therefore, any lesion with a geometric shape and accompanying chronic radiation dermatitis features located on the scapular or subscapular areas, anterolateral chest, and midback should prompt an investigation into history of fluoroscopic procedures. Treatment of chronic skin changes in FICRD depends on the clinical manifestations. Good hygiene, skin hydration, and sufficient photoprotection are crucial. Finally, long-term monitoring with skin examinations is important to assess for the development of skin cancers in the treated area.

Fluoroscopy is an imaging technique that allows for real-time visualization of internal structures in the body using continuous radiography beams. More than 1 million fluoroscopy-guided procedures are performed annually in the United States.¹ Utilization of these procedures continues to increase, and so does the probability of related complications, as prolonged exposure to ionizing radiation can cause skin injuries.² Fortunately, the incidence of radiation-induced skin injuries compared with the total number of fluoroscopic procedures performed remains small,² although one study suggested the incidence may be as high as 8.9% in at-risk populations.³

Radiation dermatitis is well recognized in dermatology as a complication of oncologic management; however, radiation dermatitis as a complication of fluoroscopic procedures is underrecognized.⁴ Fluoroscopy-induced radiation dermatitis can be categorized as acute, subacute, or chronic.⁵ Common fluoroscopic procedures that have been associated with fluoroscopy-induced radiation dermatitis include interventional cardiac procedures, neurovascular procedures, transjugular intrahepatic portosystemic shunt procedures, and endovascular abdominal aortic aneurysm repairs.^6,7

Patients with fluoroscopy-induced radiation dermatitis, particularly fluoroscopy-induced chronic radiation dermatitis (FICRD), can present to dermatology up to several years after the initial fluoroscopy procedure with no awareness of the association between the procedure and their skin findings. This presents a diagnostic challenge, and FICRD often is overlooked.^5,8-10

We conducted a literature search of PubMed articles indexed for MEDLINE using the search terms ­fluoroscopy and dermatitis. In this reappraisal, we will provide a comprehensive overview of fluoroscopy-induced ­radiation dermatitis with an emphasis on FICRD, covering its clinical manifestations, pathophysiology, risk factors, ­differential diagnosis, histology, and management. The aim of this review is to highlight the salient features and mimickers of FICRD and inform readers how to approach suspected cases, leading to accurate diagnosis and ­effective management.

Pathophysiology 

Fluoroscopy-induced radiation dermatitis is the result of dose-dependent radiation-induced tissue damage. As the peak skin dosage (PSD) of radiation increases over the course of a procedure or multiple procedures, the severity of skin injury predictably increases. During fluoroscopic procedures, the standard irradiation dosage ranges from 0.02 Gy/min to 0.05 Gy/min.¹¹ Transient skin changes may start to be seen around 2 Gy of cumulative exposure. Fluoroscopic procedures typically range in duration from 60 to 120 minutes; however, complex cases may exceed that. Additionally, multiple procedures performed within shorter intervals can result in greater PSD accumulation. Shorter intervals between procedures do not allow enough time for damage repair from the previous ­procedure and can result in further severe damage when the skin is re-exposed to radiation.² The American College of Radiology recommends medical follow-up after 10 Gy of cumulative exposure, while cumulative exposure above 15 Gy within a 6- to 12-month period is defined as a sentinel event, according to The Joint Commission.^12-14

Depending on the patient’s total radiation dosage during one or more procedures, the result of the tissue damage manifests differently at varying times: early skin changes are categorized as fluoroscopy-induced acute radiation dermatitis, and late skin changes are categorized as FICRD (Table 1).

Clinical Manifestations

Acute radiation dermatitis from fluoroscopic procedures manifests within hours to days up to 90 days following radiation exposure and can be characterized by erythema with blistering, desquamation, epilation, pigmentation changes, and even necrosis if the accumulated dosage exceeds 15 Gy.¹⁵ Chronic radiation dermatitis (which as related to fluoroscopic procedures is termed FICRD) has a longer onset of weeks to years and is clinically characterized by telangiectasias, permanent erythema, dermal atrophy, or ulcerations. Clinically, subacute radiation dermatitis shares features of both acute and chronic radiation dermatitis; therefore, it is differentiated based on its histologic features.^5,16

Although fluoroscopy-induced acute radiation dermatitis (Table 1) may precede FICRD, acute manifestations of fluoroscopy-related dermatitis can be subtle and often manifest in areas not easily visualized. Because referrals to dermatologists for full-skin examinations after fluoroscopy procedures are not standard, patients may not be aware of the association between these procedures and the development of skin lesions. Nonetheless, some patients may report a history of skin changes such as redness days or weeks after a fluoroscopic procedure with accompanying pain and pruritus limited to the fluoroscopy-exposed region, which tend to self-resolve.¹⁷ The risk for FICRD is thought to increase if a history of fluoroscopy-induced acute radiation dermatitis is present.¹⁸

The location of the skin findings correlates to the area exposed to prolonged radiation during the procedure(s). The most common areas include the scapular and subscapular regions, the right lateral trunk inferior to the axilla, the mid back, and the right anterolateral chest.^16,19,20 These regions are associated with more complex (eg, cardiac) procedures that have been reported to lead to prolonged radiation exposure. The skin findings in FICRD are described as geometric, corresponding to the squarish or rectangular radiography beam that is directed at the patient. Additionally, radiography beams spread outward as they travel in space; therefore, skin injuries are common at the region more distal to the path of origination of the beam.^21-23 Subsequently, a geometric, dyspigmented, indurated or atrophic plaque with telangiectasias and erosions or ulcerations with progressive worsening is a common manifestation of FICRD.^5,16,23 Patients also commonly present with pruritus or severe pain associated with the lesion.^24,25  

Dermatologic Manifestations of FICRD

Skin responses seen weeks to years after a fluoroscopic procedure and typically after cumulative radiation exposure of 10 Gy or greater are categorized as FICRD (Table 2). These changes also can be clinically graded based on the Radiation Therapy Oncology Group classification of radiation dermatitis (Tables 3 and 4).²⁶ Chronic changes in the skin largely result from remodeling of the vasculature and the subcutaneous tissue over time. Unlike acute changes, chronic changes typically persist and continue to worsen.²⁷

Telangiectasias—Anywhere from months to 1 year after exposure to 10 Gy of radiation, proliferation of atypical superficial vessels in the dermis can be seen, typically manifesting as telangiectasias on physical examination. Telangiectasias can increase with time and can even exhibit a dose-dependent relationship to the radiation exposure.²⁸

Atrophy—Atrophic-appearing skin after radiation exposure is the result of direct injury to both the epidermis and fibroblasts in the dermis. The destruction of keratinocytes leads to a thin epidermis, and destruction of dermal fibroblasts causes insufficient collagen production.²⁹ Clinically, this process manifests as an atrophic plaque that can be seen 12 weeks to 1 year after the procedure. 

Fibrosis—Approximately 1 year after the exposure, the initial damage can lead to disruption of molecular pathways, causing fibrosis. Transforming growth factor (TGF) β1 is the main factor involved.²⁹ Damage to the endothelial cells results in increased TGF-β1 levels, which causes increased stimulation of remaining atypical fibroblasts and thus increased irregular collagen deposition.³⁰ Further adding to this knowledge, Wei et al³¹ recently proposed that damage to the epidermal keratinocytes leads to disruption of yes-associated protein 1, which is a protective factor released from keratinocytes that regulates the dermal fibroblasts. However, extensive damage to the keratinocytes can lead to lower yes-associated protein 1 levels and its downstream activity, leading to increased levels of TGF-β1 and fibroblast activity.³¹ Clinically, this fibrotic stage is seen as indurated plaques in patients. 

Necrosis—There are 2 forms of necrosis that can be seen. Ischemic dermal necrosis typically occurs in the acute phase after 10 weeks and approximately 18 Gy of cumulative exposure. It results from substantial skin damage, including microvascular damage and reduction in dermal capillaries, leading to ischemia of the tissue.² Late dermal necrosis is the process seen in the chronic stage of FICRD and radiation dermatitis not related to ­fluoroscopy. It results from the inability of the fibrotic dermis to vascularly support the epidermis above it.² It can be seen anywhere from 1 to 4 years after the procedure. This stage clinically manifests as worsening ulcerations with major pain and increased risk for secondary infections.¹⁶ 

Dyspigmentation—Dyspigmentation at the site of the radiation exposure can be seen acutely and chronically. Dosage above 15 to 18 Gy can lead to destruction of melanocytes, which can cause hypopigmentation in exposed areas. However, melanocytes are relatively resistant to radiation; therefore, dosages below the threshold of destruction of 15 to 18 Gy can cause melanocytic hyperactivity leading to hyperpigmentation.³² Hence, pigmentary changes can vary greatly. Classically, a central area of hypopigmentation with surrounding hyperpigmentation is seen.

Histology 

Histologic appearance of radiation dermatitis varies depending on its stage. Acute radiation dermatitis primarily demonstrates superficial dermal edema, damage to the basal cell layer, small vessel dilation with thrombi, and hemorrhage along with a sparse inflammatory cell infiltrate.³³ Histology typically is the only way to characterize subacute radiation dermatitis.⁵ Lichenoid tissue reaction is its characteristic feature. Mononuclear cells are found adjected to necrotic keratinocytes along with prominent vacuolization of the basal cell layer.³³

The key histologic features of chronic radiation dermatitis include epidermal atrophy, hyperkeratosis, telangiectasias, loss of adnexal structures, and dermal fibrosis along with sparse atypical stellate fibroblasts.³⁴ However, clinical context of fluoroscopic exposure is required for the dermatopathologist to differentiate chronic radiation dermatitis from its histologic differential of morphea and lichen sclerosus. In a cross-sectional study, only 1 of 6 cases (16.7%) was correctly diagnosed as chronic radiation dermatitis in the absence of correlating clinical history.³⁵ 

Risk Factors for FICRD 

Since the diagnosis of FICRD can be a clinical challenge, understanding the risk factors can be helpful. The general likelihood of developing FICRD is related to the duration, frequency, interval, intensity, and area of radiation exposure. Procedures exceeding the normal duration of 60 to 120 minutes have been well documented as a substantial risk factor for radiation dermatitis and FICRD.^36-38 The risk tends to be higher in longer procedures because they result in more radiation exposure and higher accumulated PSD. Obesity (ie, body mass index >26) is the major risk factor that has been associated with longer procedure times, as higher radiation dosages are necessary to penetrate the body of a larger patient and a larger skin surface area is exposed.^37-39

Other risk factors associated with FICRD relate to how prone a patient is to radiation-induced DNA damage. Older patients are at higher risk due to lower intrinsic ability of the tissue to repair itself.¹¹ Patients with a history of connective tissue diseases—particularly lupus, scleroderma, and mixed connective tissue disease—are at an increased risk.⁴⁰ Furthermore, patients with genetic disorders that impair DNA repair are more susceptible to radiation-induced DNA damage; therefore, patients with ataxia-telangiectasia, xeroderma pigmentosum, Fanconi anemia, and hereditary nevoid basal cell carcinoma are at higher risk for FICRD.³⁹ Similarly, medications that can affect DNA repair also have been shown to be risk factors. These medications include chemotherapeutic agents such as actinomycin D, cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil.^2,39 Diabetes, hyperthyroidism, and tobacco use also have been shown to increase a patient’s risk for FICRD.³⁹ It also is reasonable to believe that patients with defects in fibroblasts or with elastin or collagen disorders (eg, Ehlers-Danlos syndrome) would be at higher risk, but there are no known studies highlighting the association in the literature.

Differential Diagnosis of FICRD 

Acute allergic or irritant contact dermatitis manifests with a localized area of erythematous skin accompanied by pruritus.⁴¹ Patients with FICRD can present with a localized area of erythema and hyperpigmentation with minimal atrophy. The lesion may accompany substantial pruritus, which can favor the more common diagnosis of contact dermatitis.^35,42,43

Fixed-drug eruption manifests as a well-defined, hyperpigmented plaque in a fixed location that occurs upon ingestion of a drug.⁴⁴ Fluoroscopy-induced chronic radiation dermatitis lesions are well demarcated and geometrically shaped and therefore can mimic lesions seen in fixed-drug eruptions.⁴⁵ Additionally, the patient population undergoing fluoroscopic procedures tends to have major comorbidities requiring multiple medications.⁴

Decubitus ulcers are a result of vascular compromise to an area of skin due to constant pressure and are most commonly seen in the sacral region of patients with ­obesity.⁴⁶ Ulcerated FICRD lesions can manifest on the lower midback. These lesions can be seen after endovascular repair of abdominal aortic aneurysm or prostatic artery embolization.^20,21 The location of these lesions can mimic decubitus ulcers if fluoroscopic history is unknown. As mentioned, obesity also increases the risk for FICRD. 

Morphea can manifest as a localized area of induration and hyperpigmentation of the skin.⁴⁷ When FICRD has progressed to dermal fibrosis, patients can present with indurated plaques without ulcerations, which can be hard to differentiate from morphea.^16,48 However, the presence of ulcerations or hyperkeratosis can differentiate morphea from FICRD.¹⁶

Ultimately, it is the location of FICRD lesions that remains the biggest diagnostic clue. Any suspicious lesion present on the scapular or subscapular areas, anterolateral chest, and/or mid back should prompt an investigation into recent or remote history of fluoroscopic procedures. 

Management of FICRD

Diagnosis of FICRD should be made clinically based on the history and physical examination whenever possible, since a biopsy is not recommended.³⁵ Wound healing in FICRD is delayed, and biopsies can lead to ulcerations or secondary infections.¹⁷ Therefore, it is important to remain suspicious for FICRD. Management of FICRD should correspond to the clinical findings outlined by a recent Delphi consensus survey.⁴⁹ Regardless, the core of FICRD management framework should always include good hygiene, maintenance of skin hydration to improve epithelialization, and sufficient photoprotection.^49,50

Among the first signs of FICRD are telangiectasias. Although asymptomatic, their appearance can be distressing for patients. Pulsed dye laser therapy is a first-line option that has been studied and has shown clinical efficacy for treatment of telangiectasias and vascular changes in patients with FICRD.^49,51

If patients develop fibrotic changes, treatment options are limited. Fibrosis is hard to reverse, and the management approach is limited to symptomatic relief. Mechanical and deep-friction massages have been shown to be effective at reducing skin induration in patients.⁵² Fractional ablative lasers also may be utilized for skin contractures, especially if range of motion is affected.^53,54 Although it comes with its own challenges, autologous fat grafting has shown promise in reducing postradiation fibrosis and inducing angiogenesis in tissue.⁵⁵ Oral pentoxifylline also has shown mild efficacy, as it may be able to suppress TGF-β1 levels.⁵³ However, prevention of fibrotic changes may be the most important. Wei et al³¹ suggested that low-dose oral prednisolone at 5 mg twice daily for 3 weeks might be an option to prevent the progression of skin changes and even reverse fibrosis to an extent; however, further evidence regarding its efficacy still is necessary. Additionally, no evidence was identified to support the use of topical corticosteroids for fibrotic changes seen in FICRD.⁵⁶

Patients with FICRD or even acute radiation dermatitis after fluoroscopy tend to develop superficial ulcerations from minor traumas. Good wound hygiene, antiseptic care, and absorbent dressings, such as hydrogel and hydrocolloid, may be sufficient for treating these wounds, as seen in the Figure.^42,48 However, once patients develop refractory ulcerations or necrosis, treatment options are then limited to surgical removal with a flap or graft.^5,33,42,45
 

Risk for basal cell carcinomas and squamous cell carcinomas is higher in patients with radiation exposure; however, the exact risk from fluoroscopic procedures is unknown. One study demonstrated an increased risk of 6.9% in development of skin cancer after a median radiation exposure of 15.5 Gy and a mean latency period of 38.3 years,⁵⁷ and in another retrospective study, the risk was higher in Fitzpatrick skin types I and II.⁵⁸ Unlike the development of radiodermatitis itself, which shows a dose-dependent response, development of skin cancers follows a stochastic pattern (not dose dependent).⁵⁹ Therefore, it is important to identify these high-risk patients and establish follow-up.

Conclusion

Fluoroscopy-induced chronic radiation dermatitis can be a diagnostic challenge, as skin changes may not be readily associated with the procedure by patients. Therefore, any lesion with a geometric shape and accompanying chronic radiation dermatitis features located on the scapular or subscapular areas, anterolateral chest, and midback should prompt an investigation into history of fluoroscopic procedures. Treatment of chronic skin changes in FICRD depends on the clinical manifestations. Good hygiene, skin hydration, and sufficient photoprotection are crucial. Finally, long-term monitoring with skin examinations is important to assess for the development of skin cancers in the treated area.

Fluoroscopy is an imaging technique that allows for real-time visualization of internal structures in the body using continuous radiography beams. More than 1 million fluoroscopy-guided procedures are performed annually in the United States.¹ Utilization of these procedures continues to increase, and so does the probability of related complications, as prolonged exposure to ionizing radiation can cause skin injuries.² Fortunately, the incidence of radiation-induced skin injuries compared with the total number of fluoroscopic procedures performed remains small,² although one study suggested the incidence may be as high as 8.9% in at-risk populations.³

Radiation dermatitis is well recognized in dermatology as a complication of oncologic management; however, radiation dermatitis as a complication of fluoroscopic procedures is underrecognized.⁴ Fluoroscopy-induced radiation dermatitis can be categorized as acute, subacute, or chronic.⁵ Common fluoroscopic procedures that have been associated with fluoroscopy-induced radiation dermatitis include interventional cardiac procedures, neurovascular procedures, transjugular intrahepatic portosystemic shunt procedures, and endovascular abdominal aortic aneurysm repairs.^6,7

Patients with fluoroscopy-induced radiation dermatitis, particularly fluoroscopy-induced chronic radiation dermatitis (FICRD), can present to dermatology up to several years after the initial fluoroscopy procedure with no awareness of the association between the procedure and their skin findings. This presents a diagnostic challenge, and FICRD often is overlooked.^5,8-10

We conducted a literature search of PubMed articles indexed for MEDLINE using the search terms ­fluoroscopy and dermatitis. In this reappraisal, we will provide a comprehensive overview of fluoroscopy-induced ­radiation dermatitis with an emphasis on FICRD, covering its clinical manifestations, pathophysiology, risk factors, ­differential diagnosis, histology, and management. The aim of this review is to highlight the salient features and mimickers of FICRD and inform readers how to approach suspected cases, leading to accurate diagnosis and ­effective management.

Pathophysiology 

Fluoroscopy-induced radiation dermatitis is the result of dose-dependent radiation-induced tissue damage. As the peak skin dosage (PSD) of radiation increases over the course of a procedure or multiple procedures, the severity of skin injury predictably increases. During fluoroscopic procedures, the standard irradiation dosage ranges from 0.02 Gy/min to 0.05 Gy/min.¹¹ Transient skin changes may start to be seen around 2 Gy of cumulative exposure. Fluoroscopic procedures typically range in duration from 60 to 120 minutes; however, complex cases may exceed that. Additionally, multiple procedures performed within shorter intervals can result in greater PSD accumulation. Shorter intervals between procedures do not allow enough time for damage repair from the previous ­procedure and can result in further severe damage when the skin is re-exposed to radiation.² The American College of Radiology recommends medical follow-up after 10 Gy of cumulative exposure, while cumulative exposure above 15 Gy within a 6- to 12-month period is defined as a sentinel event, according to The Joint Commission.^12-14

Depending on the patient’s total radiation dosage during one or more procedures, the result of the tissue damage manifests differently at varying times: early skin changes are categorized as fluoroscopy-induced acute radiation dermatitis, and late skin changes are categorized as FICRD (Table 1).

Clinical Manifestations

Acute radiation dermatitis from fluoroscopic procedures manifests within hours to days up to 90 days following radiation exposure and can be characterized by erythema with blistering, desquamation, epilation, pigmentation changes, and even necrosis if the accumulated dosage exceeds 15 Gy.¹⁵ Chronic radiation dermatitis (which as related to fluoroscopic procedures is termed FICRD) has a longer onset of weeks to years and is clinically characterized by telangiectasias, permanent erythema, dermal atrophy, or ulcerations. Clinically, subacute radiation dermatitis shares features of both acute and chronic radiation dermatitis; therefore, it is differentiated based on its histologic features.^5,16

Although fluoroscopy-induced acute radiation dermatitis (Table 1) may precede FICRD, acute manifestations of fluoroscopy-related dermatitis can be subtle and often manifest in areas not easily visualized. Because referrals to dermatologists for full-skin examinations after fluoroscopy procedures are not standard, patients may not be aware of the association between these procedures and the development of skin lesions. Nonetheless, some patients may report a history of skin changes such as redness days or weeks after a fluoroscopic procedure with accompanying pain and pruritus limited to the fluoroscopy-exposed region, which tend to self-resolve.¹⁷ The risk for FICRD is thought to increase if a history of fluoroscopy-induced acute radiation dermatitis is present.¹⁸

The location of the skin findings correlates to the area exposed to prolonged radiation during the procedure(s). The most common areas include the scapular and subscapular regions, the right lateral trunk inferior to the axilla, the mid back, and the right anterolateral chest.^16,19,20 These regions are associated with more complex (eg, cardiac) procedures that have been reported to lead to prolonged radiation exposure. The skin findings in FICRD are described as geometric, corresponding to the squarish or rectangular radiography beam that is directed at the patient. Additionally, radiography beams spread outward as they travel in space; therefore, skin injuries are common at the region more distal to the path of origination of the beam.^21-23 Subsequently, a geometric, dyspigmented, indurated or atrophic plaque with telangiectasias and erosions or ulcerations with progressive worsening is a common manifestation of FICRD.^5,16,23 Patients also commonly present with pruritus or severe pain associated with the lesion.^24,25  

Dermatologic Manifestations of FICRD

Skin responses seen weeks to years after a fluoroscopic procedure and typically after cumulative radiation exposure of 10 Gy or greater are categorized as FICRD (Table 2). These changes also can be clinically graded based on the Radiation Therapy Oncology Group classification of radiation dermatitis (Tables 3 and 4).²⁶ Chronic changes in the skin largely result from remodeling of the vasculature and the subcutaneous tissue over time. Unlike acute changes, chronic changes typically persist and continue to worsen.²⁷

Telangiectasias—Anywhere from months to 1 year after exposure to 10 Gy of radiation, proliferation of atypical superficial vessels in the dermis can be seen, typically manifesting as telangiectasias on physical examination. Telangiectasias can increase with time and can even exhibit a dose-dependent relationship to the radiation exposure.²⁸

Atrophy—Atrophic-appearing skin after radiation exposure is the result of direct injury to both the epidermis and fibroblasts in the dermis. The destruction of keratinocytes leads to a thin epidermis, and destruction of dermal fibroblasts causes insufficient collagen production.²⁹ Clinically, this process manifests as an atrophic plaque that can be seen 12 weeks to 1 year after the procedure. 

Fibrosis—Approximately 1 year after the exposure, the initial damage can lead to disruption of molecular pathways, causing fibrosis. Transforming growth factor (TGF) β1 is the main factor involved.²⁹ Damage to the endothelial cells results in increased TGF-β1 levels, which causes increased stimulation of remaining atypical fibroblasts and thus increased irregular collagen deposition.³⁰ Further adding to this knowledge, Wei et al³¹ recently proposed that damage to the epidermal keratinocytes leads to disruption of yes-associated protein 1, which is a protective factor released from keratinocytes that regulates the dermal fibroblasts. However, extensive damage to the keratinocytes can lead to lower yes-associated protein 1 levels and its downstream activity, leading to increased levels of TGF-β1 and fibroblast activity.³¹ Clinically, this fibrotic stage is seen as indurated plaques in patients. 

Necrosis—There are 2 forms of necrosis that can be seen. Ischemic dermal necrosis typically occurs in the acute phase after 10 weeks and approximately 18 Gy of cumulative exposure. It results from substantial skin damage, including microvascular damage and reduction in dermal capillaries, leading to ischemia of the tissue.² Late dermal necrosis is the process seen in the chronic stage of FICRD and radiation dermatitis not related to ­fluoroscopy. It results from the inability of the fibrotic dermis to vascularly support the epidermis above it.² It can be seen anywhere from 1 to 4 years after the procedure. This stage clinically manifests as worsening ulcerations with major pain and increased risk for secondary infections.¹⁶ 

Dyspigmentation—Dyspigmentation at the site of the radiation exposure can be seen acutely and chronically. Dosage above 15 to 18 Gy can lead to destruction of melanocytes, which can cause hypopigmentation in exposed areas. However, melanocytes are relatively resistant to radiation; therefore, dosages below the threshold of destruction of 15 to 18 Gy can cause melanocytic hyperactivity leading to hyperpigmentation.³² Hence, pigmentary changes can vary greatly. Classically, a central area of hypopigmentation with surrounding hyperpigmentation is seen.

Histology 

Histologic appearance of radiation dermatitis varies depending on its stage. Acute radiation dermatitis primarily demonstrates superficial dermal edema, damage to the basal cell layer, small vessel dilation with thrombi, and hemorrhage along with a sparse inflammatory cell infiltrate.³³ Histology typically is the only way to characterize subacute radiation dermatitis.⁵ Lichenoid tissue reaction is its characteristic feature. Mononuclear cells are found adjected to necrotic keratinocytes along with prominent vacuolization of the basal cell layer.³³

The key histologic features of chronic radiation dermatitis include epidermal atrophy, hyperkeratosis, telangiectasias, loss of adnexal structures, and dermal fibrosis along with sparse atypical stellate fibroblasts.³⁴ However, clinical context of fluoroscopic exposure is required for the dermatopathologist to differentiate chronic radiation dermatitis from its histologic differential of morphea and lichen sclerosus. In a cross-sectional study, only 1 of 6 cases (16.7%) was correctly diagnosed as chronic radiation dermatitis in the absence of correlating clinical history.³⁵ 

Risk Factors for FICRD 

Since the diagnosis of FICRD can be a clinical challenge, understanding the risk factors can be helpful. The general likelihood of developing FICRD is related to the duration, frequency, interval, intensity, and area of radiation exposure. Procedures exceeding the normal duration of 60 to 120 minutes have been well documented as a substantial risk factor for radiation dermatitis and FICRD.^36-38 The risk tends to be higher in longer procedures because they result in more radiation exposure and higher accumulated PSD. Obesity (ie, body mass index >26) is the major risk factor that has been associated with longer procedure times, as higher radiation dosages are necessary to penetrate the body of a larger patient and a larger skin surface area is exposed.^37-39

Other risk factors associated with FICRD relate to how prone a patient is to radiation-induced DNA damage. Older patients are at higher risk due to lower intrinsic ability of the tissue to repair itself.¹¹ Patients with a history of connective tissue diseases—particularly lupus, scleroderma, and mixed connective tissue disease—are at an increased risk.⁴⁰ Furthermore, patients with genetic disorders that impair DNA repair are more susceptible to radiation-induced DNA damage; therefore, patients with ataxia-telangiectasia, xeroderma pigmentosum, Fanconi anemia, and hereditary nevoid basal cell carcinoma are at higher risk for FICRD.³⁹ Similarly, medications that can affect DNA repair also have been shown to be risk factors. These medications include chemotherapeutic agents such as actinomycin D, cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil.^2,39 Diabetes, hyperthyroidism, and tobacco use also have been shown to increase a patient’s risk for FICRD.³⁹ It also is reasonable to believe that patients with defects in fibroblasts or with elastin or collagen disorders (eg, Ehlers-Danlos syndrome) would be at higher risk, but there are no known studies highlighting the association in the literature.

Differential Diagnosis of FICRD 

Acute allergic or irritant contact dermatitis manifests with a localized area of erythematous skin accompanied by pruritus.⁴¹ Patients with FICRD can present with a localized area of erythema and hyperpigmentation with minimal atrophy. The lesion may accompany substantial pruritus, which can favor the more common diagnosis of contact dermatitis.^35,42,43

Fixed-drug eruption manifests as a well-defined, hyperpigmented plaque in a fixed location that occurs upon ingestion of a drug.⁴⁴ Fluoroscopy-induced chronic radiation dermatitis lesions are well demarcated and geometrically shaped and therefore can mimic lesions seen in fixed-drug eruptions.⁴⁵ Additionally, the patient population undergoing fluoroscopic procedures tends to have major comorbidities requiring multiple medications.⁴

Decubitus ulcers are a result of vascular compromise to an area of skin due to constant pressure and are most commonly seen in the sacral region of patients with ­obesity.⁴⁶ Ulcerated FICRD lesions can manifest on the lower midback. These lesions can be seen after endovascular repair of abdominal aortic aneurysm or prostatic artery embolization.^20,21 The location of these lesions can mimic decubitus ulcers if fluoroscopic history is unknown. As mentioned, obesity also increases the risk for FICRD. 

Morphea can manifest as a localized area of induration and hyperpigmentation of the skin.⁴⁷ When FICRD has progressed to dermal fibrosis, patients can present with indurated plaques without ulcerations, which can be hard to differentiate from morphea.^16,48 However, the presence of ulcerations or hyperkeratosis can differentiate morphea from FICRD.¹⁶

Ultimately, it is the location of FICRD lesions that remains the biggest diagnostic clue. Any suspicious lesion present on the scapular or subscapular areas, anterolateral chest, and/or mid back should prompt an investigation into recent or remote history of fluoroscopic procedures. 

Management of FICRD

Diagnosis of FICRD should be made clinically based on the history and physical examination whenever possible, since a biopsy is not recommended.³⁵ Wound healing in FICRD is delayed, and biopsies can lead to ulcerations or secondary infections.¹⁷ Therefore, it is important to remain suspicious for FICRD. Management of FICRD should correspond to the clinical findings outlined by a recent Delphi consensus survey.⁴⁹ Regardless, the core of FICRD management framework should always include good hygiene, maintenance of skin hydration to improve epithelialization, and sufficient photoprotection.^49,50

Among the first signs of FICRD are telangiectasias. Although asymptomatic, their appearance can be distressing for patients. Pulsed dye laser therapy is a first-line option that has been studied and has shown clinical efficacy for treatment of telangiectasias and vascular changes in patients with FICRD.^49,51

If patients develop fibrotic changes, treatment options are limited. Fibrosis is hard to reverse, and the management approach is limited to symptomatic relief. Mechanical and deep-friction massages have been shown to be effective at reducing skin induration in patients.⁵² Fractional ablative lasers also may be utilized for skin contractures, especially if range of motion is affected.^53,54 Although it comes with its own challenges, autologous fat grafting has shown promise in reducing postradiation fibrosis and inducing angiogenesis in tissue.⁵⁵ Oral pentoxifylline also has shown mild efficacy, as it may be able to suppress TGF-β1 levels.⁵³ However, prevention of fibrotic changes may be the most important. Wei et al³¹ suggested that low-dose oral prednisolone at 5 mg twice daily for 3 weeks might be an option to prevent the progression of skin changes and even reverse fibrosis to an extent; however, further evidence regarding its efficacy still is necessary. Additionally, no evidence was identified to support the use of topical corticosteroids for fibrotic changes seen in FICRD.⁵⁶

Patients with FICRD or even acute radiation dermatitis after fluoroscopy tend to develop superficial ulcerations from minor traumas. Good wound hygiene, antiseptic care, and absorbent dressings, such as hydrogel and hydrocolloid, may be sufficient for treating these wounds, as seen in the Figure.^42,48 However, once patients develop refractory ulcerations or necrosis, treatment options are then limited to surgical removal with a flap or graft.^5,33,42,45
 

Risk for basal cell carcinomas and squamous cell carcinomas is higher in patients with radiation exposure; however, the exact risk from fluoroscopic procedures is unknown. One study demonstrated an increased risk of 6.9% in development of skin cancer after a median radiation exposure of 15.5 Gy and a mean latency period of 38.3 years,⁵⁷ and in another retrospective study, the risk was higher in Fitzpatrick skin types I and II.⁵⁸ Unlike the development of radiodermatitis itself, which shows a dose-dependent response, development of skin cancers follows a stochastic pattern (not dose dependent).⁵⁹ Therefore, it is important to identify these high-risk patients and establish follow-up.

Conclusion

Fluoroscopy-induced chronic radiation dermatitis can be a diagnostic challenge, as skin changes may not be readily associated with the procedure by patients. Therefore, any lesion with a geometric shape and accompanying chronic radiation dermatitis features located on the scapular or subscapular areas, anterolateral chest, and midback should prompt an investigation into history of fluoroscopic procedures. Treatment of chronic skin changes in FICRD depends on the clinical manifestations. Good hygiene, skin hydration, and sufficient photoprotection are crucial. Finally, long-term monitoring with skin examinations is important to assess for the development of skin cancers in the treated area.

The Comparison

A. Alopecia areata in a young girl with a lighter skin tone. The fine white vellus hairs are signs of regrowth. 

B. Alopecia areata in a 49-year-old man with tightly coiled hair and darker skin tone. Coiled white hairs are noted in the alopecia patches.

Alopecia areata (AA) is a common autoimmune condition characterized by hair loss resulting from a T cell–mediated attack on the hair follicles. It manifests as nonscarring patches of hair loss on the scalp, eyebrows, eyelashes, and beard area as well as more extensive complete loss of scalp and body hair. While AA may affect individuals of any age, most patients develop their first patch(es) of hair loss during childhood.¹ The treatment landscape for AA has evolved considerably in recent years, but barriers to access to newer treatments persist. 

Epidemiology 

AA is most prevalent among pediatric and adult individuals of African, Asian, or Hispanic/Latino descent.^2-4 In some studies, Black individuals had higher odds and Asian individuals had lower odds of developing AA, while other studies have reported the highest standardized prevalence among Asian individuals.⁵ In the United States, AA affects about 1.47% of adults and as many as 0.11% of children.^6-8 In Black patients, AA often manifests early with a female predominance.⁵ 

AA frequently is associated with autoimmune comorbidities, the most common being thyroid disease.^3,5 In Black patients, AA is associated with more atopic comorbidities, including asthma, atopic dermatitis, and allergic rhinitis.⁵ 

Key Clinical Features 

AA clinically manifests similarly across different skin tones; however, in patients with more tightly coiled or curly hair, the extent of scalp hair loss may be underestimated without a full examination. Culturally sensitive approaches to hair and scalp evaluation are essential, especially for Black women, whose hair care practices and scalp conditions may be overlooked or misunderstood during visits to evaluate hair loss. A thoughtful history and gentle examination of the hair and scalp that considers hair texture, cultural practices such as head coverings (eg, headwraps, turbans, hijabs), use of hair adornments (eg, clips, beads, bows), traditional braiding, and use of natural oils or herbal treatments, as well as styling methods including tight hairstyles, use of heat styling tools (eg, flat irons, curling irons), chemical application (eg, straighteners, hair color), and washing or styling frequency can improve diagnostic accuracy and help build trust in the patient-provider relationship. 

Classic signs of AA visualized with dermoscopy include yellow and/or black dots on the scalp and exclamation point hairs. The appearance of fine white vellus hairs within the alopecic patches also may indicate early regrowth. On scalp trichoscopy, black dots are more prominent, and yellow dots are less prominent, in individuals with darker skin tones vs lighter skin tones.⁹ 

Worth Noting 

In addition to a full examination of the scalp, documenting the extent of hair loss using validated severity scales, including the severity of alopecia tool (SALT), AA severity index (AASI), clinician-reported outcome assessment, and patient-reported outcome measures, can standardize disease severity assessment, facilitate timely insurance or medication approvals, and support objective tracking of treatment response, which may ultimately enhance access to care.¹⁰ 

Prompt treatment of AA is essential. Not surprisingly, patients given a diagnosis of AA may experience considerable emotional and psychological distress—regardless of the extent of the loss.¹¹ Treatment options include mid- to high-potency topical or intralesional corticosteroids and newer and more targeted systemic options, including 3 Janus kinase (JAK) inhibitors—baricitinib, ritlecitinib, and deuruxolitinib—for more extensive disease.¹² Treatment with intralesional corticosteroids may cause transient hypopigmentation, which may be more noticeable in patients with darker skin tones. Delays in treatment with JAK inhibitors can lead to a less-than-optimal response. Of the 3 JAK inhibitors that are approved by the US Food and Drug Administration for AA, only ritlecitinib is approved for children 12 years and older, leaving a therapeutic gap for younger patients that often leads to uncomfortable scalp injections, delayed or no treatment, off-label use of JAK inhibitors as well as the pairing of off-label dupilumab with oral minoxidil.¹² 

Based on adult data, patients with severe disease and a shorter duration of hair loss (ie, < 4 years) tend to respond better to JAK inhibitors than those experiencing hair loss for longer periods. Also, those with more severe AA tend to have poorer outcomes than those with less severe disease.¹³ If treatment proves less than optimal, wigs and hair pieces may need to be considered. It is worth noting that some insurance companies will cover the cost of wigs for patients when prescribed as cranial prostheses. 

Health Disparity Highlight 

Health disparities in AA can be influenced by socioeconomic status and access to care. Patients from lower-income backgrounds often face barriers to accessing dermatologic care and treatments such as JAK inhibitors, which may remain inaccessible due to high costs and insurance limitations.¹⁴ These barriers can intersect with other factors such as age, sex, and race, potentially exacerbating disparities. Women with skin of color in underserved communities may experience delayed diagnosis, limited treatment options, and greater psychosocial distress from hair loss.¹⁴ Addressing these inequities requires advocacy, education for both patients and clinicians, and improved access to treatment to ensure comprehensive care for all patients. 

The Comparison

A. Alopecia areata in a young girl with a lighter skin tone. The fine white vellus hairs are signs of regrowth. 

B. Alopecia areata in a 49-year-old man with tightly coiled hair and darker skin tone. Coiled white hairs are noted in the alopecia patches.

Alopecia areata (AA) is a common autoimmune condition characterized by hair loss resulting from a T cell–mediated attack on the hair follicles. It manifests as nonscarring patches of hair loss on the scalp, eyebrows, eyelashes, and beard area as well as more extensive complete loss of scalp and body hair. While AA may affect individuals of any age, most patients develop their first patch(es) of hair loss during childhood.¹ The treatment landscape for AA has evolved considerably in recent years, but barriers to access to newer treatments persist. 

Epidemiology 

AA is most prevalent among pediatric and adult individuals of African, Asian, or Hispanic/Latino descent.^2-4 In some studies, Black individuals had higher odds and Asian individuals had lower odds of developing AA, while other studies have reported the highest standardized prevalence among Asian individuals.⁵ In the United States, AA affects about 1.47% of adults and as many as 0.11% of children.^6-8 In Black patients, AA often manifests early with a female predominance.⁵ 

AA frequently is associated with autoimmune comorbidities, the most common being thyroid disease.^3,5 In Black patients, AA is associated with more atopic comorbidities, including asthma, atopic dermatitis, and allergic rhinitis.⁵ 

Key Clinical Features 

AA clinically manifests similarly across different skin tones; however, in patients with more tightly coiled or curly hair, the extent of scalp hair loss may be underestimated without a full examination. Culturally sensitive approaches to hair and scalp evaluation are essential, especially for Black women, whose hair care practices and scalp conditions may be overlooked or misunderstood during visits to evaluate hair loss. A thoughtful history and gentle examination of the hair and scalp that considers hair texture, cultural practices such as head coverings (eg, headwraps, turbans, hijabs), use of hair adornments (eg, clips, beads, bows), traditional braiding, and use of natural oils or herbal treatments, as well as styling methods including tight hairstyles, use of heat styling tools (eg, flat irons, curling irons), chemical application (eg, straighteners, hair color), and washing or styling frequency can improve diagnostic accuracy and help build trust in the patient-provider relationship. 

Classic signs of AA visualized with dermoscopy include yellow and/or black dots on the scalp and exclamation point hairs. The appearance of fine white vellus hairs within the alopecic patches also may indicate early regrowth. On scalp trichoscopy, black dots are more prominent, and yellow dots are less prominent, in individuals with darker skin tones vs lighter skin tones.⁹ 

Worth Noting 

In addition to a full examination of the scalp, documenting the extent of hair loss using validated severity scales, including the severity of alopecia tool (SALT), AA severity index (AASI), clinician-reported outcome assessment, and patient-reported outcome measures, can standardize disease severity assessment, facilitate timely insurance or medication approvals, and support objective tracking of treatment response, which may ultimately enhance access to care.¹⁰ 

Prompt treatment of AA is essential. Not surprisingly, patients given a diagnosis of AA may experience considerable emotional and psychological distress—regardless of the extent of the loss.¹¹ Treatment options include mid- to high-potency topical or intralesional corticosteroids and newer and more targeted systemic options, including 3 Janus kinase (JAK) inhibitors—baricitinib, ritlecitinib, and deuruxolitinib—for more extensive disease.¹² Treatment with intralesional corticosteroids may cause transient hypopigmentation, which may be more noticeable in patients with darker skin tones. Delays in treatment with JAK inhibitors can lead to a less-than-optimal response. Of the 3 JAK inhibitors that are approved by the US Food and Drug Administration for AA, only ritlecitinib is approved for children 12 years and older, leaving a therapeutic gap for younger patients that often leads to uncomfortable scalp injections, delayed or no treatment, off-label use of JAK inhibitors as well as the pairing of off-label dupilumab with oral minoxidil.¹² 

Based on adult data, patients with severe disease and a shorter duration of hair loss (ie, < 4 years) tend to respond better to JAK inhibitors than those experiencing hair loss for longer periods. Also, those with more severe AA tend to have poorer outcomes than those with less severe disease.¹³ If treatment proves less than optimal, wigs and hair pieces may need to be considered. It is worth noting that some insurance companies will cover the cost of wigs for patients when prescribed as cranial prostheses. 

Health Disparity Highlight 

Health disparities in AA can be influenced by socioeconomic status and access to care. Patients from lower-income backgrounds often face barriers to accessing dermatologic care and treatments such as JAK inhibitors, which may remain inaccessible due to high costs and insurance limitations.¹⁴ These barriers can intersect with other factors such as age, sex, and race, potentially exacerbating disparities. Women with skin of color in underserved communities may experience delayed diagnosis, limited treatment options, and greater psychosocial distress from hair loss.¹⁴ Addressing these inequities requires advocacy, education for both patients and clinicians, and improved access to treatment to ensure comprehensive care for all patients. 

The Comparison

A. Alopecia areata in a young girl with a lighter skin tone. The fine white vellus hairs are signs of regrowth. 

B. Alopecia areata in a 49-year-old man with tightly coiled hair and darker skin tone. Coiled white hairs are noted in the alopecia patches.

Alopecia areata (AA) is a common autoimmune condition characterized by hair loss resulting from a T cell–mediated attack on the hair follicles. It manifests as nonscarring patches of hair loss on the scalp, eyebrows, eyelashes, and beard area as well as more extensive complete loss of scalp and body hair. While AA may affect individuals of any age, most patients develop their first patch(es) of hair loss during childhood.¹ The treatment landscape for AA has evolved considerably in recent years, but barriers to access to newer treatments persist. 

Epidemiology 

AA is most prevalent among pediatric and adult individuals of African, Asian, or Hispanic/Latino descent.^2-4 In some studies, Black individuals had higher odds and Asian individuals had lower odds of developing AA, while other studies have reported the highest standardized prevalence among Asian individuals.⁵ In the United States, AA affects about 1.47% of adults and as many as 0.11% of children.^6-8 In Black patients, AA often manifests early with a female predominance.⁵ 

AA frequently is associated with autoimmune comorbidities, the most common being thyroid disease.^3,5 In Black patients, AA is associated with more atopic comorbidities, including asthma, atopic dermatitis, and allergic rhinitis.⁵ 

Key Clinical Features 

AA clinically manifests similarly across different skin tones; however, in patients with more tightly coiled or curly hair, the extent of scalp hair loss may be underestimated without a full examination. Culturally sensitive approaches to hair and scalp evaluation are essential, especially for Black women, whose hair care practices and scalp conditions may be overlooked or misunderstood during visits to evaluate hair loss. A thoughtful history and gentle examination of the hair and scalp that considers hair texture, cultural practices such as head coverings (eg, headwraps, turbans, hijabs), use of hair adornments (eg, clips, beads, bows), traditional braiding, and use of natural oils or herbal treatments, as well as styling methods including tight hairstyles, use of heat styling tools (eg, flat irons, curling irons), chemical application (eg, straighteners, hair color), and washing or styling frequency can improve diagnostic accuracy and help build trust in the patient-provider relationship. 

Classic signs of AA visualized with dermoscopy include yellow and/or black dots on the scalp and exclamation point hairs. The appearance of fine white vellus hairs within the alopecic patches also may indicate early regrowth. On scalp trichoscopy, black dots are more prominent, and yellow dots are less prominent, in individuals with darker skin tones vs lighter skin tones.⁹ 

Worth Noting 

In addition to a full examination of the scalp, documenting the extent of hair loss using validated severity scales, including the severity of alopecia tool (SALT), AA severity index (AASI), clinician-reported outcome assessment, and patient-reported outcome measures, can standardize disease severity assessment, facilitate timely insurance or medication approvals, and support objective tracking of treatment response, which may ultimately enhance access to care.¹⁰ 

Prompt treatment of AA is essential. Not surprisingly, patients given a diagnosis of AA may experience considerable emotional and psychological distress—regardless of the extent of the loss.¹¹ Treatment options include mid- to high-potency topical or intralesional corticosteroids and newer and more targeted systemic options, including 3 Janus kinase (JAK) inhibitors—baricitinib, ritlecitinib, and deuruxolitinib—for more extensive disease.¹² Treatment with intralesional corticosteroids may cause transient hypopigmentation, which may be more noticeable in patients with darker skin tones. Delays in treatment with JAK inhibitors can lead to a less-than-optimal response. Of the 3 JAK inhibitors that are approved by the US Food and Drug Administration for AA, only ritlecitinib is approved for children 12 years and older, leaving a therapeutic gap for younger patients that often leads to uncomfortable scalp injections, delayed or no treatment, off-label use of JAK inhibitors as well as the pairing of off-label dupilumab with oral minoxidil.¹² 

Based on adult data, patients with severe disease and a shorter duration of hair loss (ie, < 4 years) tend to respond better to JAK inhibitors than those experiencing hair loss for longer periods. Also, those with more severe AA tend to have poorer outcomes than those with less severe disease.¹³ If treatment proves less than optimal, wigs and hair pieces may need to be considered. It is worth noting that some insurance companies will cover the cost of wigs for patients when prescribed as cranial prostheses. 

Health Disparity Highlight 

Health disparities in AA can be influenced by socioeconomic status and access to care. Patients from lower-income backgrounds often face barriers to accessing dermatologic care and treatments such as JAK inhibitors, which may remain inaccessible due to high costs and insurance limitations.¹⁴ These barriers can intersect with other factors such as age, sex, and race, potentially exacerbating disparities. Women with skin of color in underserved communities may experience delayed diagnosis, limited treatment options, and greater psychosocial distress from hair loss.¹⁴ Addressing these inequities requires advocacy, education for both patients and clinicians, and improved access to treatment to ensure comprehensive care for all patients. 

Mohs micrographic surgery (MMS)—developed by Dr. Frederic Mohs in the 1930s—is the gold standard for treating various cutaneous malignancies. It provides maximal conservation of uninvolved tissues while producing higher cure rates compared to wide local excision.^1,2

We sought to assess the various characteristics that impact patient satisfaction to help Mohs surgeons incorporate relatively simple yet clinically significant practices into their patient encounters. We conducted a systematic literature search of peer-reviewed PubMed articles indexed for MEDLINE from database inception through November 2023 using the terms Mohs micrographic surgery and patient satisfaction. Among the inclusion criteria were studies involving participants having undergone MMS, with objective assessments on patient-reported satisfaction or preferences related to patient education, communication, anxiety-alleviating measures, or QOL in MMS. Studies were excluded if they failed to meet these criteria, were outdated and no longer clinically relevant, or measured unalterable factors with no significant impact on how Mohs surgeons could change clinical practice. Of the 157 nonreplicated studies identified, 34 met inclusion criteria.

Perioperative Patient Communication and Education Techniques

Perioperative Patient Communication—Many studies have evaluated the impact of perioperative patient-provider communication and education on patient satisfaction in those undergoing MMS. Studies focusing on preoperative and postoperative telephone calls, patient consultation formats, and patient-perceived impact of such communication modalities have been well documented (Table 1).^3-8 The importance of the patient follow-up after MMS was further supported by a retrospective study concluding that 88.7% (86/97) of patients regarded follow-up visits as important, and 80% (77/97) desired additional follow-up 3 months after MMS.⁹ Additional studies have highlighted the importance of thorough and open perioperative patient-provider communication during MMS (Table 2).^10-12

Patient-Education Techniques—Many studies have assessed the use of visual models to aid in patient education on MMS, specifically the preprocedural consent process (Table 3).^13-16 Additionally, 2 randomized controlled trials assessing the use of at-home and same-day in-office preoperative educational videos concluded that these interventions increased patient knowledge and confidence regarding procedural risks and benefits, with no statistically significant differences in patient anxiety or satisfaction.^17,18

Despite the availability of these educational videos, many patients often turn to online resources for self-education, which is problematic if reader literacy is incongruent with online readability. One study assessing readability of online MMS resources concluded that the most accessed articles exceeded the recommended reading level for adequate patient comprehension.¹⁹ A survey studying a wide range of variables related to patient satisfaction (eg, demographics, socioeconomics, health status) in 339 MMS patients found that those who considered themselves more involved in the decision-making process were more satisfied in the short-term, and married patients had even higher long-term satisfaction. Interestingly, this study also concluded that undergoing 3 or more MMS stages was associated with higher short- and long-term satisfaction, likely secondary to perceived effects of increased overall care, medical attention, and time spent with the provider.²⁰

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding patient education and communication^13-20:

• Preoperative and same-day postoperative telephone follow-up (TFU) do not show statistically significant impacts on patient satisfaction; however, TFU allows for identification of postoperative concerns and inadequate pain management, which may have downstream effects on long-term perception of the overall patient experience.
• The use of video-assisted consent yields improved patient satisfaction and knowledge, while video content—traditional or didactic—has no impact on satisfaction in new MMS patients.
• The use of at-home or same-day in-office preoperative educational videos can improve procedural knowledge and risk-benefit understanding of MMS while having no impact on satisfaction.
• Bedside manner and effective in-person communication by the provider often takes precedence in the patient experience; however, implementation of additional educational modalities should be considered.

Patient Anxiety and QOL

Reducing Patient Anxiety—The use of perioperative distractors to reduce patient anxiety may play an integral role when patients undergo MMS, as there often are prolonged waiting periods between stages when patients may feel increasingly vulnerable or anxious. Table 4 reviews studies on perioperative distractors that showed a statistically significant reduction in MMS patient anxiety.^21-24

Although not statistically significant, additional studies evaluating the use of intraoperative anxiety-reduction methods in MMS have demonstrated a downtrend in patient anxiety with the following interventions: engaging in small talk with clinic staff, bringing a guest, eating, watching television, communicating surgical expectations with the provider, handholding, use of a stress ball, and use of 3-dimensional educational MMS models.^25-27 Similarly, a survey of 73 patients undergoing MMS found that patients tended to enjoy complimentary beverages preprocedurally in the waiting room, reading, speaking with their guest, watching television, or using their telephone during wait times.²⁸ Table 5 lists additional perioperative factors encompassing specific patient and surgical characteristics that help reduce patient anxiety.^29-32

Patient QOL—Many methods aimed at decreasing MMS-related patient anxiety often show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience. A prospective observational study of MMS patients noted a statistically significant improvement in patient QOL scores 3 months postsurgery (P=.0007), demonstrating that MMS generally results in positive patient outcomes despite preprocedural anxiety.³³ An additional prospective study in MMS patients with nonmelanoma skin cancer concluded that sex, age, and closure type—factors often shown to affect anxiety levels—did not significantly impact patient satisfaction.³⁴ Similarly, high satisfaction levels can be expected among MMS patients undergoing treatment of melanoma in situ, with more than 90% of patients rating their treatment experience a 4 (agree) or 5 (strongly agree) out of 5 in short- and long-term satisfaction assessments (38/41 and 40/42, respectively).³⁵ This assessment, conducted 3 months postoperatively, asked patients to score the statement, “I am completely satisfied with the treatment of my skin problem,” on a scale ranging from 1 (strongly disagree) to 5 (strongly agree).

Lastly, patient perception of their surgeon’s skill may contribute to levels of patient satisfaction. Although suture spacing has not been shown to affect surgical outcomes, it has been demonstrated to impact the patient’s perception of surgical skill and is further supported by a study concluding that closures with 2-mm spacing were ranked significantly lower by patients compared with closures with either 4- or 6-mm spacing (P=.005 and P=.012, respectively).³⁶

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding anxiety-reducing measures and patient-perceived QOL^21-36:

• Factors shown to decrease patient anxiety include patient personalized music, virtual-reality experience, perioperative informational videos, and 3-dimensional–printed MMS models.
• Many methods aimed at decreasing MMS-related patient anxiety show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience.
• Higher anxiety can be associated with worse QOL scores in MMS patients, and additional factors that may have a negative impact on anxiety include female sex, younger age, and tumor location on the face.

Conclusion

Many factors affect patient satisfaction in MMS. Increased awareness and acknowledgement of these factors can foster improved clinical practice and patient experience, which can have downstream effects on patient compliance and overall psychosocial and medical well-being. With the movement toward value-based health care, patient satisfaction ratings are likely to play an increasingly important role in physician reimbursement. Adapting one’s practice to include high-quality, time-efficient, patient-centered care goes hand in hand with increasing MMS patient satisfaction. Careful evaluation and scrutiny of one’s current practices while remaining cognizant of patient population, resource availability, and clinical limitations often reveal opportunities for small adjustments that can have a great impact on patient satisfaction. This thorough assessment and review of the published literature aims to assist MMS surgeons in understanding the role that certain factors—(1) perioperative patient communication and education techniques and (2) patient anxiety, QOL, and additional considerations—have on overall satisfaction with MMS. Specific consideration should be placed on the fact that patient satisfaction is multifactorial, and many different interventions can have a positive impact on the overall patient experience.

Mohs micrographic surgery (MMS)—developed by Dr. Frederic Mohs in the 1930s—is the gold standard for treating various cutaneous malignancies. It provides maximal conservation of uninvolved tissues while producing higher cure rates compared to wide local excision.^1,2

We sought to assess the various characteristics that impact patient satisfaction to help Mohs surgeons incorporate relatively simple yet clinically significant practices into their patient encounters. We conducted a systematic literature search of peer-reviewed PubMed articles indexed for MEDLINE from database inception through November 2023 using the terms Mohs micrographic surgery and patient satisfaction. Among the inclusion criteria were studies involving participants having undergone MMS, with objective assessments on patient-reported satisfaction or preferences related to patient education, communication, anxiety-alleviating measures, or QOL in MMS. Studies were excluded if they failed to meet these criteria, were outdated and no longer clinically relevant, or measured unalterable factors with no significant impact on how Mohs surgeons could change clinical practice. Of the 157 nonreplicated studies identified, 34 met inclusion criteria.

Perioperative Patient Communication and Education Techniques

Perioperative Patient Communication—Many studies have evaluated the impact of perioperative patient-provider communication and education on patient satisfaction in those undergoing MMS. Studies focusing on preoperative and postoperative telephone calls, patient consultation formats, and patient-perceived impact of such communication modalities have been well documented (Table 1).^3-8 The importance of the patient follow-up after MMS was further supported by a retrospective study concluding that 88.7% (86/97) of patients regarded follow-up visits as important, and 80% (77/97) desired additional follow-up 3 months after MMS.⁹ Additional studies have highlighted the importance of thorough and open perioperative patient-provider communication during MMS (Table 2).^10-12

Patient-Education Techniques—Many studies have assessed the use of visual models to aid in patient education on MMS, specifically the preprocedural consent process (Table 3).^13-16 Additionally, 2 randomized controlled trials assessing the use of at-home and same-day in-office preoperative educational videos concluded that these interventions increased patient knowledge and confidence regarding procedural risks and benefits, with no statistically significant differences in patient anxiety or satisfaction.^17,18

Despite the availability of these educational videos, many patients often turn to online resources for self-education, which is problematic if reader literacy is incongruent with online readability. One study assessing readability of online MMS resources concluded that the most accessed articles exceeded the recommended reading level for adequate patient comprehension.¹⁹ A survey studying a wide range of variables related to patient satisfaction (eg, demographics, socioeconomics, health status) in 339 MMS patients found that those who considered themselves more involved in the decision-making process were more satisfied in the short-term, and married patients had even higher long-term satisfaction. Interestingly, this study also concluded that undergoing 3 or more MMS stages was associated with higher short- and long-term satisfaction, likely secondary to perceived effects of increased overall care, medical attention, and time spent with the provider.²⁰

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding patient education and communication^13-20:

• Preoperative and same-day postoperative telephone follow-up (TFU) do not show statistically significant impacts on patient satisfaction; however, TFU allows for identification of postoperative concerns and inadequate pain management, which may have downstream effects on long-term perception of the overall patient experience.
• The use of video-assisted consent yields improved patient satisfaction and knowledge, while video content—traditional or didactic—has no impact on satisfaction in new MMS patients.
• The use of at-home or same-day in-office preoperative educational videos can improve procedural knowledge and risk-benefit understanding of MMS while having no impact on satisfaction.
• Bedside manner and effective in-person communication by the provider often takes precedence in the patient experience; however, implementation of additional educational modalities should be considered.

Patient Anxiety and QOL

Reducing Patient Anxiety—The use of perioperative distractors to reduce patient anxiety may play an integral role when patients undergo MMS, as there often are prolonged waiting periods between stages when patients may feel increasingly vulnerable or anxious. Table 4 reviews studies on perioperative distractors that showed a statistically significant reduction in MMS patient anxiety.^21-24

Although not statistically significant, additional studies evaluating the use of intraoperative anxiety-reduction methods in MMS have demonstrated a downtrend in patient anxiety with the following interventions: engaging in small talk with clinic staff, bringing a guest, eating, watching television, communicating surgical expectations with the provider, handholding, use of a stress ball, and use of 3-dimensional educational MMS models.^25-27 Similarly, a survey of 73 patients undergoing MMS found that patients tended to enjoy complimentary beverages preprocedurally in the waiting room, reading, speaking with their guest, watching television, or using their telephone during wait times.²⁸ Table 5 lists additional perioperative factors encompassing specific patient and surgical characteristics that help reduce patient anxiety.^29-32

Patient QOL—Many methods aimed at decreasing MMS-related patient anxiety often show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience. A prospective observational study of MMS patients noted a statistically significant improvement in patient QOL scores 3 months postsurgery (P=.0007), demonstrating that MMS generally results in positive patient outcomes despite preprocedural anxiety.³³ An additional prospective study in MMS patients with nonmelanoma skin cancer concluded that sex, age, and closure type—factors often shown to affect anxiety levels—did not significantly impact patient satisfaction.³⁴ Similarly, high satisfaction levels can be expected among MMS patients undergoing treatment of melanoma in situ, with more than 90% of patients rating their treatment experience a 4 (agree) or 5 (strongly agree) out of 5 in short- and long-term satisfaction assessments (38/41 and 40/42, respectively).³⁵ This assessment, conducted 3 months postoperatively, asked patients to score the statement, “I am completely satisfied with the treatment of my skin problem,” on a scale ranging from 1 (strongly disagree) to 5 (strongly agree).

Lastly, patient perception of their surgeon’s skill may contribute to levels of patient satisfaction. Although suture spacing has not been shown to affect surgical outcomes, it has been demonstrated to impact the patient’s perception of surgical skill and is further supported by a study concluding that closures with 2-mm spacing were ranked significantly lower by patients compared with closures with either 4- or 6-mm spacing (P=.005 and P=.012, respectively).³⁶

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding anxiety-reducing measures and patient-perceived QOL^21-36:

• Factors shown to decrease patient anxiety include patient personalized music, virtual-reality experience, perioperative informational videos, and 3-dimensional–printed MMS models.
• Many methods aimed at decreasing MMS-related patient anxiety show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience.
• Higher anxiety can be associated with worse QOL scores in MMS patients, and additional factors that may have a negative impact on anxiety include female sex, younger age, and tumor location on the face.

Conclusion

Many factors affect patient satisfaction in MMS. Increased awareness and acknowledgement of these factors can foster improved clinical practice and patient experience, which can have downstream effects on patient compliance and overall psychosocial and medical well-being. With the movement toward value-based health care, patient satisfaction ratings are likely to play an increasingly important role in physician reimbursement. Adapting one’s practice to include high-quality, time-efficient, patient-centered care goes hand in hand with increasing MMS patient satisfaction. Careful evaluation and scrutiny of one’s current practices while remaining cognizant of patient population, resource availability, and clinical limitations often reveal opportunities for small adjustments that can have a great impact on patient satisfaction. This thorough assessment and review of the published literature aims to assist MMS surgeons in understanding the role that certain factors—(1) perioperative patient communication and education techniques and (2) patient anxiety, QOL, and additional considerations—have on overall satisfaction with MMS. Specific consideration should be placed on the fact that patient satisfaction is multifactorial, and many different interventions can have a positive impact on the overall patient experience.

Mohs micrographic surgery (MMS)—developed by Dr. Frederic Mohs in the 1930s—is the gold standard for treating various cutaneous malignancies. It provides maximal conservation of uninvolved tissues while producing higher cure rates compared to wide local excision.^1,2

We sought to assess the various characteristics that impact patient satisfaction to help Mohs surgeons incorporate relatively simple yet clinically significant practices into their patient encounters. We conducted a systematic literature search of peer-reviewed PubMed articles indexed for MEDLINE from database inception through November 2023 using the terms Mohs micrographic surgery and patient satisfaction. Among the inclusion criteria were studies involving participants having undergone MMS, with objective assessments on patient-reported satisfaction or preferences related to patient education, communication, anxiety-alleviating measures, or QOL in MMS. Studies were excluded if they failed to meet these criteria, were outdated and no longer clinically relevant, or measured unalterable factors with no significant impact on how Mohs surgeons could change clinical practice. Of the 157 nonreplicated studies identified, 34 met inclusion criteria.

Perioperative Patient Communication and Education Techniques

Perioperative Patient Communication—Many studies have evaluated the impact of perioperative patient-provider communication and education on patient satisfaction in those undergoing MMS. Studies focusing on preoperative and postoperative telephone calls, patient consultation formats, and patient-perceived impact of such communication modalities have been well documented (Table 1).^3-8 The importance of the patient follow-up after MMS was further supported by a retrospective study concluding that 88.7% (86/97) of patients regarded follow-up visits as important, and 80% (77/97) desired additional follow-up 3 months after MMS.⁹ Additional studies have highlighted the importance of thorough and open perioperative patient-provider communication during MMS (Table 2).^10-12

Patient-Education Techniques—Many studies have assessed the use of visual models to aid in patient education on MMS, specifically the preprocedural consent process (Table 3).^13-16 Additionally, 2 randomized controlled trials assessing the use of at-home and same-day in-office preoperative educational videos concluded that these interventions increased patient knowledge and confidence regarding procedural risks and benefits, with no statistically significant differences in patient anxiety or satisfaction.^17,18

Despite the availability of these educational videos, many patients often turn to online resources for self-education, which is problematic if reader literacy is incongruent with online readability. One study assessing readability of online MMS resources concluded that the most accessed articles exceeded the recommended reading level for adequate patient comprehension.¹⁹ A survey studying a wide range of variables related to patient satisfaction (eg, demographics, socioeconomics, health status) in 339 MMS patients found that those who considered themselves more involved in the decision-making process were more satisfied in the short-term, and married patients had even higher long-term satisfaction. Interestingly, this study also concluded that undergoing 3 or more MMS stages was associated with higher short- and long-term satisfaction, likely secondary to perceived effects of increased overall care, medical attention, and time spent with the provider.²⁰

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding patient education and communication^13-20:

• Preoperative and same-day postoperative telephone follow-up (TFU) do not show statistically significant impacts on patient satisfaction; however, TFU allows for identification of postoperative concerns and inadequate pain management, which may have downstream effects on long-term perception of the overall patient experience.
• The use of video-assisted consent yields improved patient satisfaction and knowledge, while video content—traditional or didactic—has no impact on satisfaction in new MMS patients.
• The use of at-home or same-day in-office preoperative educational videos can improve procedural knowledge and risk-benefit understanding of MMS while having no impact on satisfaction.
• Bedside manner and effective in-person communication by the provider often takes precedence in the patient experience; however, implementation of additional educational modalities should be considered.

Patient Anxiety and QOL

Reducing Patient Anxiety—The use of perioperative distractors to reduce patient anxiety may play an integral role when patients undergo MMS, as there often are prolonged waiting periods between stages when patients may feel increasingly vulnerable or anxious. Table 4 reviews studies on perioperative distractors that showed a statistically significant reduction in MMS patient anxiety.^21-24

Although not statistically significant, additional studies evaluating the use of intraoperative anxiety-reduction methods in MMS have demonstrated a downtrend in patient anxiety with the following interventions: engaging in small talk with clinic staff, bringing a guest, eating, watching television, communicating surgical expectations with the provider, handholding, use of a stress ball, and use of 3-dimensional educational MMS models.^25-27 Similarly, a survey of 73 patients undergoing MMS found that patients tended to enjoy complimentary beverages preprocedurally in the waiting room, reading, speaking with their guest, watching television, or using their telephone during wait times.²⁸ Table 5 lists additional perioperative factors encompassing specific patient and surgical characteristics that help reduce patient anxiety.^29-32

Patient QOL—Many methods aimed at decreasing MMS-related patient anxiety often show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience. A prospective observational study of MMS patients noted a statistically significant improvement in patient QOL scores 3 months postsurgery (P=.0007), demonstrating that MMS generally results in positive patient outcomes despite preprocedural anxiety.³³ An additional prospective study in MMS patients with nonmelanoma skin cancer concluded that sex, age, and closure type—factors often shown to affect anxiety levels—did not significantly impact patient satisfaction.³⁴ Similarly, high satisfaction levels can be expected among MMS patients undergoing treatment of melanoma in situ, with more than 90% of patients rating their treatment experience a 4 (agree) or 5 (strongly agree) out of 5 in short- and long-term satisfaction assessments (38/41 and 40/42, respectively).³⁵ This assessment, conducted 3 months postoperatively, asked patients to score the statement, “I am completely satisfied with the treatment of my skin problem,” on a scale ranging from 1 (strongly disagree) to 5 (strongly agree).

Lastly, patient perception of their surgeon’s skill may contribute to levels of patient satisfaction. Although suture spacing has not been shown to affect surgical outcomes, it has been demonstrated to impact the patient’s perception of surgical skill and is further supported by a study concluding that closures with 2-mm spacing were ranked significantly lower by patients compared with closures with either 4- or 6-mm spacing (P=.005 and P=.012, respectively).³⁶

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding anxiety-reducing measures and patient-perceived QOL^21-36:

• Factors shown to decrease patient anxiety include patient personalized music, virtual-reality experience, perioperative informational videos, and 3-dimensional–printed MMS models.
• Many methods aimed at decreasing MMS-related patient anxiety show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience.
• Higher anxiety can be associated with worse QOL scores in MMS patients, and additional factors that may have a negative impact on anxiety include female sex, younger age, and tumor location on the face.

Conclusion

Many factors affect patient satisfaction in MMS. Increased awareness and acknowledgement of these factors can foster improved clinical practice and patient experience, which can have downstream effects on patient compliance and overall psychosocial and medical well-being. With the movement toward value-based health care, patient satisfaction ratings are likely to play an increasingly important role in physician reimbursement. Adapting one’s practice to include high-quality, time-efficient, patient-centered care goes hand in hand with increasing MMS patient satisfaction. Careful evaluation and scrutiny of one’s current practices while remaining cognizant of patient population, resource availability, and clinical limitations often reveal opportunities for small adjustments that can have a great impact on patient satisfaction. This thorough assessment and review of the published literature aims to assist MMS surgeons in understanding the role that certain factors—(1) perioperative patient communication and education techniques and (2) patient anxiety, QOL, and additional considerations—have on overall satisfaction with MMS. Specific consideration should be placed on the fact that patient satisfaction is multifactorial, and many different interventions can have a positive impact on the overall patient experience.