Dermatopathology

SAN DIEGO – As with many markers for the evaluation of challenging melanocytic lesions, preferentially expressed antigen in melanoma (PRAME) has its benefits and drawbacks, according to Cora Humberson, MD.

“I’m a fan, but there are issues with it,” Dr. Humberson, dermatopathology coordinator in the department of pathology at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “It’s all in how you use it.”

PRAME is part of the cancer/testis (CT) antigens, of which more than 40 have now been identified. They are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumor types, including melanoma and carcinomas of the bladder, lung, and liver. “The biological function of these antigens is not fully understood, but they may act as a repressor of retinoic acid, potentially inhibiting differentiation, inhibiting proliferation arrest – things that we associate with malignancy,” she said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “These immunogenic proteins are being pursued as targets for therapeutic cancer vaccines,” she noted.

CT antigens are also being evaluated for their role in oncogenesis, she added. Recapitulation of portions of the germline gene-expression might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, and metastatic capacity.

According to Dr. Humberson, PRAME can be used to differentiate comingled nevus and melanoma, to distinguish between nevoid melanoma and nevus, and for melanoma margin assessment in sun-damaged skin. One potential pitfall is that sun-damaged melanocytes may express PRAME. “The older the person and the more sun damage [they have], the more likely you are to see this, but the melanocytes won’t be grouped, they’ll be scattered,” she said.

Another pitfall is that less than 15% of nevi may express PRAME. “PRAME can be expressed in scars, so if you’re looking at a spindle cell lesion, be aware that you might be looking at a scar if you’re seeing PRAME expression,” she added. She also noted that PRAME immunohistochemistry (IHC) expression is not a prognostic biomarker in thin melanomas.

If fewer than 25% of cells in a melanocytic lesion express PRAME, most published assessments of PRAME IHC favor nevi as the diagnosis. “If more than 75% are expressing it, it favors melanoma,” Dr. Humberson said. “There’s a big category in between. It’s not that 30% is more likely benign or that 60% is more likely malignant; you can’t really depend upon [PRAME] if you’re in this range.”

A diagnostic accuracy study found that when more than 75% of cells express PRAME, the marker has a sensitivity of 0.63 and a specificity of 0.97.

Selected PRAME-related published references she recommended include: J Cutan Pathol. 2021;48(9):1115-23; Diagnostics. 2022 Sep 9; 12(9):2197, and J Cutan Pathol. 2022;49(9):829-32.

Dr. Humberson reported having no relevant disclosures.

SAN DIEGO – As with many markers for the evaluation of challenging melanocytic lesions, preferentially expressed antigen in melanoma (PRAME) has its benefits and drawbacks, according to Cora Humberson, MD.

“I’m a fan, but there are issues with it,” Dr. Humberson, dermatopathology coordinator in the department of pathology at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “It’s all in how you use it.”

PRAME is part of the cancer/testis (CT) antigens, of which more than 40 have now been identified. They are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumor types, including melanoma and carcinomas of the bladder, lung, and liver. “The biological function of these antigens is not fully understood, but they may act as a repressor of retinoic acid, potentially inhibiting differentiation, inhibiting proliferation arrest – things that we associate with malignancy,” she said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “These immunogenic proteins are being pursued as targets for therapeutic cancer vaccines,” she noted.

CT antigens are also being evaluated for their role in oncogenesis, she added. Recapitulation of portions of the germline gene-expression might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, and metastatic capacity.

According to Dr. Humberson, PRAME can be used to differentiate comingled nevus and melanoma, to distinguish between nevoid melanoma and nevus, and for melanoma margin assessment in sun-damaged skin. One potential pitfall is that sun-damaged melanocytes may express PRAME. “The older the person and the more sun damage [they have], the more likely you are to see this, but the melanocytes won’t be grouped, they’ll be scattered,” she said.

Another pitfall is that less than 15% of nevi may express PRAME. “PRAME can be expressed in scars, so if you’re looking at a spindle cell lesion, be aware that you might be looking at a scar if you’re seeing PRAME expression,” she added. She also noted that PRAME immunohistochemistry (IHC) expression is not a prognostic biomarker in thin melanomas.

If fewer than 25% of cells in a melanocytic lesion express PRAME, most published assessments of PRAME IHC favor nevi as the diagnosis. “If more than 75% are expressing it, it favors melanoma,” Dr. Humberson said. “There’s a big category in between. It’s not that 30% is more likely benign or that 60% is more likely malignant; you can’t really depend upon [PRAME] if you’re in this range.”

A diagnostic accuracy study found that when more than 75% of cells express PRAME, the marker has a sensitivity of 0.63 and a specificity of 0.97.

Selected PRAME-related published references she recommended include: J Cutan Pathol. 2021;48(9):1115-23; Diagnostics. 2022 Sep 9; 12(9):2197, and J Cutan Pathol. 2022;49(9):829-32.

Dr. Humberson reported having no relevant disclosures.

SAN DIEGO – As with many markers for the evaluation of challenging melanocytic lesions, preferentially expressed antigen in melanoma (PRAME) has its benefits and drawbacks, according to Cora Humberson, MD.

“I’m a fan, but there are issues with it,” Dr. Humberson, dermatopathology coordinator in the department of pathology at Scripps MD Anderson Cancer Center, San Diego, said at the annual Cutaneous Malignancy Update. “It’s all in how you use it.”

PRAME is part of the cancer/testis (CT) antigens, of which more than 40 have now been identified. They are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumor types, including melanoma and carcinomas of the bladder, lung, and liver. “The biological function of these antigens is not fully understood, but they may act as a repressor of retinoic acid, potentially inhibiting differentiation, inhibiting proliferation arrest – things that we associate with malignancy,” she said at the meeting, which was hosted by Scripps MD Anderson Cancer Center. “These immunogenic proteins are being pursued as targets for therapeutic cancer vaccines,” she noted.

CT antigens are also being evaluated for their role in oncogenesis, she added. Recapitulation of portions of the germline gene-expression might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, and metastatic capacity.

According to Dr. Humberson, PRAME can be used to differentiate comingled nevus and melanoma, to distinguish between nevoid melanoma and nevus, and for melanoma margin assessment in sun-damaged skin. One potential pitfall is that sun-damaged melanocytes may express PRAME. “The older the person and the more sun damage [they have], the more likely you are to see this, but the melanocytes won’t be grouped, they’ll be scattered,” she said.

Another pitfall is that less than 15% of nevi may express PRAME. “PRAME can be expressed in scars, so if you’re looking at a spindle cell lesion, be aware that you might be looking at a scar if you’re seeing PRAME expression,” she added. She also noted that PRAME immunohistochemistry (IHC) expression is not a prognostic biomarker in thin melanomas.

If fewer than 25% of cells in a melanocytic lesion express PRAME, most published assessments of PRAME IHC favor nevi as the diagnosis. “If more than 75% are expressing it, it favors melanoma,” Dr. Humberson said. “There’s a big category in between. It’s not that 30% is more likely benign or that 60% is more likely malignant; you can’t really depend upon [PRAME] if you’re in this range.”

A diagnostic accuracy study found that when more than 75% of cells express PRAME, the marker has a sensitivity of 0.63 and a specificity of 0.97.

Selected PRAME-related published references she recommended include: J Cutan Pathol. 2021;48(9):1115-23; Diagnostics. 2022 Sep 9; 12(9):2197, and J Cutan Pathol. 2022;49(9):829-32.

Dr. Humberson reported having no relevant disclosures.

The Diagnosis: Marjolin Ulcer

A skin biopsy during his prior hospital admission demonstrated an ulcer with granulation tissue and mixed inflammation, and the patient was discharged with close outpatient follow-up. Two repeat skin biopsies from the peripheral margin at the time of the outpatient follow-up confirmed an invasive, well-differentiated squamous cell carcinoma (Figure), consistent with a Marjolin ulcer. Radiography demonstrated multiple left iliac chain and inguinal lymphadenopathies with extensive subcutaneous disease overlying the left medial tibia. After tumor board discussion, surgery was not recommended due to the size and likely penetration into the muscle. The patient began treatment with cemiplimab-rwlc, a PD-1 inhibitor. Within 4 cycles of treatment, he had improved pain and ambulation, and a 3-month follow-up positron emission tomography scan revealed decreased lymph node and cutaneous metabolic activity as well as clinical improvement.

Marjolin ulcers are rare and aggressive squamous cell carcinomas that arise from chronic wounds such as burn scars or pressure ulcers.¹ Although an underlying well-differentiated squamous cell carcinoma is the most common etiology, patients also may present with underlying basal cell carcinomas, melanomas, or angiosarcomas.² The exact pathogenesis underlying the malignant degeneration is unclear but appears to be driven by chronic inflammation. Patients classically present with a nonhealing ulcer associated with raised, friable, or crusty borders, as well as surrounding scar tissue. There is a median latency of 30 years after the trauma, though acute transformation within 12 months of an injury is possible.³ The diagnosis is confirmed with a peripheral wound biopsy. Surgical excision with wide margins remains the most common and effective intervention, especially for localized disease.¹ The addition of lymph node dissection remains controversial, but treatment decisions can be guided by radiographic staging.⁴

The prognosis of Marjolin ulcers remains poor, with a predicted 5-year survival rate ranging from 43% to 58%.¹ Dermatologists and trainees should be aware of Marjolin ulcers, especially as a mimicker of other chronic ulcerating conditions. Among the differential diagnosis, ulcerative lichen planus is a condition that commonly affects the oral and genital regions; however, patients with erosive lichen planus may develop an increased risk for the subsequent development of squamous cell carcinoma in the region.⁵ Furthermore, arterial ulcers typically develop on the distal lower extremities with other signs of chronic ischemia, including absent peripheral pulses, atrophic skin, hair loss, and ankle-brachial indices less than 0.5. Conversely, a venous ulcer classically affects the medial malleolus and will have evidence of venous insufficiency, including stasis dermatitis and peripheral edema.⁶

The Diagnosis: Marjolin Ulcer

A skin biopsy during his prior hospital admission demonstrated an ulcer with granulation tissue and mixed inflammation, and the patient was discharged with close outpatient follow-up. Two repeat skin biopsies from the peripheral margin at the time of the outpatient follow-up confirmed an invasive, well-differentiated squamous cell carcinoma (Figure), consistent with a Marjolin ulcer. Radiography demonstrated multiple left iliac chain and inguinal lymphadenopathies with extensive subcutaneous disease overlying the left medial tibia. After tumor board discussion, surgery was not recommended due to the size and likely penetration into the muscle. The patient began treatment with cemiplimab-rwlc, a PD-1 inhibitor. Within 4 cycles of treatment, he had improved pain and ambulation, and a 3-month follow-up positron emission tomography scan revealed decreased lymph node and cutaneous metabolic activity as well as clinical improvement.

Marjolin ulcers are rare and aggressive squamous cell carcinomas that arise from chronic wounds such as burn scars or pressure ulcers.¹ Although an underlying well-differentiated squamous cell carcinoma is the most common etiology, patients also may present with underlying basal cell carcinomas, melanomas, or angiosarcomas.² The exact pathogenesis underlying the malignant degeneration is unclear but appears to be driven by chronic inflammation. Patients classically present with a nonhealing ulcer associated with raised, friable, or crusty borders, as well as surrounding scar tissue. There is a median latency of 30 years after the trauma, though acute transformation within 12 months of an injury is possible.³ The diagnosis is confirmed with a peripheral wound biopsy. Surgical excision with wide margins remains the most common and effective intervention, especially for localized disease.¹ The addition of lymph node dissection remains controversial, but treatment decisions can be guided by radiographic staging.⁴

The prognosis of Marjolin ulcers remains poor, with a predicted 5-year survival rate ranging from 43% to 58%.¹ Dermatologists and trainees should be aware of Marjolin ulcers, especially as a mimicker of other chronic ulcerating conditions. Among the differential diagnosis, ulcerative lichen planus is a condition that commonly affects the oral and genital regions; however, patients with erosive lichen planus may develop an increased risk for the subsequent development of squamous cell carcinoma in the region.⁵ Furthermore, arterial ulcers typically develop on the distal lower extremities with other signs of chronic ischemia, including absent peripheral pulses, atrophic skin, hair loss, and ankle-brachial indices less than 0.5. Conversely, a venous ulcer classically affects the medial malleolus and will have evidence of venous insufficiency, including stasis dermatitis and peripheral edema.⁶

The Diagnosis: Marjolin Ulcer

A skin biopsy during his prior hospital admission demonstrated an ulcer with granulation tissue and mixed inflammation, and the patient was discharged with close outpatient follow-up. Two repeat skin biopsies from the peripheral margin at the time of the outpatient follow-up confirmed an invasive, well-differentiated squamous cell carcinoma (Figure), consistent with a Marjolin ulcer. Radiography demonstrated multiple left iliac chain and inguinal lymphadenopathies with extensive subcutaneous disease overlying the left medial tibia. After tumor board discussion, surgery was not recommended due to the size and likely penetration into the muscle. The patient began treatment with cemiplimab-rwlc, a PD-1 inhibitor. Within 4 cycles of treatment, he had improved pain and ambulation, and a 3-month follow-up positron emission tomography scan revealed decreased lymph node and cutaneous metabolic activity as well as clinical improvement.

Marjolin ulcers are rare and aggressive squamous cell carcinomas that arise from chronic wounds such as burn scars or pressure ulcers.¹ Although an underlying well-differentiated squamous cell carcinoma is the most common etiology, patients also may present with underlying basal cell carcinomas, melanomas, or angiosarcomas.² The exact pathogenesis underlying the malignant degeneration is unclear but appears to be driven by chronic inflammation. Patients classically present with a nonhealing ulcer associated with raised, friable, or crusty borders, as well as surrounding scar tissue. There is a median latency of 30 years after the trauma, though acute transformation within 12 months of an injury is possible.³ The diagnosis is confirmed with a peripheral wound biopsy. Surgical excision with wide margins remains the most common and effective intervention, especially for localized disease.¹ The addition of lymph node dissection remains controversial, but treatment decisions can be guided by radiographic staging.⁴

The prognosis of Marjolin ulcers remains poor, with a predicted 5-year survival rate ranging from 43% to 58%.¹ Dermatologists and trainees should be aware of Marjolin ulcers, especially as a mimicker of other chronic ulcerating conditions. Among the differential diagnosis, ulcerative lichen planus is a condition that commonly affects the oral and genital regions; however, patients with erosive lichen planus may develop an increased risk for the subsequent development of squamous cell carcinoma in the region.⁵ Furthermore, arterial ulcers typically develop on the distal lower extremities with other signs of chronic ischemia, including absent peripheral pulses, atrophic skin, hair loss, and ankle-brachial indices less than 0.5. Conversely, a venous ulcer classically affects the medial malleolus and will have evidence of venous insufficiency, including stasis dermatitis and peripheral edema.⁶

The Diagnosis: Cutaneous Crohn Disease

Kinyoun and Grocott-Gomori methenamine-silver staining of the labial biopsy were negative for mycobacteria and fungi, respectively. A complete blood cell count, erythrocyte sedimentation rate, C-reactive protein, celiac disease serologies, stool occult blood, and stool calprotectin laboratory test results were within reference range. Magnetic resonance imaging of the pelvis demonstrated an anal fissure extending from the anal verge at the 6 o’clock position, abnormal T2 bright signal in the skin of the buttocks and perineum extending to the labia, and mild mucosal enhancement of the rectal and anal mucosa. Esophagogastroduodenoscopy and magnetic resonance elastography were unremarkable. Colonoscopy demonstrated scattered superficial erythematous patches and erosions in the rectum. Histologically, there was mild to moderately active colitis in the rectum with no evidence of chronicity. Given our patient’s labial edema and exophytic papulonodule (Figure 1) in the setting of nonspecific gastrointestinal symptoms and granulomatous dermatitis seen on pathology (Figure 2), she was diagnosed with cutaneous Crohn disease (CD).

In our patient, labial biopsy was necessary to definitively diagnose CD. Prior to biopsy of the lesion, our patient was diagnosed with irritable bowel syndrome with constipation leading to an anal fissure and skin tag due to lack of laboratory, imaging, and colonoscopy findings commonly associated with CD. Her biopsy results and gastrointestinal symptoms made these diagnoses, as well as condyloma or a large sentinel skin tag, less likely.

Extraintestinal findings of CD, especially cutaneous manifestations, are relatively frequent and may be present in as many as 44% of patients.^1,2 Cutaneous CD often is characterized based on pathogenic mechanisms as either reactive, associated, or CD specific. Reactive cutaneous manifestations include erythema nodosum, pyoderma gangrenosum, and oral aphthae. Associated cutaneous manifestations include vitiligo, palmar erythema, and palmoplantar pustulosis.² Crohn disease–specific manifestations, including genital or extragenital metastatic CD (MCD), fistulas, and oral involvement, are granulomatous in nature, similar to intestinal CD. Genital manifestations of MCD include edema, erythema, fissures, and/or ulceration of the vulva, penis, or scrotum. Labial swelling is the most common presenting symptom of MCD in females in both pediatric and adult age groups.² Lymphedema, skin tags, and condylomalike growths also can be seen but are relatively less common.²

Given the labial edema, exophytic papulonodule, and granulomatous dermatitis seen on histopathology, our patient likely fit into the MCD category.² In adults, most instances of MCD arise in the setting of well-established intestinal CD disease,3 whereas in children 86% of cases occur in patients without concurrent intestinal CD.²

Given the nonspecific and variable presentation of MCD, the differential diagnosis is broad. The differential diagnosis could include infectious etiologies such as condyloma acuminatum (human papillomavirus); syphilitic chancre; or mycobacterial, bacterial, fungal, or parasitic vulvovaginitis. Sexual abuse, sarcoidosis, Behçet disease, or hidradenitis suppurativa, among other diagnoses, also should be considered. Diagnostic workup should include biopsy of the lesion with special stains, polarizing microscopy, and tissue cultures.⁴ A thorough evaluation for gastrointestinal CD should be completed after diagnosis.³

The clinical course of vulvar CD can be unpredictable, with some cases healing spontaneously but most persisting despite treatment and sometimes prompting surgical removal.^2,4 Early recognition is crucial, as long-standing MCD lesions can be therapy resistant.⁵ Due to the rarity of the condition and lack of data, there is a lack of treatment consensus for MCD. In 2014, the American Academy of Dermatology published treatment guidelines recommending superpotent topical steroids or topical tacrolimus as first-line therapy. Next-line therapy includes oral metronidazole, followed by prednisolone if still symptomatic.³ Treatment-resistant disease can warrant treatment with immunomodulators or tumor necrosis factor α inhibitors. Our patient was started on adalimumab; after just 2 months of therapy, the labial swelling decreased and the exophytic nodule was less firm and smaller.

Metastatic CD is a rare manifestation of cutaneous CD and can be present in the absence of gastrointestinal disease.³ This case demonstrates the importance of recognizing the cutaneous signs of CD and the necessity of lesional biopsy for the diagnosis of MCD, as our patient presented with nonspecific gastrointestinal symptoms and a diagnostic workup, including endoscopies, that proved inconclusive for the diagnosis of CD.

The Diagnosis: Cutaneous Crohn Disease

Kinyoun and Grocott-Gomori methenamine-silver staining of the labial biopsy were negative for mycobacteria and fungi, respectively. A complete blood cell count, erythrocyte sedimentation rate, C-reactive protein, celiac disease serologies, stool occult blood, and stool calprotectin laboratory test results were within reference range. Magnetic resonance imaging of the pelvis demonstrated an anal fissure extending from the anal verge at the 6 o’clock position, abnormal T2 bright signal in the skin of the buttocks and perineum extending to the labia, and mild mucosal enhancement of the rectal and anal mucosa. Esophagogastroduodenoscopy and magnetic resonance elastography were unremarkable. Colonoscopy demonstrated scattered superficial erythematous patches and erosions in the rectum. Histologically, there was mild to moderately active colitis in the rectum with no evidence of chronicity. Given our patient’s labial edema and exophytic papulonodule (Figure 1) in the setting of nonspecific gastrointestinal symptoms and granulomatous dermatitis seen on pathology (Figure 2), she was diagnosed with cutaneous Crohn disease (CD).

In our patient, labial biopsy was necessary to definitively diagnose CD. Prior to biopsy of the lesion, our patient was diagnosed with irritable bowel syndrome with constipation leading to an anal fissure and skin tag due to lack of laboratory, imaging, and colonoscopy findings commonly associated with CD. Her biopsy results and gastrointestinal symptoms made these diagnoses, as well as condyloma or a large sentinel skin tag, less likely.

Extraintestinal findings of CD, especially cutaneous manifestations, are relatively frequent and may be present in as many as 44% of patients.^1,2 Cutaneous CD often is characterized based on pathogenic mechanisms as either reactive, associated, or CD specific. Reactive cutaneous manifestations include erythema nodosum, pyoderma gangrenosum, and oral aphthae. Associated cutaneous manifestations include vitiligo, palmar erythema, and palmoplantar pustulosis.² Crohn disease–specific manifestations, including genital or extragenital metastatic CD (MCD), fistulas, and oral involvement, are granulomatous in nature, similar to intestinal CD. Genital manifestations of MCD include edema, erythema, fissures, and/or ulceration of the vulva, penis, or scrotum. Labial swelling is the most common presenting symptom of MCD in females in both pediatric and adult age groups.² Lymphedema, skin tags, and condylomalike growths also can be seen but are relatively less common.²

Given the labial edema, exophytic papulonodule, and granulomatous dermatitis seen on histopathology, our patient likely fit into the MCD category.² In adults, most instances of MCD arise in the setting of well-established intestinal CD disease,3 whereas in children 86% of cases occur in patients without concurrent intestinal CD.²

Given the nonspecific and variable presentation of MCD, the differential diagnosis is broad. The differential diagnosis could include infectious etiologies such as condyloma acuminatum (human papillomavirus); syphilitic chancre; or mycobacterial, bacterial, fungal, or parasitic vulvovaginitis. Sexual abuse, sarcoidosis, Behçet disease, or hidradenitis suppurativa, among other diagnoses, also should be considered. Diagnostic workup should include biopsy of the lesion with special stains, polarizing microscopy, and tissue cultures.⁴ A thorough evaluation for gastrointestinal CD should be completed after diagnosis.³

The clinical course of vulvar CD can be unpredictable, with some cases healing spontaneously but most persisting despite treatment and sometimes prompting surgical removal.^2,4 Early recognition is crucial, as long-standing MCD lesions can be therapy resistant.⁵ Due to the rarity of the condition and lack of data, there is a lack of treatment consensus for MCD. In 2014, the American Academy of Dermatology published treatment guidelines recommending superpotent topical steroids or topical tacrolimus as first-line therapy. Next-line therapy includes oral metronidazole, followed by prednisolone if still symptomatic.³ Treatment-resistant disease can warrant treatment with immunomodulators or tumor necrosis factor α inhibitors. Our patient was started on adalimumab; after just 2 months of therapy, the labial swelling decreased and the exophytic nodule was less firm and smaller.

Metastatic CD is a rare manifestation of cutaneous CD and can be present in the absence of gastrointestinal disease.³ This case demonstrates the importance of recognizing the cutaneous signs of CD and the necessity of lesional biopsy for the diagnosis of MCD, as our patient presented with nonspecific gastrointestinal symptoms and a diagnostic workup, including endoscopies, that proved inconclusive for the diagnosis of CD.

The Diagnosis: Cutaneous Crohn Disease

Kinyoun and Grocott-Gomori methenamine-silver staining of the labial biopsy were negative for mycobacteria and fungi, respectively. A complete blood cell count, erythrocyte sedimentation rate, C-reactive protein, celiac disease serologies, stool occult blood, and stool calprotectin laboratory test results were within reference range. Magnetic resonance imaging of the pelvis demonstrated an anal fissure extending from the anal verge at the 6 o’clock position, abnormal T2 bright signal in the skin of the buttocks and perineum extending to the labia, and mild mucosal enhancement of the rectal and anal mucosa. Esophagogastroduodenoscopy and magnetic resonance elastography were unremarkable. Colonoscopy demonstrated scattered superficial erythematous patches and erosions in the rectum. Histologically, there was mild to moderately active colitis in the rectum with no evidence of chronicity. Given our patient’s labial edema and exophytic papulonodule (Figure 1) in the setting of nonspecific gastrointestinal symptoms and granulomatous dermatitis seen on pathology (Figure 2), she was diagnosed with cutaneous Crohn disease (CD).

In our patient, labial biopsy was necessary to definitively diagnose CD. Prior to biopsy of the lesion, our patient was diagnosed with irritable bowel syndrome with constipation leading to an anal fissure and skin tag due to lack of laboratory, imaging, and colonoscopy findings commonly associated with CD. Her biopsy results and gastrointestinal symptoms made these diagnoses, as well as condyloma or a large sentinel skin tag, less likely.

Extraintestinal findings of CD, especially cutaneous manifestations, are relatively frequent and may be present in as many as 44% of patients.^1,2 Cutaneous CD often is characterized based on pathogenic mechanisms as either reactive, associated, or CD specific. Reactive cutaneous manifestations include erythema nodosum, pyoderma gangrenosum, and oral aphthae. Associated cutaneous manifestations include vitiligo, palmar erythema, and palmoplantar pustulosis.² Crohn disease–specific manifestations, including genital or extragenital metastatic CD (MCD), fistulas, and oral involvement, are granulomatous in nature, similar to intestinal CD. Genital manifestations of MCD include edema, erythema, fissures, and/or ulceration of the vulva, penis, or scrotum. Labial swelling is the most common presenting symptom of MCD in females in both pediatric and adult age groups.² Lymphedema, skin tags, and condylomalike growths also can be seen but are relatively less common.²

Given the labial edema, exophytic papulonodule, and granulomatous dermatitis seen on histopathology, our patient likely fit into the MCD category.² In adults, most instances of MCD arise in the setting of well-established intestinal CD disease,3 whereas in children 86% of cases occur in patients without concurrent intestinal CD.²

Given the nonspecific and variable presentation of MCD, the differential diagnosis is broad. The differential diagnosis could include infectious etiologies such as condyloma acuminatum (human papillomavirus); syphilitic chancre; or mycobacterial, bacterial, fungal, or parasitic vulvovaginitis. Sexual abuse, sarcoidosis, Behçet disease, or hidradenitis suppurativa, among other diagnoses, also should be considered. Diagnostic workup should include biopsy of the lesion with special stains, polarizing microscopy, and tissue cultures.⁴ A thorough evaluation for gastrointestinal CD should be completed after diagnosis.³

The clinical course of vulvar CD can be unpredictable, with some cases healing spontaneously but most persisting despite treatment and sometimes prompting surgical removal.^2,4 Early recognition is crucial, as long-standing MCD lesions can be therapy resistant.⁵ Due to the rarity of the condition and lack of data, there is a lack of treatment consensus for MCD. In 2014, the American Academy of Dermatology published treatment guidelines recommending superpotent topical steroids or topical tacrolimus as first-line therapy. Next-line therapy includes oral metronidazole, followed by prednisolone if still symptomatic.³ Treatment-resistant disease can warrant treatment with immunomodulators or tumor necrosis factor α inhibitors. Our patient was started on adalimumab; after just 2 months of therapy, the labial swelling decreased and the exophytic nodule was less firm and smaller.

Metastatic CD is a rare manifestation of cutaneous CD and can be present in the absence of gastrointestinal disease.³ This case demonstrates the importance of recognizing the cutaneous signs of CD and the necessity of lesional biopsy for the diagnosis of MCD, as our patient presented with nonspecific gastrointestinal symptoms and a diagnostic workup, including endoscopies, that proved inconclusive for the diagnosis of CD.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

Pseudoangiomatous squamous cell carcinoma (PSCC), a variant of acantholytic squamous cell carcinoma (SCC), is a rare epithelial neoplasm that can mimic angiosarcoma.¹ Clinically, PSCC presents as a white-gray ulcer or nodular pink tumor on sun-exposed areas, typically on the head and neck. Due to its increased potential for metastasis, this variant of SCC is considered particularly aggressive. Histologically, PSCC shows nests of acantholytic atypical keratinocytes arranged in anastomosing arrays that form pseudovascular or pseudoglandular structures.² Acantholytic spaces frequently are filled with erythrocytes. Immunohistochemically, PSCC tumor cells express classic squamous markers such as cytokeratin (CK) 5 and p63 but not vascular markers such as CD31, CD34, and von Willebrand factor.³ In our patient, histopathology of the lesion revealed invasive nests, lobules, and interconnected columns of well-differentiated squamous tumor cells that emanated from the base of the epidermis. The tumor exhibited acantholysis forming ectatic and slitlike spaces, some of which contained erythrocytes. The neoplastic cells, including those lining pseudovascular spaces, positively stained for CK5 (Figure 1A) and nuclear p63 but lacked reactivity to CD31 (Figure 1B) and CD34, corroborating squamous and not vascular differentiation. Current treatment guidelines include Mohs micrographic surgery, excisional surgery, or radiation.⁴ Our patient’s lesion was completely removed by Mohs micrographic surgery. Three months later, there was no evidence of recurrence.

Angiosarcoma is an aggressive neoplasm associated with a poor prognosis and 5-year survival rate of 30% to 40%. The etiology of angiosarcoma still is unclear, but identified risk factors include prior radiation therapy, lymphedema (Stewart-Treves syndrome), and genetic predisposition.⁵ In the skin, angiosarcoma often occurs in the head and neck region, accounting for 60% of cutaneous cases.^5,6 Early in the disease, most patients present with a bruiselike lesion on the scalp or forehead, often delaying the diagnosis.⁶ As the cancer progresses, tissue infiltration, edema, and hemorrhage contribute to the formation of violaceous nodules, which eventually prompt for biopsy. Angiosarcoma spans a broad histologic spectrum depending on the cytology of malignant cells (eg, spindle, small round, epithelioid) and their capacity for vasoformation. Welldifferentiated angiosarcoma shows retiform slitlike spaces in between collagen bundles that are lined by hyperchromatic hobnailing endothelial cells (Figure 2).⁷ Epithelioid angiosarcoma can be mistaken for SCC.⁸ Immunohistochemically, angiosarcoma stains positively for CD31, CD34, ETS-related gene 1, D2-40, and factor VIII.9 In our patient, the neoplasm was negative for vascular markers CD31 and CD34.

Bacillary angiomatosis (BA), caused by Bartonella henselae, is a rare disease that first was identified in HIV patients with diminished CD4+ T-cell counts. In the skin, BA often manifests as centrally ulcerated, single or clustered, reddish-purple nodules.¹⁰ Histologically, it is characterized by highly vascularized, histiocyterich infiltrates with admixed neutrophils and plasma cells (Figure 3). Capillaries often proliferate in a lobular fashion.¹¹ Atypical cytology with areas of necrosis may mimic angiosarcoma.¹² The pathognomonic feature of BA is the presence of enlarged histiocytes with pink-purplish cytoplasm corresponding to intracytoplasmic aggregates of bacteria, which can be revealed by Warthin-Starry or Grocott-Gomori methenamine-silver staining. Immunohistochemically, proliferative benign capillaries are highlighted by CD34 and CD31, and histiocytes are decorated by CD68.¹² This diagnosis was excluded based on the patient’s history, clinical presentation, and positive staining for CK5 and p63.

Squamoid eccrine ductal carcinoma is an exceedingly rare subtype of eccrine carcinoma that mimics SCC both clinically and histologically.¹³ It most often occurs on the head and neck of elderly patients. This neoplasm can look similar to SCC and its variants, including PSCC. Histologically, squamoid eccrine ductal carcinoma exhibits a biphasic growth pattern.¹⁴ Well-differentiated squamous dysplasia transitions to carcinoma with eccrine duct formation as the tumor percolates deep into the dermis (Figure 4). As a result, superficial skin biopsies often lead to an incorrect diagnosis.¹⁵ Unlike SCC, the risk for locoregional and widespread metastasis is elevated. Identifying ducts in the deep aspect of the tumor is critical, thus immunohistochemical staining for carcinoembryonic antigen and epithelial membrane antigen is paramount for the diagnosis.¹⁵ Pseudoangiomatous SCC will stain negative for carcinoembryonic antigen, as was the case in our patient.

Pseudoepitheliomatous hyperplasia is a benign histologic reaction that can result from trauma, chronic inflammation (ie, pyoderma gangrenosum), tattoo placement, underlying neoplasia or fungal infection, or a spider bite reaction.^14,15 It most commonly is seen as a well-demarcated nodule or plaque associated with scaling or crusting. Papules vary in size from less than 1 cm to several centimeters. Histologically, it is defined by an acanthotic proliferation of the adnexal epithelium and epidermis (Figure 5).^16,17 Irregular strands, cords, and nests of squamoid cells can extend into the dermis.¹⁸ It can closely mimic SCC, but there are a few key differences. Pseudoepitheliomatous hyperplasia will not display atypical mitotic figures or atypical nuclei and will never invade lymphatics or vascular systems.¹⁹ Pseudoepitheliomatous hyperplasia shows identical histology to well-differentiated SCC, and thus clinicopathologic correlation and mindful histologic evaluation are crucial. The presence of an increased influx of neutrophils and histiocytes should prompt for microbial stains or deeper sectioning. A superficial biopsy should be followed by a deep biopsy. In our patient, microorganismal stains were negative.

The Diagnosis: Atypical Mycobacterial Infection

The history of rapid growth followed by shrinkage as well as the craterlike clinical appearance of our patient’s lesion were suspicious for the keratoacanthoma variant of squamous cell carcinoma (SCC). Periodic acid–Schiff green staining was negative for fungal or bacterial organisms, and the biopsy findings of keratinocyte atypia and irregular epidermal proliferation seemed to confirm our suspicion for well-differentiated SCC (Figure 1). Our patient subsequently was scheduled for Mohs micrographic surgery. Fortunately, a sample of tissue had been sent for panculture—bacterial, fungal, and mycobacterial—to rule out infectious etiologies, given the history of possible traumatic inoculation, and returned positive for Mycobacterium marinum infection prior to the surgery. Mohs surgery was canceled, and he was referred to an infectious disease specialist who started antibiotic treatment with azithromycin, ethambutol, and rifabutin. After 1 month of treatment the lesion substantially improved (Figure 2), further supporting the diagnosis of M marinum infection over SCC.

The differential diagnosis also included sporotrichosis, leishmaniasis, and chromoblastomycosis. Sporotrichosis lesions typically develop as multiple nodules and ulcers along a path of lymphatic drainage and can exhibit asteroid bodies and cigar-shaped yeast forms on histology. Chromoblastomycosis may display pseudoepitheliomatous hyperplasia and granulomatous inflammation; however, pathognomonic pigmented Medlar bodies also likely would be present.¹ Leishmaniasis has a wide variety of presentations; however, it typically occurs in patients with exposure to endemic areas outside of the United States. Although leishmaniasis may demonstrate pseudoepitheliomatous hyperplasia, ulceration, and mixed inflammation on histology, it also likely would show amastigotes within dermal macrophages.²

Atypical mycobacterial infections initially may be misdiagnosed as SCC due to their tendency to induce irregular acanthosis in the form of pseudoepitheliomatous hyperplasia as well as mild keratinocyte atypia secondary to inflammation.^3,4 Our case is unique because it occurred with M marinum infection specifically. The histopathologic findings of M marinum infections are variable and may additionally include granulomas, most commonly suppurative; intraepithelial abscesses; small vessel proliferation; dermal fibrosis; multinucleated giant cells; and transepidermal elimination.^4,5 Periodic acid–Schiff, Ziehl-Neelsen (acid-fast bacilli), and Fite staining may be used to distinguish M marinum infection from SCC but have low sensitivities (approximately 30%). Culture remains the most reliable test, with a sensitivity of nearly 80%.^5-7 In our patient, a Periodic acid–Schiff stain was obtained prior to receiving culture results, and acid-fast bacilli and Fite staining were added after the culture returned positive; however, all 3 stains failed to highlight any mycobacteria.

The primary risk factor for infection with M marinum is contact with aquatic environments or marine animals, and most cases involve the fingers or the hand.⁶ After we reached the diagnosis and further discussed the patient’s history, he recalled fishing for and cleaning raw shrimp around the time that he had a splinter. The Infectious Diseases Society of America recommends a treatment course extending 1 to 2 months after clinical symptoms resolve with ethambutol in addition to clarithromycin or azithromycin.⁸ If the infection is near a joint, rifampin should be empirically added to account for a potentially deeper infection. Imaging should be obtained to evaluate for joint space involvement, with magnetic resonance imaging being the preferred modality. If joint space involvement is confirmed, surgical debridement is indicated. Surgical debridement also is indicated for infections that fail to respond to antibiotic therapy.⁸

This case highlights M marinum infection as a potential mimicker of SCC, particularly if the biopsy is relatively superficial, as often occurs when obtained via the common shave technique. The distinction is critical, as M marinum infection is highly treatable and inappropriate surgery on the typical hand and finger locations may subject patients to substantial morbidity, such as the need for a skin graft, reduced mobility from scarring, or risk for serious wound infection.⁹ For superficial biopsies of an atypical squamous process, pathologists also may consider routinely recommending tissue culture, especially for hand and finger locations or when a history of local trauma is reported, instead of recommending complete excision or repeat biopsy alone.

The Diagnosis: Atypical Mycobacterial Infection

The history of rapid growth followed by shrinkage as well as the craterlike clinical appearance of our patient’s lesion were suspicious for the keratoacanthoma variant of squamous cell carcinoma (SCC). Periodic acid–Schiff green staining was negative for fungal or bacterial organisms, and the biopsy findings of keratinocyte atypia and irregular epidermal proliferation seemed to confirm our suspicion for well-differentiated SCC (Figure 1). Our patient subsequently was scheduled for Mohs micrographic surgery. Fortunately, a sample of tissue had been sent for panculture—bacterial, fungal, and mycobacterial—to rule out infectious etiologies, given the history of possible traumatic inoculation, and returned positive for Mycobacterium marinum infection prior to the surgery. Mohs surgery was canceled, and he was referred to an infectious disease specialist who started antibiotic treatment with azithromycin, ethambutol, and rifabutin. After 1 month of treatment the lesion substantially improved (Figure 2), further supporting the diagnosis of M marinum infection over SCC.

The differential diagnosis also included sporotrichosis, leishmaniasis, and chromoblastomycosis. Sporotrichosis lesions typically develop as multiple nodules and ulcers along a path of lymphatic drainage and can exhibit asteroid bodies and cigar-shaped yeast forms on histology. Chromoblastomycosis may display pseudoepitheliomatous hyperplasia and granulomatous inflammation; however, pathognomonic pigmented Medlar bodies also likely would be present.¹ Leishmaniasis has a wide variety of presentations; however, it typically occurs in patients with exposure to endemic areas outside of the United States. Although leishmaniasis may demonstrate pseudoepitheliomatous hyperplasia, ulceration, and mixed inflammation on histology, it also likely would show amastigotes within dermal macrophages.²

Atypical mycobacterial infections initially may be misdiagnosed as SCC due to their tendency to induce irregular acanthosis in the form of pseudoepitheliomatous hyperplasia as well as mild keratinocyte atypia secondary to inflammation.^3,4 Our case is unique because it occurred with M marinum infection specifically. The histopathologic findings of M marinum infections are variable and may additionally include granulomas, most commonly suppurative; intraepithelial abscesses; small vessel proliferation; dermal fibrosis; multinucleated giant cells; and transepidermal elimination.^4,5 Periodic acid–Schiff, Ziehl-Neelsen (acid-fast bacilli), and Fite staining may be used to distinguish M marinum infection from SCC but have low sensitivities (approximately 30%). Culture remains the most reliable test, with a sensitivity of nearly 80%.^5-7 In our patient, a Periodic acid–Schiff stain was obtained prior to receiving culture results, and acid-fast bacilli and Fite staining were added after the culture returned positive; however, all 3 stains failed to highlight any mycobacteria.

The primary risk factor for infection with M marinum is contact with aquatic environments or marine animals, and most cases involve the fingers or the hand.⁶ After we reached the diagnosis and further discussed the patient’s history, he recalled fishing for and cleaning raw shrimp around the time that he had a splinter. The Infectious Diseases Society of America recommends a treatment course extending 1 to 2 months after clinical symptoms resolve with ethambutol in addition to clarithromycin or azithromycin.⁸ If the infection is near a joint, rifampin should be empirically added to account for a potentially deeper infection. Imaging should be obtained to evaluate for joint space involvement, with magnetic resonance imaging being the preferred modality. If joint space involvement is confirmed, surgical debridement is indicated. Surgical debridement also is indicated for infections that fail to respond to antibiotic therapy.⁸

This case highlights M marinum infection as a potential mimicker of SCC, particularly if the biopsy is relatively superficial, as often occurs when obtained via the common shave technique. The distinction is critical, as M marinum infection is highly treatable and inappropriate surgery on the typical hand and finger locations may subject patients to substantial morbidity, such as the need for a skin graft, reduced mobility from scarring, or risk for serious wound infection.⁹ For superficial biopsies of an atypical squamous process, pathologists also may consider routinely recommending tissue culture, especially for hand and finger locations or when a history of local trauma is reported, instead of recommending complete excision or repeat biopsy alone.

The Diagnosis: Atypical Mycobacterial Infection

The history of rapid growth followed by shrinkage as well as the craterlike clinical appearance of our patient’s lesion were suspicious for the keratoacanthoma variant of squamous cell carcinoma (SCC). Periodic acid–Schiff green staining was negative for fungal or bacterial organisms, and the biopsy findings of keratinocyte atypia and irregular epidermal proliferation seemed to confirm our suspicion for well-differentiated SCC (Figure 1). Our patient subsequently was scheduled for Mohs micrographic surgery. Fortunately, a sample of tissue had been sent for panculture—bacterial, fungal, and mycobacterial—to rule out infectious etiologies, given the history of possible traumatic inoculation, and returned positive for Mycobacterium marinum infection prior to the surgery. Mohs surgery was canceled, and he was referred to an infectious disease specialist who started antibiotic treatment with azithromycin, ethambutol, and rifabutin. After 1 month of treatment the lesion substantially improved (Figure 2), further supporting the diagnosis of M marinum infection over SCC.

The differential diagnosis also included sporotrichosis, leishmaniasis, and chromoblastomycosis. Sporotrichosis lesions typically develop as multiple nodules and ulcers along a path of lymphatic drainage and can exhibit asteroid bodies and cigar-shaped yeast forms on histology. Chromoblastomycosis may display pseudoepitheliomatous hyperplasia and granulomatous inflammation; however, pathognomonic pigmented Medlar bodies also likely would be present.¹ Leishmaniasis has a wide variety of presentations; however, it typically occurs in patients with exposure to endemic areas outside of the United States. Although leishmaniasis may demonstrate pseudoepitheliomatous hyperplasia, ulceration, and mixed inflammation on histology, it also likely would show amastigotes within dermal macrophages.²

Atypical mycobacterial infections initially may be misdiagnosed as SCC due to their tendency to induce irregular acanthosis in the form of pseudoepitheliomatous hyperplasia as well as mild keratinocyte atypia secondary to inflammation.^3,4 Our case is unique because it occurred with M marinum infection specifically. The histopathologic findings of M marinum infections are variable and may additionally include granulomas, most commonly suppurative; intraepithelial abscesses; small vessel proliferation; dermal fibrosis; multinucleated giant cells; and transepidermal elimination.^4,5 Periodic acid–Schiff, Ziehl-Neelsen (acid-fast bacilli), and Fite staining may be used to distinguish M marinum infection from SCC but have low sensitivities (approximately 30%). Culture remains the most reliable test, with a sensitivity of nearly 80%.^5-7 In our patient, a Periodic acid–Schiff stain was obtained prior to receiving culture results, and acid-fast bacilli and Fite staining were added after the culture returned positive; however, all 3 stains failed to highlight any mycobacteria.

The primary risk factor for infection with M marinum is contact with aquatic environments or marine animals, and most cases involve the fingers or the hand.⁶ After we reached the diagnosis and further discussed the patient’s history, he recalled fishing for and cleaning raw shrimp around the time that he had a splinter. The Infectious Diseases Society of America recommends a treatment course extending 1 to 2 months after clinical symptoms resolve with ethambutol in addition to clarithromycin or azithromycin.⁸ If the infection is near a joint, rifampin should be empirically added to account for a potentially deeper infection. Imaging should be obtained to evaluate for joint space involvement, with magnetic resonance imaging being the preferred modality. If joint space involvement is confirmed, surgical debridement is indicated. Surgical debridement also is indicated for infections that fail to respond to antibiotic therapy.⁸

This case highlights M marinum infection as a potential mimicker of SCC, particularly if the biopsy is relatively superficial, as often occurs when obtained via the common shave technique. The distinction is critical, as M marinum infection is highly treatable and inappropriate surgery on the typical hand and finger locations may subject patients to substantial morbidity, such as the need for a skin graft, reduced mobility from scarring, or risk for serious wound infection.⁹ For superficial biopsies of an atypical squamous process, pathologists also may consider routinely recommending tissue culture, especially for hand and finger locations or when a history of local trauma is reported, instead of recommending complete excision or repeat biopsy alone.

The Diagnosis: Sweet Syndrome (Acute Febrile Neutrophilic Dermatosis)

A skin biopsy of the right lower extremity demonstrated diffuse interstitial, perivascular, and periadnexal neutrophilic dermal infiltrate in the reticular dermis (Figure 1), consistent with a diagnosis of Sweet syndrome without evidence of leukemia cutis or infection. The firm erythematous papulonodules with follicular accentuation on the face (Figure 2) also were confirmed as Sweet syndrome on histopathology. Concern for leukemic transformation was confirmed with bone biopsy revealing acute myeloid leukemia (AML). Our patient began a short course of prednisone, and the cutaneous lesions improved during hospitalization; however, he was lost to follow-up.

Sweet syndrome (also known as acute febrile neutrophilic dermatosis) is a rare inflammatory skin condition typically characterized by asymmetric, painful, erythematous to violaceous papules, plaques, or nodules involving the arms, face, and neck.¹ It most commonly occurs in women and typically presents in patients aged 47 to 57 years. Although the pathogenesis of neutrophilic dermatoses is not completely understood, they are believed to be due to altered expression of inflammatory cytokines, irregular neutrophil function, and a genetic predisposition.² There are 3 main categories of Sweet syndrome: classical (or idiopathic), drug induced, and malignancy associated.¹ The lesions associated with Sweet syndrome vary from a few millimeters to several centimeters and may be annular or targetoid in the later stages. They also may form bullae and ulcerate. Fever, leukocytosis, and elevated acute-phase reactants also are common on presentation.1 Histopathologic analysis demonstrates an intense neutrophilic infiltrate within the reticular dermis with marked leukocytoclasia. Admixed within the neutrophil polymorphs are variable numbers of lymphocytes and histiocytes. Edema in the upper dermis also is characteristic.³ The exact pathogenesis of Sweet syndrome has yet to be elucidated but may involve a combination of cytokine dysregulation, hypersensitivity reactions, and genetics.⁴ Our case demonstrates 3 distinct morphologies of Sweet syndrome in a single patient, including classic edematous plaques, agminated targetoid plaques, and ulceration. Based on the clinical presentation, diagnostic workup for an undiagnosed malignancy was warranted, which confirmed AML. The malignancy-associated form of Sweet syndrome accounts for a substantial portion of cases, with approximately 21% of patients diagnosed with Sweet syndrome having an underlying malignancy, commonly a hematologic malignancy or myeloproliferative disorder with AML being the most common.¹

The differential diagnosis for Sweet syndrome includes cutaneous small vessel vasculitis, which commonly presents with symmetric palpable purpura of the legs. Lesions may be round, port wine–colored plaques and even may form ulcers, vesicles, and targetoid lesions. However, skin biopsy shows polymorphonuclear infiltrate affecting postcapillary venules, fibrinoid deposits, and extravasation of red blood cells.⁵ Leukemia cutis describes any type of leukemia that manifests in the skin. It typically presents as violaceous or red-brown papules, nodules, and plaques most commonly on the legs. Histopathology varies by immunophenotype but generally demonstrates perivascular or periadnexal involvement or a diffuse, interstitial, or nodular infiltrate of the dermis or subcutis.⁶ Neutrophilic eccrine hidradenitis describes an aseptic neutrophilic infiltration around eccrine coils and glands. It may present as papules or plaques that usually are erythematous but also may be pigmented. Lesions can be asymptomatic or painful as in Sweet syndrome and are distributed proximally or on the distal extremities. Histopathologic examination demonstrates the degeneration of the eccrine gland and neutrophilic inflammatory infiltrates.⁷ Lastly, necrotizing fasciitis is a life-threatening infection of the deep soft tissue and fascia, classically caused by group A Streptococcus. The infected site may have erythema, tenderness, fluctuance, necrosis, and bullae.8 Although our patient had a fever, he did not display the tachycardia, hypotension, tachypnea, and rapid deterioration that is common in necrotizing fasciitis.

Sweet syndrome may present with various morphologies within the same patient. Painful, erythematous to violaceous papules, plaques, nodules, bullae, and ulcers may be seen. A workup for an underlying malignancy may be warranted based on clinical presentation. Most patients have a rapid and dramatic response to systemic corticosteroids.

The Diagnosis: Sweet Syndrome (Acute Febrile Neutrophilic Dermatosis)

A skin biopsy of the right lower extremity demonstrated diffuse interstitial, perivascular, and periadnexal neutrophilic dermal infiltrate in the reticular dermis (Figure 1), consistent with a diagnosis of Sweet syndrome without evidence of leukemia cutis or infection. The firm erythematous papulonodules with follicular accentuation on the face (Figure 2) also were confirmed as Sweet syndrome on histopathology. Concern for leukemic transformation was confirmed with bone biopsy revealing acute myeloid leukemia (AML). Our patient began a short course of prednisone, and the cutaneous lesions improved during hospitalization; however, he was lost to follow-up.

Sweet syndrome (also known as acute febrile neutrophilic dermatosis) is a rare inflammatory skin condition typically characterized by asymmetric, painful, erythematous to violaceous papules, plaques, or nodules involving the arms, face, and neck.¹ It most commonly occurs in women and typically presents in patients aged 47 to 57 years. Although the pathogenesis of neutrophilic dermatoses is not completely understood, they are believed to be due to altered expression of inflammatory cytokines, irregular neutrophil function, and a genetic predisposition.² There are 3 main categories of Sweet syndrome: classical (or idiopathic), drug induced, and malignancy associated.¹ The lesions associated with Sweet syndrome vary from a few millimeters to several centimeters and may be annular or targetoid in the later stages. They also may form bullae and ulcerate. Fever, leukocytosis, and elevated acute-phase reactants also are common on presentation.1 Histopathologic analysis demonstrates an intense neutrophilic infiltrate within the reticular dermis with marked leukocytoclasia. Admixed within the neutrophil polymorphs are variable numbers of lymphocytes and histiocytes. Edema in the upper dermis also is characteristic.³ The exact pathogenesis of Sweet syndrome has yet to be elucidated but may involve a combination of cytokine dysregulation, hypersensitivity reactions, and genetics.⁴ Our case demonstrates 3 distinct morphologies of Sweet syndrome in a single patient, including classic edematous plaques, agminated targetoid plaques, and ulceration. Based on the clinical presentation, diagnostic workup for an undiagnosed malignancy was warranted, which confirmed AML. The malignancy-associated form of Sweet syndrome accounts for a substantial portion of cases, with approximately 21% of patients diagnosed with Sweet syndrome having an underlying malignancy, commonly a hematologic malignancy or myeloproliferative disorder with AML being the most common.¹

The differential diagnosis for Sweet syndrome includes cutaneous small vessel vasculitis, which commonly presents with symmetric palpable purpura of the legs. Lesions may be round, port wine–colored plaques and even may form ulcers, vesicles, and targetoid lesions. However, skin biopsy shows polymorphonuclear infiltrate affecting postcapillary venules, fibrinoid deposits, and extravasation of red blood cells.⁵ Leukemia cutis describes any type of leukemia that manifests in the skin. It typically presents as violaceous or red-brown papules, nodules, and plaques most commonly on the legs. Histopathology varies by immunophenotype but generally demonstrates perivascular or periadnexal involvement or a diffuse, interstitial, or nodular infiltrate of the dermis or subcutis.⁶ Neutrophilic eccrine hidradenitis describes an aseptic neutrophilic infiltration around eccrine coils and glands. It may present as papules or plaques that usually are erythematous but also may be pigmented. Lesions can be asymptomatic or painful as in Sweet syndrome and are distributed proximally or on the distal extremities. Histopathologic examination demonstrates the degeneration of the eccrine gland and neutrophilic inflammatory infiltrates.⁷ Lastly, necrotizing fasciitis is a life-threatening infection of the deep soft tissue and fascia, classically caused by group A Streptococcus. The infected site may have erythema, tenderness, fluctuance, necrosis, and bullae.8 Although our patient had a fever, he did not display the tachycardia, hypotension, tachypnea, and rapid deterioration that is common in necrotizing fasciitis.

Sweet syndrome may present with various morphologies within the same patient. Painful, erythematous to violaceous papules, plaques, nodules, bullae, and ulcers may be seen. A workup for an underlying malignancy may be warranted based on clinical presentation. Most patients have a rapid and dramatic response to systemic corticosteroids.

The Diagnosis: Sweet Syndrome (Acute Febrile Neutrophilic Dermatosis)

A skin biopsy of the right lower extremity demonstrated diffuse interstitial, perivascular, and periadnexal neutrophilic dermal infiltrate in the reticular dermis (Figure 1), consistent with a diagnosis of Sweet syndrome without evidence of leukemia cutis or infection. The firm erythematous papulonodules with follicular accentuation on the face (Figure 2) also were confirmed as Sweet syndrome on histopathology. Concern for leukemic transformation was confirmed with bone biopsy revealing acute myeloid leukemia (AML). Our patient began a short course of prednisone, and the cutaneous lesions improved during hospitalization; however, he was lost to follow-up.

Sweet syndrome (also known as acute febrile neutrophilic dermatosis) is a rare inflammatory skin condition typically characterized by asymmetric, painful, erythematous to violaceous papules, plaques, or nodules involving the arms, face, and neck.¹ It most commonly occurs in women and typically presents in patients aged 47 to 57 years. Although the pathogenesis of neutrophilic dermatoses is not completely understood, they are believed to be due to altered expression of inflammatory cytokines, irregular neutrophil function, and a genetic predisposition.² There are 3 main categories of Sweet syndrome: classical (or idiopathic), drug induced, and malignancy associated.¹ The lesions associated with Sweet syndrome vary from a few millimeters to several centimeters and may be annular or targetoid in the later stages. They also may form bullae and ulcerate. Fever, leukocytosis, and elevated acute-phase reactants also are common on presentation.1 Histopathologic analysis demonstrates an intense neutrophilic infiltrate within the reticular dermis with marked leukocytoclasia. Admixed within the neutrophil polymorphs are variable numbers of lymphocytes and histiocytes. Edema in the upper dermis also is characteristic.³ The exact pathogenesis of Sweet syndrome has yet to be elucidated but may involve a combination of cytokine dysregulation, hypersensitivity reactions, and genetics.⁴ Our case demonstrates 3 distinct morphologies of Sweet syndrome in a single patient, including classic edematous plaques, agminated targetoid plaques, and ulceration. Based on the clinical presentation, diagnostic workup for an undiagnosed malignancy was warranted, which confirmed AML. The malignancy-associated form of Sweet syndrome accounts for a substantial portion of cases, with approximately 21% of patients diagnosed with Sweet syndrome having an underlying malignancy, commonly a hematologic malignancy or myeloproliferative disorder with AML being the most common.¹

The differential diagnosis for Sweet syndrome includes cutaneous small vessel vasculitis, which commonly presents with symmetric palpable purpura of the legs. Lesions may be round, port wine–colored plaques and even may form ulcers, vesicles, and targetoid lesions. However, skin biopsy shows polymorphonuclear infiltrate affecting postcapillary venules, fibrinoid deposits, and extravasation of red blood cells.⁵ Leukemia cutis describes any type of leukemia that manifests in the skin. It typically presents as violaceous or red-brown papules, nodules, and plaques most commonly on the legs. Histopathology varies by immunophenotype but generally demonstrates perivascular or periadnexal involvement or a diffuse, interstitial, or nodular infiltrate of the dermis or subcutis.⁶ Neutrophilic eccrine hidradenitis describes an aseptic neutrophilic infiltration around eccrine coils and glands. It may present as papules or plaques that usually are erythematous but also may be pigmented. Lesions can be asymptomatic or painful as in Sweet syndrome and are distributed proximally or on the distal extremities. Histopathologic examination demonstrates the degeneration of the eccrine gland and neutrophilic inflammatory infiltrates.⁷ Lastly, necrotizing fasciitis is a life-threatening infection of the deep soft tissue and fascia, classically caused by group A Streptococcus. The infected site may have erythema, tenderness, fluctuance, necrosis, and bullae.8 Although our patient had a fever, he did not display the tachycardia, hypotension, tachypnea, and rapid deterioration that is common in necrotizing fasciitis.

Sweet syndrome may present with various morphologies within the same patient. Painful, erythematous to violaceous papules, plaques, nodules, bullae, and ulcers may be seen. A workup for an underlying malignancy may be warranted based on clinical presentation. Most patients have a rapid and dramatic response to systemic corticosteroids.

The Diagnosis: Hybrid Schwannoma-Perineurioma

Hybrid nerve sheath tumors are rare entities that display features of more than one nerve sheath tumor such as neurofibromas, schwannomas, and perineuriomas.¹ These tumors often are found in the dermis or subcutaneous tissue of the extremities and abdomen²; however, cases of hybrid peripheral nerve sheath tumors have been reported in many anatomical locations without a gender predilection.³ The most common type of hybrid nerve sheath tumor is a schwannoma-perineurioma.^3,4 Histologically, they are well-circumscribed lesions composed of both spindled Schwann cells with plump nuclei and spindled perineural cells with more elongated thin nuclei.⁵ Although the Schwann cell component tends to predominate, the 2 cell populations interdigitate, making it challenging to definitively distinguish them by hematoxylin and eosin staining alone.4 However, immunohistochemical (IHC) staining can be used to help distinguish the 2 separate cell populations. Staining for S-100 and SRY-box transcription factor 10 (SOX-10) will be positive in the Schwann cell component, and staining for epithelial membrane antigen, Claudin-1, or glucose transporter-1 (Figure 1) will be positive in the perineural component. Other hybrid forms of benign nerve sheath tumors include neurofibroma-schwannoma and neurofibromaperineurioma.⁴ Neurofibroma-schwannomas usually have a schwannoma component containing Antoni A areas with palisading Verocay bodies. The neurofibroma cells typically have wavy elongated nuclei, fibroblasts, and mucinous myxoid material.³ Neurofibroma-perineurioma is the least common hybrid tumor. These hybrid tumors have a plexiform neurofibroma appearance with areas of perineural differentiation, which can be difficult to identify on routine histology and typically will require IHC staining to appreciate. The neurofibroma component will stain positive for S-100 and negative for markers of perineural differentiation, including epithelial membrane antigen, glucose transporter-1, and Claudin-1.³ Although schwannoma-perineuriomas are benign sporadic tumors not associated with neurofibromatosis, neurofibromaschwannomas are associated with neurofibromatosis types 1 and 2 (NF1 and NF2). Neurofibroma-perineurioma tumors usually are associated with only NF1.^3,6

Schwannomas typically present in middle-aged patients as tumors located on flexor surfaces.⁷ Although perineural cells can be seen at the periphery of a schwannoma forming a capsule, they do not interdigitate between the Schwann cells. Schwannomas are composed almost entirely of well-differentiated Schwann cells.^1,4,8 Schwannomas classically are well-circumscribed, encapsulated, biphasic lesions with alternating compact areas (Antoni A) and loosely arranged areas (Antoni B). The spindled cells occasionally may display nuclear palisading within the Antoni A areas, known as Verocay bodies (Figure 2). Antoni B areas are more disorganized and hypocellular with variable macrophage infiltrate.^1,4,8 The Schwann cells predominantly will have bland cytologic features, but scattered areas of degenerative nuclear atypia (also known as ancient change) may be present.⁴ Multiple schwannomas are associated with NF2 gene mutations and loss of merlin protein.8 There are different subtypes of schwannomas, including cellular and plexiform schwannomas.⁴ Because schwannomas are benign nerve sheath lesions, treatment typically consists of excision with careful dissection around the involved nerve.⁹

Neurofibromas are the most common peripheral nerve sheath tumors of the skin with no notable anatomic prediction, though one study found them to be more prevalent in the upper extremities.¹⁰ They typically present as sporadic solitary lesions, but multiple lesions may appear as superficial pedunculated growths that present in those aged 20 to 30 years.¹¹ Microscopically, neurofibromas typically are not well circumscribed and have an infiltrative growth pattern. Neurofibromas are composed of cytologically bland spindled Schwann cells with thin wavy nuclei in a variable myxoid stroma (Figure 3). In addition to Schwann cells, neurofibromas contain other cell components, including fibroblasts, mast cells, perineurial-like cells, and residual axons.⁴ Neurofibromas typically are located in the dermis but may extend into the subcutaneous tissue. Clinically, the overlying skin may show hyperpigmentation.8 Neurofibromas can be localized, diffuse, or plexiform, with the majority being localized. Diffuse neurofibromas clinically have a raised plaque appearance. Treatment is unnecessary because these lesions are benign.⁷

Desmoplastic melanoma (DM) is another diagnosis in the differential for this case. Patients with DM are older compared to non-DM melanoma patients, with a male predilection.¹² Desmoplastic melanomas are more likely to be located on the head and neck. In approximately one-third of cases, no in situ component will be identified, leading to confusion of the dermal lesion as a neural lesion or an area of scar formation. Microscopically, DM presents as a variable cellular infiltrative tumor composed of spindle cells with varying degrees of nuclear atypia. The spindled melanocytes are within a collagenous (desmoplastic) stroma (Figure 4).¹³ Desmoplastic melanoma has been described with a low mitotic index, leading to misdiagnosis with benign spindle cell neoplasms.¹⁴ The spindle cells should be positive for S-100 and SOX-10 with IHC staining. Unlike other melanomas, human melanoma black 45 and Melan-A often are negative or only focally positive. Treatment of DM is similar to non-DM in that wide local excision usually is employed. A systematic review evaluating sentinel lymph node biopsy (SLNB) recommended consideration of SLNB in mixed DM but not for pure DM, as rates of positive SLNB were much lower in the latter.¹⁵

Patients with malignant peripheral nerve sheath tumor (MPNST) usually present with an enlarging mass, pain, or neurologic symptoms. Most cases of MPNST are located on the trunk or extremities.¹⁶ Plexiform neurofibromas, especially in adults with NF1, have the potential to transform into an MPNST.⁴ In fact, MPNST is the most common malignancy in patients with NF1.¹⁷ Pediatric cancer survivors also are predisposed to MPNST, with a 40-fold increase in incidence compared to the general population.¹⁸ Transformation from schwannoma to MPNST is rare but has been reported.⁸ Histologically, spindle cells easily can be appreciated with a fasciculated growth pattern (Figure 5). Mitotic activity and tumor necrosis may be present. Diagnosis of these tumors historically has been challenging, though recent research has identified inactivation of polycomb repressive complex 2 in 70% to 90% of MPNSTs. Because of polycomb repressive complex 2 inactivation, there is loss of stone H3K27 trimethylation that can be capitalized on for MPNST diagnosis.¹⁹ Negative IHC staining for H3K27 trimethylation has been found to be highly specific for MPNST. Negative staining for different cytokeratin and melanoma markers can be helpful in differentiating it from carcinomas and melanoma. The only curative treatment for MPNST is complete excision, leaving patients with recurrent, refractory, and metastatic cases to be encouraged for enrollment in clinical trials. The 5-year survival rates for patients with MPNST reported in the literature range from 20% to 50%.²⁰

The Diagnosis: Hybrid Schwannoma-Perineurioma

Hybrid nerve sheath tumors are rare entities that display features of more than one nerve sheath tumor such as neurofibromas, schwannomas, and perineuriomas.¹ These tumors often are found in the dermis or subcutaneous tissue of the extremities and abdomen²; however, cases of hybrid peripheral nerve sheath tumors have been reported in many anatomical locations without a gender predilection.³ The most common type of hybrid nerve sheath tumor is a schwannoma-perineurioma.^3,4 Histologically, they are well-circumscribed lesions composed of both spindled Schwann cells with plump nuclei and spindled perineural cells with more elongated thin nuclei.⁵ Although the Schwann cell component tends to predominate, the 2 cell populations interdigitate, making it challenging to definitively distinguish them by hematoxylin and eosin staining alone.4 However, immunohistochemical (IHC) staining can be used to help distinguish the 2 separate cell populations. Staining for S-100 and SRY-box transcription factor 10 (SOX-10) will be positive in the Schwann cell component, and staining for epithelial membrane antigen, Claudin-1, or glucose transporter-1 (Figure 1) will be positive in the perineural component. Other hybrid forms of benign nerve sheath tumors include neurofibroma-schwannoma and neurofibromaperineurioma.⁴ Neurofibroma-schwannomas usually have a schwannoma component containing Antoni A areas with palisading Verocay bodies. The neurofibroma cells typically have wavy elongated nuclei, fibroblasts, and mucinous myxoid material.³ Neurofibroma-perineurioma is the least common hybrid tumor. These hybrid tumors have a plexiform neurofibroma appearance with areas of perineural differentiation, which can be difficult to identify on routine histology and typically will require IHC staining to appreciate. The neurofibroma component will stain positive for S-100 and negative for markers of perineural differentiation, including epithelial membrane antigen, glucose transporter-1, and Claudin-1.³ Although schwannoma-perineuriomas are benign sporadic tumors not associated with neurofibromatosis, neurofibromaschwannomas are associated with neurofibromatosis types 1 and 2 (NF1 and NF2). Neurofibroma-perineurioma tumors usually are associated with only NF1.^3,6

Schwannomas typically present in middle-aged patients as tumors located on flexor surfaces.⁷ Although perineural cells can be seen at the periphery of a schwannoma forming a capsule, they do not interdigitate between the Schwann cells. Schwannomas are composed almost entirely of well-differentiated Schwann cells.^1,4,8 Schwannomas classically are well-circumscribed, encapsulated, biphasic lesions with alternating compact areas (Antoni A) and loosely arranged areas (Antoni B). The spindled cells occasionally may display nuclear palisading within the Antoni A areas, known as Verocay bodies (Figure 2). Antoni B areas are more disorganized and hypocellular with variable macrophage infiltrate.^1,4,8 The Schwann cells predominantly will have bland cytologic features, but scattered areas of degenerative nuclear atypia (also known as ancient change) may be present.⁴ Multiple schwannomas are associated with NF2 gene mutations and loss of merlin protein.8 There are different subtypes of schwannomas, including cellular and plexiform schwannomas.⁴ Because schwannomas are benign nerve sheath lesions, treatment typically consists of excision with careful dissection around the involved nerve.⁹

Neurofibromas are the most common peripheral nerve sheath tumors of the skin with no notable anatomic prediction, though one study found them to be more prevalent in the upper extremities.¹⁰ They typically present as sporadic solitary lesions, but multiple lesions may appear as superficial pedunculated growths that present in those aged 20 to 30 years.¹¹ Microscopically, neurofibromas typically are not well circumscribed and have an infiltrative growth pattern. Neurofibromas are composed of cytologically bland spindled Schwann cells with thin wavy nuclei in a variable myxoid stroma (Figure 3). In addition to Schwann cells, neurofibromas contain other cell components, including fibroblasts, mast cells, perineurial-like cells, and residual axons.⁴ Neurofibromas typically are located in the dermis but may extend into the subcutaneous tissue. Clinically, the overlying skin may show hyperpigmentation.8 Neurofibromas can be localized, diffuse, or plexiform, with the majority being localized. Diffuse neurofibromas clinically have a raised plaque appearance. Treatment is unnecessary because these lesions are benign.⁷

Desmoplastic melanoma (DM) is another diagnosis in the differential for this case. Patients with DM are older compared to non-DM melanoma patients, with a male predilection.¹² Desmoplastic melanomas are more likely to be located on the head and neck. In approximately one-third of cases, no in situ component will be identified, leading to confusion of the dermal lesion as a neural lesion or an area of scar formation. Microscopically, DM presents as a variable cellular infiltrative tumor composed of spindle cells with varying degrees of nuclear atypia. The spindled melanocytes are within a collagenous (desmoplastic) stroma (Figure 4).¹³ Desmoplastic melanoma has been described with a low mitotic index, leading to misdiagnosis with benign spindle cell neoplasms.¹⁴ The spindle cells should be positive for S-100 and SOX-10 with IHC staining. Unlike other melanomas, human melanoma black 45 and Melan-A often are negative or only focally positive. Treatment of DM is similar to non-DM in that wide local excision usually is employed. A systematic review evaluating sentinel lymph node biopsy (SLNB) recommended consideration of SLNB in mixed DM but not for pure DM, as rates of positive SLNB were much lower in the latter.¹⁵

Patients with malignant peripheral nerve sheath tumor (MPNST) usually present with an enlarging mass, pain, or neurologic symptoms. Most cases of MPNST are located on the trunk or extremities.¹⁶ Plexiform neurofibromas, especially in adults with NF1, have the potential to transform into an MPNST.⁴ In fact, MPNST is the most common malignancy in patients with NF1.¹⁷ Pediatric cancer survivors also are predisposed to MPNST, with a 40-fold increase in incidence compared to the general population.¹⁸ Transformation from schwannoma to MPNST is rare but has been reported.⁸ Histologically, spindle cells easily can be appreciated with a fasciculated growth pattern (Figure 5). Mitotic activity and tumor necrosis may be present. Diagnosis of these tumors historically has been challenging, though recent research has identified inactivation of polycomb repressive complex 2 in 70% to 90% of MPNSTs. Because of polycomb repressive complex 2 inactivation, there is loss of stone H3K27 trimethylation that can be capitalized on for MPNST diagnosis.¹⁹ Negative IHC staining for H3K27 trimethylation has been found to be highly specific for MPNST. Negative staining for different cytokeratin and melanoma markers can be helpful in differentiating it from carcinomas and melanoma. The only curative treatment for MPNST is complete excision, leaving patients with recurrent, refractory, and metastatic cases to be encouraged for enrollment in clinical trials. The 5-year survival rates for patients with MPNST reported in the literature range from 20% to 50%.²⁰

The Diagnosis: Hybrid Schwannoma-Perineurioma

Hybrid nerve sheath tumors are rare entities that display features of more than one nerve sheath tumor such as neurofibromas, schwannomas, and perineuriomas.¹ These tumors often are found in the dermis or subcutaneous tissue of the extremities and abdomen²; however, cases of hybrid peripheral nerve sheath tumors have been reported in many anatomical locations without a gender predilection.³ The most common type of hybrid nerve sheath tumor is a schwannoma-perineurioma.^3,4 Histologically, they are well-circumscribed lesions composed of both spindled Schwann cells with plump nuclei and spindled perineural cells with more elongated thin nuclei.⁵ Although the Schwann cell component tends to predominate, the 2 cell populations interdigitate, making it challenging to definitively distinguish them by hematoxylin and eosin staining alone.4 However, immunohistochemical (IHC) staining can be used to help distinguish the 2 separate cell populations. Staining for S-100 and SRY-box transcription factor 10 (SOX-10) will be positive in the Schwann cell component, and staining for epithelial membrane antigen, Claudin-1, or glucose transporter-1 (Figure 1) will be positive in the perineural component. Other hybrid forms of benign nerve sheath tumors include neurofibroma-schwannoma and neurofibromaperineurioma.⁴ Neurofibroma-schwannomas usually have a schwannoma component containing Antoni A areas with palisading Verocay bodies. The neurofibroma cells typically have wavy elongated nuclei, fibroblasts, and mucinous myxoid material.³ Neurofibroma-perineurioma is the least common hybrid tumor. These hybrid tumors have a plexiform neurofibroma appearance with areas of perineural differentiation, which can be difficult to identify on routine histology and typically will require IHC staining to appreciate. The neurofibroma component will stain positive for S-100 and negative for markers of perineural differentiation, including epithelial membrane antigen, glucose transporter-1, and Claudin-1.³ Although schwannoma-perineuriomas are benign sporadic tumors not associated with neurofibromatosis, neurofibromaschwannomas are associated with neurofibromatosis types 1 and 2 (NF1 and NF2). Neurofibroma-perineurioma tumors usually are associated with only NF1.^3,6

Schwannomas typically present in middle-aged patients as tumors located on flexor surfaces.⁷ Although perineural cells can be seen at the periphery of a schwannoma forming a capsule, they do not interdigitate between the Schwann cells. Schwannomas are composed almost entirely of well-differentiated Schwann cells.^1,4,8 Schwannomas classically are well-circumscribed, encapsulated, biphasic lesions with alternating compact areas (Antoni A) and loosely arranged areas (Antoni B). The spindled cells occasionally may display nuclear palisading within the Antoni A areas, known as Verocay bodies (Figure 2). Antoni B areas are more disorganized and hypocellular with variable macrophage infiltrate.^1,4,8 The Schwann cells predominantly will have bland cytologic features, but scattered areas of degenerative nuclear atypia (also known as ancient change) may be present.⁴ Multiple schwannomas are associated with NF2 gene mutations and loss of merlin protein.8 There are different subtypes of schwannomas, including cellular and plexiform schwannomas.⁴ Because schwannomas are benign nerve sheath lesions, treatment typically consists of excision with careful dissection around the involved nerve.⁹

Neurofibromas are the most common peripheral nerve sheath tumors of the skin with no notable anatomic prediction, though one study found them to be more prevalent in the upper extremities.¹⁰ They typically present as sporadic solitary lesions, but multiple lesions may appear as superficial pedunculated growths that present in those aged 20 to 30 years.¹¹ Microscopically, neurofibromas typically are not well circumscribed and have an infiltrative growth pattern. Neurofibromas are composed of cytologically bland spindled Schwann cells with thin wavy nuclei in a variable myxoid stroma (Figure 3). In addition to Schwann cells, neurofibromas contain other cell components, including fibroblasts, mast cells, perineurial-like cells, and residual axons.⁴ Neurofibromas typically are located in the dermis but may extend into the subcutaneous tissue. Clinically, the overlying skin may show hyperpigmentation.8 Neurofibromas can be localized, diffuse, or plexiform, with the majority being localized. Diffuse neurofibromas clinically have a raised plaque appearance. Treatment is unnecessary because these lesions are benign.⁷

Desmoplastic melanoma (DM) is another diagnosis in the differential for this case. Patients with DM are older compared to non-DM melanoma patients, with a male predilection.¹² Desmoplastic melanomas are more likely to be located on the head and neck. In approximately one-third of cases, no in situ component will be identified, leading to confusion of the dermal lesion as a neural lesion or an area of scar formation. Microscopically, DM presents as a variable cellular infiltrative tumor composed of spindle cells with varying degrees of nuclear atypia. The spindled melanocytes are within a collagenous (desmoplastic) stroma (Figure 4).¹³ Desmoplastic melanoma has been described with a low mitotic index, leading to misdiagnosis with benign spindle cell neoplasms.¹⁴ The spindle cells should be positive for S-100 and SOX-10 with IHC staining. Unlike other melanomas, human melanoma black 45 and Melan-A often are negative or only focally positive. Treatment of DM is similar to non-DM in that wide local excision usually is employed. A systematic review evaluating sentinel lymph node biopsy (SLNB) recommended consideration of SLNB in mixed DM but not for pure DM, as rates of positive SLNB were much lower in the latter.¹⁵

Patients with malignant peripheral nerve sheath tumor (MPNST) usually present with an enlarging mass, pain, or neurologic symptoms. Most cases of MPNST are located on the trunk or extremities.¹⁶ Plexiform neurofibromas, especially in adults with NF1, have the potential to transform into an MPNST.⁴ In fact, MPNST is the most common malignancy in patients with NF1.¹⁷ Pediatric cancer survivors also are predisposed to MPNST, with a 40-fold increase in incidence compared to the general population.¹⁸ Transformation from schwannoma to MPNST is rare but has been reported.⁸ Histologically, spindle cells easily can be appreciated with a fasciculated growth pattern (Figure 5). Mitotic activity and tumor necrosis may be present. Diagnosis of these tumors historically has been challenging, though recent research has identified inactivation of polycomb repressive complex 2 in 70% to 90% of MPNSTs. Because of polycomb repressive complex 2 inactivation, there is loss of stone H3K27 trimethylation that can be capitalized on for MPNST diagnosis.¹⁹ Negative IHC staining for H3K27 trimethylation has been found to be highly specific for MPNST. Negative staining for different cytokeratin and melanoma markers can be helpful in differentiating it from carcinomas and melanoma. The only curative treatment for MPNST is complete excision, leaving patients with recurrent, refractory, and metastatic cases to be encouraged for enrollment in clinical trials. The 5-year survival rates for patients with MPNST reported in the literature range from 20% to 50%.²⁰

New Year, New Codes: A Win-Win for Digital Pathology

In July 2022, the American Medical Association CPT (Current Procedural Terminology) Editorial Panel released 13 new digital pathology add-on Category III codes for 2023 that the College of American Pathologists successfully advocated for inclusion.¹ These codes are for reporting additional clinical staff work and service requirements associated with digitizing glass microscope slides for primary diagnosis (Table). They go into effect on January 1, 2023.

Although there is no additional compensation with the new Category III codes, dermatopathology laboratories will be able to report when they have made a diagnosis using digital pathology. The new CPT codes will provide payers with data they need to directly understand the utilization and increased value of digital pathology, which will bring dermatopathology laboratories one step closer to receiving additional reimbursement for digital interpretation.

The adoption of digital pathology has been accelerating in the United States but still lags behind many European countries where reimbursement for digital pathology has been established for many years. Many of the barriers to digital pathology have improved—cloud storage is more affordable, scanners have a higher throughput, digital pathology platforms have improved, and the US Food and Drug Administration has granted approvals for digital pathology. Digital pathology allows for more efficient workflow, which results in increased productivity and a reduction in turnaround times. It also allows for a wide spectrum of clinical applications and more innovation as well as research and educational applications.

The new Category III codes cannot be reported solely for archival purposes (eg, after the Category I service has already been performed and reported), solely for educational purposes (eg, when services are not used for individual patient reporting), solely for developing a database for training or validation of artificial intelligence algorithms, and solely for clinical conference presentations (eg, tumor board interdisciplinary conferences).

The new codes are a major victory for the adoption and future compensation for digital pathology.

New Year, New Cuts: Proposed 2023 Medicare Policy and Payment Changes for Dermatologists

The United States Spent $3.8 Trillion on Health Care in 2019: Where Did It Go?—In 2019, approximately $3.8 trillion was spent on health care in the United States (Figure 1). Physician services accounted for approximately 15% of total health care spending.²

Medicare Payments for Physician Services—Medicare payments for physician services are determined by a relative value unit (RVU) multiplied by a conversion factor (CF). Relative value units were set up in 1992 by what is now the Centers for Medicare & Medicaid Services, and they calculated the time it took a physician to complete a task or RVU and multiplied it by $32.00 (CF).³

Thirty years later—in 2022—the CF is $34.61. If the CF had increased with inflation, it would be $59.00. If the Proposed Rule is adopted, the 2023 fee schedule payment formula would decrease by 4.4% (to $33.08) relative to that of the 2022 fee schedule ($34.61), which is a decrease of 8.2% since 2019 ($36.04). This decrease is due to expiration of the 3% increase to Medicare fee schedule payments for 2022 required by the Protecting Medicare and American Farmers from Sequester Cuts Act and the required budget neutrality adjustment required by changes in RVUs. Medicare physician payment has declined 22% from 2001 to 2022 (Figure 2).^4,5

The adjustments to the CF typically are made based on 3 factors: (1) the Medicare Economic Index; (2) expenditure target “performance adjustment”; and (3) miscellaneous adjustments, including those for “budget neutrality” required by law.

Medicare Physician Payments Compared With Other Provider Types and Inflation—The proposed Medicare physician payment policy is unsustainable for outpatient dermatologists. Practice overhead has increased markedly since 1992. Other service providers, such as those in skilled nursing facilities and hospitals (Figure 3), have received favorable payment increases compared with practice cost inflation and the Consumer Price Index.^3-6 Flat reimbursement affects all physicians who accept insurance, as even private insurers base their reimbursement on Medicare.

In addition, there are other issues resulting in decreased physician payments when evaluation and management services are reported with same-day procedures using modifier −25 as well as preserving or finding alternative strategies for 10- and 90-day global period payments for medical procedures. When Medicare cuts physician payments, dermatologists find it difficult to own and operate their own practices, resulting in health market consolidation, limited competition, increased health care costs, limited patient access to care, and decreased quality of health care.

Medicare Payment Reform—Medicare payment reform is necessary to stop annual payment cuts and create a stable predictable payment system that ensures patient access to quality, value-based care. Medicare physician payment reform needs to happen at a national level. The American Academy of Dermatology Association (AADA) is working with the House of Medicine and the medical specialty community to develop specific proposals, such as “Characteristics of a Rational Medicare Physician Payment System,” to reform Medicare’s payment system.⁷ Advocacy groups, including the AADA, have been working to mitigate the proposed 2023 cuts by engaging with Congress and urging them to act before these changes go into effect on January 1, 2023.

Make Advocacy Your New Year’s Resolution: AADA’s Top Advocacy Priorities

The AADA’s top priority is Medicare payment policies.³ In addition, the AADA is working on drug access and cost by cutting the bureaucratic red tape caused by prior authorization (PA) and step therapy policies. The AADA collaborates with manufacturers, the health care community, policymakers, private payers, pharmacists, pharmacy benefit managers, and patients to minimize and/or eliminate barriers that patients face in accessing needed medications. Specifically, the AADA advocates for legislation that limits obstacles associated with health insurance step therapy requirements, streamlines PA, and prohibits mid-year formulary changes.⁸

Step therapy requires that patients first try a medication specified by the insurance company; the therapy must fail before the patient is placed on the medication originally prescribed by the provider. Regarding PA, the AADA tries to ensure that determinations are standardized, requires the speed of determinations to be quantified and minimized, and ensures that PA and appeals policies do not unduly burden physicians or patients in accessing optimal drug therapy.⁸

Another advocacy priority is telehealth. The AADA is advocating for legislation on expansion of telehealth in underserved areas and modifications to state licensure requirements, liability issues, and reimbursement for store-and-forward technology. The AADA is involved in protecting scope of practice, truth in advertising, and access to specialty care, as well as monitoring legislation and regulation concerning the potential environmental impact of sunscreen ingredients, indoor tanning restrictions, and skin cancer prevention.⁸

Advocacy Matters and Makes a Difference—It is important to learn about and support advocacy priorities and efforts and join forces to protect your practice. The AADA advocacy priorities are to protect the value of dermatology services, mobilize dermatologists for political action, ensure dermatologists can participate in new payment models, and strengthen the profession.⁹ Physician advocacy is no longer an elective pursuit. We need to be involved and engaged through our medical societies to help patients, communities, and ourselves. All of us are in it together, and a collaborative collective voice can make a difference. Take action, join the AADA, and contact Congress today to stop Medicare payment cuts (https://takeaction.aad.org/).

New Year, New Codes: A Win-Win for Digital Pathology

In July 2022, the American Medical Association CPT (Current Procedural Terminology) Editorial Panel released 13 new digital pathology add-on Category III codes for 2023 that the College of American Pathologists successfully advocated for inclusion.¹ These codes are for reporting additional clinical staff work and service requirements associated with digitizing glass microscope slides for primary diagnosis (Table). They go into effect on January 1, 2023.

Although there is no additional compensation with the new Category III codes, dermatopathology laboratories will be able to report when they have made a diagnosis using digital pathology. The new CPT codes will provide payers with data they need to directly understand the utilization and increased value of digital pathology, which will bring dermatopathology laboratories one step closer to receiving additional reimbursement for digital interpretation.

The adoption of digital pathology has been accelerating in the United States but still lags behind many European countries where reimbursement for digital pathology has been established for many years. Many of the barriers to digital pathology have improved—cloud storage is more affordable, scanners have a higher throughput, digital pathology platforms have improved, and the US Food and Drug Administration has granted approvals for digital pathology. Digital pathology allows for more efficient workflow, which results in increased productivity and a reduction in turnaround times. It also allows for a wide spectrum of clinical applications and more innovation as well as research and educational applications.

The new Category III codes cannot be reported solely for archival purposes (eg, after the Category I service has already been performed and reported), solely for educational purposes (eg, when services are not used for individual patient reporting), solely for developing a database for training or validation of artificial intelligence algorithms, and solely for clinical conference presentations (eg, tumor board interdisciplinary conferences).

The new codes are a major victory for the adoption and future compensation for digital pathology.

New Year, New Cuts: Proposed 2023 Medicare Policy and Payment Changes for Dermatologists

The United States Spent $3.8 Trillion on Health Care in 2019: Where Did It Go?—In 2019, approximately $3.8 trillion was spent on health care in the United States (Figure 1). Physician services accounted for approximately 15% of total health care spending.²

Medicare Payments for Physician Services—Medicare payments for physician services are determined by a relative value unit (RVU) multiplied by a conversion factor (CF). Relative value units were set up in 1992 by what is now the Centers for Medicare & Medicaid Services, and they calculated the time it took a physician to complete a task or RVU and multiplied it by $32.00 (CF).³

Thirty years later—in 2022—the CF is $34.61. If the CF had increased with inflation, it would be $59.00. If the Proposed Rule is adopted, the 2023 fee schedule payment formula would decrease by 4.4% (to $33.08) relative to that of the 2022 fee schedule ($34.61), which is a decrease of 8.2% since 2019 ($36.04). This decrease is due to expiration of the 3% increase to Medicare fee schedule payments for 2022 required by the Protecting Medicare and American Farmers from Sequester Cuts Act and the required budget neutrality adjustment required by changes in RVUs. Medicare physician payment has declined 22% from 2001 to 2022 (Figure 2).^4,5

The adjustments to the CF typically are made based on 3 factors: (1) the Medicare Economic Index; (2) expenditure target “performance adjustment”; and (3) miscellaneous adjustments, including those for “budget neutrality” required by law.

Medicare Physician Payments Compared With Other Provider Types and Inflation—The proposed Medicare physician payment policy is unsustainable for outpatient dermatologists. Practice overhead has increased markedly since 1992. Other service providers, such as those in skilled nursing facilities and hospitals (Figure 3), have received favorable payment increases compared with practice cost inflation and the Consumer Price Index.^3-6 Flat reimbursement affects all physicians who accept insurance, as even private insurers base their reimbursement on Medicare.

In addition, there are other issues resulting in decreased physician payments when evaluation and management services are reported with same-day procedures using modifier −25 as well as preserving or finding alternative strategies for 10- and 90-day global period payments for medical procedures. When Medicare cuts physician payments, dermatologists find it difficult to own and operate their own practices, resulting in health market consolidation, limited competition, increased health care costs, limited patient access to care, and decreased quality of health care.

Medicare Payment Reform—Medicare payment reform is necessary to stop annual payment cuts and create a stable predictable payment system that ensures patient access to quality, value-based care. Medicare physician payment reform needs to happen at a national level. The American Academy of Dermatology Association (AADA) is working with the House of Medicine and the medical specialty community to develop specific proposals, such as “Characteristics of a Rational Medicare Physician Payment System,” to reform Medicare’s payment system.⁷ Advocacy groups, including the AADA, have been working to mitigate the proposed 2023 cuts by engaging with Congress and urging them to act before these changes go into effect on January 1, 2023.

Make Advocacy Your New Year’s Resolution: AADA’s Top Advocacy Priorities

The AADA’s top priority is Medicare payment policies.³ In addition, the AADA is working on drug access and cost by cutting the bureaucratic red tape caused by prior authorization (PA) and step therapy policies. The AADA collaborates with manufacturers, the health care community, policymakers, private payers, pharmacists, pharmacy benefit managers, and patients to minimize and/or eliminate barriers that patients face in accessing needed medications. Specifically, the AADA advocates for legislation that limits obstacles associated with health insurance step therapy requirements, streamlines PA, and prohibits mid-year formulary changes.⁸

Step therapy requires that patients first try a medication specified by the insurance company; the therapy must fail before the patient is placed on the medication originally prescribed by the provider. Regarding PA, the AADA tries to ensure that determinations are standardized, requires the speed of determinations to be quantified and minimized, and ensures that PA and appeals policies do not unduly burden physicians or patients in accessing optimal drug therapy.⁸

Another advocacy priority is telehealth. The AADA is advocating for legislation on expansion of telehealth in underserved areas and modifications to state licensure requirements, liability issues, and reimbursement for store-and-forward technology. The AADA is involved in protecting scope of practice, truth in advertising, and access to specialty care, as well as monitoring legislation and regulation concerning the potential environmental impact of sunscreen ingredients, indoor tanning restrictions, and skin cancer prevention.⁸

Advocacy Matters and Makes a Difference—It is important to learn about and support advocacy priorities and efforts and join forces to protect your practice. The AADA advocacy priorities are to protect the value of dermatology services, mobilize dermatologists for political action, ensure dermatologists can participate in new payment models, and strengthen the profession.⁹ Physician advocacy is no longer an elective pursuit. We need to be involved and engaged through our medical societies to help patients, communities, and ourselves. All of us are in it together, and a collaborative collective voice can make a difference. Take action, join the AADA, and contact Congress today to stop Medicare payment cuts (https://takeaction.aad.org/).

New Year, New Codes: A Win-Win for Digital Pathology

In July 2022, the American Medical Association CPT (Current Procedural Terminology) Editorial Panel released 13 new digital pathology add-on Category III codes for 2023 that the College of American Pathologists successfully advocated for inclusion.¹ These codes are for reporting additional clinical staff work and service requirements associated with digitizing glass microscope slides for primary diagnosis (Table). They go into effect on January 1, 2023.

Although there is no additional compensation with the new Category III codes, dermatopathology laboratories will be able to report when they have made a diagnosis using digital pathology. The new CPT codes will provide payers with data they need to directly understand the utilization and increased value of digital pathology, which will bring dermatopathology laboratories one step closer to receiving additional reimbursement for digital interpretation.

The adoption of digital pathology has been accelerating in the United States but still lags behind many European countries where reimbursement for digital pathology has been established for many years. Many of the barriers to digital pathology have improved—cloud storage is more affordable, scanners have a higher throughput, digital pathology platforms have improved, and the US Food and Drug Administration has granted approvals for digital pathology. Digital pathology allows for more efficient workflow, which results in increased productivity and a reduction in turnaround times. It also allows for a wide spectrum of clinical applications and more innovation as well as research and educational applications.

The new Category III codes cannot be reported solely for archival purposes (eg, after the Category I service has already been performed and reported), solely for educational purposes (eg, when services are not used for individual patient reporting), solely for developing a database for training or validation of artificial intelligence algorithms, and solely for clinical conference presentations (eg, tumor board interdisciplinary conferences).

The new codes are a major victory for the adoption and future compensation for digital pathology.

New Year, New Cuts: Proposed 2023 Medicare Policy and Payment Changes for Dermatologists

The United States Spent $3.8 Trillion on Health Care in 2019: Where Did It Go?—In 2019, approximately $3.8 trillion was spent on health care in the United States (Figure 1). Physician services accounted for approximately 15% of total health care spending.²

Medicare Payments for Physician Services—Medicare payments for physician services are determined by a relative value unit (RVU) multiplied by a conversion factor (CF). Relative value units were set up in 1992 by what is now the Centers for Medicare & Medicaid Services, and they calculated the time it took a physician to complete a task or RVU and multiplied it by $32.00 (CF).³

Thirty years later—in 2022—the CF is $34.61. If the CF had increased with inflation, it would be $59.00. If the Proposed Rule is adopted, the 2023 fee schedule payment formula would decrease by 4.4% (to $33.08) relative to that of the 2022 fee schedule ($34.61), which is a decrease of 8.2% since 2019 ($36.04). This decrease is due to expiration of the 3% increase to Medicare fee schedule payments for 2022 required by the Protecting Medicare and American Farmers from Sequester Cuts Act and the required budget neutrality adjustment required by changes in RVUs. Medicare physician payment has declined 22% from 2001 to 2022 (Figure 2).^4,5

The adjustments to the CF typically are made based on 3 factors: (1) the Medicare Economic Index; (2) expenditure target “performance adjustment”; and (3) miscellaneous adjustments, including those for “budget neutrality” required by law.

Medicare Physician Payments Compared With Other Provider Types and Inflation—The proposed Medicare physician payment policy is unsustainable for outpatient dermatologists. Practice overhead has increased markedly since 1992. Other service providers, such as those in skilled nursing facilities and hospitals (Figure 3), have received favorable payment increases compared with practice cost inflation and the Consumer Price Index.^3-6 Flat reimbursement affects all physicians who accept insurance, as even private insurers base their reimbursement on Medicare.

In addition, there are other issues resulting in decreased physician payments when evaluation and management services are reported with same-day procedures using modifier −25 as well as preserving or finding alternative strategies for 10- and 90-day global period payments for medical procedures. When Medicare cuts physician payments, dermatologists find it difficult to own and operate their own practices, resulting in health market consolidation, limited competition, increased health care costs, limited patient access to care, and decreased quality of health care.

Medicare Payment Reform—Medicare payment reform is necessary to stop annual payment cuts and create a stable predictable payment system that ensures patient access to quality, value-based care. Medicare physician payment reform needs to happen at a national level. The American Academy of Dermatology Association (AADA) is working with the House of Medicine and the medical specialty community to develop specific proposals, such as “Characteristics of a Rational Medicare Physician Payment System,” to reform Medicare’s payment system.⁷ Advocacy groups, including the AADA, have been working to mitigate the proposed 2023 cuts by engaging with Congress and urging them to act before these changes go into effect on January 1, 2023.

Make Advocacy Your New Year’s Resolution: AADA’s Top Advocacy Priorities

The AADA’s top priority is Medicare payment policies.³ In addition, the AADA is working on drug access and cost by cutting the bureaucratic red tape caused by prior authorization (PA) and step therapy policies. The AADA collaborates with manufacturers, the health care community, policymakers, private payers, pharmacists, pharmacy benefit managers, and patients to minimize and/or eliminate barriers that patients face in accessing needed medications. Specifically, the AADA advocates for legislation that limits obstacles associated with health insurance step therapy requirements, streamlines PA, and prohibits mid-year formulary changes.⁸

Step therapy requires that patients first try a medication specified by the insurance company; the therapy must fail before the patient is placed on the medication originally prescribed by the provider. Regarding PA, the AADA tries to ensure that determinations are standardized, requires the speed of determinations to be quantified and minimized, and ensures that PA and appeals policies do not unduly burden physicians or patients in accessing optimal drug therapy.⁸

Another advocacy priority is telehealth. The AADA is advocating for legislation on expansion of telehealth in underserved areas and modifications to state licensure requirements, liability issues, and reimbursement for store-and-forward technology. The AADA is involved in protecting scope of practice, truth in advertising, and access to specialty care, as well as monitoring legislation and regulation concerning the potential environmental impact of sunscreen ingredients, indoor tanning restrictions, and skin cancer prevention.⁸

Advocacy Matters and Makes a Difference—It is important to learn about and support advocacy priorities and efforts and join forces to protect your practice. The AADA advocacy priorities are to protect the value of dermatology services, mobilize dermatologists for political action, ensure dermatologists can participate in new payment models, and strengthen the profession.⁹ Physician advocacy is no longer an elective pursuit. We need to be involved and engaged through our medical societies to help patients, communities, and ourselves. All of us are in it together, and a collaborative collective voice can make a difference. Take action, join the AADA, and contact Congress today to stop Medicare payment cuts (https://takeaction.aad.org/).

The Diagnosis: Mid-Borderline Multibacillary Leprosy

The biopsies showed a granulomatous dermatitis involving the dermis and subcutaneous adipose tissue (Figure, A). Fite staining also revealed numerous acid-fast bacilli (AFB) throughout the dermis (Figure, B); however, polymerase chain reaction (PCR) for Mycobacterium tuberculosis was negative, and concomitant AFB tissue culture showed no growth after 8 weeks of incubation from the left wrist biopsy (Table). Interestingly, a left inguinal lymph node biopsy performed 6 months prior to presentation that helped to establish the diagnosis of follicular lymphoma also revealed nonnecrotizing granulomas and the presence of rare AFB; this formalin-fixed specimen subsequently tested negative for M tuberculosis and nontuberculous mycobacteria (NTM) by broad-range PCR. Due to a high index of suspicion, another unpreserved skin biopsy of the right knee was sent for NTM testing with PCR. Primers to 16S ribosomal RNA and the beta subunit of RNA polymerase, rpoB, gene detected Mycobacterium leprae DNA, leading to the diagnosis of mid-borderline (or borderline-borderline) multibacillary leprosy. Our patient subsequently reported subtle hypoesthesia of the plaques on the knees. He recalled eating undercooked armadillo meat in the southern United States more than 30 years prior to admission. In addition, he had a history of being incarcerated in the northeastern United States. This case was reported to the National Hansen’s Disease Program, and our patient was started on a 2-year course of daily clarithromycin, daily minocycline, and once-monthly moxifloxacin. His family also was evaluated and did not have any skin lesions concerning for leprosy.

Leprosy is a major global health concern, transmitted via breaks in the skin, respiratory secretions, and contact with armadillos. It continues to be endemic in India, Brazil, and Indonesia.¹ In the United States where leprosy is nonendemic, 159 new cases were detected in 2020; the most notable risk factors in the United States are armadillo exposure and travel history.^2,3 Mycobacterium leprae are intracellular bacilli that preferentially infect macrophages and Schwann cells, resulting in erythematous or hypopigmented skin lesions that often are anesthetic. Mycobacterium leprae has the longest doubling time of all bacteria with unknown in vitro growth requirements and a typical in vivo incubation period of 2 to 10 years.⁴ Therefore, in vitro cultures will yield no growth, as seen in our case. In our patient, Fite stain showed acid-fast organisms in multiple tissue specimens, but AFB cultures demonstrated no growth after 8 weeks of incubation. Although clinicopathologic correlation is most important, PCR analysis can help to assist in the diagnosis of leprosy. Unpreserved tissue should be used when possible, as the fixation process may adversely affect the analytic sensitivity of subsequent PCR-based assays.⁵ In our case, NTM were not detected by PCR in the inguinal lymph node specimen despite demonstrating rare AFB staining. This result likely was multifactorial, including the effect of formalin fixation and paraffin embedding as well as concomitant low biomass.

Leprosy is known as a great imitator, and clinical manifestations (both neurologic and cutaneous) depend on host immune response to the mycobacteria. Although tuberculoid leprosy (associated with T helper type 1 immune response) is distinguished by few asymmetric, well-demarcated, and often hypopigmented plaques, lepromatous leprosy (associated with T helper type 2 response) is characterized by numerous symmetric and poorly defined lesions. Borderline leprosy, as seen in our patient, is the most common type of leprosy and shows features of both tuberculoid and lepromatous leprosy.⁴ It also may be particularly difficult to diagnose.^6,7 Borderline-borderline leprosy involves lesions that mostly are of the lepromatous type and symmetric but also may include raised plaques, as in tuberculoid leprosy.⁴ Plaques in an annular configuration with central clearing, as seen in our patient, are considered suggestive.⁸ Histopathology of borderline-borderline leprosy lesions shows subepidermal clear zones, and granulomas are more diffuse than in tuberculoid leprosy.⁴

Given the noncaseating granulomatous dermatitis seen on histopathology and the relatively higher incidence of sarcoidosis in our region of practice, our initial differential included sarcoidosis and other granulomatous disorders such as granuloma annulare. Interestingly, sarcoidosis has been misdiagnosed as leprosy on multiple occasions in countries where leprosy is endemic.^9,10 Localized cutaneous leishmaniasis typically presents with infiltrated plaques and nodules that may ulcerate; diffuse and disseminated as well as mucocutaneous presentations may occur depending on the species and severity of infection. Parasitized macrophages containing amastigotes may be seen in the dermis highlighted by CD1a immunostaining. Mycosis fungoides presents as papulosquamous patches or plaques, often favoring sunprotected sites; the hypopigmented variant may mimic the central clearing seen in leprosy.

The diagnosis of leprosy can be challenging due to varying clinical presentation; indolent growth of the causative organism; and indeterminate nature of stains, including the Fite stain. Although leprosy is an uncommon diagnosis, this case underscores the need to keep it in the differential of granulomatous dermatoses in the appropriate clinical setting, particularly in patients with risk factors for exposure.⁸

The Diagnosis: Mid-Borderline Multibacillary Leprosy

The biopsies showed a granulomatous dermatitis involving the dermis and subcutaneous adipose tissue (Figure, A). Fite staining also revealed numerous acid-fast bacilli (AFB) throughout the dermis (Figure, B); however, polymerase chain reaction (PCR) for Mycobacterium tuberculosis was negative, and concomitant AFB tissue culture showed no growth after 8 weeks of incubation from the left wrist biopsy (Table). Interestingly, a left inguinal lymph node biopsy performed 6 months prior to presentation that helped to establish the diagnosis of follicular lymphoma also revealed nonnecrotizing granulomas and the presence of rare AFB; this formalin-fixed specimen subsequently tested negative for M tuberculosis and nontuberculous mycobacteria (NTM) by broad-range PCR. Due to a high index of suspicion, another unpreserved skin biopsy of the right knee was sent for NTM testing with PCR. Primers to 16S ribosomal RNA and the beta subunit of RNA polymerase, rpoB, gene detected Mycobacterium leprae DNA, leading to the diagnosis of mid-borderline (or borderline-borderline) multibacillary leprosy. Our patient subsequently reported subtle hypoesthesia of the plaques on the knees. He recalled eating undercooked armadillo meat in the southern United States more than 30 years prior to admission. In addition, he had a history of being incarcerated in the northeastern United States. This case was reported to the National Hansen’s Disease Program, and our patient was started on a 2-year course of daily clarithromycin, daily minocycline, and once-monthly moxifloxacin. His family also was evaluated and did not have any skin lesions concerning for leprosy.

Leprosy is a major global health concern, transmitted via breaks in the skin, respiratory secretions, and contact with armadillos. It continues to be endemic in India, Brazil, and Indonesia.¹ In the United States where leprosy is nonendemic, 159 new cases were detected in 2020; the most notable risk factors in the United States are armadillo exposure and travel history.^2,3 Mycobacterium leprae are intracellular bacilli that preferentially infect macrophages and Schwann cells, resulting in erythematous or hypopigmented skin lesions that often are anesthetic. Mycobacterium leprae has the longest doubling time of all bacteria with unknown in vitro growth requirements and a typical in vivo incubation period of 2 to 10 years.⁴ Therefore, in vitro cultures will yield no growth, as seen in our case. In our patient, Fite stain showed acid-fast organisms in multiple tissue specimens, but AFB cultures demonstrated no growth after 8 weeks of incubation. Although clinicopathologic correlation is most important, PCR analysis can help to assist in the diagnosis of leprosy. Unpreserved tissue should be used when possible, as the fixation process may adversely affect the analytic sensitivity of subsequent PCR-based assays.⁵ In our case, NTM were not detected by PCR in the inguinal lymph node specimen despite demonstrating rare AFB staining. This result likely was multifactorial, including the effect of formalin fixation and paraffin embedding as well as concomitant low biomass.

Leprosy is known as a great imitator, and clinical manifestations (both neurologic and cutaneous) depend on host immune response to the mycobacteria. Although tuberculoid leprosy (associated with T helper type 1 immune response) is distinguished by few asymmetric, well-demarcated, and often hypopigmented plaques, lepromatous leprosy (associated with T helper type 2 response) is characterized by numerous symmetric and poorly defined lesions. Borderline leprosy, as seen in our patient, is the most common type of leprosy and shows features of both tuberculoid and lepromatous leprosy.⁴ It also may be particularly difficult to diagnose.^6,7 Borderline-borderline leprosy involves lesions that mostly are of the lepromatous type and symmetric but also may include raised plaques, as in tuberculoid leprosy.⁴ Plaques in an annular configuration with central clearing, as seen in our patient, are considered suggestive.⁸ Histopathology of borderline-borderline leprosy lesions shows subepidermal clear zones, and granulomas are more diffuse than in tuberculoid leprosy.⁴

Given the noncaseating granulomatous dermatitis seen on histopathology and the relatively higher incidence of sarcoidosis in our region of practice, our initial differential included sarcoidosis and other granulomatous disorders such as granuloma annulare. Interestingly, sarcoidosis has been misdiagnosed as leprosy on multiple occasions in countries where leprosy is endemic.^9,10 Localized cutaneous leishmaniasis typically presents with infiltrated plaques and nodules that may ulcerate; diffuse and disseminated as well as mucocutaneous presentations may occur depending on the species and severity of infection. Parasitized macrophages containing amastigotes may be seen in the dermis highlighted by CD1a immunostaining. Mycosis fungoides presents as papulosquamous patches or plaques, often favoring sunprotected sites; the hypopigmented variant may mimic the central clearing seen in leprosy.

The diagnosis of leprosy can be challenging due to varying clinical presentation; indolent growth of the causative organism; and indeterminate nature of stains, including the Fite stain. Although leprosy is an uncommon diagnosis, this case underscores the need to keep it in the differential of granulomatous dermatoses in the appropriate clinical setting, particularly in patients with risk factors for exposure.⁸

The Diagnosis: Mid-Borderline Multibacillary Leprosy

The biopsies showed a granulomatous dermatitis involving the dermis and subcutaneous adipose tissue (Figure, A). Fite staining also revealed numerous acid-fast bacilli (AFB) throughout the dermis (Figure, B); however, polymerase chain reaction (PCR) for Mycobacterium tuberculosis was negative, and concomitant AFB tissue culture showed no growth after 8 weeks of incubation from the left wrist biopsy (Table). Interestingly, a left inguinal lymph node biopsy performed 6 months prior to presentation that helped to establish the diagnosis of follicular lymphoma also revealed nonnecrotizing granulomas and the presence of rare AFB; this formalin-fixed specimen subsequently tested negative for M tuberculosis and nontuberculous mycobacteria (NTM) by broad-range PCR. Due to a high index of suspicion, another unpreserved skin biopsy of the right knee was sent for NTM testing with PCR. Primers to 16S ribosomal RNA and the beta subunit of RNA polymerase, rpoB, gene detected Mycobacterium leprae DNA, leading to the diagnosis of mid-borderline (or borderline-borderline) multibacillary leprosy. Our patient subsequently reported subtle hypoesthesia of the plaques on the knees. He recalled eating undercooked armadillo meat in the southern United States more than 30 years prior to admission. In addition, he had a history of being incarcerated in the northeastern United States. This case was reported to the National Hansen’s Disease Program, and our patient was started on a 2-year course of daily clarithromycin, daily minocycline, and once-monthly moxifloxacin. His family also was evaluated and did not have any skin lesions concerning for leprosy.

Leprosy is a major global health concern, transmitted via breaks in the skin, respiratory secretions, and contact with armadillos. It continues to be endemic in India, Brazil, and Indonesia.¹ In the United States where leprosy is nonendemic, 159 new cases were detected in 2020; the most notable risk factors in the United States are armadillo exposure and travel history.^2,3 Mycobacterium leprae are intracellular bacilli that preferentially infect macrophages and Schwann cells, resulting in erythematous or hypopigmented skin lesions that often are anesthetic. Mycobacterium leprae has the longest doubling time of all bacteria with unknown in vitro growth requirements and a typical in vivo incubation period of 2 to 10 years.⁴ Therefore, in vitro cultures will yield no growth, as seen in our case. In our patient, Fite stain showed acid-fast organisms in multiple tissue specimens, but AFB cultures demonstrated no growth after 8 weeks of incubation. Although clinicopathologic correlation is most important, PCR analysis can help to assist in the diagnosis of leprosy. Unpreserved tissue should be used when possible, as the fixation process may adversely affect the analytic sensitivity of subsequent PCR-based assays.⁵ In our case, NTM were not detected by PCR in the inguinal lymph node specimen despite demonstrating rare AFB staining. This result likely was multifactorial, including the effect of formalin fixation and paraffin embedding as well as concomitant low biomass.

Leprosy is known as a great imitator, and clinical manifestations (both neurologic and cutaneous) depend on host immune response to the mycobacteria. Although tuberculoid leprosy (associated with T helper type 1 immune response) is distinguished by few asymmetric, well-demarcated, and often hypopigmented plaques, lepromatous leprosy (associated with T helper type 2 response) is characterized by numerous symmetric and poorly defined lesions. Borderline leprosy, as seen in our patient, is the most common type of leprosy and shows features of both tuberculoid and lepromatous leprosy.⁴ It also may be particularly difficult to diagnose.^6,7 Borderline-borderline leprosy involves lesions that mostly are of the lepromatous type and symmetric but also may include raised plaques, as in tuberculoid leprosy.⁴ Plaques in an annular configuration with central clearing, as seen in our patient, are considered suggestive.⁸ Histopathology of borderline-borderline leprosy lesions shows subepidermal clear zones, and granulomas are more diffuse than in tuberculoid leprosy.⁴

Given the noncaseating granulomatous dermatitis seen on histopathology and the relatively higher incidence of sarcoidosis in our region of practice, our initial differential included sarcoidosis and other granulomatous disorders such as granuloma annulare. Interestingly, sarcoidosis has been misdiagnosed as leprosy on multiple occasions in countries where leprosy is endemic.^9,10 Localized cutaneous leishmaniasis typically presents with infiltrated plaques and nodules that may ulcerate; diffuse and disseminated as well as mucocutaneous presentations may occur depending on the species and severity of infection. Parasitized macrophages containing amastigotes may be seen in the dermis highlighted by CD1a immunostaining. Mycosis fungoides presents as papulosquamous patches or plaques, often favoring sunprotected sites; the hypopigmented variant may mimic the central clearing seen in leprosy.

The diagnosis of leprosy can be challenging due to varying clinical presentation; indolent growth of the causative organism; and indeterminate nature of stains, including the Fite stain. Although leprosy is an uncommon diagnosis, this case underscores the need to keep it in the differential of granulomatous dermatoses in the appropriate clinical setting, particularly in patients with risk factors for exposure.⁸

The Diagnosis: Solitary Sclerotic Fibroma

Based on the clinical and histologic findings, the patient was diagnosed with solitary sclerotic fibroma (SF). Sclerotic fibroma is a rare benign tumor that first was described in 1972 by Weary et al¹ in the oral mucosa of a patient with Cowden syndrome, a genodermatosis associated with multiple benign and malignant tumors. Rapini and Golitz² reported solitary SF in 11 otherwise-healthy individuals with no signs of multiple hamartoma syndrome. Solitary SF is a sporadic benign condition, whereas multiple lesions are suggestive of Cowden syndrome. Solitary SF most commonly appears as an asymptomatic white-yellow papule or nodule on the head or neck, though larger tumors have been reported on the trunk and extremities.³ Histologic features of solitary SF include a well-circumscribed dermal nodule composed of eosinophilic dense collagen bundles arranged in a plywoodlike pattern (Figure). Immunohistochemistry is positive for CD34 and vimentin but negative for S-100, epithelial membrane antigen, and neuron-specific enolase.⁴

The differential diagnosis of solitary SF of the head and neck includes sebaceous adenoma, pilar cyst, nodular basal cell carcinoma, and giant molluscum contagiosum. Sebaceous adenomas usually are solitary yellow nodules less than 1 cm in diameter and located on the head and neck. They are the most common sebaceous neoplasm associated with Muir-Torre syndrome, an autosomal-dominant disorder characterized by sebaceous adenoma or carcinoma and colorectal cancer. Histopathology demonstrates well-circumscribed, round aggregations of mature lipid-filled sebocytes with a rim of basaloid germinative cells at the periphery. Pilar cysts typically are flesh-colored subcutaneous nodules on the scalp that are freely mobile over underlying tissue. Histopathology shows stratified squamous epithelium lining and trichilemmal keratinization. Nodular basal cell carcinoma has a pearly translucent appearance and arborizing telangiectases. Histopathology demonstrates nests of basaloid cells with palisading of the cells at the periphery. Giant solitary molluscum contagiosum is a dome-shaped, flesh-colored nodule with central umbilication. Histopathology reveals hyperplastic squamous epithelium with characteristic eosinophilic inclusion bodies above the basal layer.

Solitary SF can be difficult to diagnose based solely on the clinical presentation; thus biopsy with histologic evaluation is recommended. If SF is confirmed, the clinician should inquire about a family history of Cowden syndrome and then perform a total-body skin examination to check for multiple SF and other clinical hamartomas of Cowden syndrome such as trichilemmomas, acral keratosis, and oral papillomas.

The Diagnosis: Solitary Sclerotic Fibroma

Based on the clinical and histologic findings, the patient was diagnosed with solitary sclerotic fibroma (SF). Sclerotic fibroma is a rare benign tumor that first was described in 1972 by Weary et al¹ in the oral mucosa of a patient with Cowden syndrome, a genodermatosis associated with multiple benign and malignant tumors. Rapini and Golitz² reported solitary SF in 11 otherwise-healthy individuals with no signs of multiple hamartoma syndrome. Solitary SF is a sporadic benign condition, whereas multiple lesions are suggestive of Cowden syndrome. Solitary SF most commonly appears as an asymptomatic white-yellow papule or nodule on the head or neck, though larger tumors have been reported on the trunk and extremities.³ Histologic features of solitary SF include a well-circumscribed dermal nodule composed of eosinophilic dense collagen bundles arranged in a plywoodlike pattern (Figure). Immunohistochemistry is positive for CD34 and vimentin but negative for S-100, epithelial membrane antigen, and neuron-specific enolase.⁴

The differential diagnosis of solitary SF of the head and neck includes sebaceous adenoma, pilar cyst, nodular basal cell carcinoma, and giant molluscum contagiosum. Sebaceous adenomas usually are solitary yellow nodules less than 1 cm in diameter and located on the head and neck. They are the most common sebaceous neoplasm associated with Muir-Torre syndrome, an autosomal-dominant disorder characterized by sebaceous adenoma or carcinoma and colorectal cancer. Histopathology demonstrates well-circumscribed, round aggregations of mature lipid-filled sebocytes with a rim of basaloid germinative cells at the periphery. Pilar cysts typically are flesh-colored subcutaneous nodules on the scalp that are freely mobile over underlying tissue. Histopathology shows stratified squamous epithelium lining and trichilemmal keratinization. Nodular basal cell carcinoma has a pearly translucent appearance and arborizing telangiectases. Histopathology demonstrates nests of basaloid cells with palisading of the cells at the periphery. Giant solitary molluscum contagiosum is a dome-shaped, flesh-colored nodule with central umbilication. Histopathology reveals hyperplastic squamous epithelium with characteristic eosinophilic inclusion bodies above the basal layer.

Solitary SF can be difficult to diagnose based solely on the clinical presentation; thus biopsy with histologic evaluation is recommended. If SF is confirmed, the clinician should inquire about a family history of Cowden syndrome and then perform a total-body skin examination to check for multiple SF and other clinical hamartomas of Cowden syndrome such as trichilemmomas, acral keratosis, and oral papillomas.

The Diagnosis: Solitary Sclerotic Fibroma

Based on the clinical and histologic findings, the patient was diagnosed with solitary sclerotic fibroma (SF). Sclerotic fibroma is a rare benign tumor that first was described in 1972 by Weary et al¹ in the oral mucosa of a patient with Cowden syndrome, a genodermatosis associated with multiple benign and malignant tumors. Rapini and Golitz² reported solitary SF in 11 otherwise-healthy individuals with no signs of multiple hamartoma syndrome. Solitary SF is a sporadic benign condition, whereas multiple lesions are suggestive of Cowden syndrome. Solitary SF most commonly appears as an asymptomatic white-yellow papule or nodule on the head or neck, though larger tumors have been reported on the trunk and extremities.³ Histologic features of solitary SF include a well-circumscribed dermal nodule composed of eosinophilic dense collagen bundles arranged in a plywoodlike pattern (Figure). Immunohistochemistry is positive for CD34 and vimentin but negative for S-100, epithelial membrane antigen, and neuron-specific enolase.⁴

The differential diagnosis of solitary SF of the head and neck includes sebaceous adenoma, pilar cyst, nodular basal cell carcinoma, and giant molluscum contagiosum. Sebaceous adenomas usually are solitary yellow nodules less than 1 cm in diameter and located on the head and neck. They are the most common sebaceous neoplasm associated with Muir-Torre syndrome, an autosomal-dominant disorder characterized by sebaceous adenoma or carcinoma and colorectal cancer. Histopathology demonstrates well-circumscribed, round aggregations of mature lipid-filled sebocytes with a rim of basaloid germinative cells at the periphery. Pilar cysts typically are flesh-colored subcutaneous nodules on the scalp that are freely mobile over underlying tissue. Histopathology shows stratified squamous epithelium lining and trichilemmal keratinization. Nodular basal cell carcinoma has a pearly translucent appearance and arborizing telangiectases. Histopathology demonstrates nests of basaloid cells with palisading of the cells at the periphery. Giant solitary molluscum contagiosum is a dome-shaped, flesh-colored nodule with central umbilication. Histopathology reveals hyperplastic squamous epithelium with characteristic eosinophilic inclusion bodies above the basal layer.

Solitary SF can be difficult to diagnose based solely on the clinical presentation; thus biopsy with histologic evaluation is recommended. If SF is confirmed, the clinician should inquire about a family history of Cowden syndrome and then perform a total-body skin examination to check for multiple SF and other clinical hamartomas of Cowden syndrome such as trichilemmomas, acral keratosis, and oral papillomas.