Nonmelanoma Skin Cancer

To the Editor:

Treatment of cancer, including cutaneous malignancy, has been transformed by the use of immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte-associated antigen 4, programmed cell-death protein 1 (PD-1), or programmed cell-death ligand 1 (PD-L1). However, these drugs are associated with a distinct set of immune-related adverse events (IRAEs). We present a case of generalized eruptive keratoacanthoma of Grzybowski associated with the ICI cemiplimab.

A 94-year-old White woman presented to the dermatology clinic with acute onset of extensive, locally advanced cutaneous squamous cell carcinoma (cSCC) of the upper right posterolateral calf as well as multiple noninvasive cSCCs of the arms and legs. Her medical history was remarkable for widespread actinic keratoses and numerous cSCCs. The patient had no personal or family history of melanoma. Various cSCCs had required treatment with electrodesiccation and curettage, topical or intralesional 5-fluorouracil, and Mohs micrographic surgery. Approximately 1 year prior to presentation, oral acitretin was initiated to help control the cSCC. Given the extent of locally advanced disease, which was considered unresectable, she was referred to oncology but continued to follow up with dermatology. Positron emission tomography was remarkable for hypermetabolic cutaneous thickening in the upper right posterolateral calf with no evidence of visceral disease.

The patient was started on cemiplimab, an anti-PD-1 monoclonal antibody ICI indicated for the treatment of both metastatic and advanced cSCC. After 4 cycles of intravenous cemiplimab, the patient developed widespread nodules covering the arms and legs (Figure 1) as well as associated tenderness and pruritus. Biopsies of nodules revealed superficially invasive, well-differentiated cSCC consistent with keratoacanthoma. Although a lymphocytic infiltrate was present, no other specific reaction pattern, such as a lichenoid infiltrate, was present (Figure 2).

Positron emission tomography was repeated, demonstrating resolution of the right calf lesion; however, new diffuse cutaneous lesions and inguinal lymph node involvement were present, again without evidence of visceral disease. Given the clinical and histologic findings, a diagnosis of generalized eruptive keratoacanthoma of Grzybowski was made. Cemiplimab was discontinued after the fifth cycle. The patient declined further systemic treatment, instead choosing a regimen of topical steroids and an emollient. 

Immunotherapeutics have transformed cancer therapy, which includes ICIs that target cytotoxic T lymphocyte-associated antigen 4, PD-1, or PD-L1. Increased activity of these checkpoints allows tumor cells to downregulate T-cell activation, thereby evading immune destruction. When PD-1 on T cells binds PD-L1 on tumor cells, T lymphocytes are inhibited from cytotoxic-mediated killing. Therefore, anti-PD-1 ICIs such as cemiplimab permit T-lymphocyte activation and destruction of malignant cells. However, this unique mechanism of immunotherapy is associated with an array of IRAEs, which often manifest in a delayed and prolonged fashion.¹ Immune-related adverse events most commonly affect the gastrointestinal tract as well as the endocrine and dermatologic systems.² Notably, patients with certain tumors who experience these adverse effects might be more likely to have superior overall survival; therefore, IRAEs are sometimes used as an indicator of favorable treatment response.^2,3

Dermatologic IRAEs associated with the use of a PD-1 inhibitor include lichenoid reactions, pruritus, morbilliform eruptions, vitiligo, and bullous pemphigoid.^4,5 Eruptions of keratoacanthoma rarely have been reported following treatment with the PD-1 inhibitors nivolumab and pembrolizumab.^3,6,7 In our patient, we believe the profound and generalized eruptive keratoacanthoma—a well-differentiated cSCC variant—was related to treatment of locally advanced cSCC with cemiplimab. The mechanism underlying the formation of anti-PD-1 eruptive keratoacanthoma is not well understood. In susceptible patients, it is plausible that the inflammatory environment permitted by ICIs paradoxically induces regression of tumors such as locally invasive cSCC and simultaneously promotes formation of keratoacanthoma.

The role of inflammation in the pathogenesis and progression of cSCC is complex and possibly involves contrasting roles of leukocyte subpopulations.⁸ The increased incidence of cSCC in the immunocompromised population,⁸ PD-L1 overexpression in cSCC,^9,10 and successful treatment of cSCC with PD-1 inhibition¹⁰ all suggest that inhibition of specific inflammatory pathways is pivotal in tumor pathogenesis. However, increased inflammation, particularly inflammation driven by T lymphocytes and Langerhans cells, also is believed to play a key role in the formation of cSCCs, including the degeneration of actinic keratosis into cSCC. Moreover, because keratoacanthomas are believed to be a cSCC variant and also are associated with PD-L1 overexpression,⁹ it is perplexing that PD-1 blockade may result in eruptive keratoacanthoma in some patients while also treating locally advanced cSCC, as seen in our patient. Successful treatment of keratoacanthoma with anti-inflammatory intralesional or topical corticosteroids adds to this complicated picture.³

We hypothesize that the pathogenesis of invasive cSCC and keratoacanthoma shares certain immune-mediated mechanisms but also differs in distinct manners. To understand the relationship between systemic treatment of cSCC and eruptive keratoacanthoma, further research is required.

In addition, the RAS/BRAF/MEK oncogenic pathway may be involved in the development of cSCCs associated with anti-PD-1. It is hypothesized that BRAF and MEK inhibition increases T-cell infiltration and increases PD-L1 expression on tumor cells,¹¹ thus increasing the susceptibility of those cells to PD-1 blockade. Further supporting a relationship between the RAS/BRAF/MEK and PD-1 pathways, BRAF inhibitors are associated with development of SCCs and verrucal keratosis by upregulation of the RAS pathway.^12,13 Perhaps a common mechanism underlying these pathways results in their shared association for an increased risk for cSCC upon blockade. More research is needed to fully elucidate the underlying biochemical mechanism of immunotherapy and formation of SCCs, such as keratoacanthoma. 

Treatment of solitary keratoacanthoma often involves surgical excision; however, the sheer number of lesions in eruptive keratoacanthoma presents a larger dilemma. Because oral systemic retinoids have been shown to be most effective for treating eruptive keratoacanthoma, they are considered first-line therapy as monotherapy or in combination with surgical excision.³ Other treatment options include intralesional or topical corticosteroids, cyclosporine, 5-fluorouracil, imiquimod, and cryotherapy.^3,6

The development of ICIs has revolutionized the treatment of cutaneous malignancy, yet we have a great deal more to comprehend on the systemic effects of these medications. Although IRAEs may signal a better response to therapy, some of these effects regrettably can be dose limiting. In our patient, cemiplimab was successful in treating locally advanced cSCC, but treatment also resulted in devastating widespread eruptive keratoacanthoma. The mechanism of this kind of eruption has yet to be understood; we hypothesize that it likely involves T lymphocyte–driven inflammation and the interplay of molecular and immune-mediated pathways.

To the Editor:

Treatment of cancer, including cutaneous malignancy, has been transformed by the use of immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte-associated antigen 4, programmed cell-death protein 1 (PD-1), or programmed cell-death ligand 1 (PD-L1). However, these drugs are associated with a distinct set of immune-related adverse events (IRAEs). We present a case of generalized eruptive keratoacanthoma of Grzybowski associated with the ICI cemiplimab.

A 94-year-old White woman presented to the dermatology clinic with acute onset of extensive, locally advanced cutaneous squamous cell carcinoma (cSCC) of the upper right posterolateral calf as well as multiple noninvasive cSCCs of the arms and legs. Her medical history was remarkable for widespread actinic keratoses and numerous cSCCs. The patient had no personal or family history of melanoma. Various cSCCs had required treatment with electrodesiccation and curettage, topical or intralesional 5-fluorouracil, and Mohs micrographic surgery. Approximately 1 year prior to presentation, oral acitretin was initiated to help control the cSCC. Given the extent of locally advanced disease, which was considered unresectable, she was referred to oncology but continued to follow up with dermatology. Positron emission tomography was remarkable for hypermetabolic cutaneous thickening in the upper right posterolateral calf with no evidence of visceral disease.

The patient was started on cemiplimab, an anti-PD-1 monoclonal antibody ICI indicated for the treatment of both metastatic and advanced cSCC. After 4 cycles of intravenous cemiplimab, the patient developed widespread nodules covering the arms and legs (Figure 1) as well as associated tenderness and pruritus. Biopsies of nodules revealed superficially invasive, well-differentiated cSCC consistent with keratoacanthoma. Although a lymphocytic infiltrate was present, no other specific reaction pattern, such as a lichenoid infiltrate, was present (Figure 2).

Positron emission tomography was repeated, demonstrating resolution of the right calf lesion; however, new diffuse cutaneous lesions and inguinal lymph node involvement were present, again without evidence of visceral disease. Given the clinical and histologic findings, a diagnosis of generalized eruptive keratoacanthoma of Grzybowski was made. Cemiplimab was discontinued after the fifth cycle. The patient declined further systemic treatment, instead choosing a regimen of topical steroids and an emollient. 

Immunotherapeutics have transformed cancer therapy, which includes ICIs that target cytotoxic T lymphocyte-associated antigen 4, PD-1, or PD-L1. Increased activity of these checkpoints allows tumor cells to downregulate T-cell activation, thereby evading immune destruction. When PD-1 on T cells binds PD-L1 on tumor cells, T lymphocytes are inhibited from cytotoxic-mediated killing. Therefore, anti-PD-1 ICIs such as cemiplimab permit T-lymphocyte activation and destruction of malignant cells. However, this unique mechanism of immunotherapy is associated with an array of IRAEs, which often manifest in a delayed and prolonged fashion.¹ Immune-related adverse events most commonly affect the gastrointestinal tract as well as the endocrine and dermatologic systems.² Notably, patients with certain tumors who experience these adverse effects might be more likely to have superior overall survival; therefore, IRAEs are sometimes used as an indicator of favorable treatment response.^2,3

Dermatologic IRAEs associated with the use of a PD-1 inhibitor include lichenoid reactions, pruritus, morbilliform eruptions, vitiligo, and bullous pemphigoid.^4,5 Eruptions of keratoacanthoma rarely have been reported following treatment with the PD-1 inhibitors nivolumab and pembrolizumab.^3,6,7 In our patient, we believe the profound and generalized eruptive keratoacanthoma—a well-differentiated cSCC variant—was related to treatment of locally advanced cSCC with cemiplimab. The mechanism underlying the formation of anti-PD-1 eruptive keratoacanthoma is not well understood. In susceptible patients, it is plausible that the inflammatory environment permitted by ICIs paradoxically induces regression of tumors such as locally invasive cSCC and simultaneously promotes formation of keratoacanthoma.

The role of inflammation in the pathogenesis and progression of cSCC is complex and possibly involves contrasting roles of leukocyte subpopulations.⁸ The increased incidence of cSCC in the immunocompromised population,⁸ PD-L1 overexpression in cSCC,^9,10 and successful treatment of cSCC with PD-1 inhibition¹⁰ all suggest that inhibition of specific inflammatory pathways is pivotal in tumor pathogenesis. However, increased inflammation, particularly inflammation driven by T lymphocytes and Langerhans cells, also is believed to play a key role in the formation of cSCCs, including the degeneration of actinic keratosis into cSCC. Moreover, because keratoacanthomas are believed to be a cSCC variant and also are associated with PD-L1 overexpression,⁹ it is perplexing that PD-1 blockade may result in eruptive keratoacanthoma in some patients while also treating locally advanced cSCC, as seen in our patient. Successful treatment of keratoacanthoma with anti-inflammatory intralesional or topical corticosteroids adds to this complicated picture.³

We hypothesize that the pathogenesis of invasive cSCC and keratoacanthoma shares certain immune-mediated mechanisms but also differs in distinct manners. To understand the relationship between systemic treatment of cSCC and eruptive keratoacanthoma, further research is required.

In addition, the RAS/BRAF/MEK oncogenic pathway may be involved in the development of cSCCs associated with anti-PD-1. It is hypothesized that BRAF and MEK inhibition increases T-cell infiltration and increases PD-L1 expression on tumor cells,¹¹ thus increasing the susceptibility of those cells to PD-1 blockade. Further supporting a relationship between the RAS/BRAF/MEK and PD-1 pathways, BRAF inhibitors are associated with development of SCCs and verrucal keratosis by upregulation of the RAS pathway.^12,13 Perhaps a common mechanism underlying these pathways results in their shared association for an increased risk for cSCC upon blockade. More research is needed to fully elucidate the underlying biochemical mechanism of immunotherapy and formation of SCCs, such as keratoacanthoma. 

Treatment of solitary keratoacanthoma often involves surgical excision; however, the sheer number of lesions in eruptive keratoacanthoma presents a larger dilemma. Because oral systemic retinoids have been shown to be most effective for treating eruptive keratoacanthoma, they are considered first-line therapy as monotherapy or in combination with surgical excision.³ Other treatment options include intralesional or topical corticosteroids, cyclosporine, 5-fluorouracil, imiquimod, and cryotherapy.^3,6

The development of ICIs has revolutionized the treatment of cutaneous malignancy, yet we have a great deal more to comprehend on the systemic effects of these medications. Although IRAEs may signal a better response to therapy, some of these effects regrettably can be dose limiting. In our patient, cemiplimab was successful in treating locally advanced cSCC, but treatment also resulted in devastating widespread eruptive keratoacanthoma. The mechanism of this kind of eruption has yet to be understood; we hypothesize that it likely involves T lymphocyte–driven inflammation and the interplay of molecular and immune-mediated pathways.

To the Editor:

Treatment of cancer, including cutaneous malignancy, has been transformed by the use of immunotherapeutic agents such as immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte-associated antigen 4, programmed cell-death protein 1 (PD-1), or programmed cell-death ligand 1 (PD-L1). However, these drugs are associated with a distinct set of immune-related adverse events (IRAEs). We present a case of generalized eruptive keratoacanthoma of Grzybowski associated with the ICI cemiplimab.

A 94-year-old White woman presented to the dermatology clinic with acute onset of extensive, locally advanced cutaneous squamous cell carcinoma (cSCC) of the upper right posterolateral calf as well as multiple noninvasive cSCCs of the arms and legs. Her medical history was remarkable for widespread actinic keratoses and numerous cSCCs. The patient had no personal or family history of melanoma. Various cSCCs had required treatment with electrodesiccation and curettage, topical or intralesional 5-fluorouracil, and Mohs micrographic surgery. Approximately 1 year prior to presentation, oral acitretin was initiated to help control the cSCC. Given the extent of locally advanced disease, which was considered unresectable, she was referred to oncology but continued to follow up with dermatology. Positron emission tomography was remarkable for hypermetabolic cutaneous thickening in the upper right posterolateral calf with no evidence of visceral disease.

The patient was started on cemiplimab, an anti-PD-1 monoclonal antibody ICI indicated for the treatment of both metastatic and advanced cSCC. After 4 cycles of intravenous cemiplimab, the patient developed widespread nodules covering the arms and legs (Figure 1) as well as associated tenderness and pruritus. Biopsies of nodules revealed superficially invasive, well-differentiated cSCC consistent with keratoacanthoma. Although a lymphocytic infiltrate was present, no other specific reaction pattern, such as a lichenoid infiltrate, was present (Figure 2).

Positron emission tomography was repeated, demonstrating resolution of the right calf lesion; however, new diffuse cutaneous lesions and inguinal lymph node involvement were present, again without evidence of visceral disease. Given the clinical and histologic findings, a diagnosis of generalized eruptive keratoacanthoma of Grzybowski was made. Cemiplimab was discontinued after the fifth cycle. The patient declined further systemic treatment, instead choosing a regimen of topical steroids and an emollient. 

Immunotherapeutics have transformed cancer therapy, which includes ICIs that target cytotoxic T lymphocyte-associated antigen 4, PD-1, or PD-L1. Increased activity of these checkpoints allows tumor cells to downregulate T-cell activation, thereby evading immune destruction. When PD-1 on T cells binds PD-L1 on tumor cells, T lymphocytes are inhibited from cytotoxic-mediated killing. Therefore, anti-PD-1 ICIs such as cemiplimab permit T-lymphocyte activation and destruction of malignant cells. However, this unique mechanism of immunotherapy is associated with an array of IRAEs, which often manifest in a delayed and prolonged fashion.¹ Immune-related adverse events most commonly affect the gastrointestinal tract as well as the endocrine and dermatologic systems.² Notably, patients with certain tumors who experience these adverse effects might be more likely to have superior overall survival; therefore, IRAEs are sometimes used as an indicator of favorable treatment response.^2,3

Dermatologic IRAEs associated with the use of a PD-1 inhibitor include lichenoid reactions, pruritus, morbilliform eruptions, vitiligo, and bullous pemphigoid.^4,5 Eruptions of keratoacanthoma rarely have been reported following treatment with the PD-1 inhibitors nivolumab and pembrolizumab.^3,6,7 In our patient, we believe the profound and generalized eruptive keratoacanthoma—a well-differentiated cSCC variant—was related to treatment of locally advanced cSCC with cemiplimab. The mechanism underlying the formation of anti-PD-1 eruptive keratoacanthoma is not well understood. In susceptible patients, it is plausible that the inflammatory environment permitted by ICIs paradoxically induces regression of tumors such as locally invasive cSCC and simultaneously promotes formation of keratoacanthoma.

The role of inflammation in the pathogenesis and progression of cSCC is complex and possibly involves contrasting roles of leukocyte subpopulations.⁸ The increased incidence of cSCC in the immunocompromised population,⁸ PD-L1 overexpression in cSCC,^9,10 and successful treatment of cSCC with PD-1 inhibition¹⁰ all suggest that inhibition of specific inflammatory pathways is pivotal in tumor pathogenesis. However, increased inflammation, particularly inflammation driven by T lymphocytes and Langerhans cells, also is believed to play a key role in the formation of cSCCs, including the degeneration of actinic keratosis into cSCC. Moreover, because keratoacanthomas are believed to be a cSCC variant and also are associated with PD-L1 overexpression,⁹ it is perplexing that PD-1 blockade may result in eruptive keratoacanthoma in some patients while also treating locally advanced cSCC, as seen in our patient. Successful treatment of keratoacanthoma with anti-inflammatory intralesional or topical corticosteroids adds to this complicated picture.³

We hypothesize that the pathogenesis of invasive cSCC and keratoacanthoma shares certain immune-mediated mechanisms but also differs in distinct manners. To understand the relationship between systemic treatment of cSCC and eruptive keratoacanthoma, further research is required.

In addition, the RAS/BRAF/MEK oncogenic pathway may be involved in the development of cSCCs associated with anti-PD-1. It is hypothesized that BRAF and MEK inhibition increases T-cell infiltration and increases PD-L1 expression on tumor cells,¹¹ thus increasing the susceptibility of those cells to PD-1 blockade. Further supporting a relationship between the RAS/BRAF/MEK and PD-1 pathways, BRAF inhibitors are associated with development of SCCs and verrucal keratosis by upregulation of the RAS pathway.^12,13 Perhaps a common mechanism underlying these pathways results in their shared association for an increased risk for cSCC upon blockade. More research is needed to fully elucidate the underlying biochemical mechanism of immunotherapy and formation of SCCs, such as keratoacanthoma. 

Treatment of solitary keratoacanthoma often involves surgical excision; however, the sheer number of lesions in eruptive keratoacanthoma presents a larger dilemma. Because oral systemic retinoids have been shown to be most effective for treating eruptive keratoacanthoma, they are considered first-line therapy as monotherapy or in combination with surgical excision.³ Other treatment options include intralesional or topical corticosteroids, cyclosporine, 5-fluorouracil, imiquimod, and cryotherapy.^3,6

The development of ICIs has revolutionized the treatment of cutaneous malignancy, yet we have a great deal more to comprehend on the systemic effects of these medications. Although IRAEs may signal a better response to therapy, some of these effects regrettably can be dose limiting. In our patient, cemiplimab was successful in treating locally advanced cSCC, but treatment also resulted in devastating widespread eruptive keratoacanthoma. The mechanism of this kind of eruption has yet to be understood; we hypothesize that it likely involves T lymphocyte–driven inflammation and the interplay of molecular and immune-mediated pathways.

Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.¹ Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.² The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.³

Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.² Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.⁴ Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.⁵ We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.

Methods

We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.

Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.

Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.

Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.

Results

A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).

A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.

Comment

Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.^18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.²⁰ The advantages and limitations of TB staining of BCC are presented in Table 2.

Humphreys et al⁶ suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.⁶ The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.²¹ This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.⁶

The margin behavior of BCC stained with TB was further characterized by Goldberg et al,⁸ who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.⁸

The nasal surface has a predilection for BCC.²² The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.²² When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.¹⁰ None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.¹⁰

The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.⁹ Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.⁹

Bennett and Taher⁷ described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.⁷

Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues⁶ of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.⁶

Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.¹² All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.¹² The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.¹³ Drosou et al¹³ suggested that TB may enhance the diagnostic accuracy for perineural SCC.

Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.¹⁵

Although PCACC is rare, the recurrence rate is high.²³ Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.¹⁴

Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.¹⁷ In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.⁶

Conclusion

Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.

Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.¹ Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.² The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.³

Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.² Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.⁴ Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.⁵ We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.

Methods

We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.

Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.

Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.

Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.

Results

A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).

A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.

Comment

Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.^18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.²⁰ The advantages and limitations of TB staining of BCC are presented in Table 2.

Humphreys et al⁶ suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.⁶ The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.²¹ This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.⁶

The margin behavior of BCC stained with TB was further characterized by Goldberg et al,⁸ who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.⁸

The nasal surface has a predilection for BCC.²² The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.²² When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.¹⁰ None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.¹⁰

The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.⁹ Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.⁹

Bennett and Taher⁷ described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.⁷

Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues⁶ of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.⁶

Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.¹² All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.¹² The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.¹³ Drosou et al¹³ suggested that TB may enhance the diagnostic accuracy for perineural SCC.

Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.¹⁵

Although PCACC is rare, the recurrence rate is high.²³ Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.¹⁴

Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.¹⁷ In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.⁶

Conclusion

Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.

Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.¹ Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.² The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.³

Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.² Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.⁴ Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.⁵ We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.

Methods

We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.

Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.

Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.

Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.

Results

A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).

A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.

Comment

Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.^18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.²⁰ The advantages and limitations of TB staining of BCC are presented in Table 2.

Humphreys et al⁶ suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.⁶ The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.²¹ This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.⁶

The margin behavior of BCC stained with TB was further characterized by Goldberg et al,⁸ who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.⁸

The nasal surface has a predilection for BCC.²² The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.²² When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.¹⁰ None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.¹⁰

The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.⁹ Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.⁹

Bennett and Taher⁷ described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.⁷

Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues⁶ of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.⁶

Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.¹² All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.¹² The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.¹³ Drosou et al¹³ suggested that TB may enhance the diagnostic accuracy for perineural SCC.

Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.¹⁵

Although PCACC is rare, the recurrence rate is high.²³ Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.¹⁴

Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.¹⁷ In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.⁶

Conclusion

Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.

The Diagnosis: Carcinoma en Cuirasse

Histopathology demonstrated a cellular infiltrate filling the dermis with sparing of the papillary and superficial reticular dermis (Figure 1A). The cells were arranged in strands and cords that infiltrated between sclerotic collagen bundles. Cytomorphologically, the cells ranged from epithelioid with large vesicular nuclei and prominent nucleoli to cuboidal with hyperchromatic nuclei with irregular contours and a high nuclear to cytoplasmic ratio (Figure 1B). Occasional mitotic figures were identified, and cells demonstrated diffuse nuclear positivity for GATA-3 (Figure 1C); 55% of the cells demonstrated estrogen receptor positivity, and immunohistochemistry of progesterone receptors was negative. These findings confirmed our patient’s diagnosis of breast carcinoma en cuirasse (CeC) as the primary manifestation of metastatic invasive ductal carcinoma. Our patient was treated with intravenous chemotherapy and tamoxifen.

Histopathologic findings of morphea include thickened hyalinized collagen bundles and loss of adventitial fat.¹ A diagnosis of chronic radiation dermatitis was inconsistent with our patient’s medical history and biopsy results, as pathology should reveal hyalinized collagen or stellate radiation fibroblasts.^2,3 Nests of squamous epithelial cells with abundant eosinophilic cytoplasm and large vesicular nuclei were not seen, excluding squamous cell carcinoma as a possible diagnosis.⁴ Although sclerosing sweat duct carcinoma is characterized by infiltrating cords in sclerotic dermis, the cells were not arranged in ductlike structures 1– to 2–cell layers thick, excluding this diagnosis.⁵

Carcinoma en cuirasse—named for skin involvement that appears similar to the metal breastplate of a cuirassier—is a rare form of cutaneous metastasis that typically presents with extensive infiltrative plaques resulting in fibrosis of the skin and subcutaneous tissue.^6,7 Carcinoma en cuirasse most commonly metastasizes from the breast but also may represent metastases from the lungs, gastrointestinal tract, or genitourinary systems.⁸ In the setting of a primary breast malignancy, metastatic plaques of CeC tend to represent tumor recurrence following a mastectomy procedure; however, in rare cases CeC can present as the primary manifestation of breast cancer or as a result of untreated malignancy.^6,9 In our patient, CeC was the primary manifestation of metastatic invasive ductal carcinoma with additional paraneoplastic ichthyosis (Figure 2).

Carcinoma en cuirasse comprises 3% to 6% of cutaneous metastases originating from the breast.^10,11 Breast cancer is the most common primary neoplasm displaying extracutaneous metastasis, comprising 70% of all cutaneous metastases in females.¹¹ Cutaneous metastasis often indicates late stage of disease, portending a poor prognosis. In our patient, the cutaneous nodules were present for approximately 3 years prior to the diagnosis of stage IV invasive ductal cell carcinoma with metastasis to the skin and lungs. Prior to admission, she had not been diagnosed with breast cancer, thus no treatments had been administered. It is uncommon for CeC to present as the initial finding and without prior treatment of the underlying malignancy. The median length of survival after diagnosis of cutaneous metastasis from breast cancer is 13.8 months, with a 10-year survival rate of 3.1%.¹²

In addition to cutaneous metastasis, breast cancer also may present with paraneoplastic dermatoses such as ichthyosis.¹³ Ichthyosis is characterized by extreme dryness, flaking, thickening, and mild pruritus.¹⁴ It most commonly is an inherited condition, but it may be acquired due to malignancy. Acquired ichthyosis may manifest in systemic diseases including systemic lupus erythematosus, sarcoidosis, and hypothyroidism.15 Although acquired ichthyosis is rare, it has been reported in cases of internal malignancy, most commonly lymphoproliferative malignancies and less frequently carcinoma of the breasts, cervix, and lungs. Patients who acquire ichthyosis in association with malignancy usually present with late-stage disease.¹⁵ Our patient acquired ichthyosis 3 months prior to admission and had never experienced it previously. Although the exact mechanism for acquiring ichthyosis remains unknown, it is uncertain if ichthyosis associated with malignancy is paraneoplastic or a result of chemotherapy.^14,16 In this case, the patient had not yet started chemotherapy at the time of the ichthyosis diagnosis, suggesting a paraneoplastic etiology.

Carcinoma en cuirasse and paraneoplastic ichthyosis individually are extremely rare manifestations of breast cancer. Thus, it is even rarer for these conditions to present concurrently. Treatment options for CeC include chemotherapy, radiotherapy, hormonal antagonists, and snake venom.¹¹ Systemic chemotherapy targeting the histopathologic type of the primary tumor is the treatment of choice. Other treatment methods usually are chosen for late stages of disease progression.10 Paraneoplastic ichthyosis has been reported to show improvement with treatment of the underlying primary malignancy by surgical removal or chemotherapy.^14,17 Tamoxifen less commonly is used for systemic treatment of CeC, but one case in the literature reported favorable outcomes.¹⁸

We describe 2 rare cutaneous manifestations of breast cancer occurring concomitantly: CeC and paraneoplastic ichthyosis. The combination of clinical and pathologic findings presented in this case solidified the diagnosis of metastatic invasive ductal carcinoma. We aim to improve recognition of paraneoplastic skin findings to accelerate the process of effective and efficient treatment.

The Diagnosis: Carcinoma en Cuirasse

Histopathology demonstrated a cellular infiltrate filling the dermis with sparing of the papillary and superficial reticular dermis (Figure 1A). The cells were arranged in strands and cords that infiltrated between sclerotic collagen bundles. Cytomorphologically, the cells ranged from epithelioid with large vesicular nuclei and prominent nucleoli to cuboidal with hyperchromatic nuclei with irregular contours and a high nuclear to cytoplasmic ratio (Figure 1B). Occasional mitotic figures were identified, and cells demonstrated diffuse nuclear positivity for GATA-3 (Figure 1C); 55% of the cells demonstrated estrogen receptor positivity, and immunohistochemistry of progesterone receptors was negative. These findings confirmed our patient’s diagnosis of breast carcinoma en cuirasse (CeC) as the primary manifestation of metastatic invasive ductal carcinoma. Our patient was treated with intravenous chemotherapy and tamoxifen.

Histopathologic findings of morphea include thickened hyalinized collagen bundles and loss of adventitial fat.¹ A diagnosis of chronic radiation dermatitis was inconsistent with our patient’s medical history and biopsy results, as pathology should reveal hyalinized collagen or stellate radiation fibroblasts.^2,3 Nests of squamous epithelial cells with abundant eosinophilic cytoplasm and large vesicular nuclei were not seen, excluding squamous cell carcinoma as a possible diagnosis.⁴ Although sclerosing sweat duct carcinoma is characterized by infiltrating cords in sclerotic dermis, the cells were not arranged in ductlike structures 1– to 2–cell layers thick, excluding this diagnosis.⁵

Carcinoma en cuirasse—named for skin involvement that appears similar to the metal breastplate of a cuirassier—is a rare form of cutaneous metastasis that typically presents with extensive infiltrative plaques resulting in fibrosis of the skin and subcutaneous tissue.^6,7 Carcinoma en cuirasse most commonly metastasizes from the breast but also may represent metastases from the lungs, gastrointestinal tract, or genitourinary systems.⁸ In the setting of a primary breast malignancy, metastatic plaques of CeC tend to represent tumor recurrence following a mastectomy procedure; however, in rare cases CeC can present as the primary manifestation of breast cancer or as a result of untreated malignancy.^6,9 In our patient, CeC was the primary manifestation of metastatic invasive ductal carcinoma with additional paraneoplastic ichthyosis (Figure 2).

Carcinoma en cuirasse comprises 3% to 6% of cutaneous metastases originating from the breast.^10,11 Breast cancer is the most common primary neoplasm displaying extracutaneous metastasis, comprising 70% of all cutaneous metastases in females.¹¹ Cutaneous metastasis often indicates late stage of disease, portending a poor prognosis. In our patient, the cutaneous nodules were present for approximately 3 years prior to the diagnosis of stage IV invasive ductal cell carcinoma with metastasis to the skin and lungs. Prior to admission, she had not been diagnosed with breast cancer, thus no treatments had been administered. It is uncommon for CeC to present as the initial finding and without prior treatment of the underlying malignancy. The median length of survival after diagnosis of cutaneous metastasis from breast cancer is 13.8 months, with a 10-year survival rate of 3.1%.¹²

In addition to cutaneous metastasis, breast cancer also may present with paraneoplastic dermatoses such as ichthyosis.¹³ Ichthyosis is characterized by extreme dryness, flaking, thickening, and mild pruritus.¹⁴ It most commonly is an inherited condition, but it may be acquired due to malignancy. Acquired ichthyosis may manifest in systemic diseases including systemic lupus erythematosus, sarcoidosis, and hypothyroidism.15 Although acquired ichthyosis is rare, it has been reported in cases of internal malignancy, most commonly lymphoproliferative malignancies and less frequently carcinoma of the breasts, cervix, and lungs. Patients who acquire ichthyosis in association with malignancy usually present with late-stage disease.¹⁵ Our patient acquired ichthyosis 3 months prior to admission and had never experienced it previously. Although the exact mechanism for acquiring ichthyosis remains unknown, it is uncertain if ichthyosis associated with malignancy is paraneoplastic or a result of chemotherapy.^14,16 In this case, the patient had not yet started chemotherapy at the time of the ichthyosis diagnosis, suggesting a paraneoplastic etiology.

Carcinoma en cuirasse and paraneoplastic ichthyosis individually are extremely rare manifestations of breast cancer. Thus, it is even rarer for these conditions to present concurrently. Treatment options for CeC include chemotherapy, radiotherapy, hormonal antagonists, and snake venom.¹¹ Systemic chemotherapy targeting the histopathologic type of the primary tumor is the treatment of choice. Other treatment methods usually are chosen for late stages of disease progression.10 Paraneoplastic ichthyosis has been reported to show improvement with treatment of the underlying primary malignancy by surgical removal or chemotherapy.^14,17 Tamoxifen less commonly is used for systemic treatment of CeC, but one case in the literature reported favorable outcomes.¹⁸

We describe 2 rare cutaneous manifestations of breast cancer occurring concomitantly: CeC and paraneoplastic ichthyosis. The combination of clinical and pathologic findings presented in this case solidified the diagnosis of metastatic invasive ductal carcinoma. We aim to improve recognition of paraneoplastic skin findings to accelerate the process of effective and efficient treatment.

The Diagnosis: Carcinoma en Cuirasse

Histopathology demonstrated a cellular infiltrate filling the dermis with sparing of the papillary and superficial reticular dermis (Figure 1A). The cells were arranged in strands and cords that infiltrated between sclerotic collagen bundles. Cytomorphologically, the cells ranged from epithelioid with large vesicular nuclei and prominent nucleoli to cuboidal with hyperchromatic nuclei with irregular contours and a high nuclear to cytoplasmic ratio (Figure 1B). Occasional mitotic figures were identified, and cells demonstrated diffuse nuclear positivity for GATA-3 (Figure 1C); 55% of the cells demonstrated estrogen receptor positivity, and immunohistochemistry of progesterone receptors was negative. These findings confirmed our patient’s diagnosis of breast carcinoma en cuirasse (CeC) as the primary manifestation of metastatic invasive ductal carcinoma. Our patient was treated with intravenous chemotherapy and tamoxifen.

Histopathologic findings of morphea include thickened hyalinized collagen bundles and loss of adventitial fat.¹ A diagnosis of chronic radiation dermatitis was inconsistent with our patient’s medical history and biopsy results, as pathology should reveal hyalinized collagen or stellate radiation fibroblasts.^2,3 Nests of squamous epithelial cells with abundant eosinophilic cytoplasm and large vesicular nuclei were not seen, excluding squamous cell carcinoma as a possible diagnosis.⁴ Although sclerosing sweat duct carcinoma is characterized by infiltrating cords in sclerotic dermis, the cells were not arranged in ductlike structures 1– to 2–cell layers thick, excluding this diagnosis.⁵

Carcinoma en cuirasse—named for skin involvement that appears similar to the metal breastplate of a cuirassier—is a rare form of cutaneous metastasis that typically presents with extensive infiltrative plaques resulting in fibrosis of the skin and subcutaneous tissue.^6,7 Carcinoma en cuirasse most commonly metastasizes from the breast but also may represent metastases from the lungs, gastrointestinal tract, or genitourinary systems.⁸ In the setting of a primary breast malignancy, metastatic plaques of CeC tend to represent tumor recurrence following a mastectomy procedure; however, in rare cases CeC can present as the primary manifestation of breast cancer or as a result of untreated malignancy.^6,9 In our patient, CeC was the primary manifestation of metastatic invasive ductal carcinoma with additional paraneoplastic ichthyosis (Figure 2).

Carcinoma en cuirasse comprises 3% to 6% of cutaneous metastases originating from the breast.^10,11 Breast cancer is the most common primary neoplasm displaying extracutaneous metastasis, comprising 70% of all cutaneous metastases in females.¹¹ Cutaneous metastasis often indicates late stage of disease, portending a poor prognosis. In our patient, the cutaneous nodules were present for approximately 3 years prior to the diagnosis of stage IV invasive ductal cell carcinoma with metastasis to the skin and lungs. Prior to admission, she had not been diagnosed with breast cancer, thus no treatments had been administered. It is uncommon for CeC to present as the initial finding and without prior treatment of the underlying malignancy. The median length of survival after diagnosis of cutaneous metastasis from breast cancer is 13.8 months, with a 10-year survival rate of 3.1%.¹²

In addition to cutaneous metastasis, breast cancer also may present with paraneoplastic dermatoses such as ichthyosis.¹³ Ichthyosis is characterized by extreme dryness, flaking, thickening, and mild pruritus.¹⁴ It most commonly is an inherited condition, but it may be acquired due to malignancy. Acquired ichthyosis may manifest in systemic diseases including systemic lupus erythematosus, sarcoidosis, and hypothyroidism.15 Although acquired ichthyosis is rare, it has been reported in cases of internal malignancy, most commonly lymphoproliferative malignancies and less frequently carcinoma of the breasts, cervix, and lungs. Patients who acquire ichthyosis in association with malignancy usually present with late-stage disease.¹⁵ Our patient acquired ichthyosis 3 months prior to admission and had never experienced it previously. Although the exact mechanism for acquiring ichthyosis remains unknown, it is uncertain if ichthyosis associated with malignancy is paraneoplastic or a result of chemotherapy.^14,16 In this case, the patient had not yet started chemotherapy at the time of the ichthyosis diagnosis, suggesting a paraneoplastic etiology.

Carcinoma en cuirasse and paraneoplastic ichthyosis individually are extremely rare manifestations of breast cancer. Thus, it is even rarer for these conditions to present concurrently. Treatment options for CeC include chemotherapy, radiotherapy, hormonal antagonists, and snake venom.¹¹ Systemic chemotherapy targeting the histopathologic type of the primary tumor is the treatment of choice. Other treatment methods usually are chosen for late stages of disease progression.10 Paraneoplastic ichthyosis has been reported to show improvement with treatment of the underlying primary malignancy by surgical removal or chemotherapy.^14,17 Tamoxifen less commonly is used for systemic treatment of CeC, but one case in the literature reported favorable outcomes.¹⁸

We describe 2 rare cutaneous manifestations of breast cancer occurring concomitantly: CeC and paraneoplastic ichthyosis. The combination of clinical and pathologic findings presented in this case solidified the diagnosis of metastatic invasive ductal carcinoma. We aim to improve recognition of paraneoplastic skin findings to accelerate the process of effective and efficient treatment.

The Diagnosis: Merkel Cell Carcinoma

Multiple diagnoses should be considered for a small, round, blue cell neoplasm of the skin, including both primary and metastatic entities. In our patient, histopathology revealed sheets and nests of infiltrative neoplastic cells with dispersed chromatin, minimal cytoplasm, and multiple mitoses (quiz image 1).¹ The lesional cells were in the dermis and superficial subcutaneous tissue but did not appear to be arising from the epidermis. Lymphovascular invasion also was evident on additional sections. Metastatic disease was identified in 3 sentinel lymph nodes from the right inguinal and right iliac regions. These features were compatible with a diagnosis of Merkel cell carcinoma (MCC).

Merkel cell carcinoma is a rare malignant neuroendocrine cutaneous tumor with a worldwide incidence of 0.1 to 1.6 cases per 100,000 individuals annually.² The typical patient is older than 75 years with fair skin and a history of extensive sun exposure. Immunocompromised individuals are predisposed and more susceptible to infection with the Merkel cell polyomavirus, which promotes oncogenesis in the majority of MCCs. Our patient’s history of combined variable immunodeficiency likely explains her presentation at a younger age.

The prognosis in patients with MCC is poor, with 5-year survival rates of 51% for local disease, 35% for nodal disease, and 14% for systemic metastases. Survival also is reduced in cases with head/ neck primary tumors and polyomavirus-negative tumors, as well as in immunocompromised patients.² Treatment of resectable MCC consists of Mohs micrographic surgery or wide local excision depending on the patient’s cosmetic concerns. Radiation therapy is recommended for cases with increased risk for recurrence or positive surgical margins, as well as when additional resection is impossible. A study investigating immunotherapy with nivolumab demonstrated complete pathologic response and radiographic tumor regression in nearly half of patients when given 4 weeks prior to surgery.³

Immunohistochemistry is essential in discerning MCC from other small blue cell tumors. Most MCC cases show positive expression of neuroendocrine markers such as synaptophysin, chromogranin, and insulinomaassociated protein 1. Perinuclear dotlike staining with cytokeratin (CK) 20 (quiz image 2) commonly is seen, but up to 15% of cases may be CK20 negative. Many of these CK20-negative cases also express CK7. This tumor also may stain with paired box 5 (PAX-5), CD99, terminal deoxynucleotidyl transferase, Ber-EP4, and CD117^1,4; melanoma stains (ie, human melanoma black [HMB] 45, SRYrelated HMB-box 10 [SOX-10], S-100, melanoma antigen recognized by T-cells 1 [MART-1]) should be negative. However, PAX-5 expression may be a potential pitfall given that B-cell lymphomas also would express that marker and could mimic MCC histologically. Therefore, other universal lymphoid markers such as CD45 should be ordered to rule out this entity. Even with one or a few aberrant stains, a diagnosis of MCC still can be rendered using the histomorphology and the overall staining profile.⁴ Of prognostic significance, p63 expression is associated with more aggressive tumors, while Bcl-2 expression is favorable, as it offers an additional targeted treatment option.^5,6

Basal cell carcinoma (BCC) is linked to excessive sun exposure and is the most common skin cancer. Similar to MCC, it typically is mitotically active and hyperchromatic; however, lymphovascular invasion or metastasis almost never is observed in BCC, whereas approximately one-third of MCC cases have metastasized by the time of diagnosis. Additionally, BCC lacks the perinuclear dotlike staining seen with CK20.^2,7 Features present in BCC that are unusual for MCC include peripheral nuclear palisading, mucin, and retraction artifact on paraffin-embedded sections (Figure 1).⁷

Leukemia cutis (or cutaneous infiltrates of leukemia) commonly displays a perivascular and periadnexal pattern in the dermis and subcutis. These infiltrates of neoplastic leukocytes can congregate into sheets, sometimes with an overlying Grenz zone, or form single-file infiltrates (Figure 2).^1,4 The neoplastic cells can be monomorphic or atypical and commonly are susceptible to crush artifact.⁴ Although the immunohistochemical profile varies depending on the etiology of the underlying leukemia, broad hematologic markers such as CD43 and CD45 are helpful to discern these malignancies from MCC.⁴

Being neuroendocrine in origin, metastatic small cell carcinoma (Figure 3) strongly mimics MCC histologically and usually stains with synaptophysin, chromogranin, and insulinoma-associated protein 1. Both tumor cells typically exhibit nuclear molding and high mitotic rates. Although small cell carcinoma is more likely to stain with high-molecular-weight cytokeratins (ie, CK7), it is not uncommon for these tumors to express lowmolecular- weight cytokeratins such as CK20. Because most cases originate from the lungs, these lesions should be positive for thyroid transcription factor 1 and negative for PAX-5, whereas MCC would show the reverse for those stains.¹ Ultimately, however, clinical correlation with imaging results is the single best methodology for differentiation.

Small cell melanoma, a variant of nevoid melanoma, can strongly resemble an MCC or a lymphoma. Usually located on the scalp or arising from a congenital nevus, small cell melanomas are aggressive and confer an unfavorable prognosis. Histologically, they consist of nests to sheets of atypical cells within the epidermis and dermis. These cells typically exhibit hyperchromatic nuclei, minimal cytoplasm, and frequent mitoses (Figure 4). Furthermore, the cells do not display maturation based on depth.⁸ These tumors usually are positive for HMB45, S-100, MART-1, SOX-10, and tyrosinase, all of which are extremely unlikely to stain an MCC.¹

The Diagnosis: Merkel Cell Carcinoma

Multiple diagnoses should be considered for a small, round, blue cell neoplasm of the skin, including both primary and metastatic entities. In our patient, histopathology revealed sheets and nests of infiltrative neoplastic cells with dispersed chromatin, minimal cytoplasm, and multiple mitoses (quiz image 1).¹ The lesional cells were in the dermis and superficial subcutaneous tissue but did not appear to be arising from the epidermis. Lymphovascular invasion also was evident on additional sections. Metastatic disease was identified in 3 sentinel lymph nodes from the right inguinal and right iliac regions. These features were compatible with a diagnosis of Merkel cell carcinoma (MCC).

Merkel cell carcinoma is a rare malignant neuroendocrine cutaneous tumor with a worldwide incidence of 0.1 to 1.6 cases per 100,000 individuals annually.² The typical patient is older than 75 years with fair skin and a history of extensive sun exposure. Immunocompromised individuals are predisposed and more susceptible to infection with the Merkel cell polyomavirus, which promotes oncogenesis in the majority of MCCs. Our patient’s history of combined variable immunodeficiency likely explains her presentation at a younger age.

The prognosis in patients with MCC is poor, with 5-year survival rates of 51% for local disease, 35% for nodal disease, and 14% for systemic metastases. Survival also is reduced in cases with head/ neck primary tumors and polyomavirus-negative tumors, as well as in immunocompromised patients.² Treatment of resectable MCC consists of Mohs micrographic surgery or wide local excision depending on the patient’s cosmetic concerns. Radiation therapy is recommended for cases with increased risk for recurrence or positive surgical margins, as well as when additional resection is impossible. A study investigating immunotherapy with nivolumab demonstrated complete pathologic response and radiographic tumor regression in nearly half of patients when given 4 weeks prior to surgery.³

Immunohistochemistry is essential in discerning MCC from other small blue cell tumors. Most MCC cases show positive expression of neuroendocrine markers such as synaptophysin, chromogranin, and insulinomaassociated protein 1. Perinuclear dotlike staining with cytokeratin (CK) 20 (quiz image 2) commonly is seen, but up to 15% of cases may be CK20 negative. Many of these CK20-negative cases also express CK7. This tumor also may stain with paired box 5 (PAX-5), CD99, terminal deoxynucleotidyl transferase, Ber-EP4, and CD117^1,4; melanoma stains (ie, human melanoma black [HMB] 45, SRYrelated HMB-box 10 [SOX-10], S-100, melanoma antigen recognized by T-cells 1 [MART-1]) should be negative. However, PAX-5 expression may be a potential pitfall given that B-cell lymphomas also would express that marker and could mimic MCC histologically. Therefore, other universal lymphoid markers such as CD45 should be ordered to rule out this entity. Even with one or a few aberrant stains, a diagnosis of MCC still can be rendered using the histomorphology and the overall staining profile.⁴ Of prognostic significance, p63 expression is associated with more aggressive tumors, while Bcl-2 expression is favorable, as it offers an additional targeted treatment option.^5,6

Basal cell carcinoma (BCC) is linked to excessive sun exposure and is the most common skin cancer. Similar to MCC, it typically is mitotically active and hyperchromatic; however, lymphovascular invasion or metastasis almost never is observed in BCC, whereas approximately one-third of MCC cases have metastasized by the time of diagnosis. Additionally, BCC lacks the perinuclear dotlike staining seen with CK20.^2,7 Features present in BCC that are unusual for MCC include peripheral nuclear palisading, mucin, and retraction artifact on paraffin-embedded sections (Figure 1).⁷

Leukemia cutis (or cutaneous infiltrates of leukemia) commonly displays a perivascular and periadnexal pattern in the dermis and subcutis. These infiltrates of neoplastic leukocytes can congregate into sheets, sometimes with an overlying Grenz zone, or form single-file infiltrates (Figure 2).^1,4 The neoplastic cells can be monomorphic or atypical and commonly are susceptible to crush artifact.⁴ Although the immunohistochemical profile varies depending on the etiology of the underlying leukemia, broad hematologic markers such as CD43 and CD45 are helpful to discern these malignancies from MCC.⁴

Being neuroendocrine in origin, metastatic small cell carcinoma (Figure 3) strongly mimics MCC histologically and usually stains with synaptophysin, chromogranin, and insulinoma-associated protein 1. Both tumor cells typically exhibit nuclear molding and high mitotic rates. Although small cell carcinoma is more likely to stain with high-molecular-weight cytokeratins (ie, CK7), it is not uncommon for these tumors to express lowmolecular- weight cytokeratins such as CK20. Because most cases originate from the lungs, these lesions should be positive for thyroid transcription factor 1 and negative for PAX-5, whereas MCC would show the reverse for those stains.¹ Ultimately, however, clinical correlation with imaging results is the single best methodology for differentiation.

Small cell melanoma, a variant of nevoid melanoma, can strongly resemble an MCC or a lymphoma. Usually located on the scalp or arising from a congenital nevus, small cell melanomas are aggressive and confer an unfavorable prognosis. Histologically, they consist of nests to sheets of atypical cells within the epidermis and dermis. These cells typically exhibit hyperchromatic nuclei, minimal cytoplasm, and frequent mitoses (Figure 4). Furthermore, the cells do not display maturation based on depth.⁸ These tumors usually are positive for HMB45, S-100, MART-1, SOX-10, and tyrosinase, all of which are extremely unlikely to stain an MCC.¹

The Diagnosis: Merkel Cell Carcinoma

Multiple diagnoses should be considered for a small, round, blue cell neoplasm of the skin, including both primary and metastatic entities. In our patient, histopathology revealed sheets and nests of infiltrative neoplastic cells with dispersed chromatin, minimal cytoplasm, and multiple mitoses (quiz image 1).¹ The lesional cells were in the dermis and superficial subcutaneous tissue but did not appear to be arising from the epidermis. Lymphovascular invasion also was evident on additional sections. Metastatic disease was identified in 3 sentinel lymph nodes from the right inguinal and right iliac regions. These features were compatible with a diagnosis of Merkel cell carcinoma (MCC).

Merkel cell carcinoma is a rare malignant neuroendocrine cutaneous tumor with a worldwide incidence of 0.1 to 1.6 cases per 100,000 individuals annually.² The typical patient is older than 75 years with fair skin and a history of extensive sun exposure. Immunocompromised individuals are predisposed and more susceptible to infection with the Merkel cell polyomavirus, which promotes oncogenesis in the majority of MCCs. Our patient’s history of combined variable immunodeficiency likely explains her presentation at a younger age.

The prognosis in patients with MCC is poor, with 5-year survival rates of 51% for local disease, 35% for nodal disease, and 14% for systemic metastases. Survival also is reduced in cases with head/ neck primary tumors and polyomavirus-negative tumors, as well as in immunocompromised patients.² Treatment of resectable MCC consists of Mohs micrographic surgery or wide local excision depending on the patient’s cosmetic concerns. Radiation therapy is recommended for cases with increased risk for recurrence or positive surgical margins, as well as when additional resection is impossible. A study investigating immunotherapy with nivolumab demonstrated complete pathologic response and radiographic tumor regression in nearly half of patients when given 4 weeks prior to surgery.³

Immunohistochemistry is essential in discerning MCC from other small blue cell tumors. Most MCC cases show positive expression of neuroendocrine markers such as synaptophysin, chromogranin, and insulinomaassociated protein 1. Perinuclear dotlike staining with cytokeratin (CK) 20 (quiz image 2) commonly is seen, but up to 15% of cases may be CK20 negative. Many of these CK20-negative cases also express CK7. This tumor also may stain with paired box 5 (PAX-5), CD99, terminal deoxynucleotidyl transferase, Ber-EP4, and CD117^1,4; melanoma stains (ie, human melanoma black [HMB] 45, SRYrelated HMB-box 10 [SOX-10], S-100, melanoma antigen recognized by T-cells 1 [MART-1]) should be negative. However, PAX-5 expression may be a potential pitfall given that B-cell lymphomas also would express that marker and could mimic MCC histologically. Therefore, other universal lymphoid markers such as CD45 should be ordered to rule out this entity. Even with one or a few aberrant stains, a diagnosis of MCC still can be rendered using the histomorphology and the overall staining profile.⁴ Of prognostic significance, p63 expression is associated with more aggressive tumors, while Bcl-2 expression is favorable, as it offers an additional targeted treatment option.^5,6

Basal cell carcinoma (BCC) is linked to excessive sun exposure and is the most common skin cancer. Similar to MCC, it typically is mitotically active and hyperchromatic; however, lymphovascular invasion or metastasis almost never is observed in BCC, whereas approximately one-third of MCC cases have metastasized by the time of diagnosis. Additionally, BCC lacks the perinuclear dotlike staining seen with CK20.^2,7 Features present in BCC that are unusual for MCC include peripheral nuclear palisading, mucin, and retraction artifact on paraffin-embedded sections (Figure 1).⁷

Leukemia cutis (or cutaneous infiltrates of leukemia) commonly displays a perivascular and periadnexal pattern in the dermis and subcutis. These infiltrates of neoplastic leukocytes can congregate into sheets, sometimes with an overlying Grenz zone, or form single-file infiltrates (Figure 2).^1,4 The neoplastic cells can be monomorphic or atypical and commonly are susceptible to crush artifact.⁴ Although the immunohistochemical profile varies depending on the etiology of the underlying leukemia, broad hematologic markers such as CD43 and CD45 are helpful to discern these malignancies from MCC.⁴

Being neuroendocrine in origin, metastatic small cell carcinoma (Figure 3) strongly mimics MCC histologically and usually stains with synaptophysin, chromogranin, and insulinoma-associated protein 1. Both tumor cells typically exhibit nuclear molding and high mitotic rates. Although small cell carcinoma is more likely to stain with high-molecular-weight cytokeratins (ie, CK7), it is not uncommon for these tumors to express lowmolecular- weight cytokeratins such as CK20. Because most cases originate from the lungs, these lesions should be positive for thyroid transcription factor 1 and negative for PAX-5, whereas MCC would show the reverse for those stains.¹ Ultimately, however, clinical correlation with imaging results is the single best methodology for differentiation.

Small cell melanoma, a variant of nevoid melanoma, can strongly resemble an MCC or a lymphoma. Usually located on the scalp or arising from a congenital nevus, small cell melanomas are aggressive and confer an unfavorable prognosis. Histologically, they consist of nests to sheets of atypical cells within the epidermis and dermis. These cells typically exhibit hyperchromatic nuclei, minimal cytoplasm, and frequent mitoses (Figure 4). Furthermore, the cells do not display maturation based on depth.⁸ These tumors usually are positive for HMB45, S-100, MART-1, SOX-10, and tyrosinase, all of which are extremely unlikely to stain an MCC.¹

TOPLINE:

Lower-extremity (LE) lymphedema increases the risk for all types of skin cancer on the lower extremities.

METHODOLOGY:

• In the retrospective cohort study, researchers reviewed reports at Mayo Clinic for all patients who had LE lymphedema, limiting the review to those who had an ICD code for lymphedema.
• 4,437 patients with the ICD code from 2000 to 2020 were compared with 4,437 matched controls.
• The records of patients with skin cancer diagnoses were reviewed manually to determine whether the skin cancer, its management, or both were a cause of lymphedema; cancers that caused secondary lymphedema were excluded.
• This is the first large-scale study evaluating the association between LE lymphedema and LE skin cancer.

TAKEAWAY:

• 211 patients (4.6%) in the LE lymphedema group had any ICD code for LE skin cancer, compared with 89 (2%) in the control group.
• Among those with LE lymphedema, the risk for skin cancer was 1.98 times greater compared with those without lymphedema (95% confidence interval, 1.43-2.74; P < .001). Cases included all types of skin cancer.
• Nineteen of 24 patients with unilateral LE lymphedema had a history of immunosuppression.
• In the group of 24 patients with unilateral LE lymphedema, the lymphedematous LE was more likely to have one or more skin cancers than were the unaffected LE (87.5% vs. 33.3%; P < .05), and skin cancer was 2.65 times more likely to develop on the affected LE than in the unaffected LE (95% CI, 1.17-5.99; P = .02).

IN PRACTICE:

“Our findings suggest the need for a relatively high degree of suspicion of skin cancer at sites with lymphedema,” senior author, Afsaneh Alavi, MD, professor of dermatology at the Mayo Clinic, said in a Mayo Clinic press release reporting the results.

SOURCE:

The study was conducted by researchers at the Mayo Clinic and Meharry Medical College, Nashville. It was published in the November 2023 Mayo Clinic Proceedings.

LIMITATIONS:

This was a single-center retrospective study, and patients with LE lymphedema may be overdiagnosed with LE skin cancer because they have a greater number of examinations.

DISCLOSURES:

Dr. Alavi reports having been a consultant for AbbVie, Boehringer Ingelheim, InflaRx, Novartis, and UCB SA and an investigator for Processa Pharmaceuticals and Boehringer Ingelheim. The other authors had no disclosures.

A version of this article first appeared on Medscape.com.

TOPLINE:

Lower-extremity (LE) lymphedema increases the risk for all types of skin cancer on the lower extremities.

METHODOLOGY:

• In the retrospective cohort study, researchers reviewed reports at Mayo Clinic for all patients who had LE lymphedema, limiting the review to those who had an ICD code for lymphedema.
• 4,437 patients with the ICD code from 2000 to 2020 were compared with 4,437 matched controls.
• The records of patients with skin cancer diagnoses were reviewed manually to determine whether the skin cancer, its management, or both were a cause of lymphedema; cancers that caused secondary lymphedema were excluded.
• This is the first large-scale study evaluating the association between LE lymphedema and LE skin cancer.

TAKEAWAY:

• 211 patients (4.6%) in the LE lymphedema group had any ICD code for LE skin cancer, compared with 89 (2%) in the control group.
• Among those with LE lymphedema, the risk for skin cancer was 1.98 times greater compared with those without lymphedema (95% confidence interval, 1.43-2.74; P < .001). Cases included all types of skin cancer.
• Nineteen of 24 patients with unilateral LE lymphedema had a history of immunosuppression.
• In the group of 24 patients with unilateral LE lymphedema, the lymphedematous LE was more likely to have one or more skin cancers than were the unaffected LE (87.5% vs. 33.3%; P < .05), and skin cancer was 2.65 times more likely to develop on the affected LE than in the unaffected LE (95% CI, 1.17-5.99; P = .02).

IN PRACTICE:

“Our findings suggest the need for a relatively high degree of suspicion of skin cancer at sites with lymphedema,” senior author, Afsaneh Alavi, MD, professor of dermatology at the Mayo Clinic, said in a Mayo Clinic press release reporting the results.

SOURCE:

The study was conducted by researchers at the Mayo Clinic and Meharry Medical College, Nashville. It was published in the November 2023 Mayo Clinic Proceedings.

LIMITATIONS:

This was a single-center retrospective study, and patients with LE lymphedema may be overdiagnosed with LE skin cancer because they have a greater number of examinations.

DISCLOSURES:

Dr. Alavi reports having been a consultant for AbbVie, Boehringer Ingelheim, InflaRx, Novartis, and UCB SA and an investigator for Processa Pharmaceuticals and Boehringer Ingelheim. The other authors had no disclosures.

A version of this article first appeared on Medscape.com.

TOPLINE:

Lower-extremity (LE) lymphedema increases the risk for all types of skin cancer on the lower extremities.

METHODOLOGY:

• In the retrospective cohort study, researchers reviewed reports at Mayo Clinic for all patients who had LE lymphedema, limiting the review to those who had an ICD code for lymphedema.
• 4,437 patients with the ICD code from 2000 to 2020 were compared with 4,437 matched controls.
• The records of patients with skin cancer diagnoses were reviewed manually to determine whether the skin cancer, its management, or both were a cause of lymphedema; cancers that caused secondary lymphedema were excluded.
• This is the first large-scale study evaluating the association between LE lymphedema and LE skin cancer.

TAKEAWAY:

• 211 patients (4.6%) in the LE lymphedema group had any ICD code for LE skin cancer, compared with 89 (2%) in the control group.
• Among those with LE lymphedema, the risk for skin cancer was 1.98 times greater compared with those without lymphedema (95% confidence interval, 1.43-2.74; P < .001). Cases included all types of skin cancer.
• Nineteen of 24 patients with unilateral LE lymphedema had a history of immunosuppression.
• In the group of 24 patients with unilateral LE lymphedema, the lymphedematous LE was more likely to have one or more skin cancers than were the unaffected LE (87.5% vs. 33.3%; P < .05), and skin cancer was 2.65 times more likely to develop on the affected LE than in the unaffected LE (95% CI, 1.17-5.99; P = .02).

IN PRACTICE:

“Our findings suggest the need for a relatively high degree of suspicion of skin cancer at sites with lymphedema,” senior author, Afsaneh Alavi, MD, professor of dermatology at the Mayo Clinic, said in a Mayo Clinic press release reporting the results.

SOURCE:

The study was conducted by researchers at the Mayo Clinic and Meharry Medical College, Nashville. It was published in the November 2023 Mayo Clinic Proceedings.

LIMITATIONS:

This was a single-center retrospective study, and patients with LE lymphedema may be overdiagnosed with LE skin cancer because they have a greater number of examinations.

DISCLOSURES:

Dr. Alavi reports having been a consultant for AbbVie, Boehringer Ingelheim, InflaRx, Novartis, and UCB SA and an investigator for Processa Pharmaceuticals and Boehringer Ingelheim. The other authors had no disclosures.

A version of this article first appeared on Medscape.com.

TOPLINE:

More than half of Mohs surgeons report at least one sharps injury in the past year, mostly self-inflicted, survey finds.

METHODOLOGY:

• Data on the incidence of sharps injuries among dermatologic surgeons is limited.
• In a cross-sectional analysis of anonymous survey responses from members of the American College of , researchers aimed to determine the incidence and types of sharps injuries among Mohs surgeons.
• The researchers used descriptive statistics for continuous and nominal variables (percentage and frequencies) to report survey data and Fisher exact or chi-square analysis of categorical variables to obtain P values.

TAKEAWAY:

• Of the 60 survey respondents, more than half (56.7%) were from single-specialty group practices, 26.6% were from academic practices, and fewer than half (43.3%) had been in practice for 15 or more years.
• In the past year, 56.7% of respondents experienced at least one sharps injury. Of these, 14.7% involved exposure to a blood-borne pathogen, which translated into an annual exposure risk of 7.6% for any given Mohs surgeon.
• The top two types of sharps injuries were self-inflicted suture needlestick (76.5%) and other types of self-inflicted needlestick injuries (26.5%).
• Of respondents who sustained a sharps injury, 44.1% did not report them, while 95% of all survey respondents said they had access to postexposure prophylaxis/protocols at their workplace.
• The researchers determined that the average annual rate of sharps injury was 0.87.

IN PRACTICE:

• “In best practices to prevent sharps injuries, the authors recommend that a standardized sharps handling protocol be developed and disseminated for dermatologic surgeons and their staff,” the researchers wrote.

STUDY DETAILS:

• Faezeh Talebi-Liasi, MD, and Jesse M. Lewin, MD, department of dermatology, Icahn School of Medicine at Mount Sinai, New York, conducted the research. The study was published in Dermatologic Surgery.

LIMITATIONS:

• The study’s cross-sectional observational design and small sample size was skewed toward single-specialty and academic practices.

DISCLOSURES:

• The authors reported having no relevant financial disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

More than half of Mohs surgeons report at least one sharps injury in the past year, mostly self-inflicted, survey finds.

METHODOLOGY:

• Data on the incidence of sharps injuries among dermatologic surgeons is limited.
• In a cross-sectional analysis of anonymous survey responses from members of the American College of , researchers aimed to determine the incidence and types of sharps injuries among Mohs surgeons.
• The researchers used descriptive statistics for continuous and nominal variables (percentage and frequencies) to report survey data and Fisher exact or chi-square analysis of categorical variables to obtain P values.

TAKEAWAY:

• Of the 60 survey respondents, more than half (56.7%) were from single-specialty group practices, 26.6% were from academic practices, and fewer than half (43.3%) had been in practice for 15 or more years.
• In the past year, 56.7% of respondents experienced at least one sharps injury. Of these, 14.7% involved exposure to a blood-borne pathogen, which translated into an annual exposure risk of 7.6% for any given Mohs surgeon.
• The top two types of sharps injuries were self-inflicted suture needlestick (76.5%) and other types of self-inflicted needlestick injuries (26.5%).
• Of respondents who sustained a sharps injury, 44.1% did not report them, while 95% of all survey respondents said they had access to postexposure prophylaxis/protocols at their workplace.
• The researchers determined that the average annual rate of sharps injury was 0.87.

IN PRACTICE:

• “In best practices to prevent sharps injuries, the authors recommend that a standardized sharps handling protocol be developed and disseminated for dermatologic surgeons and their staff,” the researchers wrote.

STUDY DETAILS:

• Faezeh Talebi-Liasi, MD, and Jesse M. Lewin, MD, department of dermatology, Icahn School of Medicine at Mount Sinai, New York, conducted the research. The study was published in Dermatologic Surgery.

LIMITATIONS:

• The study’s cross-sectional observational design and small sample size was skewed toward single-specialty and academic practices.

DISCLOSURES:

• The authors reported having no relevant financial disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

More than half of Mohs surgeons report at least one sharps injury in the past year, mostly self-inflicted, survey finds.

METHODOLOGY:

• Data on the incidence of sharps injuries among dermatologic surgeons is limited.
• In a cross-sectional analysis of anonymous survey responses from members of the American College of , researchers aimed to determine the incidence and types of sharps injuries among Mohs surgeons.
• The researchers used descriptive statistics for continuous and nominal variables (percentage and frequencies) to report survey data and Fisher exact or chi-square analysis of categorical variables to obtain P values.

TAKEAWAY:

• Of the 60 survey respondents, more than half (56.7%) were from single-specialty group practices, 26.6% were from academic practices, and fewer than half (43.3%) had been in practice for 15 or more years.
• In the past year, 56.7% of respondents experienced at least one sharps injury. Of these, 14.7% involved exposure to a blood-borne pathogen, which translated into an annual exposure risk of 7.6% for any given Mohs surgeon.
• The top two types of sharps injuries were self-inflicted suture needlestick (76.5%) and other types of self-inflicted needlestick injuries (26.5%).
• Of respondents who sustained a sharps injury, 44.1% did not report them, while 95% of all survey respondents said they had access to postexposure prophylaxis/protocols at their workplace.
• The researchers determined that the average annual rate of sharps injury was 0.87.

IN PRACTICE:

• “In best practices to prevent sharps injuries, the authors recommend that a standardized sharps handling protocol be developed and disseminated for dermatologic surgeons and their staff,” the researchers wrote.

STUDY DETAILS:

• Faezeh Talebi-Liasi, MD, and Jesse M. Lewin, MD, department of dermatology, Icahn School of Medicine at Mount Sinai, New York, conducted the research. The study was published in Dermatologic Surgery.

LIMITATIONS:

• The study’s cross-sectional observational design and small sample size was skewed toward single-specialty and academic practices.

DISCLOSURES:

• The authors reported having no relevant financial disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

Older adults with actinic keratoses (AKs) have a higher risk for skin cancers, including squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma.

METHODOLOGY:

• AKs have been associated with a small risk for cutaneous SCC, but associations with risk for other skin cancers have not been well studied.
• AKs may be a marker of overall skin cancer risk, but guidelines for AK management lack recommendations for follow-up cancer surveillance.
• The researchers reviewed data from a random sample of 5 million fee-for-service Medicare beneficiaries treated for AKs from 2009 through 2018 in the United States. Patients with seborrheic keratoses (SKs) were included as comparators, and patients with a history of skin cancer were excluded.
• The primary outcome was the first surgically treated skin cancer, including SCC, BCC, and melanoma.

TAKEAWAY:

• A total of 555,945 adults with AKs and 481,024 with SKs were included. The mean age was approximately 74.0 years. More than half were female. Most were non-Hispanic White.
• Among patients with AKs, the absolute risk for any skin cancer after the first AK was 6.3%, 18.4%, and 28.5% at 1, 3, and 5 years, respectively.
• Patients with AKs had a significantly increased relative risk for any skin cancer compared with those with SKs (adjusted hazard ratio [aHR], 2.17) and separately for keratinocyte carcinoma (aHR, 2.20), SCC (aHR, 2.63), BCC (aHR, 1.85), and melanoma (aHR, 1.67).
• Although AKs are not considered a biological precursor of melanoma or BCC, the results suggest that AKs may be clinical indicators of increased UV exposure that subsequently increases the risk for skin cancer.

IN PRACTICE:

“The present results highlight the importance of developing evidence-based guidelines for follow-up skin cancer surveillance in patients with AKs, optimally including measures of AK burden,” the researchers wrote.

SOURCE:

The lead author on the study was Cassandra Mohr, BS, with corresponding author Mackenzie R. Wehner, MD, MPhil, of The University of Texas MD Anderson Cancer Center, Houston. The study was published online in JAMA Dermatology .

LIMITATIONS:

The study population of Medicare beneficiaries aged 65 years or older may not be a nationally representative sample, and surveillance bias may contribute to the increased risk for skin cancer in patients with AKs. The use of both ICD and CPT codes may underestimate the number of skin cancers because of cases that were treated nonsurgically.

DISCLOSURES:

The study was supported by the National Cancer Institute of the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, and The University of Texas Rising STARS program. The researchers had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

TOPLINE:

Older adults with actinic keratoses (AKs) have a higher risk for skin cancers, including squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma.

METHODOLOGY:

• AKs have been associated with a small risk for cutaneous SCC, but associations with risk for other skin cancers have not been well studied.
• AKs may be a marker of overall skin cancer risk, but guidelines for AK management lack recommendations for follow-up cancer surveillance.
• The researchers reviewed data from a random sample of 5 million fee-for-service Medicare beneficiaries treated for AKs from 2009 through 2018 in the United States. Patients with seborrheic keratoses (SKs) were included as comparators, and patients with a history of skin cancer were excluded.
• The primary outcome was the first surgically treated skin cancer, including SCC, BCC, and melanoma.

TAKEAWAY:

• A total of 555,945 adults with AKs and 481,024 with SKs were included. The mean age was approximately 74.0 years. More than half were female. Most were non-Hispanic White.
• Among patients with AKs, the absolute risk for any skin cancer after the first AK was 6.3%, 18.4%, and 28.5% at 1, 3, and 5 years, respectively.
• Patients with AKs had a significantly increased relative risk for any skin cancer compared with those with SKs (adjusted hazard ratio [aHR], 2.17) and separately for keratinocyte carcinoma (aHR, 2.20), SCC (aHR, 2.63), BCC (aHR, 1.85), and melanoma (aHR, 1.67).
• Although AKs are not considered a biological precursor of melanoma or BCC, the results suggest that AKs may be clinical indicators of increased UV exposure that subsequently increases the risk for skin cancer.

IN PRACTICE:

“The present results highlight the importance of developing evidence-based guidelines for follow-up skin cancer surveillance in patients with AKs, optimally including measures of AK burden,” the researchers wrote.

SOURCE:

The lead author on the study was Cassandra Mohr, BS, with corresponding author Mackenzie R. Wehner, MD, MPhil, of The University of Texas MD Anderson Cancer Center, Houston. The study was published online in JAMA Dermatology .

LIMITATIONS:

The study population of Medicare beneficiaries aged 65 years or older may not be a nationally representative sample, and surveillance bias may contribute to the increased risk for skin cancer in patients with AKs. The use of both ICD and CPT codes may underestimate the number of skin cancers because of cases that were treated nonsurgically.

DISCLOSURES:

The study was supported by the National Cancer Institute of the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, and The University of Texas Rising STARS program. The researchers had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

TOPLINE:

Older adults with actinic keratoses (AKs) have a higher risk for skin cancers, including squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma.

METHODOLOGY:

• AKs have been associated with a small risk for cutaneous SCC, but associations with risk for other skin cancers have not been well studied.
• AKs may be a marker of overall skin cancer risk, but guidelines for AK management lack recommendations for follow-up cancer surveillance.
• The researchers reviewed data from a random sample of 5 million fee-for-service Medicare beneficiaries treated for AKs from 2009 through 2018 in the United States. Patients with seborrheic keratoses (SKs) were included as comparators, and patients with a history of skin cancer were excluded.
• The primary outcome was the first surgically treated skin cancer, including SCC, BCC, and melanoma.

TAKEAWAY:

• A total of 555,945 adults with AKs and 481,024 with SKs were included. The mean age was approximately 74.0 years. More than half were female. Most were non-Hispanic White.
• Among patients with AKs, the absolute risk for any skin cancer after the first AK was 6.3%, 18.4%, and 28.5% at 1, 3, and 5 years, respectively.
• Patients with AKs had a significantly increased relative risk for any skin cancer compared with those with SKs (adjusted hazard ratio [aHR], 2.17) and separately for keratinocyte carcinoma (aHR, 2.20), SCC (aHR, 2.63), BCC (aHR, 1.85), and melanoma (aHR, 1.67).
• Although AKs are not considered a biological precursor of melanoma or BCC, the results suggest that AKs may be clinical indicators of increased UV exposure that subsequently increases the risk for skin cancer.

IN PRACTICE:

“The present results highlight the importance of developing evidence-based guidelines for follow-up skin cancer surveillance in patients with AKs, optimally including measures of AK burden,” the researchers wrote.

SOURCE:

The lead author on the study was Cassandra Mohr, BS, with corresponding author Mackenzie R. Wehner, MD, MPhil, of The University of Texas MD Anderson Cancer Center, Houston. The study was published online in JAMA Dermatology .

LIMITATIONS:

The study population of Medicare beneficiaries aged 65 years or older may not be a nationally representative sample, and surveillance bias may contribute to the increased risk for skin cancer in patients with AKs. The use of both ICD and CPT codes may underestimate the number of skin cancers because of cases that were treated nonsurgically.

DISCLOSURES:

The study was supported by the National Cancer Institute of the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, and The University of Texas Rising STARS program. The researchers had no financial conflicts to disclose.

A version of this article appeared on Medscape.com.

A new artificial intelligence (AI) model can detect the deadliest skin cancer with 100% accuracy, highlighting the rapid improvement of AI in medicine, say researchers from the United Kingdom. AI detected more than 99% of all skin cancers.

The researchers tested the AI by integrating it into a clinical diagnosis process – anticipating a future in which AI helps doctors catch skin cancer faster and triage patients.

Skin cancer is the most common cancer in the United States;  one in five 5 Americans develop skin cancer by age 70. With melanoma, the deadliest skin cancer, the 5-year survival rate is better than 99% if caught early, though only about three-quarters of melanomas are caught at this stage.

Amid rising skin cancer rates come concerns that the number of dermatologists in the workforce isn’t keeping pace. That may be why the average wait time for a dermatology appointment is trending up – in 2022, it reached 34.5 days.

The study, which was presented at the European Academy of Dermatology and Venereology Congress recently and has not yet been published, involved 6,900 patients in the United Kingdom with suspected skin cancer. The patients had been referred by their primary care physicians. The researchers took images of the suspicious areas and uploaded them to the AI software. The AI’s assessment was then shared with a dermatologist.

“Note that the diagnosis issued by the AI was not hidden from the dermatologist doing the second assessment,” said lead researcher Kashini Andrew, MBBS, a dermatologist and specialist registrar at University Hospitals Birmingham NHS Foundation Trust.

Dr. Andrew acknowledged that this may have influenced the dermatologist’s opinion. But that’s the vision of how doctors could use this tool.

The AI caught 59 of 59 melanomas and 189 of 190 total skin cancers (99.5%). (The one case that the AI missed was caught by the dermatologist.) It also flagged 541 of 585 precancerous lesions (92.5%). This represented a big improvement from a 2021 version of the model, which detected 86% of melanomas, 84% of all skin cancers, and 54% of precancerous lesions.

Over the 10-month period of the study, the system saved more than 1,000 face-to-face consultations, freeing dermatologists’ time to catch more cancers and serve more patients.

Limitations

The patients in the study were from “one hospital in a single region of the UK,” and the sample was not large enough to allow broad statements to be made about the use of AI in dermatology, Dr. Andrew said.

But it can open the conversation. Roxana Daneshjou, MD, PhD, a dermatologist at Stanford (Calif.) University who has studied the pros and cons of AI in medicine, had some concerns. For one thing, doctors can gather more in-depth information during an in-person exam than AI can glean from a photo, Dr. Daneshjou noted. They can examine skin texture, gather patient history, and take photos with special lighting and magnification.

Christopher Smith

And the AI needs to get better at ruling out malignancy, Dr. Daneshjou said. In this study, the AI identified 75% of benign lesions, a decline from the earlier version. The researchers noted in the abstract that this is a potential trade-off for increased sensitivity.

“[Unnecessary] biopsies can clog up the health care system, cost money, and cause stress and scarring,” said Dr. Daneshjou. “You don’t want to increase the burden of that.”

Still, if AI software such as the kind used in the study proves just as accurate in larger, more diverse sample sizes, then it could be a powerful tool for triage, Dr. Daneshjou said. “If AI gets particularly good at finding malignancy and also ruling it out, that would be a win.”

A version of this article appeared on Medscape.com.

A new artificial intelligence (AI) model can detect the deadliest skin cancer with 100% accuracy, highlighting the rapid improvement of AI in medicine, say researchers from the United Kingdom. AI detected more than 99% of all skin cancers.

The researchers tested the AI by integrating it into a clinical diagnosis process – anticipating a future in which AI helps doctors catch skin cancer faster and triage patients.

Skin cancer is the most common cancer in the United States;  one in five 5 Americans develop skin cancer by age 70. With melanoma, the deadliest skin cancer, the 5-year survival rate is better than 99% if caught early, though only about three-quarters of melanomas are caught at this stage.

Amid rising skin cancer rates come concerns that the number of dermatologists in the workforce isn’t keeping pace. That may be why the average wait time for a dermatology appointment is trending up – in 2022, it reached 34.5 days.

The study, which was presented at the European Academy of Dermatology and Venereology Congress recently and has not yet been published, involved 6,900 patients in the United Kingdom with suspected skin cancer. The patients had been referred by their primary care physicians. The researchers took images of the suspicious areas and uploaded them to the AI software. The AI’s assessment was then shared with a dermatologist.

“Note that the diagnosis issued by the AI was not hidden from the dermatologist doing the second assessment,” said lead researcher Kashini Andrew, MBBS, a dermatologist and specialist registrar at University Hospitals Birmingham NHS Foundation Trust.

Dr. Andrew acknowledged that this may have influenced the dermatologist’s opinion. But that’s the vision of how doctors could use this tool.

The AI caught 59 of 59 melanomas and 189 of 190 total skin cancers (99.5%). (The one case that the AI missed was caught by the dermatologist.) It also flagged 541 of 585 precancerous lesions (92.5%). This represented a big improvement from a 2021 version of the model, which detected 86% of melanomas, 84% of all skin cancers, and 54% of precancerous lesions.

Over the 10-month period of the study, the system saved more than 1,000 face-to-face consultations, freeing dermatologists’ time to catch more cancers and serve more patients.

Limitations

The patients in the study were from “one hospital in a single region of the UK,” and the sample was not large enough to allow broad statements to be made about the use of AI in dermatology, Dr. Andrew said.

But it can open the conversation. Roxana Daneshjou, MD, PhD, a dermatologist at Stanford (Calif.) University who has studied the pros and cons of AI in medicine, had some concerns. For one thing, doctors can gather more in-depth information during an in-person exam than AI can glean from a photo, Dr. Daneshjou noted. They can examine skin texture, gather patient history, and take photos with special lighting and magnification.

Christopher Smith

And the AI needs to get better at ruling out malignancy, Dr. Daneshjou said. In this study, the AI identified 75% of benign lesions, a decline from the earlier version. The researchers noted in the abstract that this is a potential trade-off for increased sensitivity.

“[Unnecessary] biopsies can clog up the health care system, cost money, and cause stress and scarring,” said Dr. Daneshjou. “You don’t want to increase the burden of that.”

Still, if AI software such as the kind used in the study proves just as accurate in larger, more diverse sample sizes, then it could be a powerful tool for triage, Dr. Daneshjou said. “If AI gets particularly good at finding malignancy and also ruling it out, that would be a win.”

A version of this article appeared on Medscape.com.

A new artificial intelligence (AI) model can detect the deadliest skin cancer with 100% accuracy, highlighting the rapid improvement of AI in medicine, say researchers from the United Kingdom. AI detected more than 99% of all skin cancers.

The researchers tested the AI by integrating it into a clinical diagnosis process – anticipating a future in which AI helps doctors catch skin cancer faster and triage patients.

Skin cancer is the most common cancer in the United States;  one in five 5 Americans develop skin cancer by age 70. With melanoma, the deadliest skin cancer, the 5-year survival rate is better than 99% if caught early, though only about three-quarters of melanomas are caught at this stage.

Amid rising skin cancer rates come concerns that the number of dermatologists in the workforce isn’t keeping pace. That may be why the average wait time for a dermatology appointment is trending up – in 2022, it reached 34.5 days.

The study, which was presented at the European Academy of Dermatology and Venereology Congress recently and has not yet been published, involved 6,900 patients in the United Kingdom with suspected skin cancer. The patients had been referred by their primary care physicians. The researchers took images of the suspicious areas and uploaded them to the AI software. The AI’s assessment was then shared with a dermatologist.

“Note that the diagnosis issued by the AI was not hidden from the dermatologist doing the second assessment,” said lead researcher Kashini Andrew, MBBS, a dermatologist and specialist registrar at University Hospitals Birmingham NHS Foundation Trust.

Dr. Andrew acknowledged that this may have influenced the dermatologist’s opinion. But that’s the vision of how doctors could use this tool.

The AI caught 59 of 59 melanomas and 189 of 190 total skin cancers (99.5%). (The one case that the AI missed was caught by the dermatologist.) It also flagged 541 of 585 precancerous lesions (92.5%). This represented a big improvement from a 2021 version of the model, which detected 86% of melanomas, 84% of all skin cancers, and 54% of precancerous lesions.

Over the 10-month period of the study, the system saved more than 1,000 face-to-face consultations, freeing dermatologists’ time to catch more cancers and serve more patients.

Limitations

The patients in the study were from “one hospital in a single region of the UK,” and the sample was not large enough to allow broad statements to be made about the use of AI in dermatology, Dr. Andrew said.

But it can open the conversation. Roxana Daneshjou, MD, PhD, a dermatologist at Stanford (Calif.) University who has studied the pros and cons of AI in medicine, had some concerns. For one thing, doctors can gather more in-depth information during an in-person exam than AI can glean from a photo, Dr. Daneshjou noted. They can examine skin texture, gather patient history, and take photos with special lighting and magnification.

Christopher Smith

And the AI needs to get better at ruling out malignancy, Dr. Daneshjou said. In this study, the AI identified 75% of benign lesions, a decline from the earlier version. The researchers noted in the abstract that this is a potential trade-off for increased sensitivity.

“[Unnecessary] biopsies can clog up the health care system, cost money, and cause stress and scarring,” said Dr. Daneshjou. “You don’t want to increase the burden of that.”

Still, if AI software such as the kind used in the study proves just as accurate in larger, more diverse sample sizes, then it could be a powerful tool for triage, Dr. Daneshjou said. “If AI gets particularly good at finding malignancy and also ruling it out, that would be a win.”

A version of this article appeared on Medscape.com.

To the Editor:

Plaquelike or plaque-type syringoma is a lesser-known variant of syringoma that can appear histologically indistinguishable from the superficial portion of microcystic adnexal carcinoma (MAC). The plaquelike variant of syringoma holds a benign clinical course, and no treatment is necessary. Microcystic adnexal carcinoma is distinguished from plaquelike syringoma by an aggressive growth pattern with a high risk for local invasion and recurrence if inadequately treated. Thus, treatment with Mohs micrographic surgery (MMS) has been recommended as the mainstay for MAC. If superficial biopsy specimens reveal suspicion for MAC and patients are referred for MMS, careful consideration should be made to differentiate MAC and plaquelike syringoma early to prevent unnecessary morbidity.

A 78-year-old woman was referred for MMS for a left forehead lesion that was diagnosed via shave biopsy as a desmoplastic and cystic adnexal neoplasm with suspicion for desmoplastic trichoepithelioma or MAC (Figure 1). Upon presentation for MMS, a well-healed, 1.0×0.9-cm scar at the biopsy site on the left forehead was observed (Figure 2A). One stage was obtained by standard MMS technique and sent for intraoperative processing (Figure 2B). Frozen section examination of the first stage demonstrated peripheral margin involvement with syringomatous change confined to the superficial and mid dermis (Figure 3). Before proceeding further, these findings were reviewed with an in-house dermatopathologist, and it was determined that no infiltrative tumor, perineural involvement, or other features to indicate malignancy were noted. A decision was made to refrain from obtaining any additional layers and to send excised Burow triangles for permanent section analysis. A primary linear closure was performed without complication, and the patient was discharged from the ambulatory surgery suite. Histopathologic examination of the Burow triangles later confirmed findings consistent with plaquelike syringoma with no evidence of malignancy (Figure 4).

Syringomas present as small flesh-colored papules in the periorbital areas. These benign neoplasms previously have been classified into 4 major clinical variants: localized, generalized, Down syndrome associated, and familial.¹ The lesser-known plaquelike variant of syringoma was first described by Kikuchi et al² in 1979. Aside from our report, a PubMed search of articles indexed for MEDLINE using the terms plaquelike or plaque-type syringoma yielded 16 cases in the literature.^2-14 Of these, 6 were referred to or encountered in the MMS setting.^8,9,11,12,14 Plaquelike syringoma can be solitary or multiple in presentation.⁶ It most commonly involves the head and neck but also can present on the trunk, arms, legs, and groin areas. The clinical size of plaquelike syringoma is variable, with the largest reported cases extending several centimeters in diameter.^2,6 Similar to reported associations with conventional syringoma, the plaquelike subtype of syringoma has been reported in association with Down syndrome.¹³

Histopathologically, plaquelike syringoma shares features with MAC as well as desmoplastic trichoepithelioma and desmoplastic basal cell carcinoma. Plaquelike syringoma demonstrates broad proliferations of small tubules morphologically reminiscent of tadpoles confined within the dermis. Ducts typically are lined with 2 or 3 layers of small cuboidal cells. Microcystic adnexal carcinoma typically features asymmetric ductal structures lined with single cells extending from the dermis into the subcutis and even underlying muscle, cartilage, or bone.⁸ There are no reliable immunohistochemical stains to differentiate between these 2 entities; thus, the primary distinction lies in the depth of involvement. Desmoplastic trichoepithelioma is composed of narrow cords and nests of basaloid cells of follicular origin commonly admixed with small cornifying cysts appearing in the dermis.⁸ Colonizing Merkel cells positive for cytokeratin 20 often are present in desmoplastic trichoepithelioma and not in syringoma or MAC.¹⁵ Desmoplastic basal cell carcinoma demonstrates narrow strands of basaloid cells of follicular origin appearing in the dermis. Desmoplastic trichoepithelioma and desmoplastic basal cell carcinoma are each fundamentally differentiated from plaquelike syringoma in that proliferations of cords and nests are not of eccrine or apocrine origin.

Several cases of plaquelike syringoma have been challenging to distinguish from MAC in performing MMS.^8,9,11 Underlying extension of this syringoma variant can be far-reaching, extending to several centimeters in size and involving multiple cosmetic subunits.^6,11,14 Inadvertent overtreatment with multiple MMS stages can be avoided with careful recognition of the differentiating histopathologic features. Syringomatous lesions commonly are encountered in MMS and may even be present at the edge of other tumor types. Plaquelike syringoma has been reported as a coexistent entity with nodular basal cell carcinoma.¹² Boos et al¹⁶ similarly reported the presence of deceptive ductal proliferations along the immediate peripheral margin of MAC, which prompted multiple re-excisions. Pursuit of permanent section analysis in these cases revealed the appearance of small syringomas, and a diagnosis of benign subclinical syringomatous proliferations was made, averting further intervention.¹⁶

Our case sheds light on the threat of commission bias in dermatologic surgery, which is the tendency for action rather than inaction.¹⁷ In this context, it is important to avoid the perspective that harm to the patient can only be prevented by active intervention. Cognitive bias has been increasingly recognized as a source of medical error, and methods to mitigate bias in medical practice have been well described.¹⁷ Microcystic adnexal carcinoma and plaquelike syringoma can be hard to differentiate especially initially, as demonstrated in our case, which particularly illustrates the importance of slowing down a surgical case at the appropriate time, considering and revisiting alternative diagnoses, implementing checklists, and seeking histopathologic collaboration with colleagues when necessary. Our attempted implementation of these principles, especially early collaboration with colleagues, led to intraoperative recognition of plaquelike syringoma within the first stage of MMS.

We seek to raise the index of suspicion for plaquelike syringoma among dermatologists and dermatologic surgeons, especially when syringomatous structures are limited to the superficial dermis. We encourage familiarity with the plaquelike syringoma entity as well as careful consideration of further investigation via scouting biopsies or permanent section analysis when other characteristic features of MAC are unclear or lacking. Adequate sampling as well as collaboration with a dermatopathologist in cases of suspected syringoma can help to reduce the susceptibility to commission bias and prevent histopathologic pitfalls and unwarranted surgical morbidity.

To the Editor:

Plaquelike or plaque-type syringoma is a lesser-known variant of syringoma that can appear histologically indistinguishable from the superficial portion of microcystic adnexal carcinoma (MAC). The plaquelike variant of syringoma holds a benign clinical course, and no treatment is necessary. Microcystic adnexal carcinoma is distinguished from plaquelike syringoma by an aggressive growth pattern with a high risk for local invasion and recurrence if inadequately treated. Thus, treatment with Mohs micrographic surgery (MMS) has been recommended as the mainstay for MAC. If superficial biopsy specimens reveal suspicion for MAC and patients are referred for MMS, careful consideration should be made to differentiate MAC and plaquelike syringoma early to prevent unnecessary morbidity.

A 78-year-old woman was referred for MMS for a left forehead lesion that was diagnosed via shave biopsy as a desmoplastic and cystic adnexal neoplasm with suspicion for desmoplastic trichoepithelioma or MAC (Figure 1). Upon presentation for MMS, a well-healed, 1.0×0.9-cm scar at the biopsy site on the left forehead was observed (Figure 2A). One stage was obtained by standard MMS technique and sent for intraoperative processing (Figure 2B). Frozen section examination of the first stage demonstrated peripheral margin involvement with syringomatous change confined to the superficial and mid dermis (Figure 3). Before proceeding further, these findings were reviewed with an in-house dermatopathologist, and it was determined that no infiltrative tumor, perineural involvement, or other features to indicate malignancy were noted. A decision was made to refrain from obtaining any additional layers and to send excised Burow triangles for permanent section analysis. A primary linear closure was performed without complication, and the patient was discharged from the ambulatory surgery suite. Histopathologic examination of the Burow triangles later confirmed findings consistent with plaquelike syringoma with no evidence of malignancy (Figure 4).

Syringomas present as small flesh-colored papules in the periorbital areas. These benign neoplasms previously have been classified into 4 major clinical variants: localized, generalized, Down syndrome associated, and familial.¹ The lesser-known plaquelike variant of syringoma was first described by Kikuchi et al² in 1979. Aside from our report, a PubMed search of articles indexed for MEDLINE using the terms plaquelike or plaque-type syringoma yielded 16 cases in the literature.^2-14 Of these, 6 were referred to or encountered in the MMS setting.^8,9,11,12,14 Plaquelike syringoma can be solitary or multiple in presentation.⁶ It most commonly involves the head and neck but also can present on the trunk, arms, legs, and groin areas. The clinical size of plaquelike syringoma is variable, with the largest reported cases extending several centimeters in diameter.^2,6 Similar to reported associations with conventional syringoma, the plaquelike subtype of syringoma has been reported in association with Down syndrome.¹³

Histopathologically, plaquelike syringoma shares features with MAC as well as desmoplastic trichoepithelioma and desmoplastic basal cell carcinoma. Plaquelike syringoma demonstrates broad proliferations of small tubules morphologically reminiscent of tadpoles confined within the dermis. Ducts typically are lined with 2 or 3 layers of small cuboidal cells. Microcystic adnexal carcinoma typically features asymmetric ductal structures lined with single cells extending from the dermis into the subcutis and even underlying muscle, cartilage, or bone.⁸ There are no reliable immunohistochemical stains to differentiate between these 2 entities; thus, the primary distinction lies in the depth of involvement. Desmoplastic trichoepithelioma is composed of narrow cords and nests of basaloid cells of follicular origin commonly admixed with small cornifying cysts appearing in the dermis.⁸ Colonizing Merkel cells positive for cytokeratin 20 often are present in desmoplastic trichoepithelioma and not in syringoma or MAC.¹⁵ Desmoplastic basal cell carcinoma demonstrates narrow strands of basaloid cells of follicular origin appearing in the dermis. Desmoplastic trichoepithelioma and desmoplastic basal cell carcinoma are each fundamentally differentiated from plaquelike syringoma in that proliferations of cords and nests are not of eccrine or apocrine origin.

Several cases of plaquelike syringoma have been challenging to distinguish from MAC in performing MMS.^8,9,11 Underlying extension of this syringoma variant can be far-reaching, extending to several centimeters in size and involving multiple cosmetic subunits.^6,11,14 Inadvertent overtreatment with multiple MMS stages can be avoided with careful recognition of the differentiating histopathologic features. Syringomatous lesions commonly are encountered in MMS and may even be present at the edge of other tumor types. Plaquelike syringoma has been reported as a coexistent entity with nodular basal cell carcinoma.¹² Boos et al¹⁶ similarly reported the presence of deceptive ductal proliferations along the immediate peripheral margin of MAC, which prompted multiple re-excisions. Pursuit of permanent section analysis in these cases revealed the appearance of small syringomas, and a diagnosis of benign subclinical syringomatous proliferations was made, averting further intervention.¹⁶

Our case sheds light on the threat of commission bias in dermatologic surgery, which is the tendency for action rather than inaction.¹⁷ In this context, it is important to avoid the perspective that harm to the patient can only be prevented by active intervention. Cognitive bias has been increasingly recognized as a source of medical error, and methods to mitigate bias in medical practice have been well described.¹⁷ Microcystic adnexal carcinoma and plaquelike syringoma can be hard to differentiate especially initially, as demonstrated in our case, which particularly illustrates the importance of slowing down a surgical case at the appropriate time, considering and revisiting alternative diagnoses, implementing checklists, and seeking histopathologic collaboration with colleagues when necessary. Our attempted implementation of these principles, especially early collaboration with colleagues, led to intraoperative recognition of plaquelike syringoma within the first stage of MMS.

We seek to raise the index of suspicion for plaquelike syringoma among dermatologists and dermatologic surgeons, especially when syringomatous structures are limited to the superficial dermis. We encourage familiarity with the plaquelike syringoma entity as well as careful consideration of further investigation via scouting biopsies or permanent section analysis when other characteristic features of MAC are unclear or lacking. Adequate sampling as well as collaboration with a dermatopathologist in cases of suspected syringoma can help to reduce the susceptibility to commission bias and prevent histopathologic pitfalls and unwarranted surgical morbidity.

To the Editor:

Plaquelike or plaque-type syringoma is a lesser-known variant of syringoma that can appear histologically indistinguishable from the superficial portion of microcystic adnexal carcinoma (MAC). The plaquelike variant of syringoma holds a benign clinical course, and no treatment is necessary. Microcystic adnexal carcinoma is distinguished from plaquelike syringoma by an aggressive growth pattern with a high risk for local invasion and recurrence if inadequately treated. Thus, treatment with Mohs micrographic surgery (MMS) has been recommended as the mainstay for MAC. If superficial biopsy specimens reveal suspicion for MAC and patients are referred for MMS, careful consideration should be made to differentiate MAC and plaquelike syringoma early to prevent unnecessary morbidity.

A 78-year-old woman was referred for MMS for a left forehead lesion that was diagnosed via shave biopsy as a desmoplastic and cystic adnexal neoplasm with suspicion for desmoplastic trichoepithelioma or MAC (Figure 1). Upon presentation for MMS, a well-healed, 1.0×0.9-cm scar at the biopsy site on the left forehead was observed (Figure 2A). One stage was obtained by standard MMS technique and sent for intraoperative processing (Figure 2B). Frozen section examination of the first stage demonstrated peripheral margin involvement with syringomatous change confined to the superficial and mid dermis (Figure 3). Before proceeding further, these findings were reviewed with an in-house dermatopathologist, and it was determined that no infiltrative tumor, perineural involvement, or other features to indicate malignancy were noted. A decision was made to refrain from obtaining any additional layers and to send excised Burow triangles for permanent section analysis. A primary linear closure was performed without complication, and the patient was discharged from the ambulatory surgery suite. Histopathologic examination of the Burow triangles later confirmed findings consistent with plaquelike syringoma with no evidence of malignancy (Figure 4).

Syringomas present as small flesh-colored papules in the periorbital areas. These benign neoplasms previously have been classified into 4 major clinical variants: localized, generalized, Down syndrome associated, and familial.¹ The lesser-known plaquelike variant of syringoma was first described by Kikuchi et al² in 1979. Aside from our report, a PubMed search of articles indexed for MEDLINE using the terms plaquelike or plaque-type syringoma yielded 16 cases in the literature.^2-14 Of these, 6 were referred to or encountered in the MMS setting.^8,9,11,12,14 Plaquelike syringoma can be solitary or multiple in presentation.⁶ It most commonly involves the head and neck but also can present on the trunk, arms, legs, and groin areas. The clinical size of plaquelike syringoma is variable, with the largest reported cases extending several centimeters in diameter.^2,6 Similar to reported associations with conventional syringoma, the plaquelike subtype of syringoma has been reported in association with Down syndrome.¹³

Histopathologically, plaquelike syringoma shares features with MAC as well as desmoplastic trichoepithelioma and desmoplastic basal cell carcinoma. Plaquelike syringoma demonstrates broad proliferations of small tubules morphologically reminiscent of tadpoles confined within the dermis. Ducts typically are lined with 2 or 3 layers of small cuboidal cells. Microcystic adnexal carcinoma typically features asymmetric ductal structures lined with single cells extending from the dermis into the subcutis and even underlying muscle, cartilage, or bone.⁸ There are no reliable immunohistochemical stains to differentiate between these 2 entities; thus, the primary distinction lies in the depth of involvement. Desmoplastic trichoepithelioma is composed of narrow cords and nests of basaloid cells of follicular origin commonly admixed with small cornifying cysts appearing in the dermis.⁸ Colonizing Merkel cells positive for cytokeratin 20 often are present in desmoplastic trichoepithelioma and not in syringoma or MAC.¹⁵ Desmoplastic basal cell carcinoma demonstrates narrow strands of basaloid cells of follicular origin appearing in the dermis. Desmoplastic trichoepithelioma and desmoplastic basal cell carcinoma are each fundamentally differentiated from plaquelike syringoma in that proliferations of cords and nests are not of eccrine or apocrine origin.

Several cases of plaquelike syringoma have been challenging to distinguish from MAC in performing MMS.^8,9,11 Underlying extension of this syringoma variant can be far-reaching, extending to several centimeters in size and involving multiple cosmetic subunits.^6,11,14 Inadvertent overtreatment with multiple MMS stages can be avoided with careful recognition of the differentiating histopathologic features. Syringomatous lesions commonly are encountered in MMS and may even be present at the edge of other tumor types. Plaquelike syringoma has been reported as a coexistent entity with nodular basal cell carcinoma.¹² Boos et al¹⁶ similarly reported the presence of deceptive ductal proliferations along the immediate peripheral margin of MAC, which prompted multiple re-excisions. Pursuit of permanent section analysis in these cases revealed the appearance of small syringomas, and a diagnosis of benign subclinical syringomatous proliferations was made, averting further intervention.¹⁶

Our case sheds light on the threat of commission bias in dermatologic surgery, which is the tendency for action rather than inaction.¹⁷ In this context, it is important to avoid the perspective that harm to the patient can only be prevented by active intervention. Cognitive bias has been increasingly recognized as a source of medical error, and methods to mitigate bias in medical practice have been well described.¹⁷ Microcystic adnexal carcinoma and plaquelike syringoma can be hard to differentiate especially initially, as demonstrated in our case, which particularly illustrates the importance of slowing down a surgical case at the appropriate time, considering and revisiting alternative diagnoses, implementing checklists, and seeking histopathologic collaboration with colleagues when necessary. Our attempted implementation of these principles, especially early collaboration with colleagues, led to intraoperative recognition of plaquelike syringoma within the first stage of MMS.

We seek to raise the index of suspicion for plaquelike syringoma among dermatologists and dermatologic surgeons, especially when syringomatous structures are limited to the superficial dermis. We encourage familiarity with the plaquelike syringoma entity as well as careful consideration of further investigation via scouting biopsies or permanent section analysis when other characteristic features of MAC are unclear or lacking. Adequate sampling as well as collaboration with a dermatopathologist in cases of suspected syringoma can help to reduce the susceptibility to commission bias and prevent histopathologic pitfalls and unwarranted surgical morbidity.

The Diagnosis: Cutaneous Langerhans Cell Histiocytosis

Histopathologic findings of the left axillary lesion included a diffuse infiltrate of irregular hematolymphoid cells with reniform nuclei that strongly and diffusely stained positively with CD1a and S-100 but were negative for CD138 and CD163 (Figure). Numerous eosinophils also were present. The surrounding lymphocytic infiltrate stained positively with CD45. Polymerase chain reaction of the vaginal lesion was negative for herpes simplex virus types 1 and 2. Biopsy of the vaginal lesion revealed a mildly acanthotic epidermis and an aggregation of epithelioid cells with reniform nuclei in the papillary dermis. Positron emission tomography revealed widely disseminated disease. Sequencing of the mitogen-activated protein kinase/extracellular signalregulated kinase pathway showed amplified expression of these genes but found no mutations. These results led to a diagnosis of cutaneous Langerhans cell histiocytosis (LCH) with a background of hidradenitis suppurativa (HS). Our patient has since initiated therapy with trametinib leading to disease improvement without known recurrence.

Langerhans cell histiocytosis is a rare disease of clonal dendritic cells (Langerhans cells) that can present in any organ.¹ Most LCH diagnoses are made in pediatric patients, most often presenting in the bones, with other presentations in the skin, hypophysis, liver, lymph nodes, lungs, and spleen occurring less commonly.² Proto-oncogene BRAF V600E mutations are a common determinant of LCH, with half of cases linked with this mutation that leads to enhanced activation of the mitogen-activated protein kinase pathway, though other mutations have been reported.^3,4 These genetic alterations suggest LCH is neoplastic in nature; however, this is controversial, as spontaneous regression among pulmonary LCH has been observed, pointing to a reactive inflammatory process.⁵ Cutaneous LCH can present as a distinct papular or nodular lesion or multiple lesions with possible ulceration, but it is rare that LCH first presents on the skin.^2,6 There is a substantial association of cutaneous LCH with the development of systemically disseminated LCH as well as other blood tumors, such as myelomonocytic leukemia, histiocytic sarcoma, and multiple lymphomas; this association is thought to be due to the common origin of LCH and other blood diseases in the bone marrow.⁶

Histopathology of LCH shows a diffuse papillary dermal infiltrate of clonal proliferation of reniform or cleaved histiocytes.⁵ Epidermal ulceration and epidermotropism also are common. Neoplastic cells are found admixed with variable levels of eosinophils, lymphocytes, plasma cells, and neutrophils, though eosinophils typically are elevated. Immunohistochemistry characteristically shows the expression of CD1a, S-100, and/or CD207, and the absence of CD163 expression.

Treatment of LCH is primarily dependent on disease dissemination status, with splenic and hepatic involvement, genetic panel results, and central nervous system risk considered in the treatment plan.⁵ Langerhans cell histiocytosis localized to the skin may require follow-up and monitoring, as spontaneous regression of cutaneous LCH is common. However, topical steroids or psoralen and long-wave UV radiation are potential treatments. Physicians who diagnose unifocal cutaneous LCH should have high clinical suspicion of disseminated LCH, and laboratory and radiographic evaluation may be necessary to rule out systemic disease, as more than 40% of patients with cutaneous LCH have systemic disease upon full evaluation.⁷ With systemic involvement, systemic chemotherapy may reduce morbidity and mortality, but clinical response should be monitored after 6 weeks of treatment, as results are variably effective. Vinblastine is the most common chemotherapy regimen, with an 84% survival rate and 51.5% event-free survival rate after 8 years.⁸ Targeted therapy for common genetic mutations also is possible, as vemurafenib has been used to treat patients with the BRAF V600E mutation.

Due to the variable clinical presentation of cutaneous LCH, the lesions can mimic other common skin diseases such as eczema or seborrheic dermatitis.⁷ However, there are limited data on LCH presenting in infiltrative skin disease. Langerhans cell histiocytosis that was misdiagnosed as HS has been reported,^9-11 but LCH presenting alongside long-standing HS is rare. Although LCH often mimics infiltrative skin diseases, its simultaneous presentation with a previously confirmed diagnosis of HS was notable in our patient.

In our patient, the differential diagnosis included HS, Actinomyces infection, lymphomatoid papulosis, and dermatofibrosarcoma protuberans. Cutaneous findings in HS include chronic acneform nodules with follicular plugging, ruptured ducts leading to epithelized sinuses, inflammation, and abscesses in the axillae or inguinal and perineal areas.¹¹ Histopathology reveals follicular occlusion and hyperkeratinization, which cause destruction of the pilosebaceous glands. Hidradenitis suppurativa features on immunohistochemistry often are conflicting, but there consistently is co-localization of keratinocyte hyperplasia with CD3-, CD4-, CD8-, and CD68-positive staining of cells that produce tumor necrosis factor α, IL-12, IL-23, and IL-32, with CD1a staining variable.¹² An infection with Actinomyces, a slow-progressing anaerobic or microaerophilic bacteria, may present in the skin with chronic suppurative inflammation on the neck, trunk, and abdomen. The classic presentation is subcutaneous nodules with localized infiltration of abscesses, fistulas, and draining sinuses.¹³ Morphologically, Actinomyces causes chronic granulomatous infection with 0.1- to 1-mm sulfur granules, which are seen as basophilic masses with eosinophilic terminal clubs on hematoxylin and eosin staining.¹⁴ Histopathology reveals grampositive filamentous Actinomyces bacteria that branch at the edge of the granules. Lymphomatoid papulosis, a nonaggressive T-cell lymphoma, presents as papulonodular and sometimes necrotic disseminated lesions that spontaneously can regress or can cause a higher risk for the development of more aggressive lymphomas.¹⁵ Histopathology shows consistently dense, dermal, lymphocytic infiltration. Immunohistochemistry is characterized by lymphocytes expressing CD30 of varying degrees: type A with many CD30 staining cells, type B presenting similar to mycosis fungoides with little CD30 staining, and type C with lymphocytic CD30-staining plaques. Dermatofibrosarcoma protuberans is a low-grade soft-tissue malignant tumor with extensive local infiltration characterized by asymptomatic plaques on the trunk and proximal extremities that are indurated and adhered to the skin.¹⁶ Histopathology shows extensive invasion into the adjacent tissue far from the original focus of the tumor.

The Diagnosis: Cutaneous Langerhans Cell Histiocytosis

Histopathologic findings of the left axillary lesion included a diffuse infiltrate of irregular hematolymphoid cells with reniform nuclei that strongly and diffusely stained positively with CD1a and S-100 but were negative for CD138 and CD163 (Figure). Numerous eosinophils also were present. The surrounding lymphocytic infiltrate stained positively with CD45. Polymerase chain reaction of the vaginal lesion was negative for herpes simplex virus types 1 and 2. Biopsy of the vaginal lesion revealed a mildly acanthotic epidermis and an aggregation of epithelioid cells with reniform nuclei in the papillary dermis. Positron emission tomography revealed widely disseminated disease. Sequencing of the mitogen-activated protein kinase/extracellular signalregulated kinase pathway showed amplified expression of these genes but found no mutations. These results led to a diagnosis of cutaneous Langerhans cell histiocytosis (LCH) with a background of hidradenitis suppurativa (HS). Our patient has since initiated therapy with trametinib leading to disease improvement without known recurrence.

Langerhans cell histiocytosis is a rare disease of clonal dendritic cells (Langerhans cells) that can present in any organ.¹ Most LCH diagnoses are made in pediatric patients, most often presenting in the bones, with other presentations in the skin, hypophysis, liver, lymph nodes, lungs, and spleen occurring less commonly.² Proto-oncogene BRAF V600E mutations are a common determinant of LCH, with half of cases linked with this mutation that leads to enhanced activation of the mitogen-activated protein kinase pathway, though other mutations have been reported.^3,4 These genetic alterations suggest LCH is neoplastic in nature; however, this is controversial, as spontaneous regression among pulmonary LCH has been observed, pointing to a reactive inflammatory process.⁵ Cutaneous LCH can present as a distinct papular or nodular lesion or multiple lesions with possible ulceration, but it is rare that LCH first presents on the skin.^2,6 There is a substantial association of cutaneous LCH with the development of systemically disseminated LCH as well as other blood tumors, such as myelomonocytic leukemia, histiocytic sarcoma, and multiple lymphomas; this association is thought to be due to the common origin of LCH and other blood diseases in the bone marrow.⁶

Histopathology of LCH shows a diffuse papillary dermal infiltrate of clonal proliferation of reniform or cleaved histiocytes.⁵ Epidermal ulceration and epidermotropism also are common. Neoplastic cells are found admixed with variable levels of eosinophils, lymphocytes, plasma cells, and neutrophils, though eosinophils typically are elevated. Immunohistochemistry characteristically shows the expression of CD1a, S-100, and/or CD207, and the absence of CD163 expression.

Treatment of LCH is primarily dependent on disease dissemination status, with splenic and hepatic involvement, genetic panel results, and central nervous system risk considered in the treatment plan.⁵ Langerhans cell histiocytosis localized to the skin may require follow-up and monitoring, as spontaneous regression of cutaneous LCH is common. However, topical steroids or psoralen and long-wave UV radiation are potential treatments. Physicians who diagnose unifocal cutaneous LCH should have high clinical suspicion of disseminated LCH, and laboratory and radiographic evaluation may be necessary to rule out systemic disease, as more than 40% of patients with cutaneous LCH have systemic disease upon full evaluation.⁷ With systemic involvement, systemic chemotherapy may reduce morbidity and mortality, but clinical response should be monitored after 6 weeks of treatment, as results are variably effective. Vinblastine is the most common chemotherapy regimen, with an 84% survival rate and 51.5% event-free survival rate after 8 years.⁸ Targeted therapy for common genetic mutations also is possible, as vemurafenib has been used to treat patients with the BRAF V600E mutation.

Due to the variable clinical presentation of cutaneous LCH, the lesions can mimic other common skin diseases such as eczema or seborrheic dermatitis.⁷ However, there are limited data on LCH presenting in infiltrative skin disease. Langerhans cell histiocytosis that was misdiagnosed as HS has been reported,^9-11 but LCH presenting alongside long-standing HS is rare. Although LCH often mimics infiltrative skin diseases, its simultaneous presentation with a previously confirmed diagnosis of HS was notable in our patient.

In our patient, the differential diagnosis included HS, Actinomyces infection, lymphomatoid papulosis, and dermatofibrosarcoma protuberans. Cutaneous findings in HS include chronic acneform nodules with follicular plugging, ruptured ducts leading to epithelized sinuses, inflammation, and abscesses in the axillae or inguinal and perineal areas.¹¹ Histopathology reveals follicular occlusion and hyperkeratinization, which cause destruction of the pilosebaceous glands. Hidradenitis suppurativa features on immunohistochemistry often are conflicting, but there consistently is co-localization of keratinocyte hyperplasia with CD3-, CD4-, CD8-, and CD68-positive staining of cells that produce tumor necrosis factor α, IL-12, IL-23, and IL-32, with CD1a staining variable.¹² An infection with Actinomyces, a slow-progressing anaerobic or microaerophilic bacteria, may present in the skin with chronic suppurative inflammation on the neck, trunk, and abdomen. The classic presentation is subcutaneous nodules with localized infiltration of abscesses, fistulas, and draining sinuses.¹³ Morphologically, Actinomyces causes chronic granulomatous infection with 0.1- to 1-mm sulfur granules, which are seen as basophilic masses with eosinophilic terminal clubs on hematoxylin and eosin staining.¹⁴ Histopathology reveals grampositive filamentous Actinomyces bacteria that branch at the edge of the granules. Lymphomatoid papulosis, a nonaggressive T-cell lymphoma, presents as papulonodular and sometimes necrotic disseminated lesions that spontaneously can regress or can cause a higher risk for the development of more aggressive lymphomas.¹⁵ Histopathology shows consistently dense, dermal, lymphocytic infiltration. Immunohistochemistry is characterized by lymphocytes expressing CD30 of varying degrees: type A with many CD30 staining cells, type B presenting similar to mycosis fungoides with little CD30 staining, and type C with lymphocytic CD30-staining plaques. Dermatofibrosarcoma protuberans is a low-grade soft-tissue malignant tumor with extensive local infiltration characterized by asymptomatic plaques on the trunk and proximal extremities that are indurated and adhered to the skin.¹⁶ Histopathology shows extensive invasion into the adjacent tissue far from the original focus of the tumor.

The Diagnosis: Cutaneous Langerhans Cell Histiocytosis

Histopathologic findings of the left axillary lesion included a diffuse infiltrate of irregular hematolymphoid cells with reniform nuclei that strongly and diffusely stained positively with CD1a and S-100 but were negative for CD138 and CD163 (Figure). Numerous eosinophils also were present. The surrounding lymphocytic infiltrate stained positively with CD45. Polymerase chain reaction of the vaginal lesion was negative for herpes simplex virus types 1 and 2. Biopsy of the vaginal lesion revealed a mildly acanthotic epidermis and an aggregation of epithelioid cells with reniform nuclei in the papillary dermis. Positron emission tomography revealed widely disseminated disease. Sequencing of the mitogen-activated protein kinase/extracellular signalregulated kinase pathway showed amplified expression of these genes but found no mutations. These results led to a diagnosis of cutaneous Langerhans cell histiocytosis (LCH) with a background of hidradenitis suppurativa (HS). Our patient has since initiated therapy with trametinib leading to disease improvement without known recurrence.

Langerhans cell histiocytosis is a rare disease of clonal dendritic cells (Langerhans cells) that can present in any organ.¹ Most LCH diagnoses are made in pediatric patients, most often presenting in the bones, with other presentations in the skin, hypophysis, liver, lymph nodes, lungs, and spleen occurring less commonly.² Proto-oncogene BRAF V600E mutations are a common determinant of LCH, with half of cases linked with this mutation that leads to enhanced activation of the mitogen-activated protein kinase pathway, though other mutations have been reported.^3,4 These genetic alterations suggest LCH is neoplastic in nature; however, this is controversial, as spontaneous regression among pulmonary LCH has been observed, pointing to a reactive inflammatory process.⁵ Cutaneous LCH can present as a distinct papular or nodular lesion or multiple lesions with possible ulceration, but it is rare that LCH first presents on the skin.^2,6 There is a substantial association of cutaneous LCH with the development of systemically disseminated LCH as well as other blood tumors, such as myelomonocytic leukemia, histiocytic sarcoma, and multiple lymphomas; this association is thought to be due to the common origin of LCH and other blood diseases in the bone marrow.⁶

Histopathology of LCH shows a diffuse papillary dermal infiltrate of clonal proliferation of reniform or cleaved histiocytes.⁵ Epidermal ulceration and epidermotropism also are common. Neoplastic cells are found admixed with variable levels of eosinophils, lymphocytes, plasma cells, and neutrophils, though eosinophils typically are elevated. Immunohistochemistry characteristically shows the expression of CD1a, S-100, and/or CD207, and the absence of CD163 expression.

Treatment of LCH is primarily dependent on disease dissemination status, with splenic and hepatic involvement, genetic panel results, and central nervous system risk considered in the treatment plan.⁵ Langerhans cell histiocytosis localized to the skin may require follow-up and monitoring, as spontaneous regression of cutaneous LCH is common. However, topical steroids or psoralen and long-wave UV radiation are potential treatments. Physicians who diagnose unifocal cutaneous LCH should have high clinical suspicion of disseminated LCH, and laboratory and radiographic evaluation may be necessary to rule out systemic disease, as more than 40% of patients with cutaneous LCH have systemic disease upon full evaluation.⁷ With systemic involvement, systemic chemotherapy may reduce morbidity and mortality, but clinical response should be monitored after 6 weeks of treatment, as results are variably effective. Vinblastine is the most common chemotherapy regimen, with an 84% survival rate and 51.5% event-free survival rate after 8 years.⁸ Targeted therapy for common genetic mutations also is possible, as vemurafenib has been used to treat patients with the BRAF V600E mutation.

Due to the variable clinical presentation of cutaneous LCH, the lesions can mimic other common skin diseases such as eczema or seborrheic dermatitis.⁷ However, there are limited data on LCH presenting in infiltrative skin disease. Langerhans cell histiocytosis that was misdiagnosed as HS has been reported,^9-11 but LCH presenting alongside long-standing HS is rare. Although LCH often mimics infiltrative skin diseases, its simultaneous presentation with a previously confirmed diagnosis of HS was notable in our patient.

In our patient, the differential diagnosis included HS, Actinomyces infection, lymphomatoid papulosis, and dermatofibrosarcoma protuberans. Cutaneous findings in HS include chronic acneform nodules with follicular plugging, ruptured ducts leading to epithelized sinuses, inflammation, and abscesses in the axillae or inguinal and perineal areas.¹¹ Histopathology reveals follicular occlusion and hyperkeratinization, which cause destruction of the pilosebaceous glands. Hidradenitis suppurativa features on immunohistochemistry often are conflicting, but there consistently is co-localization of keratinocyte hyperplasia with CD3-, CD4-, CD8-, and CD68-positive staining of cells that produce tumor necrosis factor α, IL-12, IL-23, and IL-32, with CD1a staining variable.¹² An infection with Actinomyces, a slow-progressing anaerobic or microaerophilic bacteria, may present in the skin with chronic suppurative inflammation on the neck, trunk, and abdomen. The classic presentation is subcutaneous nodules with localized infiltration of abscesses, fistulas, and draining sinuses.¹³ Morphologically, Actinomyces causes chronic granulomatous infection with 0.1- to 1-mm sulfur granules, which are seen as basophilic masses with eosinophilic terminal clubs on hematoxylin and eosin staining.¹⁴ Histopathology reveals grampositive filamentous Actinomyces bacteria that branch at the edge of the granules. Lymphomatoid papulosis, a nonaggressive T-cell lymphoma, presents as papulonodular and sometimes necrotic disseminated lesions that spontaneously can regress or can cause a higher risk for the development of more aggressive lymphomas.¹⁵ Histopathology shows consistently dense, dermal, lymphocytic infiltration. Immunohistochemistry is characterized by lymphocytes expressing CD30 of varying degrees: type A with many CD30 staining cells, type B presenting similar to mycosis fungoides with little CD30 staining, and type C with lymphocytic CD30-staining plaques. Dermatofibrosarcoma protuberans is a low-grade soft-tissue malignant tumor with extensive local infiltration characterized by asymptomatic plaques on the trunk and proximal extremities that are indurated and adhered to the skin.¹⁶ Histopathology shows extensive invasion into the adjacent tissue far from the original focus of the tumor.