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THE DIAGNOSIS: Atypical Spitz Tumor

The shave biopsy revealed extensive dermal proliferation with spitzoid cytomorphology containing large, spindled nuclei; prominent nucleoli; and abundant homogenous cytoplasm arranged in haphazard fascicles. The proliferation was associated with prominent pseudoepitheliomatous hyperplasia of the overlying epidermis, and anaplastic lymphoma kinase immunohistochemistry showed diffuse strong positivity. Fluorescence in situ hybridization confirmed fusion of the tropomyosin 3 (TPM3) and anaplastic lymphoma kinase (ALK) genes, which finalized the diagnosis of an ALK-mutated atypical spitz tumor. Due to the location and size of the lesion, Mohs micrographic surgery was performed to excise the tumor and clear the margins.

Spitz nevi are uncommon benign melanocytic neoplasms that typically occur in pediatric populations.¹ Atypical spitz nevi comprised fewer than 17% of all childhood melanocytic nevi in the United States and can be considered in the broader category of spitzoid tumors. Spitz nevi are divided into 3 classes: Spitz nevus, atypical Spitz nevus, and spitzoid melanoma. Atypical Spitz nevi have typical Spitz nevus and spitzoid melanoma features and often can be difficult to distinguish on dermoscopy. Malignant Spitz tumors typically occur in the fifth decade of life, though the age distribution can vary widely.¹

Black patients are less likely to be diagnosed with Spitz nevi, potentially due to a lower prevalence in this population, thus limiting the clinician’s clinical exposure and leading to increased rates of misdiagnoses.² Spitz nevi usually manifest as well-circumscribed, dome-shaped papules and frequently are described as pink to red due to increased vascularity and limited melanin content¹; however, these lesions may appear more violaceous, dusky, or dark brown in darker skin types. Additionally, approximately 71% of patients in a clinical review of Spitz nevi had a pigmented lesion, ranging from light brown to black.³ It is important for dermatologists to understand that the contrast in color between the nevus and the surrounding skin may not be as striking, prominent, or clinically concerning, particularly in darker skin types, such as in our patient.

Spitz nevi frequently manifest as rapidly growing solitary lesions most frequently developing in the lower legs (shown in 41% of lesions in one report).⁴ However, a recent retrospective review indicated that Spitz nevi in Black patients most commonly were found on the upper extremities, as was seen in our patient.² Compared to typical and common Spitz nevi, atypical Spitz nevi often are greater than 10 mm in diameter and have features of ulceration.

Diagnosing atypical spitzoid melanocytic lesions requires adequate clinical suspicion and confirmation via biopsy. Under dermoscopy, typical Spitz nevi often display a starburst or globular pattern with pinpoint vessels, though it can have variable manifestations of both patterns. Atypical Spitz nevi can be challenging to distinguish from melanoma on dermoscopy since both conditions can have atypical pigment networks or structureless homogenous areas.¹ Consequently, there often is a lower threshold for biopsy and possible follow-up excision for atypical Spitz nevi. Histopathology of atypical Spitz nevi includes epithelioid and spindle melanocytes but can share features of melanomas, including areas of prominent pagetoid spread, asymmetry, and poor circumscription.⁵ Furthermore, atypical Spitz nevi with ALK gene fusion, as seen in our patient, have been shown in the literature to demonstrate distinct histopathologic features, such as wedge-shaped extension into the dermis or a bulbous lower border that can resemble pseudoepitheliomatous hyperplasia.⁶

The differential diagnosis for this rapidly growing scaly nodule also should include pyogenic granuloma, bacillary angiomatosis, Kaposi sarcoma, and amelanotic melanoma. Pyogenic granuloma is a rapidly growing, benign, vascular tumor that often becomes ulcerated and can occur in any age group.⁷ Pyogenic granuloma frequently appears at sites of trauma as a solitary, bright pink to red, friable, pedunculated papule and often manifests on the arms, hands, and face, similar to atypical Spitz nevi, though they can appear anywhere on the body. Histology shows a lobular capillary network with a central feeder vessel.⁷

Bacillary angiomatosis is an uncommon cutaneous infection associated with vascular proliferation and neovascularization due to the gram-negative organism Bartonella henselae.⁸ Bacillary nodules typically are reddish to purple and appear on the arms, sometimes with central ulceration and bleeding. Patients may present with multiple papules and nodules of varying sizes, as the lesions can arise in crops and follow a sporotrichoid pattern. Most patients with bacillary angiomatosis are immunosuppressed, though it rarely can affect immunocompetent patients. Histologically, bacillary angiomatosis is similar to pyogenic granuloma, though Gram or Warthin-Starry stains can help differentiate B henselae.⁸

Kaposi sarcoma is a malignant vascular neoplasm that often manifests in immunocompromised patients as violaceous, purple, or red patches, plaques, and nodules on the skin or oral mucosa. Histopathology shows spindle cell proliferation of irregular complex vascular channels dissecting through the dermis. Human herpesvirus 8 immunohistochemistry can be used to confirm diagnosis on histopathology.⁹ In contrast, amelanotic melanoma consists of lack of pigmentation, asymmetry with polymorphous vascular pattern, and high mitotic rate and is commonly found in sun-exposed areas. Dermoscopic features include irregular globules with blue-whitish veil.¹⁰

Treatment of atypical Spitz nevi depends mainly on the age of the patient and the histologic features of the nevus. Adults with atypical Spitz nevi frequently require excision, while the preferred choice for treatment in children with common Spitz nevi is regular clinical monitoring when there are no concerning clinical, dermoscopic, or histologic features.⁸ Compared to common Spitz nevi, atypical Spitz nevi have more melanoma-like features, resulting in a stronger recommendation for excision. Excision allows for a more thorough histologic evaluation and minimizes the likelihood of a recurrent atypical lesion.¹¹ In all cases, close clinical follow-up is recommended to monitor for reoccurrence.

THE DIAGNOSIS: Atypical Spitz Tumor

The shave biopsy revealed extensive dermal proliferation with spitzoid cytomorphology containing large, spindled nuclei; prominent nucleoli; and abundant homogenous cytoplasm arranged in haphazard fascicles. The proliferation was associated with prominent pseudoepitheliomatous hyperplasia of the overlying epidermis, and anaplastic lymphoma kinase immunohistochemistry showed diffuse strong positivity. Fluorescence in situ hybridization confirmed fusion of the tropomyosin 3 (TPM3) and anaplastic lymphoma kinase (ALK) genes, which finalized the diagnosis of an ALK-mutated atypical spitz tumor. Due to the location and size of the lesion, Mohs micrographic surgery was performed to excise the tumor and clear the margins.

Spitz nevi are uncommon benign melanocytic neoplasms that typically occur in pediatric populations.¹ Atypical spitz nevi comprised fewer than 17% of all childhood melanocytic nevi in the United States and can be considered in the broader category of spitzoid tumors. Spitz nevi are divided into 3 classes: Spitz nevus, atypical Spitz nevus, and spitzoid melanoma. Atypical Spitz nevi have typical Spitz nevus and spitzoid melanoma features and often can be difficult to distinguish on dermoscopy. Malignant Spitz tumors typically occur in the fifth decade of life, though the age distribution can vary widely.¹

Black patients are less likely to be diagnosed with Spitz nevi, potentially due to a lower prevalence in this population, thus limiting the clinician’s clinical exposure and leading to increased rates of misdiagnoses.² Spitz nevi usually manifest as well-circumscribed, dome-shaped papules and frequently are described as pink to red due to increased vascularity and limited melanin content¹; however, these lesions may appear more violaceous, dusky, or dark brown in darker skin types. Additionally, approximately 71% of patients in a clinical review of Spitz nevi had a pigmented lesion, ranging from light brown to black.³ It is important for dermatologists to understand that the contrast in color between the nevus and the surrounding skin may not be as striking, prominent, or clinically concerning, particularly in darker skin types, such as in our patient.

Spitz nevi frequently manifest as rapidly growing solitary lesions most frequently developing in the lower legs (shown in 41% of lesions in one report).⁴ However, a recent retrospective review indicated that Spitz nevi in Black patients most commonly were found on the upper extremities, as was seen in our patient.² Compared to typical and common Spitz nevi, atypical Spitz nevi often are greater than 10 mm in diameter and have features of ulceration.

Diagnosing atypical spitzoid melanocytic lesions requires adequate clinical suspicion and confirmation via biopsy. Under dermoscopy, typical Spitz nevi often display a starburst or globular pattern with pinpoint vessels, though it can have variable manifestations of both patterns. Atypical Spitz nevi can be challenging to distinguish from melanoma on dermoscopy since both conditions can have atypical pigment networks or structureless homogenous areas.¹ Consequently, there often is a lower threshold for biopsy and possible follow-up excision for atypical Spitz nevi. Histopathology of atypical Spitz nevi includes epithelioid and spindle melanocytes but can share features of melanomas, including areas of prominent pagetoid spread, asymmetry, and poor circumscription.⁵ Furthermore, atypical Spitz nevi with ALK gene fusion, as seen in our patient, have been shown in the literature to demonstrate distinct histopathologic features, such as wedge-shaped extension into the dermis or a bulbous lower border that can resemble pseudoepitheliomatous hyperplasia.⁶

The differential diagnosis for this rapidly growing scaly nodule also should include pyogenic granuloma, bacillary angiomatosis, Kaposi sarcoma, and amelanotic melanoma. Pyogenic granuloma is a rapidly growing, benign, vascular tumor that often becomes ulcerated and can occur in any age group.⁷ Pyogenic granuloma frequently appears at sites of trauma as a solitary, bright pink to red, friable, pedunculated papule and often manifests on the arms, hands, and face, similar to atypical Spitz nevi, though they can appear anywhere on the body. Histology shows a lobular capillary network with a central feeder vessel.⁷

Bacillary angiomatosis is an uncommon cutaneous infection associated with vascular proliferation and neovascularization due to the gram-negative organism Bartonella henselae.⁸ Bacillary nodules typically are reddish to purple and appear on the arms, sometimes with central ulceration and bleeding. Patients may present with multiple papules and nodules of varying sizes, as the lesions can arise in crops and follow a sporotrichoid pattern. Most patients with bacillary angiomatosis are immunosuppressed, though it rarely can affect immunocompetent patients. Histologically, bacillary angiomatosis is similar to pyogenic granuloma, though Gram or Warthin-Starry stains can help differentiate B henselae.⁸

Kaposi sarcoma is a malignant vascular neoplasm that often manifests in immunocompromised patients as violaceous, purple, or red patches, plaques, and nodules on the skin or oral mucosa. Histopathology shows spindle cell proliferation of irregular complex vascular channels dissecting through the dermis. Human herpesvirus 8 immunohistochemistry can be used to confirm diagnosis on histopathology.⁹ In contrast, amelanotic melanoma consists of lack of pigmentation, asymmetry with polymorphous vascular pattern, and high mitotic rate and is commonly found in sun-exposed areas. Dermoscopic features include irregular globules with blue-whitish veil.¹⁰

Treatment of atypical Spitz nevi depends mainly on the age of the patient and the histologic features of the nevus. Adults with atypical Spitz nevi frequently require excision, while the preferred choice for treatment in children with common Spitz nevi is regular clinical monitoring when there are no concerning clinical, dermoscopic, or histologic features.⁸ Compared to common Spitz nevi, atypical Spitz nevi have more melanoma-like features, resulting in a stronger recommendation for excision. Excision allows for a more thorough histologic evaluation and minimizes the likelihood of a recurrent atypical lesion.¹¹ In all cases, close clinical follow-up is recommended to monitor for reoccurrence.

THE DIAGNOSIS: Atypical Spitz Tumor

The shave biopsy revealed extensive dermal proliferation with spitzoid cytomorphology containing large, spindled nuclei; prominent nucleoli; and abundant homogenous cytoplasm arranged in haphazard fascicles. The proliferation was associated with prominent pseudoepitheliomatous hyperplasia of the overlying epidermis, and anaplastic lymphoma kinase immunohistochemistry showed diffuse strong positivity. Fluorescence in situ hybridization confirmed fusion of the tropomyosin 3 (TPM3) and anaplastic lymphoma kinase (ALK) genes, which finalized the diagnosis of an ALK-mutated atypical spitz tumor. Due to the location and size of the lesion, Mohs micrographic surgery was performed to excise the tumor and clear the margins.

Spitz nevi are uncommon benign melanocytic neoplasms that typically occur in pediatric populations.¹ Atypical spitz nevi comprised fewer than 17% of all childhood melanocytic nevi in the United States and can be considered in the broader category of spitzoid tumors. Spitz nevi are divided into 3 classes: Spitz nevus, atypical Spitz nevus, and spitzoid melanoma. Atypical Spitz nevi have typical Spitz nevus and spitzoid melanoma features and often can be difficult to distinguish on dermoscopy. Malignant Spitz tumors typically occur in the fifth decade of life, though the age distribution can vary widely.¹

Black patients are less likely to be diagnosed with Spitz nevi, potentially due to a lower prevalence in this population, thus limiting the clinician’s clinical exposure and leading to increased rates of misdiagnoses.² Spitz nevi usually manifest as well-circumscribed, dome-shaped papules and frequently are described as pink to red due to increased vascularity and limited melanin content¹; however, these lesions may appear more violaceous, dusky, or dark brown in darker skin types. Additionally, approximately 71% of patients in a clinical review of Spitz nevi had a pigmented lesion, ranging from light brown to black.³ It is important for dermatologists to understand that the contrast in color between the nevus and the surrounding skin may not be as striking, prominent, or clinically concerning, particularly in darker skin types, such as in our patient.

Spitz nevi frequently manifest as rapidly growing solitary lesions most frequently developing in the lower legs (shown in 41% of lesions in one report).⁴ However, a recent retrospective review indicated that Spitz nevi in Black patients most commonly were found on the upper extremities, as was seen in our patient.² Compared to typical and common Spitz nevi, atypical Spitz nevi often are greater than 10 mm in diameter and have features of ulceration.

Diagnosing atypical spitzoid melanocytic lesions requires adequate clinical suspicion and confirmation via biopsy. Under dermoscopy, typical Spitz nevi often display a starburst or globular pattern with pinpoint vessels, though it can have variable manifestations of both patterns. Atypical Spitz nevi can be challenging to distinguish from melanoma on dermoscopy since both conditions can have atypical pigment networks or structureless homogenous areas.¹ Consequently, there often is a lower threshold for biopsy and possible follow-up excision for atypical Spitz nevi. Histopathology of atypical Spitz nevi includes epithelioid and spindle melanocytes but can share features of melanomas, including areas of prominent pagetoid spread, asymmetry, and poor circumscription.⁵ Furthermore, atypical Spitz nevi with ALK gene fusion, as seen in our patient, have been shown in the literature to demonstrate distinct histopathologic features, such as wedge-shaped extension into the dermis or a bulbous lower border that can resemble pseudoepitheliomatous hyperplasia.⁶

The differential diagnosis for this rapidly growing scaly nodule also should include pyogenic granuloma, bacillary angiomatosis, Kaposi sarcoma, and amelanotic melanoma. Pyogenic granuloma is a rapidly growing, benign, vascular tumor that often becomes ulcerated and can occur in any age group.⁷ Pyogenic granuloma frequently appears at sites of trauma as a solitary, bright pink to red, friable, pedunculated papule and often manifests on the arms, hands, and face, similar to atypical Spitz nevi, though they can appear anywhere on the body. Histology shows a lobular capillary network with a central feeder vessel.⁷

Bacillary angiomatosis is an uncommon cutaneous infection associated with vascular proliferation and neovascularization due to the gram-negative organism Bartonella henselae.⁸ Bacillary nodules typically are reddish to purple and appear on the arms, sometimes with central ulceration and bleeding. Patients may present with multiple papules and nodules of varying sizes, as the lesions can arise in crops and follow a sporotrichoid pattern. Most patients with bacillary angiomatosis are immunosuppressed, though it rarely can affect immunocompetent patients. Histologically, bacillary angiomatosis is similar to pyogenic granuloma, though Gram or Warthin-Starry stains can help differentiate B henselae.⁸

Kaposi sarcoma is a malignant vascular neoplasm that often manifests in immunocompromised patients as violaceous, purple, or red patches, plaques, and nodules on the skin or oral mucosa. Histopathology shows spindle cell proliferation of irregular complex vascular channels dissecting through the dermis. Human herpesvirus 8 immunohistochemistry can be used to confirm diagnosis on histopathology.⁹ In contrast, amelanotic melanoma consists of lack of pigmentation, asymmetry with polymorphous vascular pattern, and high mitotic rate and is commonly found in sun-exposed areas. Dermoscopic features include irregular globules with blue-whitish veil.¹⁰

Treatment of atypical Spitz nevi depends mainly on the age of the patient and the histologic features of the nevus. Adults with atypical Spitz nevi frequently require excision, while the preferred choice for treatment in children with common Spitz nevi is regular clinical monitoring when there are no concerning clinical, dermoscopic, or histologic features.⁸ Compared to common Spitz nevi, atypical Spitz nevi have more melanoma-like features, resulting in a stronger recommendation for excision. Excision allows for a more thorough histologic evaluation and minimizes the likelihood of a recurrent atypical lesion.¹¹ In all cases, close clinical follow-up is recommended to monitor for reoccurrence.

THE DIAGNOSIS: Hypertrophic Lupus Erythematosus

The biopsy of the face collected at the initial appointment revealed interface dermatitis with epidermal hyperplasia with no parakeratosis or eosinophils (Figure 1). Microscopic findings were suggestive of hypertrophic lupus erythematosus (HLE) or hypertrophic lichen planus. The rapid plasma reagin and HIV labs collected at the initial appointment were negative, and a review of systems was negative for systemic symptoms. Considering these results and the clinical distribution of the lesions primarily affecting sun-exposed areas of the upper body, a final diagnosis of HLE was made. The patient was counseled on the importance of photoprotection and was started on hydroxychloroquine.

Hypertrophic lupus erythematosus, a rare variant of chronic cutaneous lupus erythematosus (CCLE), typically manifests as verrucous plaques or nodules commonly found on sun-exposed areas of the body, as was observed in our patient on the face, scalp (Figures 2 and 3), chest, and upper extremities.¹ Lesions can have a variable appearance, from hyperkeratotic ulcers to depigmented plaques and keratoacanthomalike lesions.² On histopathology, HLE falls into the category of lichenoid interface dermatitis and commonly demonstrates hyperkeratosis, acanthosis, follicular plugging, superficial and deep infiltrate, and increased mucin deposition in the dermis.³

Although rare, it is critical to remain vigilant for the development of squamous cell carcinoma in patients with chronic untreated CCLE. Hypertrophic lupus erythematosus, specifically, is the most likely variant to give rise to invasive squamous cell carcinoma and can be more aggressive as a result of this malignant transformation.^3,4 Ruling out squamous cell carcinoma in the setting of HLE can be achieved by staining for CD123, as HLE commonly is associated with many CD123+ plasmacytoid dendritic cells adjacent to the epithelium, unlike squamous cell carcinoma.³ Fortunately no evidence of invasive squamous cell carcinoma, including cellular atypia or increased mitotic figures, was seen on histology in our patient.

A thorough history and physical examination are essential for screening for HLE, as positive antinuclear antibodies are observed only in half of the patients diagnosed with CCLE.⁵ Furthermore, antinuclear antibodies sometimes can be negative in patients with HLE who have end-stage organ involvement.

Hypertrophic lupus erythematosus can be challenging to treat. First-line therapies include antimalarials, topical steroids, and sun-protective measures. Intralesional triamcinolone injection also can be used as an adjunctive therapy to expedite the treatment response.⁶ Evidence supports good response following treatment with acitretin or a combination of isotretinoin and hydroxychloroquine.² Another therapeutic strategy is implementing immunosuppressants such as methotrexate, mycophenolate mofetil, and azathioprine for persistent disease. Immunomodulators such as thalidomide historically have been shown to treat severe recalcitrant cases of HLE but typically are reserved for extreme cases due to adverse effects. Biologic agents such as intravenous immunoglobulins and rituximab have been shown to treat CCLE successfully, but routine use is limited due to high cost and lack of strong clinical trials.⁷

There have been reports of experimental therapies such as monoclonal antibodies (eg, anifrolumab and tocilizumab therapy) providing remission for patients with refractory CCLE, but information on their efficacy—specifically in patients with HLE—is lacking.⁸ Chronic cutaneous lupus erythematosus and its variants require further investigation regarding which treatment options provide the greatest benefit while minimizing adverse effects.

It is important to distinguish HLE from other potential diagnoses. Features of HLE can mimic hypertrophic lichen planus; however, the latter typically appears on the legs while HLE appears more commonly on the upper extremities and face in a photodistributed pattern.⁹ Since HLE has a lichenoid appearance histologically, it may appear clinically similar to hypertrophic lichen planus. Although not performed in our patient due to cost, direct immunofluorescence can aid in distinguishing HLE from hypertrophic lichen planus. Chronic cutaneous lupus erythematosus shows a granular pattern of deposition of IgM (primarily), IgG, IgA, and C3. In contrast, hypertrophic lichen planus exhibits cytoid bodies that stain positive for IgM as well as linear deposition of fibrinogen along the basement membrane.^3,10

Blastomycosis also can lead to development of verrucous plaques in sun-exposed areas, but the lesions typically originate as pustules that ulcerate over time. Lesions also can manifest with central scarring and a heaped edge.³ Unlike HLE, pseudoepitheliomatous hyperplasia with mixed infiltrate and intradermal pustules are seen in blastomycosis.³ Fungal organisms often are seen on pathology and are relatively large and uniform in size and shape, are found within giant cells, and have a thick refractile asymmetrical wall.¹¹ In rupioid psoriasis, skin lesions mostly are widespread and are not limited to sun-exposed areas. Additionally, biopsies from active rupioid lesions typically show psoriasiform epidermal hyperplasia with parakeratosis with no interface inflammation—a key differentiator.¹² In secondary syphilis, chancres often are missed and are not reported by patients. Clinically, secondary syphilis often manifests as scaly patches and plaques with palmar involvement and positive rapid plasma reagin, which was negative in our patient.¹³ Histologically, secondary syphilis can exhibit a vacuolar or lichenoid interface dermatitis; however, it typically exhibits slender acanthosis with long rete ridges and neutrophils in the stratum corneum.³ Furthermore, plasma cells are present in about two-thirds of cases in the United States, with obliteration of the lumen of small vessels and perivascular histiocytes and lymphocytes with apparent cytoplasm commonly seen on pathology. Silver staining or immunostaining for Treponema pallidum may reveal the spirochetes that cause this condition.³

THE DIAGNOSIS: Hypertrophic Lupus Erythematosus

The biopsy of the face collected at the initial appointment revealed interface dermatitis with epidermal hyperplasia with no parakeratosis or eosinophils (Figure 1). Microscopic findings were suggestive of hypertrophic lupus erythematosus (HLE) or hypertrophic lichen planus. The rapid plasma reagin and HIV labs collected at the initial appointment were negative, and a review of systems was negative for systemic symptoms. Considering these results and the clinical distribution of the lesions primarily affecting sun-exposed areas of the upper body, a final diagnosis of HLE was made. The patient was counseled on the importance of photoprotection and was started on hydroxychloroquine.

Hypertrophic lupus erythematosus, a rare variant of chronic cutaneous lupus erythematosus (CCLE), typically manifests as verrucous plaques or nodules commonly found on sun-exposed areas of the body, as was observed in our patient on the face, scalp (Figures 2 and 3), chest, and upper extremities.¹ Lesions can have a variable appearance, from hyperkeratotic ulcers to depigmented plaques and keratoacanthomalike lesions.² On histopathology, HLE falls into the category of lichenoid interface dermatitis and commonly demonstrates hyperkeratosis, acanthosis, follicular plugging, superficial and deep infiltrate, and increased mucin deposition in the dermis.³

Although rare, it is critical to remain vigilant for the development of squamous cell carcinoma in patients with chronic untreated CCLE. Hypertrophic lupus erythematosus, specifically, is the most likely variant to give rise to invasive squamous cell carcinoma and can be more aggressive as a result of this malignant transformation.^3,4 Ruling out squamous cell carcinoma in the setting of HLE can be achieved by staining for CD123, as HLE commonly is associated with many CD123+ plasmacytoid dendritic cells adjacent to the epithelium, unlike squamous cell carcinoma.³ Fortunately no evidence of invasive squamous cell carcinoma, including cellular atypia or increased mitotic figures, was seen on histology in our patient.

A thorough history and physical examination are essential for screening for HLE, as positive antinuclear antibodies are observed only in half of the patients diagnosed with CCLE.⁵ Furthermore, antinuclear antibodies sometimes can be negative in patients with HLE who have end-stage organ involvement.

Hypertrophic lupus erythematosus can be challenging to treat. First-line therapies include antimalarials, topical steroids, and sun-protective measures. Intralesional triamcinolone injection also can be used as an adjunctive therapy to expedite the treatment response.⁶ Evidence supports good response following treatment with acitretin or a combination of isotretinoin and hydroxychloroquine.² Another therapeutic strategy is implementing immunosuppressants such as methotrexate, mycophenolate mofetil, and azathioprine for persistent disease. Immunomodulators such as thalidomide historically have been shown to treat severe recalcitrant cases of HLE but typically are reserved for extreme cases due to adverse effects. Biologic agents such as intravenous immunoglobulins and rituximab have been shown to treat CCLE successfully, but routine use is limited due to high cost and lack of strong clinical trials.⁷

There have been reports of experimental therapies such as monoclonal antibodies (eg, anifrolumab and tocilizumab therapy) providing remission for patients with refractory CCLE, but information on their efficacy—specifically in patients with HLE—is lacking.⁸ Chronic cutaneous lupus erythematosus and its variants require further investigation regarding which treatment options provide the greatest benefit while minimizing adverse effects.

It is important to distinguish HLE from other potential diagnoses. Features of HLE can mimic hypertrophic lichen planus; however, the latter typically appears on the legs while HLE appears more commonly on the upper extremities and face in a photodistributed pattern.⁹ Since HLE has a lichenoid appearance histologically, it may appear clinically similar to hypertrophic lichen planus. Although not performed in our patient due to cost, direct immunofluorescence can aid in distinguishing HLE from hypertrophic lichen planus. Chronic cutaneous lupus erythematosus shows a granular pattern of deposition of IgM (primarily), IgG, IgA, and C3. In contrast, hypertrophic lichen planus exhibits cytoid bodies that stain positive for IgM as well as linear deposition of fibrinogen along the basement membrane.^3,10

Blastomycosis also can lead to development of verrucous plaques in sun-exposed areas, but the lesions typically originate as pustules that ulcerate over time. Lesions also can manifest with central scarring and a heaped edge.³ Unlike HLE, pseudoepitheliomatous hyperplasia with mixed infiltrate and intradermal pustules are seen in blastomycosis.³ Fungal organisms often are seen on pathology and are relatively large and uniform in size and shape, are found within giant cells, and have a thick refractile asymmetrical wall.¹¹ In rupioid psoriasis, skin lesions mostly are widespread and are not limited to sun-exposed areas. Additionally, biopsies from active rupioid lesions typically show psoriasiform epidermal hyperplasia with parakeratosis with no interface inflammation—a key differentiator.¹² In secondary syphilis, chancres often are missed and are not reported by patients. Clinically, secondary syphilis often manifests as scaly patches and plaques with palmar involvement and positive rapid plasma reagin, which was negative in our patient.¹³ Histologically, secondary syphilis can exhibit a vacuolar or lichenoid interface dermatitis; however, it typically exhibits slender acanthosis with long rete ridges and neutrophils in the stratum corneum.³ Furthermore, plasma cells are present in about two-thirds of cases in the United States, with obliteration of the lumen of small vessels and perivascular histiocytes and lymphocytes with apparent cytoplasm commonly seen on pathology. Silver staining or immunostaining for Treponema pallidum may reveal the spirochetes that cause this condition.³

THE DIAGNOSIS: Hypertrophic Lupus Erythematosus

The biopsy of the face collected at the initial appointment revealed interface dermatitis with epidermal hyperplasia with no parakeratosis or eosinophils (Figure 1). Microscopic findings were suggestive of hypertrophic lupus erythematosus (HLE) or hypertrophic lichen planus. The rapid plasma reagin and HIV labs collected at the initial appointment were negative, and a review of systems was negative for systemic symptoms. Considering these results and the clinical distribution of the lesions primarily affecting sun-exposed areas of the upper body, a final diagnosis of HLE was made. The patient was counseled on the importance of photoprotection and was started on hydroxychloroquine.

Hypertrophic lupus erythematosus, a rare variant of chronic cutaneous lupus erythematosus (CCLE), typically manifests as verrucous plaques or nodules commonly found on sun-exposed areas of the body, as was observed in our patient on the face, scalp (Figures 2 and 3), chest, and upper extremities.¹ Lesions can have a variable appearance, from hyperkeratotic ulcers to depigmented plaques and keratoacanthomalike lesions.² On histopathology, HLE falls into the category of lichenoid interface dermatitis and commonly demonstrates hyperkeratosis, acanthosis, follicular plugging, superficial and deep infiltrate, and increased mucin deposition in the dermis.³

Although rare, it is critical to remain vigilant for the development of squamous cell carcinoma in patients with chronic untreated CCLE. Hypertrophic lupus erythematosus, specifically, is the most likely variant to give rise to invasive squamous cell carcinoma and can be more aggressive as a result of this malignant transformation.^3,4 Ruling out squamous cell carcinoma in the setting of HLE can be achieved by staining for CD123, as HLE commonly is associated with many CD123+ plasmacytoid dendritic cells adjacent to the epithelium, unlike squamous cell carcinoma.³ Fortunately no evidence of invasive squamous cell carcinoma, including cellular atypia or increased mitotic figures, was seen on histology in our patient.

A thorough history and physical examination are essential for screening for HLE, as positive antinuclear antibodies are observed only in half of the patients diagnosed with CCLE.⁵ Furthermore, antinuclear antibodies sometimes can be negative in patients with HLE who have end-stage organ involvement.

Hypertrophic lupus erythematosus can be challenging to treat. First-line therapies include antimalarials, topical steroids, and sun-protective measures. Intralesional triamcinolone injection also can be used as an adjunctive therapy to expedite the treatment response.⁶ Evidence supports good response following treatment with acitretin or a combination of isotretinoin and hydroxychloroquine.² Another therapeutic strategy is implementing immunosuppressants such as methotrexate, mycophenolate mofetil, and azathioprine for persistent disease. Immunomodulators such as thalidomide historically have been shown to treat severe recalcitrant cases of HLE but typically are reserved for extreme cases due to adverse effects. Biologic agents such as intravenous immunoglobulins and rituximab have been shown to treat CCLE successfully, but routine use is limited due to high cost and lack of strong clinical trials.⁷

There have been reports of experimental therapies such as monoclonal antibodies (eg, anifrolumab and tocilizumab therapy) providing remission for patients with refractory CCLE, but information on their efficacy—specifically in patients with HLE—is lacking.⁸ Chronic cutaneous lupus erythematosus and its variants require further investigation regarding which treatment options provide the greatest benefit while minimizing adverse effects.

It is important to distinguish HLE from other potential diagnoses. Features of HLE can mimic hypertrophic lichen planus; however, the latter typically appears on the legs while HLE appears more commonly on the upper extremities and face in a photodistributed pattern.⁹ Since HLE has a lichenoid appearance histologically, it may appear clinically similar to hypertrophic lichen planus. Although not performed in our patient due to cost, direct immunofluorescence can aid in distinguishing HLE from hypertrophic lichen planus. Chronic cutaneous lupus erythematosus shows a granular pattern of deposition of IgM (primarily), IgG, IgA, and C3. In contrast, hypertrophic lichen planus exhibits cytoid bodies that stain positive for IgM as well as linear deposition of fibrinogen along the basement membrane.^3,10

Blastomycosis also can lead to development of verrucous plaques in sun-exposed areas, but the lesions typically originate as pustules that ulcerate over time. Lesions also can manifest with central scarring and a heaped edge.³ Unlike HLE, pseudoepitheliomatous hyperplasia with mixed infiltrate and intradermal pustules are seen in blastomycosis.³ Fungal organisms often are seen on pathology and are relatively large and uniform in size and shape, are found within giant cells, and have a thick refractile asymmetrical wall.¹¹ In rupioid psoriasis, skin lesions mostly are widespread and are not limited to sun-exposed areas. Additionally, biopsies from active rupioid lesions typically show psoriasiform epidermal hyperplasia with parakeratosis with no interface inflammation—a key differentiator.¹² In secondary syphilis, chancres often are missed and are not reported by patients. Clinically, secondary syphilis often manifests as scaly patches and plaques with palmar involvement and positive rapid plasma reagin, which was negative in our patient.¹³ Histologically, secondary syphilis can exhibit a vacuolar or lichenoid interface dermatitis; however, it typically exhibits slender acanthosis with long rete ridges and neutrophils in the stratum corneum.³ Furthermore, plasma cells are present in about two-thirds of cases in the United States, with obliteration of the lumen of small vessels and perivascular histiocytes and lymphocytes with apparent cytoplasm commonly seen on pathology. Silver staining or immunostaining for Treponema pallidum may reveal the spirochetes that cause this condition.³

THE DIAGNOSIS: Rheumatoid Vasculitis

A diagnosis of rheumatoid vasculitis (RV) was made based on the clinical features, histopathology, and laboratory results in the setting of rheumatoid arthritis (RA). The distal gangrene was surgically managed with bilateral transmetatarsal amputation followed by ankle collagen graft placement. The patient was started on a prednisone taper for 1 month (40 mg/d for 3 days, then 30 mg/d for 3 days, then 20 mg/d for 24 days) before transitioning to rituximab (375 mg/m² once weekly for 4 weeks), which improved the size and depth of the ulcers.

Rheumatoid vasculitis is an inflammatory disease that affects small- to medium-sized blood vessels in patients with RA. The pathogenesis involves immune complex deposition and complement system activation, leading to vessel wall destruction.¹ Rheumatoid vasculitis is an extra-articular complication of RA that primarily is observed in seropositive patients with long-standing severe disease.^1,2 The mean duration between RA diagnosis and RV onset is 10 to 14 years.² Rheumatoid vasculitis manifests heterogeneously and can affect many organs; however, it most frequently affects the skin. Cutaneous manifestations vary in severity. Palpable purpura, pyoderma gangrenosum, and distal ulcers can be seen in addition to extensive digital ischemia with necrosis, as was present in our patient.¹

When RA patients present with skin changes that are concerning for vasculitis, RV should be suspected. Currently, there are no validated diagnostic criteria for RV. Diagnosis is made based on clinical presentation and tissue biopsy. Histopathology shows small- and medium-sized vessel wall destruction with neutrophilic, granulomatous, or lymphocytic infiltration, which may be observed only in the lower dermis sparing superficial vessels.³ Direct immunofluorescence shows IgM, IgA, and C3 deposition within and around vessels.^3,4 Laboratory findings including elevated inflammatory markers, positive rheumatoid factor, positive anti–cyclic citrullinated peptide, and hypocomplementemia support a diagnosis of RV.^1,2

Mortality rates for RV remain high, necessitating aggressive treatment. High-dose corticosteroids typically are combined with immunosuppressant or biologic agents, frequently cyclophosphamide or rituximab.¹ Consistent with other reported cases, our patient’s ulcers improved with rituximab and oral steroids.

The differential diagnosis for our patient included type I cryoglobulinemia, cutaneous polyarteritis nodosa (CPAN), peripheral vascular disease (PVD), and nonuremic calciphylaxis. Type I cryoglobulinemia manifests due to direct occlusion of vessels by precipitation of monoclonal immunoglobulin.⁵ It commonly is associated with lymphoproliferative diseases such as Waldenström macroglobulinemia and multiple myeloma. While our patient’s history of RA was a risk factor for mixed cryoglobulinemia as opposed to type I cryoglobulinemia, the clinical presentation aligned more closely with type I cryoglobulinemia. The clinical manifestations of type I cryoglobulinemia are related to intravascular obstruction, including Raynaud phenomenon, retiform purpura, ischemic ulcers, distal gangrene, and cold-induced urticaria.^6-8 Type I cryoglobulinemia also frequently has neurologic and renal manifestations. Histopathology, along with the detection of serum cryoglobulins, is the gold standard for diagnosing cryoglobulinemia.⁶ On histopathology, type I cryoglobulinemia typically shows a thrombotic vasculopathy with amorphous eosinophilic periodic acid–Schiff–positive thrombi.⁷ False-negative results are particularly common with serum cryoglobulins, so repeat testing often is needed. While many clinical features overlap, RV is the most likely diagnosis in a patient with long-standing RA who is negative for cryoglobulins and has no history of lymphoproliferative disorders.

Cutaneous polyarteritis nodosa is a necrotizing vasculitis that similarly affects small- and medium-sized vessels. The exact etiology is unknown, but the high prevalence of anti–phosphatidylserine/prothrombin complex antibodies among patients with CPAN suggests that prothrombin bound to apoptotic endothelial cells may initiate the immune response.⁹ Underlying infection and inflammatory and autoimmune diseases (including group A beta-hemolytic streptococcus, hepatitis B, inflammatory bowel disease, myasthenia gravis, and RA) also may trigger CPAN.^9,10,11 The most common clinical manifestations of CPAN are tender subcutaneous nodules, livedo reticularis, leg ulcers, and cutaneous necrosis. Extracutaneous symptoms such as myalgias and arthralgias also can be associated with CPAN. There is no specific serologic test to diagnose CPAN; the diagnosis is made based on clinicopathologic correlation, with characteristic histopathology showing leukocytoclastic vasculitis in the small- and medium-sized arteries of the deep dermis or hypodermis.⁹

Peripheral vascular disease is a manifestation of atherosclerosis that affects the legs. Risk factors for atherosclerosis, especially smoking and diabetes mellitus, similarly increase the risk for PVD.¹² The most common clinical manifestation of PVD is intermittent claudication, but rarely PVD can progress to critical limb ischemia, which is characterized by pain at rest, nonhealing ulcers, or gangrene of the legs.¹² Common findings on physical examination include diminished or absent pedal pulses, abnormal skin color, and skin that is cool to the touch.¹² The standard diagnostic test for PVD affecting the legs is evaluation via the ankle-brachial index, with a score of 0.90 or lower being diagnostic of PVD, a score of 0.91 to 1.00 being borderline, and a score of 1.01 to 1.40 being normal.¹³

Calciphylaxis most frequently is seen in patients with end-stage kidney disease; however, it also has been less commonly reported in patients with normal kidney function, known as nonuremic calciphylaxis. It is characterized by calcification of arteries, arterioles, and soft tissues, which can lead to thrombosis and eventually ischemia and necrosis of the skin.¹⁴ Calciphylaxis initially causes tender, indurated, erythematous to purpuric plaques that quickly progress to retiform and stellate ulcers with overlying necrotic eschars.¹⁵ Disease typically occurs on the legs and areas that are rich in adipose tissue, such as the abdomen and thighs.¹⁶ Skin biopsy is needed for diagnosis of calciphylaxis. Characteristic histopathologic findings include calcification, microvascular thrombosis, and fibrointimal hyperplasia of small dermal and subcutaneous arteries and arterioles.¹⁶

We present a rare case of RV in a patient with well-controlled RA. While the incidence of RV is decreasing in the United States and United Kingdom due to the initiation of earlier and more aggressive RA therapies, mortality remains high.¹ Thus, it is important to include RV in the differential diagnosis when there are skin changes concerning vasculitis in patients with seropositive, longstanding RA, even if the RA is well controlled.

THE DIAGNOSIS: Rheumatoid Vasculitis

A diagnosis of rheumatoid vasculitis (RV) was made based on the clinical features, histopathology, and laboratory results in the setting of rheumatoid arthritis (RA). The distal gangrene was surgically managed with bilateral transmetatarsal amputation followed by ankle collagen graft placement. The patient was started on a prednisone taper for 1 month (40 mg/d for 3 days, then 30 mg/d for 3 days, then 20 mg/d for 24 days) before transitioning to rituximab (375 mg/m² once weekly for 4 weeks), which improved the size and depth of the ulcers.

Rheumatoid vasculitis is an inflammatory disease that affects small- to medium-sized blood vessels in patients with RA. The pathogenesis involves immune complex deposition and complement system activation, leading to vessel wall destruction.¹ Rheumatoid vasculitis is an extra-articular complication of RA that primarily is observed in seropositive patients with long-standing severe disease.^1,2 The mean duration between RA diagnosis and RV onset is 10 to 14 years.² Rheumatoid vasculitis manifests heterogeneously and can affect many organs; however, it most frequently affects the skin. Cutaneous manifestations vary in severity. Palpable purpura, pyoderma gangrenosum, and distal ulcers can be seen in addition to extensive digital ischemia with necrosis, as was present in our patient.¹

When RA patients present with skin changes that are concerning for vasculitis, RV should be suspected. Currently, there are no validated diagnostic criteria for RV. Diagnosis is made based on clinical presentation and tissue biopsy. Histopathology shows small- and medium-sized vessel wall destruction with neutrophilic, granulomatous, or lymphocytic infiltration, which may be observed only in the lower dermis sparing superficial vessels.³ Direct immunofluorescence shows IgM, IgA, and C3 deposition within and around vessels.^3,4 Laboratory findings including elevated inflammatory markers, positive rheumatoid factor, positive anti–cyclic citrullinated peptide, and hypocomplementemia support a diagnosis of RV.^1,2

Mortality rates for RV remain high, necessitating aggressive treatment. High-dose corticosteroids typically are combined with immunosuppressant or biologic agents, frequently cyclophosphamide or rituximab.¹ Consistent with other reported cases, our patient’s ulcers improved with rituximab and oral steroids.

The differential diagnosis for our patient included type I cryoglobulinemia, cutaneous polyarteritis nodosa (CPAN), peripheral vascular disease (PVD), and nonuremic calciphylaxis. Type I cryoglobulinemia manifests due to direct occlusion of vessels by precipitation of monoclonal immunoglobulin.⁵ It commonly is associated with lymphoproliferative diseases such as Waldenström macroglobulinemia and multiple myeloma. While our patient’s history of RA was a risk factor for mixed cryoglobulinemia as opposed to type I cryoglobulinemia, the clinical presentation aligned more closely with type I cryoglobulinemia. The clinical manifestations of type I cryoglobulinemia are related to intravascular obstruction, including Raynaud phenomenon, retiform purpura, ischemic ulcers, distal gangrene, and cold-induced urticaria.^6-8 Type I cryoglobulinemia also frequently has neurologic and renal manifestations. Histopathology, along with the detection of serum cryoglobulins, is the gold standard for diagnosing cryoglobulinemia.⁶ On histopathology, type I cryoglobulinemia typically shows a thrombotic vasculopathy with amorphous eosinophilic periodic acid–Schiff–positive thrombi.⁷ False-negative results are particularly common with serum cryoglobulins, so repeat testing often is needed. While many clinical features overlap, RV is the most likely diagnosis in a patient with long-standing RA who is negative for cryoglobulins and has no history of lymphoproliferative disorders.

Cutaneous polyarteritis nodosa is a necrotizing vasculitis that similarly affects small- and medium-sized vessels. The exact etiology is unknown, but the high prevalence of anti–phosphatidylserine/prothrombin complex antibodies among patients with CPAN suggests that prothrombin bound to apoptotic endothelial cells may initiate the immune response.⁹ Underlying infection and inflammatory and autoimmune diseases (including group A beta-hemolytic streptococcus, hepatitis B, inflammatory bowel disease, myasthenia gravis, and RA) also may trigger CPAN.^9,10,11 The most common clinical manifestations of CPAN are tender subcutaneous nodules, livedo reticularis, leg ulcers, and cutaneous necrosis. Extracutaneous symptoms such as myalgias and arthralgias also can be associated with CPAN. There is no specific serologic test to diagnose CPAN; the diagnosis is made based on clinicopathologic correlation, with characteristic histopathology showing leukocytoclastic vasculitis in the small- and medium-sized arteries of the deep dermis or hypodermis.⁹

Peripheral vascular disease is a manifestation of atherosclerosis that affects the legs. Risk factors for atherosclerosis, especially smoking and diabetes mellitus, similarly increase the risk for PVD.¹² The most common clinical manifestation of PVD is intermittent claudication, but rarely PVD can progress to critical limb ischemia, which is characterized by pain at rest, nonhealing ulcers, or gangrene of the legs.¹² Common findings on physical examination include diminished or absent pedal pulses, abnormal skin color, and skin that is cool to the touch.¹² The standard diagnostic test for PVD affecting the legs is evaluation via the ankle-brachial index, with a score of 0.90 or lower being diagnostic of PVD, a score of 0.91 to 1.00 being borderline, and a score of 1.01 to 1.40 being normal.¹³

Calciphylaxis most frequently is seen in patients with end-stage kidney disease; however, it also has been less commonly reported in patients with normal kidney function, known as nonuremic calciphylaxis. It is characterized by calcification of arteries, arterioles, and soft tissues, which can lead to thrombosis and eventually ischemia and necrosis of the skin.¹⁴ Calciphylaxis initially causes tender, indurated, erythematous to purpuric plaques that quickly progress to retiform and stellate ulcers with overlying necrotic eschars.¹⁵ Disease typically occurs on the legs and areas that are rich in adipose tissue, such as the abdomen and thighs.¹⁶ Skin biopsy is needed for diagnosis of calciphylaxis. Characteristic histopathologic findings include calcification, microvascular thrombosis, and fibrointimal hyperplasia of small dermal and subcutaneous arteries and arterioles.¹⁶

We present a rare case of RV in a patient with well-controlled RA. While the incidence of RV is decreasing in the United States and United Kingdom due to the initiation of earlier and more aggressive RA therapies, mortality remains high.¹ Thus, it is important to include RV in the differential diagnosis when there are skin changes concerning vasculitis in patients with seropositive, longstanding RA, even if the RA is well controlled.

THE DIAGNOSIS: Rheumatoid Vasculitis

A diagnosis of rheumatoid vasculitis (RV) was made based on the clinical features, histopathology, and laboratory results in the setting of rheumatoid arthritis (RA). The distal gangrene was surgically managed with bilateral transmetatarsal amputation followed by ankle collagen graft placement. The patient was started on a prednisone taper for 1 month (40 mg/d for 3 days, then 30 mg/d for 3 days, then 20 mg/d for 24 days) before transitioning to rituximab (375 mg/m² once weekly for 4 weeks), which improved the size and depth of the ulcers.

Rheumatoid vasculitis is an inflammatory disease that affects small- to medium-sized blood vessels in patients with RA. The pathogenesis involves immune complex deposition and complement system activation, leading to vessel wall destruction.¹ Rheumatoid vasculitis is an extra-articular complication of RA that primarily is observed in seropositive patients with long-standing severe disease.^1,2 The mean duration between RA diagnosis and RV onset is 10 to 14 years.² Rheumatoid vasculitis manifests heterogeneously and can affect many organs; however, it most frequently affects the skin. Cutaneous manifestations vary in severity. Palpable purpura, pyoderma gangrenosum, and distal ulcers can be seen in addition to extensive digital ischemia with necrosis, as was present in our patient.¹

When RA patients present with skin changes that are concerning for vasculitis, RV should be suspected. Currently, there are no validated diagnostic criteria for RV. Diagnosis is made based on clinical presentation and tissue biopsy. Histopathology shows small- and medium-sized vessel wall destruction with neutrophilic, granulomatous, or lymphocytic infiltration, which may be observed only in the lower dermis sparing superficial vessels.³ Direct immunofluorescence shows IgM, IgA, and C3 deposition within and around vessels.^3,4 Laboratory findings including elevated inflammatory markers, positive rheumatoid factor, positive anti–cyclic citrullinated peptide, and hypocomplementemia support a diagnosis of RV.^1,2

Mortality rates for RV remain high, necessitating aggressive treatment. High-dose corticosteroids typically are combined with immunosuppressant or biologic agents, frequently cyclophosphamide or rituximab.¹ Consistent with other reported cases, our patient’s ulcers improved with rituximab and oral steroids.

The differential diagnosis for our patient included type I cryoglobulinemia, cutaneous polyarteritis nodosa (CPAN), peripheral vascular disease (PVD), and nonuremic calciphylaxis. Type I cryoglobulinemia manifests due to direct occlusion of vessels by precipitation of monoclonal immunoglobulin.⁵ It commonly is associated with lymphoproliferative diseases such as Waldenström macroglobulinemia and multiple myeloma. While our patient’s history of RA was a risk factor for mixed cryoglobulinemia as opposed to type I cryoglobulinemia, the clinical presentation aligned more closely with type I cryoglobulinemia. The clinical manifestations of type I cryoglobulinemia are related to intravascular obstruction, including Raynaud phenomenon, retiform purpura, ischemic ulcers, distal gangrene, and cold-induced urticaria.^6-8 Type I cryoglobulinemia also frequently has neurologic and renal manifestations. Histopathology, along with the detection of serum cryoglobulins, is the gold standard for diagnosing cryoglobulinemia.⁶ On histopathology, type I cryoglobulinemia typically shows a thrombotic vasculopathy with amorphous eosinophilic periodic acid–Schiff–positive thrombi.⁷ False-negative results are particularly common with serum cryoglobulins, so repeat testing often is needed. While many clinical features overlap, RV is the most likely diagnosis in a patient with long-standing RA who is negative for cryoglobulins and has no history of lymphoproliferative disorders.

Cutaneous polyarteritis nodosa is a necrotizing vasculitis that similarly affects small- and medium-sized vessels. The exact etiology is unknown, but the high prevalence of anti–phosphatidylserine/prothrombin complex antibodies among patients with CPAN suggests that prothrombin bound to apoptotic endothelial cells may initiate the immune response.⁹ Underlying infection and inflammatory and autoimmune diseases (including group A beta-hemolytic streptococcus, hepatitis B, inflammatory bowel disease, myasthenia gravis, and RA) also may trigger CPAN.^9,10,11 The most common clinical manifestations of CPAN are tender subcutaneous nodules, livedo reticularis, leg ulcers, and cutaneous necrosis. Extracutaneous symptoms such as myalgias and arthralgias also can be associated with CPAN. There is no specific serologic test to diagnose CPAN; the diagnosis is made based on clinicopathologic correlation, with characteristic histopathology showing leukocytoclastic vasculitis in the small- and medium-sized arteries of the deep dermis or hypodermis.⁹

Peripheral vascular disease is a manifestation of atherosclerosis that affects the legs. Risk factors for atherosclerosis, especially smoking and diabetes mellitus, similarly increase the risk for PVD.¹² The most common clinical manifestation of PVD is intermittent claudication, but rarely PVD can progress to critical limb ischemia, which is characterized by pain at rest, nonhealing ulcers, or gangrene of the legs.¹² Common findings on physical examination include diminished or absent pedal pulses, abnormal skin color, and skin that is cool to the touch.¹² The standard diagnostic test for PVD affecting the legs is evaluation via the ankle-brachial index, with a score of 0.90 or lower being diagnostic of PVD, a score of 0.91 to 1.00 being borderline, and a score of 1.01 to 1.40 being normal.¹³

Calciphylaxis most frequently is seen in patients with end-stage kidney disease; however, it also has been less commonly reported in patients with normal kidney function, known as nonuremic calciphylaxis. It is characterized by calcification of arteries, arterioles, and soft tissues, which can lead to thrombosis and eventually ischemia and necrosis of the skin.¹⁴ Calciphylaxis initially causes tender, indurated, erythematous to purpuric plaques that quickly progress to retiform and stellate ulcers with overlying necrotic eschars.¹⁵ Disease typically occurs on the legs and areas that are rich in adipose tissue, such as the abdomen and thighs.¹⁶ Skin biopsy is needed for diagnosis of calciphylaxis. Characteristic histopathologic findings include calcification, microvascular thrombosis, and fibrointimal hyperplasia of small dermal and subcutaneous arteries and arterioles.¹⁶

We present a rare case of RV in a patient with well-controlled RA. While the incidence of RV is decreasing in the United States and United Kingdom due to the initiation of earlier and more aggressive RA therapies, mortality remains high.¹ Thus, it is important to include RV in the differential diagnosis when there are skin changes concerning vasculitis in patients with seropositive, longstanding RA, even if the RA is well controlled.

THE DIAGNOSIS: Trichodiscoma

Histologic evaluation revealed an unremarkable epidermal surface and a subjacent well-demarcated superficial dermal nodule showing a proliferation, sometimes fascicular, of wavy and spindled fibroblasts with some stellate forms within a variably loose fibrous stroma. Some angioplasia and vascular ectasia also were seen (Figure). A diagnosis of trichodiscoma was made based on these histologic findings.

While the patient’s personal and family history of pneumothorax originally had been attributed to other causes, the diagnosis of trichodiscoma raised suspicion for Birt-Hogg-Dubé syndrome due to the classic association of skin lesions (often trichodiscomas), renal cell carcinoma, and spontaneous pneumothorax in this condition. The patient was sent for genetic testing for the associated folliculin (FLCN) gene, which was positive and thereby confirmed the diagnosis of Birt-Hogg-Dubé syndrome. At the most recent follow-up almost 2 years after initial presentation, the lesions on the earlobe were stable. The patient has since undergone screening for abdominal and renal neoplasia with negative results, and he has had no other occurrences of pneumothorax.

Our case highlights the association between trichodiscomas and Birt-Hogg-Dubé syndrome, which necessitates screening for renal cell carcinoma, pneumothorax, and lung cysts.¹ Birt-Hogg-Dubé syndrome is an autosomal- dominant disorder of the skin and lungs that is characterized by a predisposition for renal carcinoma, pneumothorax, and colon polyps as well as cutaneous markers that include fibrofolliculomas, acrochordons, and trichodiscomas; the trichodiscomas tend to manifest as numerous smooth, flesh-colored or grayish-white papules on the face, ears, neck, and/or upper trunk.¹

Trichodiscomas are benign lesions and do not require treatment²; however, if they are cosmetically bothersome to the patient, surgical excision is an option for single lesions. For more widespread cutaneous disease, combination therapy with a CO₂ laser and erbium-doped yttrium aluminum garnet laser may be utilized.³ The differential diagnosis for trichodiscoma includes basal cell carcinoma, fibrous papule, dermal nevus, and trichofolliculoma.

Basal cell carcinoma is the most common type of skin cancer.⁴ Clinically, it typically manifests as pink or flesh-colored papules on the head or neck, often with overlying ulceration or telangiectasia. Due to its association with chronic sun exposure, the median age of diagnosis for basal cell carcinoma is 68 years. Histopathologically, basal cell carcinoma is characterized by islands or nests of atypical basaloid cells with palisading cells at the periphery.⁴ Treatment depends on the location and size of the lesion, but Mohs micrographic surgery is the most common intervention on the face and ears.⁵

In contrast, fibrous papules are benign lesions that manifest clinically as small, firm, flesh-colored papules that most commonly are found on the nose.^6,7 On dermatopathology, classic findings include fibrovascular proliferation and scattered multinucleated triangular or stellate cells in the upper dermis.⁷ Due to the benign nature of the lesion, treatment is not required⁶; however, shave excision, electrodessication, and laser therapies can be attempted if the patient chooses to pursue treatment.⁸

Dermal nevus is a type of benign acquired melanocytic nevus that manifests clinically as a light-brown to flesh-colored, dome-shaped or papillomatous papule.⁹ It typically develops in areas that are exposed to the sun, including the face.¹⁰ There also have been cases of dermal nevi on the ear.¹¹ Histopathology shows melanocytic nevus cells that have completely detached from the epidermis and are located entirely in the dermis.¹² While dermal nevi are benign and treatment is not necessary, surgical excision is an option for patients who request removal.¹³

Trichofolliculoma is a benign tumor of the adnexa that shows follicular differentiation on histopathology.¹⁴ On physical examination, it manifests as an isolated flesh-colored papule or nodule with a central pore from which tufted hairs protrude. These lesions usually appear on the face or scalp and occur more commonly in women than in men. While these may be clinically indistinguishable from trichodiscomas, the absence of protruding hair in our patient’s case makes trichofolliculoma less likely. When biopsied, histopathology classically shows a cystically dilated hair follicle with keratinous material and several mature and immature branched follicular structures. Preferred treatment for trichofolliculomas is surgical excision, and recurrence is rare.¹⁴

THE DIAGNOSIS: Trichodiscoma

Histologic evaluation revealed an unremarkable epidermal surface and a subjacent well-demarcated superficial dermal nodule showing a proliferation, sometimes fascicular, of wavy and spindled fibroblasts with some stellate forms within a variably loose fibrous stroma. Some angioplasia and vascular ectasia also were seen (Figure). A diagnosis of trichodiscoma was made based on these histologic findings.

While the patient’s personal and family history of pneumothorax originally had been attributed to other causes, the diagnosis of trichodiscoma raised suspicion for Birt-Hogg-Dubé syndrome due to the classic association of skin lesions (often trichodiscomas), renal cell carcinoma, and spontaneous pneumothorax in this condition. The patient was sent for genetic testing for the associated folliculin (FLCN) gene, which was positive and thereby confirmed the diagnosis of Birt-Hogg-Dubé syndrome. At the most recent follow-up almost 2 years after initial presentation, the lesions on the earlobe were stable. The patient has since undergone screening for abdominal and renal neoplasia with negative results, and he has had no other occurrences of pneumothorax.

Our case highlights the association between trichodiscomas and Birt-Hogg-Dubé syndrome, which necessitates screening for renal cell carcinoma, pneumothorax, and lung cysts.¹ Birt-Hogg-Dubé syndrome is an autosomal- dominant disorder of the skin and lungs that is characterized by a predisposition for renal carcinoma, pneumothorax, and colon polyps as well as cutaneous markers that include fibrofolliculomas, acrochordons, and trichodiscomas; the trichodiscomas tend to manifest as numerous smooth, flesh-colored or grayish-white papules on the face, ears, neck, and/or upper trunk.¹

Trichodiscomas are benign lesions and do not require treatment²; however, if they are cosmetically bothersome to the patient, surgical excision is an option for single lesions. For more widespread cutaneous disease, combination therapy with a CO₂ laser and erbium-doped yttrium aluminum garnet laser may be utilized.³ The differential diagnosis for trichodiscoma includes basal cell carcinoma, fibrous papule, dermal nevus, and trichofolliculoma.

Basal cell carcinoma is the most common type of skin cancer.⁴ Clinically, it typically manifests as pink or flesh-colored papules on the head or neck, often with overlying ulceration or telangiectasia. Due to its association with chronic sun exposure, the median age of diagnosis for basal cell carcinoma is 68 years. Histopathologically, basal cell carcinoma is characterized by islands or nests of atypical basaloid cells with palisading cells at the periphery.⁴ Treatment depends on the location and size of the lesion, but Mohs micrographic surgery is the most common intervention on the face and ears.⁵

In contrast, fibrous papules are benign lesions that manifest clinically as small, firm, flesh-colored papules that most commonly are found on the nose.^6,7 On dermatopathology, classic findings include fibrovascular proliferation and scattered multinucleated triangular or stellate cells in the upper dermis.⁷ Due to the benign nature of the lesion, treatment is not required⁶; however, shave excision, electrodessication, and laser therapies can be attempted if the patient chooses to pursue treatment.⁸

Dermal nevus is a type of benign acquired melanocytic nevus that manifests clinically as a light-brown to flesh-colored, dome-shaped or papillomatous papule.⁹ It typically develops in areas that are exposed to the sun, including the face.¹⁰ There also have been cases of dermal nevi on the ear.¹¹ Histopathology shows melanocytic nevus cells that have completely detached from the epidermis and are located entirely in the dermis.¹² While dermal nevi are benign and treatment is not necessary, surgical excision is an option for patients who request removal.¹³

Trichofolliculoma is a benign tumor of the adnexa that shows follicular differentiation on histopathology.¹⁴ On physical examination, it manifests as an isolated flesh-colored papule or nodule with a central pore from which tufted hairs protrude. These lesions usually appear on the face or scalp and occur more commonly in women than in men. While these may be clinically indistinguishable from trichodiscomas, the absence of protruding hair in our patient’s case makes trichofolliculoma less likely. When biopsied, histopathology classically shows a cystically dilated hair follicle with keratinous material and several mature and immature branched follicular structures. Preferred treatment for trichofolliculomas is surgical excision, and recurrence is rare.¹⁴

THE DIAGNOSIS: Trichodiscoma

Histologic evaluation revealed an unremarkable epidermal surface and a subjacent well-demarcated superficial dermal nodule showing a proliferation, sometimes fascicular, of wavy and spindled fibroblasts with some stellate forms within a variably loose fibrous stroma. Some angioplasia and vascular ectasia also were seen (Figure). A diagnosis of trichodiscoma was made based on these histologic findings.

While the patient’s personal and family history of pneumothorax originally had been attributed to other causes, the diagnosis of trichodiscoma raised suspicion for Birt-Hogg-Dubé syndrome due to the classic association of skin lesions (often trichodiscomas), renal cell carcinoma, and spontaneous pneumothorax in this condition. The patient was sent for genetic testing for the associated folliculin (FLCN) gene, which was positive and thereby confirmed the diagnosis of Birt-Hogg-Dubé syndrome. At the most recent follow-up almost 2 years after initial presentation, the lesions on the earlobe were stable. The patient has since undergone screening for abdominal and renal neoplasia with negative results, and he has had no other occurrences of pneumothorax.

Our case highlights the association between trichodiscomas and Birt-Hogg-Dubé syndrome, which necessitates screening for renal cell carcinoma, pneumothorax, and lung cysts.¹ Birt-Hogg-Dubé syndrome is an autosomal- dominant disorder of the skin and lungs that is characterized by a predisposition for renal carcinoma, pneumothorax, and colon polyps as well as cutaneous markers that include fibrofolliculomas, acrochordons, and trichodiscomas; the trichodiscomas tend to manifest as numerous smooth, flesh-colored or grayish-white papules on the face, ears, neck, and/or upper trunk.¹

Trichodiscomas are benign lesions and do not require treatment²; however, if they are cosmetically bothersome to the patient, surgical excision is an option for single lesions. For more widespread cutaneous disease, combination therapy with a CO₂ laser and erbium-doped yttrium aluminum garnet laser may be utilized.³ The differential diagnosis for trichodiscoma includes basal cell carcinoma, fibrous papule, dermal nevus, and trichofolliculoma.

Basal cell carcinoma is the most common type of skin cancer.⁴ Clinically, it typically manifests as pink or flesh-colored papules on the head or neck, often with overlying ulceration or telangiectasia. Due to its association with chronic sun exposure, the median age of diagnosis for basal cell carcinoma is 68 years. Histopathologically, basal cell carcinoma is characterized by islands or nests of atypical basaloid cells with palisading cells at the periphery.⁴ Treatment depends on the location and size of the lesion, but Mohs micrographic surgery is the most common intervention on the face and ears.⁵

In contrast, fibrous papules are benign lesions that manifest clinically as small, firm, flesh-colored papules that most commonly are found on the nose.^6,7 On dermatopathology, classic findings include fibrovascular proliferation and scattered multinucleated triangular or stellate cells in the upper dermis.⁷ Due to the benign nature of the lesion, treatment is not required⁶; however, shave excision, electrodessication, and laser therapies can be attempted if the patient chooses to pursue treatment.⁸

Dermal nevus is a type of benign acquired melanocytic nevus that manifests clinically as a light-brown to flesh-colored, dome-shaped or papillomatous papule.⁹ It typically develops in areas that are exposed to the sun, including the face.¹⁰ There also have been cases of dermal nevi on the ear.¹¹ Histopathology shows melanocytic nevus cells that have completely detached from the epidermis and are located entirely in the dermis.¹² While dermal nevi are benign and treatment is not necessary, surgical excision is an option for patients who request removal.¹³

Trichofolliculoma is a benign tumor of the adnexa that shows follicular differentiation on histopathology.¹⁴ On physical examination, it manifests as an isolated flesh-colored papule or nodule with a central pore from which tufted hairs protrude. These lesions usually appear on the face or scalp and occur more commonly in women than in men. While these may be clinically indistinguishable from trichodiscomas, the absence of protruding hair in our patient’s case makes trichofolliculoma less likely. When biopsied, histopathology classically shows a cystically dilated hair follicle with keratinous material and several mature and immature branched follicular structures. Preferred treatment for trichofolliculomas is surgical excision, and recurrence is rare.¹⁴

THE DIAGNOSIS: Hidradenocarcinoma

Both the original and recurrent lesions were interpreted as a chondroid syringoma, a benign adnexal tumor; however, the third biopsy of the lesion revealed a low-grade adnexal neoplasm with irregular nests of variably sized epithelial cells demonstrating mild nuclear atypia and low mitotic activity. Given the multiple recurrences, accelerated growth, and more aggressive histologic findings, the patient was referred to our clinic for surgical management.

We elected to perform modified Mohs micrographic surgery (MMS) with permanent tissue sections to enable the application of immunohistochemical stains to fully characterize the tumor. Histopathology showed a poorly circumscribed infiltrative dermal neoplasm composed of basaloid cells with a solid and cystic growth pattern in a background of hyalinized, fibrotic stroma (Figure, A and B). There were focal clear cell and squamous features as well as focal ductal differentiation (Figure, C and D). No obvious papillary structures were noted. The tumor cells were positive for D2-40, and staining for CD31 failed to reveal lymphovascular invasion. Based on the infiltrative features in conjunction with the findings from the prior biopsies, a diagnosis of hidradenocarcinoma (HAC) was made. Deep and peripheral margins were cleared after 2 stages of MMS.

Initially described in 1954, HAC is an exceedingly rare adnexal tumor of apocrine and eccrine derivation.¹ Historically, nomenclature for this entity has varied in the literature, including synonyms such as malignant nodular hidradenoma, malignant acrospiroma, solid-cystic adenocarcinoma, and malignant clear cell myoepithelioma.^2,3 Approximately 6% of all malignant eccrine tumors worldwide are HACs, which account for only 1 in 13,000 dermatopathology specimens.¹ These tumors may transform from clear cell hidradenomas (their benign counterparts) but more commonly arise de novo. Compared to benign hidradenomas, HACs are poorly circumscribed with infiltrative growth patterns on histopathology and may exhibit nuclear pleomorphism, prominent mitotic activity, necrosis, and perineural or vascular invasion.²

Clinically, HAC manifests as a 1- to 5-cm, solitary, firm, intradermal pink or violaceous nodule with possible ulceration.^2,4 The nodule often is asymptomatic but may be tender, as in our patient. There seems to be no clear anatomic site of predilection, with approximately 42% of HACs localized to the head and neck and the remainder occurring on the trunk, arms, and legs.^3,5-7 Females and males are affected equally, and lesions tend to arise in the seventh decade of life.⁷

Reports in the literature suggest that HAC is a very aggressive tumor with a generally poor prognosis.¹ Several studies have found that up to half of tumors locally recur despite aggressive surgical management, and metastasis occurs in 20% to 60% of patients.^3,8 However, a large study of US Surveillance, Epidemiology, and End Results data investigating the clinicopathologic characteristics of 289 patients with HAC revealed a more favorable prognosis.⁷ Mean overall survival and cancer-specific survival were greater than 13 years, and 10-year overall survival and cancer-specific survival rates were 60.2% and 90.5%, respectively.

Traditionally used to treat keratinocyte carcinomas, including basal cell carcinoma and squamous cell carcinoma, complete margin assessment with MMS is increasingly being utilized in the management of other cutaneous malignancies, including adnexal tumors.⁸ Due to its rarity, there remains no standard optimal treatment approach for HAC. One small retrospective study of 10 patients with HAC treated with MMS demonstrated favorable outcomes with no cases of recurrence, metastasis, or diseaserelated mortality in a mean 7-year follow-up period.⁹

Whole-body positron emission tomography/computed tomography performed in our patient approximately 1 month after MMS revealed mildly hypermetabolic left inguinal lymph nodes, which were thought to be reactive, and a question of small hypermetabolic foci in the liver. Follow-up computed tomography of the abdomen subsequently was performed and was negative for hepatic metastases. The patient will be monitored closely for local recurrence; however, the clearance of the tumor with MMS, which allowed complete margin assessment, is encouraging and supports MMS as superior to traditional surgical excision in the treatment of HAC. At his most recent examination 17 months after Mohs surgery, the patient remained tumor free.

Aggressive digital papillary adenocarcinoma (ADPA) is a rare malignant tumor originating in the sweat glands that can occur on the first toe but most commonly arises on the fingers. While both HAC and ADPA can manifest with an infiltrative growth pattern and cytologic atypia, ADPA classically reveals a well-circumscribed multinodular tumor in the dermis comprised of solid and cystic proliferation as well as papillary projections. In addition, ADPA has been described as having back-to-back glandular and ductal structures.¹⁰ Giant cell tumor of the tendon sheath is a benign fibrohistiocytic tumor that also typically manifests on the fingers but rarely can occur on the foot, including the first toe.^11,12 This tumor is more common in women and most frequently affects individuals aged 30 to 50 years.¹² Microscopically, giant cell tumor of the tendon sheath is characterized by a proliferation of osteoclastlike giant cells, epithelioid histiocytelike cells, mononuclear cells, and xanthomatous cells among collagenous bands.¹¹

Osteosarcoma is an uncommon tumor of osteoidproducing cells that usually arises in the metaphysis of long bones and manifests as a tender subcutaneous mass. It has a bimodal age distribution, peaking in adolescents and adults older than 65 years.¹³ While very rare, osteosarcoma has been reported to occur in the bones of the feet, including the phalanges.¹⁴ Given the recurrent nature of our patient’s tumor, metastasis should always be considered; however, in his case, full-body imaging was negative for additional malignancy.

THE DIAGNOSIS: Hidradenocarcinoma

Both the original and recurrent lesions were interpreted as a chondroid syringoma, a benign adnexal tumor; however, the third biopsy of the lesion revealed a low-grade adnexal neoplasm with irregular nests of variably sized epithelial cells demonstrating mild nuclear atypia and low mitotic activity. Given the multiple recurrences, accelerated growth, and more aggressive histologic findings, the patient was referred to our clinic for surgical management.

We elected to perform modified Mohs micrographic surgery (MMS) with permanent tissue sections to enable the application of immunohistochemical stains to fully characterize the tumor. Histopathology showed a poorly circumscribed infiltrative dermal neoplasm composed of basaloid cells with a solid and cystic growth pattern in a background of hyalinized, fibrotic stroma (Figure, A and B). There were focal clear cell and squamous features as well as focal ductal differentiation (Figure, C and D). No obvious papillary structures were noted. The tumor cells were positive for D2-40, and staining for CD31 failed to reveal lymphovascular invasion. Based on the infiltrative features in conjunction with the findings from the prior biopsies, a diagnosis of hidradenocarcinoma (HAC) was made. Deep and peripheral margins were cleared after 2 stages of MMS.

Initially described in 1954, HAC is an exceedingly rare adnexal tumor of apocrine and eccrine derivation.¹ Historically, nomenclature for this entity has varied in the literature, including synonyms such as malignant nodular hidradenoma, malignant acrospiroma, solid-cystic adenocarcinoma, and malignant clear cell myoepithelioma.^2,3 Approximately 6% of all malignant eccrine tumors worldwide are HACs, which account for only 1 in 13,000 dermatopathology specimens.¹ These tumors may transform from clear cell hidradenomas (their benign counterparts) but more commonly arise de novo. Compared to benign hidradenomas, HACs are poorly circumscribed with infiltrative growth patterns on histopathology and may exhibit nuclear pleomorphism, prominent mitotic activity, necrosis, and perineural or vascular invasion.²

Clinically, HAC manifests as a 1- to 5-cm, solitary, firm, intradermal pink or violaceous nodule with possible ulceration.^2,4 The nodule often is asymptomatic but may be tender, as in our patient. There seems to be no clear anatomic site of predilection, with approximately 42% of HACs localized to the head and neck and the remainder occurring on the trunk, arms, and legs.^3,5-7 Females and males are affected equally, and lesions tend to arise in the seventh decade of life.⁷

Reports in the literature suggest that HAC is a very aggressive tumor with a generally poor prognosis.¹ Several studies have found that up to half of tumors locally recur despite aggressive surgical management, and metastasis occurs in 20% to 60% of patients.^3,8 However, a large study of US Surveillance, Epidemiology, and End Results data investigating the clinicopathologic characteristics of 289 patients with HAC revealed a more favorable prognosis.⁷ Mean overall survival and cancer-specific survival were greater than 13 years, and 10-year overall survival and cancer-specific survival rates were 60.2% and 90.5%, respectively.

Traditionally used to treat keratinocyte carcinomas, including basal cell carcinoma and squamous cell carcinoma, complete margin assessment with MMS is increasingly being utilized in the management of other cutaneous malignancies, including adnexal tumors.⁸ Due to its rarity, there remains no standard optimal treatment approach for HAC. One small retrospective study of 10 patients with HAC treated with MMS demonstrated favorable outcomes with no cases of recurrence, metastasis, or diseaserelated mortality in a mean 7-year follow-up period.⁹

Whole-body positron emission tomography/computed tomography performed in our patient approximately 1 month after MMS revealed mildly hypermetabolic left inguinal lymph nodes, which were thought to be reactive, and a question of small hypermetabolic foci in the liver. Follow-up computed tomography of the abdomen subsequently was performed and was negative for hepatic metastases. The patient will be monitored closely for local recurrence; however, the clearance of the tumor with MMS, which allowed complete margin assessment, is encouraging and supports MMS as superior to traditional surgical excision in the treatment of HAC. At his most recent examination 17 months after Mohs surgery, the patient remained tumor free.

Aggressive digital papillary adenocarcinoma (ADPA) is a rare malignant tumor originating in the sweat glands that can occur on the first toe but most commonly arises on the fingers. While both HAC and ADPA can manifest with an infiltrative growth pattern and cytologic atypia, ADPA classically reveals a well-circumscribed multinodular tumor in the dermis comprised of solid and cystic proliferation as well as papillary projections. In addition, ADPA has been described as having back-to-back glandular and ductal structures.¹⁰ Giant cell tumor of the tendon sheath is a benign fibrohistiocytic tumor that also typically manifests on the fingers but rarely can occur on the foot, including the first toe.^11,12 This tumor is more common in women and most frequently affects individuals aged 30 to 50 years.¹² Microscopically, giant cell tumor of the tendon sheath is characterized by a proliferation of osteoclastlike giant cells, epithelioid histiocytelike cells, mononuclear cells, and xanthomatous cells among collagenous bands.¹¹

Osteosarcoma is an uncommon tumor of osteoidproducing cells that usually arises in the metaphysis of long bones and manifests as a tender subcutaneous mass. It has a bimodal age distribution, peaking in adolescents and adults older than 65 years.¹³ While very rare, osteosarcoma has been reported to occur in the bones of the feet, including the phalanges.¹⁴ Given the recurrent nature of our patient’s tumor, metastasis should always be considered; however, in his case, full-body imaging was negative for additional malignancy.

THE DIAGNOSIS: Hidradenocarcinoma

Both the original and recurrent lesions were interpreted as a chondroid syringoma, a benign adnexal tumor; however, the third biopsy of the lesion revealed a low-grade adnexal neoplasm with irregular nests of variably sized epithelial cells demonstrating mild nuclear atypia and low mitotic activity. Given the multiple recurrences, accelerated growth, and more aggressive histologic findings, the patient was referred to our clinic for surgical management.

We elected to perform modified Mohs micrographic surgery (MMS) with permanent tissue sections to enable the application of immunohistochemical stains to fully characterize the tumor. Histopathology showed a poorly circumscribed infiltrative dermal neoplasm composed of basaloid cells with a solid and cystic growth pattern in a background of hyalinized, fibrotic stroma (Figure, A and B). There were focal clear cell and squamous features as well as focal ductal differentiation (Figure, C and D). No obvious papillary structures were noted. The tumor cells were positive for D2-40, and staining for CD31 failed to reveal lymphovascular invasion. Based on the infiltrative features in conjunction with the findings from the prior biopsies, a diagnosis of hidradenocarcinoma (HAC) was made. Deep and peripheral margins were cleared after 2 stages of MMS.

Initially described in 1954, HAC is an exceedingly rare adnexal tumor of apocrine and eccrine derivation.¹ Historically, nomenclature for this entity has varied in the literature, including synonyms such as malignant nodular hidradenoma, malignant acrospiroma, solid-cystic adenocarcinoma, and malignant clear cell myoepithelioma.^2,3 Approximately 6% of all malignant eccrine tumors worldwide are HACs, which account for only 1 in 13,000 dermatopathology specimens.¹ These tumors may transform from clear cell hidradenomas (their benign counterparts) but more commonly arise de novo. Compared to benign hidradenomas, HACs are poorly circumscribed with infiltrative growth patterns on histopathology and may exhibit nuclear pleomorphism, prominent mitotic activity, necrosis, and perineural or vascular invasion.²

Clinically, HAC manifests as a 1- to 5-cm, solitary, firm, intradermal pink or violaceous nodule with possible ulceration.^2,4 The nodule often is asymptomatic but may be tender, as in our patient. There seems to be no clear anatomic site of predilection, with approximately 42% of HACs localized to the head and neck and the remainder occurring on the trunk, arms, and legs.^3,5-7 Females and males are affected equally, and lesions tend to arise in the seventh decade of life.⁷

Reports in the literature suggest that HAC is a very aggressive tumor with a generally poor prognosis.¹ Several studies have found that up to half of tumors locally recur despite aggressive surgical management, and metastasis occurs in 20% to 60% of patients.^3,8 However, a large study of US Surveillance, Epidemiology, and End Results data investigating the clinicopathologic characteristics of 289 patients with HAC revealed a more favorable prognosis.⁷ Mean overall survival and cancer-specific survival were greater than 13 years, and 10-year overall survival and cancer-specific survival rates were 60.2% and 90.5%, respectively.

Traditionally used to treat keratinocyte carcinomas, including basal cell carcinoma and squamous cell carcinoma, complete margin assessment with MMS is increasingly being utilized in the management of other cutaneous malignancies, including adnexal tumors.⁸ Due to its rarity, there remains no standard optimal treatment approach for HAC. One small retrospective study of 10 patients with HAC treated with MMS demonstrated favorable outcomes with no cases of recurrence, metastasis, or diseaserelated mortality in a mean 7-year follow-up period.⁹

Whole-body positron emission tomography/computed tomography performed in our patient approximately 1 month after MMS revealed mildly hypermetabolic left inguinal lymph nodes, which were thought to be reactive, and a question of small hypermetabolic foci in the liver. Follow-up computed tomography of the abdomen subsequently was performed and was negative for hepatic metastases. The patient will be monitored closely for local recurrence; however, the clearance of the tumor with MMS, which allowed complete margin assessment, is encouraging and supports MMS as superior to traditional surgical excision in the treatment of HAC. At his most recent examination 17 months after Mohs surgery, the patient remained tumor free.

Aggressive digital papillary adenocarcinoma (ADPA) is a rare malignant tumor originating in the sweat glands that can occur on the first toe but most commonly arises on the fingers. While both HAC and ADPA can manifest with an infiltrative growth pattern and cytologic atypia, ADPA classically reveals a well-circumscribed multinodular tumor in the dermis comprised of solid and cystic proliferation as well as papillary projections. In addition, ADPA has been described as having back-to-back glandular and ductal structures.¹⁰ Giant cell tumor of the tendon sheath is a benign fibrohistiocytic tumor that also typically manifests on the fingers but rarely can occur on the foot, including the first toe.^11,12 This tumor is more common in women and most frequently affects individuals aged 30 to 50 years.¹² Microscopically, giant cell tumor of the tendon sheath is characterized by a proliferation of osteoclastlike giant cells, epithelioid histiocytelike cells, mononuclear cells, and xanthomatous cells among collagenous bands.¹¹

Osteosarcoma is an uncommon tumor of osteoidproducing cells that usually arises in the metaphysis of long bones and manifests as a tender subcutaneous mass. It has a bimodal age distribution, peaking in adolescents and adults older than 65 years.¹³ While very rare, osteosarcoma has been reported to occur in the bones of the feet, including the phalanges.¹⁴ Given the recurrent nature of our patient’s tumor, metastasis should always be considered; however, in his case, full-body imaging was negative for additional malignancy.

THE DIAGNOSIS: Pemphigus Vegetans

Histopathologic examination of the biopsies from the scalp and left anterior thigh revealed suprabasal clefting with acantholytic cells extending into the follicular infundibulum with eosinophilic pustules within the epidermis. The dermis contained perivascular lymphohistiocytic and eosinophilic inflammatory infiltrates without viral cytopathic effects (Figure 1). Direct immunofluorescence revealed strong IgG and moderate IgA pericellular deposition around keratinocyte cytoplasms (Figure 2). Serologic evaluation demonstrated anti–desmoglein 3 antibodies. Based on the clinical presentation and histopathologic correlation, a diagnosis of pemphigus vegetans was made.

Pemphigus vegetans is a vesiculobullous autoimmune disease that is similar to pemphigus vulgaris but is characterized by the formation of vegetative plaques along the intertriginous areas and on the oral mucosa.¹ It is the rarest variant of all pemphigus subtypes and was first described by Neumann in 1876.² There are 2 subtypes of this variant: Hallopeau and Neumann, each with unique characteristics and physical manifestations. The Hallopeau type initially manifests with pustular lesions that rupture and evolve into erosions that commonly become infected. Gradually they merge and multiply to become more painful and vegetative.³ It has a more indolent course and typically responds well to treatment, and prolonged remission can be reached.⁴ The Neumann type is more severe and manifests with large vesiculobullous and erosive lesions that rupture and ulcerate, forming verrucous crusted vegetative plaques over the erosions.⁵ The erosions along the edge of the lesions induce new vegetation, becoming dry, hyperkeratotic, and fissured.³ The Neumann type often requires higher-dose steroids and typically is resistant to treatment.⁴ Patients can present with oral stomatitis and occasionally can develop a fissured or cerebriform appearance of the tongue, as seen in our patient (Figure 3).^1,2 Nail changes include onychorrhexis, onychomadesis, subungual pustules, and ultimately nail atrophy.⁵

Pemphigus diseases are characterized by IgG autoantibodies against desmoglein 3 and/or desmoglein 1. These are components of desmosomes that are responsible for keratinocyte adhesion, disruption of which results in the blister formation seen in pemphigus subtypes. The unique physical manifestation of pemphigus vegetans is thought to be due not only to autoantibodies against desmogleins 1 and 3 but also to autoantibodies against desmocollin 1 and 2.¹

Histopathologic examination reveals hyperkeratosis and pseudoepitheliomatous hyperplasia with acantholysis that creates a suprabasal cleft. Basal cells remain intact to the basement membrane by hemidesmosomes, resulting in a tombstone appearance. The Hallopeau type typically manifests with a large eosinophilic inflammatory response, leading to eosinophilic spongiosis and intraepidermal microabscesses. The Neumann type manifests with more of a neutrophilic and lymphocytic infiltrate, accompanied by the eosinophilic response.¹ For evaluation, obtain histopathology as well as direct immunofluorescence or enzyme-linked immunosorbent assay to look for intracellular deposition of desmoglein autoantibodies.

First-line treatment for pemphigus vulgaris and its variants is rituximab, an anti-CD20 monoclonal antibody. It has also been shown to have therapeutic benefit with combination of corticosteroids and rituximab. Corticosteroids should be given at a dose of 1 mg/kg daily for 2 to 4 weeks. Other immunosuppressive agents (steroid sparing) include azathioprine, dapsone, mycophenolate mofetil, methotrexate, cyclophosphamide, cyclosporine, and intravenous immunoglobulin. Pulse therapy with intermittent intravenous corticosteroids and immunosuppressants is another second-line therapeutic option. Topical therapeutic options include steroids, tacrolimus, and nicotinamide with oral tetracycline at onset and relapse. The goal of therapy is to maintain remission for 1 year then slowly taper treatment over another year.¹

Our patient initially was treated with prednisone, and subsequent courses of azathioprine and mycophenolate mofetil failed. He then was treated with 2 infusions of rituximab that were given 2 weeks apart. He was able to taper off the prednisone 1 month after the last infusion with complete remission of disease. He has been disease free for more than 9 months postinfusion.

Differential diagnoses for pemphigus vegetans can include bullous pemphigoid, bullous systemic lupus erythematosus, dermatitis herpetiformis, and pemphigus vulgaris. Lesion characteristics are key to differentiating pemphigus vegetans from other autoimmune blistering disorders. Bullous pemphigoid will manifest with tense blisters where pemphigus vulgaris will be flaccid; this is due to the difference in autoantibody targets between the conditions. Diagnosis depends on clinical presentation and histopathologic findings.

THE DIAGNOSIS: Pemphigus Vegetans

Histopathologic examination of the biopsies from the scalp and left anterior thigh revealed suprabasal clefting with acantholytic cells extending into the follicular infundibulum with eosinophilic pustules within the epidermis. The dermis contained perivascular lymphohistiocytic and eosinophilic inflammatory infiltrates without viral cytopathic effects (Figure 1). Direct immunofluorescence revealed strong IgG and moderate IgA pericellular deposition around keratinocyte cytoplasms (Figure 2). Serologic evaluation demonstrated anti–desmoglein 3 antibodies. Based on the clinical presentation and histopathologic correlation, a diagnosis of pemphigus vegetans was made.

Pemphigus vegetans is a vesiculobullous autoimmune disease that is similar to pemphigus vulgaris but is characterized by the formation of vegetative plaques along the intertriginous areas and on the oral mucosa.¹ It is the rarest variant of all pemphigus subtypes and was first described by Neumann in 1876.² There are 2 subtypes of this variant: Hallopeau and Neumann, each with unique characteristics and physical manifestations. The Hallopeau type initially manifests with pustular lesions that rupture and evolve into erosions that commonly become infected. Gradually they merge and multiply to become more painful and vegetative.³ It has a more indolent course and typically responds well to treatment, and prolonged remission can be reached.⁴ The Neumann type is more severe and manifests with large vesiculobullous and erosive lesions that rupture and ulcerate, forming verrucous crusted vegetative plaques over the erosions.⁵ The erosions along the edge of the lesions induce new vegetation, becoming dry, hyperkeratotic, and fissured.³ The Neumann type often requires higher-dose steroids and typically is resistant to treatment.⁴ Patients can present with oral stomatitis and occasionally can develop a fissured or cerebriform appearance of the tongue, as seen in our patient (Figure 3).^1,2 Nail changes include onychorrhexis, onychomadesis, subungual pustules, and ultimately nail atrophy.⁵

Pemphigus diseases are characterized by IgG autoantibodies against desmoglein 3 and/or desmoglein 1. These are components of desmosomes that are responsible for keratinocyte adhesion, disruption of which results in the blister formation seen in pemphigus subtypes. The unique physical manifestation of pemphigus vegetans is thought to be due not only to autoantibodies against desmogleins 1 and 3 but also to autoantibodies against desmocollin 1 and 2.¹

Histopathologic examination reveals hyperkeratosis and pseudoepitheliomatous hyperplasia with acantholysis that creates a suprabasal cleft. Basal cells remain intact to the basement membrane by hemidesmosomes, resulting in a tombstone appearance. The Hallopeau type typically manifests with a large eosinophilic inflammatory response, leading to eosinophilic spongiosis and intraepidermal microabscesses. The Neumann type manifests with more of a neutrophilic and lymphocytic infiltrate, accompanied by the eosinophilic response.¹ For evaluation, obtain histopathology as well as direct immunofluorescence or enzyme-linked immunosorbent assay to look for intracellular deposition of desmoglein autoantibodies.

First-line treatment for pemphigus vulgaris and its variants is rituximab, an anti-CD20 monoclonal antibody. It has also been shown to have therapeutic benefit with combination of corticosteroids and rituximab. Corticosteroids should be given at a dose of 1 mg/kg daily for 2 to 4 weeks. Other immunosuppressive agents (steroid sparing) include azathioprine, dapsone, mycophenolate mofetil, methotrexate, cyclophosphamide, cyclosporine, and intravenous immunoglobulin. Pulse therapy with intermittent intravenous corticosteroids and immunosuppressants is another second-line therapeutic option. Topical therapeutic options include steroids, tacrolimus, and nicotinamide with oral tetracycline at onset and relapse. The goal of therapy is to maintain remission for 1 year then slowly taper treatment over another year.¹

Our patient initially was treated with prednisone, and subsequent courses of azathioprine and mycophenolate mofetil failed. He then was treated with 2 infusions of rituximab that were given 2 weeks apart. He was able to taper off the prednisone 1 month after the last infusion with complete remission of disease. He has been disease free for more than 9 months postinfusion.

Differential diagnoses for pemphigus vegetans can include bullous pemphigoid, bullous systemic lupus erythematosus, dermatitis herpetiformis, and pemphigus vulgaris. Lesion characteristics are key to differentiating pemphigus vegetans from other autoimmune blistering disorders. Bullous pemphigoid will manifest with tense blisters where pemphigus vulgaris will be flaccid; this is due to the difference in autoantibody targets between the conditions. Diagnosis depends on clinical presentation and histopathologic findings.

THE DIAGNOSIS: Pemphigus Vegetans

Histopathologic examination of the biopsies from the scalp and left anterior thigh revealed suprabasal clefting with acantholytic cells extending into the follicular infundibulum with eosinophilic pustules within the epidermis. The dermis contained perivascular lymphohistiocytic and eosinophilic inflammatory infiltrates without viral cytopathic effects (Figure 1). Direct immunofluorescence revealed strong IgG and moderate IgA pericellular deposition around keratinocyte cytoplasms (Figure 2). Serologic evaluation demonstrated anti–desmoglein 3 antibodies. Based on the clinical presentation and histopathologic correlation, a diagnosis of pemphigus vegetans was made.

Pemphigus vegetans is a vesiculobullous autoimmune disease that is similar to pemphigus vulgaris but is characterized by the formation of vegetative plaques along the intertriginous areas and on the oral mucosa.¹ It is the rarest variant of all pemphigus subtypes and was first described by Neumann in 1876.² There are 2 subtypes of this variant: Hallopeau and Neumann, each with unique characteristics and physical manifestations. The Hallopeau type initially manifests with pustular lesions that rupture and evolve into erosions that commonly become infected. Gradually they merge and multiply to become more painful and vegetative.³ It has a more indolent course and typically responds well to treatment, and prolonged remission can be reached.⁴ The Neumann type is more severe and manifests with large vesiculobullous and erosive lesions that rupture and ulcerate, forming verrucous crusted vegetative plaques over the erosions.⁵ The erosions along the edge of the lesions induce new vegetation, becoming dry, hyperkeratotic, and fissured.³ The Neumann type often requires higher-dose steroids and typically is resistant to treatment.⁴ Patients can present with oral stomatitis and occasionally can develop a fissured or cerebriform appearance of the tongue, as seen in our patient (Figure 3).^1,2 Nail changes include onychorrhexis, onychomadesis, subungual pustules, and ultimately nail atrophy.⁵

Pemphigus diseases are characterized by IgG autoantibodies against desmoglein 3 and/or desmoglein 1. These are components of desmosomes that are responsible for keratinocyte adhesion, disruption of which results in the blister formation seen in pemphigus subtypes. The unique physical manifestation of pemphigus vegetans is thought to be due not only to autoantibodies against desmogleins 1 and 3 but also to autoantibodies against desmocollin 1 and 2.¹

Histopathologic examination reveals hyperkeratosis and pseudoepitheliomatous hyperplasia with acantholysis that creates a suprabasal cleft. Basal cells remain intact to the basement membrane by hemidesmosomes, resulting in a tombstone appearance. The Hallopeau type typically manifests with a large eosinophilic inflammatory response, leading to eosinophilic spongiosis and intraepidermal microabscesses. The Neumann type manifests with more of a neutrophilic and lymphocytic infiltrate, accompanied by the eosinophilic response.¹ For evaluation, obtain histopathology as well as direct immunofluorescence or enzyme-linked immunosorbent assay to look for intracellular deposition of desmoglein autoantibodies.

First-line treatment for pemphigus vulgaris and its variants is rituximab, an anti-CD20 monoclonal antibody. It has also been shown to have therapeutic benefit with combination of corticosteroids and rituximab. Corticosteroids should be given at a dose of 1 mg/kg daily for 2 to 4 weeks. Other immunosuppressive agents (steroid sparing) include azathioprine, dapsone, mycophenolate mofetil, methotrexate, cyclophosphamide, cyclosporine, and intravenous immunoglobulin. Pulse therapy with intermittent intravenous corticosteroids and immunosuppressants is another second-line therapeutic option. Topical therapeutic options include steroids, tacrolimus, and nicotinamide with oral tetracycline at onset and relapse. The goal of therapy is to maintain remission for 1 year then slowly taper treatment over another year.¹

Our patient initially was treated with prednisone, and subsequent courses of azathioprine and mycophenolate mofetil failed. He then was treated with 2 infusions of rituximab that were given 2 weeks apart. He was able to taper off the prednisone 1 month after the last infusion with complete remission of disease. He has been disease free for more than 9 months postinfusion.

Differential diagnoses for pemphigus vegetans can include bullous pemphigoid, bullous systemic lupus erythematosus, dermatitis herpetiformis, and pemphigus vulgaris. Lesion characteristics are key to differentiating pemphigus vegetans from other autoimmune blistering disorders. Bullous pemphigoid will manifest with tense blisters where pemphigus vulgaris will be flaccid; this is due to the difference in autoantibody targets between the conditions. Diagnosis depends on clinical presentation and histopathologic findings.

THE DIAGNOSIS: Fixed Drug Eruption

Based on the patient’s clinical presentation and history of similar eruptions, a diagnosis of levofloxacin-induced fixed drug eruption (FDE) was made. After cessation of the drug, the lesions resolved within 1 week without any residual postinflammatory hyperpigmentation.

Fixed drug eruption is an adverse cutaneous reaction characterized by the onset of a rash at a fixed location each time a specific medication is administered. Patients typically report a history of similar eruptions, often involving the upper and lower extremities, genital area, or mucous membranes. The most common causative agents vary, but retrospective analyses primarily implicate nonsteroidal anti-inflammatory drugs followed by antibiotics (eg, amoxicillin, levofloxacin, doxycycline) and antiepileptics.^1,2

While FDE can be solitary or scattered, most patients have 5 or fewer lesions, with a mean interval of 48 hours from exposure to the causative agent to onset of the rash.¹ The lesions can be differentiated by their typically solitary, well-demarcated, round or oval appearance; they also are erythematous to purple with a dusky center. The lesions may increase in size and number with each additional exposure to the offending medication.^1,3 Postinflammatory hyperpigmentation may last for weeks to months after the acute inflammatory response has resolved.

The high risk for recurrence of FDE may be explained by the presence of tissue resident memory T (TRM) cells in the affected skin that evoke a characteristic clinical manifestation upon administration of a causative agent.^2,3 Intraepidermal CD8⁺ TRM cells, which have an effectormemory phenotype, may contribute to the development of localized tissue damage; these cells demonstrate their effector function by the rapid increase in interferon gamma after challenge.² Within 24 hours of administration of the offending medication, CD8⁺ TRM cells migrate upward in the epidermis, and their activity leads to the epidermal necrosis observed with FDE. The self-limiting nature of FDE can be explained by the action of CD4+ Foxp3+ regulatory T cells that migrate similarly and induce the production of IL-10, which limits the damage inflicted by the CD8⁺ T cells.¹

Type I hypersensitivity reactions are IgE mediated; typically occur much more rapidly than FDE; and involve a raised urticarial rash, pruritus, and flushing. Urticaria is useful in identifying IgE-mediated reactions and mast cell degranulation. Previous exposure to the drug in question is required for diagnosis.⁴

Type IV delayed hypersensitivity reactions—including contact dermatitis and FDE—are mediated by T cells rather than IgE. These reactions occur at least 48 to 72 hours after drug exposure.⁴ Contact dermatitis follows exposure to an irritant but generally is limited to the site of contact and manifests with burning or stinging. Chronic contact dermatitis is characterized by erythema, scaling, and lichenification that may be associated with burning pain.

The target lesions of erythema multiforme are associated with the use of medications such as nonsteroidal anti-inflammatory drugs, antiepileptics, and antibiotics in fewer than 10% of cases. Infections are the predominant cause, with herpes simplex virus 1 being the most common etiology.⁵ Erythema multiforme lesions have 3 concentric segments: a dark red inflammatory zone surrounded by a pale ring of edema, both of which are surrounded by an erythematous halo. Lesions initially are distributed symmetrically on the extensor surfaces of the upper and lower extremities, but mucosal involvement may be present.⁵

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, involves fever and peripheral neutrophilia in addition to cutaneous erythematous eruptions and dermal neutrophilic infiltration on histopathology.⁶ Most cases are idiopathic but may occur in the setting of malignancy or drug administration. A major criterion for drug-induced Sweet syndrome is abrupt onset of painful erythematous plaques or nodules with pyrexia.⁶

THE DIAGNOSIS: Fixed Drug Eruption

Based on the patient’s clinical presentation and history of similar eruptions, a diagnosis of levofloxacin-induced fixed drug eruption (FDE) was made. After cessation of the drug, the lesions resolved within 1 week without any residual postinflammatory hyperpigmentation.

Fixed drug eruption is an adverse cutaneous reaction characterized by the onset of a rash at a fixed location each time a specific medication is administered. Patients typically report a history of similar eruptions, often involving the upper and lower extremities, genital area, or mucous membranes. The most common causative agents vary, but retrospective analyses primarily implicate nonsteroidal anti-inflammatory drugs followed by antibiotics (eg, amoxicillin, levofloxacin, doxycycline) and antiepileptics.^1,2

While FDE can be solitary or scattered, most patients have 5 or fewer lesions, with a mean interval of 48 hours from exposure to the causative agent to onset of the rash.¹ The lesions can be differentiated by their typically solitary, well-demarcated, round or oval appearance; they also are erythematous to purple with a dusky center. The lesions may increase in size and number with each additional exposure to the offending medication.^1,3 Postinflammatory hyperpigmentation may last for weeks to months after the acute inflammatory response has resolved.

The high risk for recurrence of FDE may be explained by the presence of tissue resident memory T (TRM) cells in the affected skin that evoke a characteristic clinical manifestation upon administration of a causative agent.^2,3 Intraepidermal CD8⁺ TRM cells, which have an effectormemory phenotype, may contribute to the development of localized tissue damage; these cells demonstrate their effector function by the rapid increase in interferon gamma after challenge.² Within 24 hours of administration of the offending medication, CD8⁺ TRM cells migrate upward in the epidermis, and their activity leads to the epidermal necrosis observed with FDE. The self-limiting nature of FDE can be explained by the action of CD4+ Foxp3+ regulatory T cells that migrate similarly and induce the production of IL-10, which limits the damage inflicted by the CD8⁺ T cells.¹

Type I hypersensitivity reactions are IgE mediated; typically occur much more rapidly than FDE; and involve a raised urticarial rash, pruritus, and flushing. Urticaria is useful in identifying IgE-mediated reactions and mast cell degranulation. Previous exposure to the drug in question is required for diagnosis.⁴

Type IV delayed hypersensitivity reactions—including contact dermatitis and FDE—are mediated by T cells rather than IgE. These reactions occur at least 48 to 72 hours after drug exposure.⁴ Contact dermatitis follows exposure to an irritant but generally is limited to the site of contact and manifests with burning or stinging. Chronic contact dermatitis is characterized by erythema, scaling, and lichenification that may be associated with burning pain.

The target lesions of erythema multiforme are associated with the use of medications such as nonsteroidal anti-inflammatory drugs, antiepileptics, and antibiotics in fewer than 10% of cases. Infections are the predominant cause, with herpes simplex virus 1 being the most common etiology.⁵ Erythema multiforme lesions have 3 concentric segments: a dark red inflammatory zone surrounded by a pale ring of edema, both of which are surrounded by an erythematous halo. Lesions initially are distributed symmetrically on the extensor surfaces of the upper and lower extremities, but mucosal involvement may be present.⁵

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, involves fever and peripheral neutrophilia in addition to cutaneous erythematous eruptions and dermal neutrophilic infiltration on histopathology.⁶ Most cases are idiopathic but may occur in the setting of malignancy or drug administration. A major criterion for drug-induced Sweet syndrome is abrupt onset of painful erythematous plaques or nodules with pyrexia.⁶

THE DIAGNOSIS: Fixed Drug Eruption

Based on the patient’s clinical presentation and history of similar eruptions, a diagnosis of levofloxacin-induced fixed drug eruption (FDE) was made. After cessation of the drug, the lesions resolved within 1 week without any residual postinflammatory hyperpigmentation.

Fixed drug eruption is an adverse cutaneous reaction characterized by the onset of a rash at a fixed location each time a specific medication is administered. Patients typically report a history of similar eruptions, often involving the upper and lower extremities, genital area, or mucous membranes. The most common causative agents vary, but retrospective analyses primarily implicate nonsteroidal anti-inflammatory drugs followed by antibiotics (eg, amoxicillin, levofloxacin, doxycycline) and antiepileptics.^1,2

While FDE can be solitary or scattered, most patients have 5 or fewer lesions, with a mean interval of 48 hours from exposure to the causative agent to onset of the rash.¹ The lesions can be differentiated by their typically solitary, well-demarcated, round or oval appearance; they also are erythematous to purple with a dusky center. The lesions may increase in size and number with each additional exposure to the offending medication.^1,3 Postinflammatory hyperpigmentation may last for weeks to months after the acute inflammatory response has resolved.

The high risk for recurrence of FDE may be explained by the presence of tissue resident memory T (TRM) cells in the affected skin that evoke a characteristic clinical manifestation upon administration of a causative agent.^2,3 Intraepidermal CD8⁺ TRM cells, which have an effectormemory phenotype, may contribute to the development of localized tissue damage; these cells demonstrate their effector function by the rapid increase in interferon gamma after challenge.² Within 24 hours of administration of the offending medication, CD8⁺ TRM cells migrate upward in the epidermis, and their activity leads to the epidermal necrosis observed with FDE. The self-limiting nature of FDE can be explained by the action of CD4+ Foxp3+ regulatory T cells that migrate similarly and induce the production of IL-10, which limits the damage inflicted by the CD8⁺ T cells.¹

Type I hypersensitivity reactions are IgE mediated; typically occur much more rapidly than FDE; and involve a raised urticarial rash, pruritus, and flushing. Urticaria is useful in identifying IgE-mediated reactions and mast cell degranulation. Previous exposure to the drug in question is required for diagnosis.⁴

Type IV delayed hypersensitivity reactions—including contact dermatitis and FDE—are mediated by T cells rather than IgE. These reactions occur at least 48 to 72 hours after drug exposure.⁴ Contact dermatitis follows exposure to an irritant but generally is limited to the site of contact and manifests with burning or stinging. Chronic contact dermatitis is characterized by erythema, scaling, and lichenification that may be associated with burning pain.

The target lesions of erythema multiforme are associated with the use of medications such as nonsteroidal anti-inflammatory drugs, antiepileptics, and antibiotics in fewer than 10% of cases. Infections are the predominant cause, with herpes simplex virus 1 being the most common etiology.⁵ Erythema multiforme lesions have 3 concentric segments: a dark red inflammatory zone surrounded by a pale ring of edema, both of which are surrounded by an erythematous halo. Lesions initially are distributed symmetrically on the extensor surfaces of the upper and lower extremities, but mucosal involvement may be present.⁵

Sweet syndrome, also known as acute febrile neutrophilic dermatosis, involves fever and peripheral neutrophilia in addition to cutaneous erythematous eruptions and dermal neutrophilic infiltration on histopathology.⁶ Most cases are idiopathic but may occur in the setting of malignancy or drug administration. A major criterion for drug-induced Sweet syndrome is abrupt onset of painful erythematous plaques or nodules with pyrexia.⁶

The Diagnosis: Accessory Breast

A diagnosis of accessory breast was confirmed on histopathology, which demonstrated a slightly hyperplastic and hyperpigmented epidermis. The dermis contained an increased number of smooth muscle bundles with the presence of apocrine glands and mammary lobules (Figure). Tenderness of the mass fluctuated according to the patient’s menstrual cycle, which supported a diagnosis of accessory breast over lipoma. The patient had no signs of infection or other systemic symptoms that were suggestive of lymphadenopathy. Unlike an epidermoid inclusion cyst, our patient’s mass presented as poorly defined and boggy in texture. Biopsy results were not consistent with malignancy, ruling out soft tissue sarcoma. 

Accessory breasts are characterized by the presence of breast tissue outside the breast and can be found anywhere along the milk line from the axillae to the vulva.¹ The prevalence of accessory breasts is 2% to 6% of women, with an average age of presentation for treatment of 42 years.² Ninety percent of accessory breasts are found in the thorax, 5% are found in the abdomen, and 5% are found in the axillae.³ Incidence is uncommon in adolescents; however, in addition to our patient, there are several cases in the literature of adolescents with accessory breasts in the axillae.^4,5 

Ectopic mammary tissue is divided into 8 classes based on the Kajava classification system (Table). In a retrospective study of adolescent females with accessory breasts, 91% (10/11) of patients were classified as class IV, and 1 was class II.⁶ Similarly, our patient was classified as class IV since her accessory breast was composed entirely of glandular tissue and did not include an areola and nipple. 

Supernumerary breast structures such as areolas and nipples typically are diagnosed at birth, whereas supernumerary breast tissue is not diagnosed until after hormonal stimulation typically seen during puberty, pregnancy, or breastfeeding. Common symptoms include cyclic pain with menstruation, fluctuation in the size of the mass, and tenderness of the ectopic tissue. There also can be restricted range of motion and increased irritation from clothing. Ultrasonography generally shows a hypoechoic septate indicative of mammary tissue.⁶ Diagnosis is confirmed by histopathologic studies that show mammary lobules in the dermis with smooth muscle, mammary ducts connected to the nipple, and connective stroma.⁶ 

If bothersome, ectopic breast tissue can be surgically removed, either by direct excision or suction lipectomy depending on the size of the mass.² Postoperative complications are low but can include seroma, bleeding, infection, remnant tissue, or undesired cosmetic results. As with normal breast tissue, ectopic breast tissue can manifest with benign and malignant pathologies. 

In conclusion, accessory breast is a benign condition that can cause cyclical pain with menstruation, restricted range of motion, discomfort, anxiety, and cosmetic problems. It is important to keep this diagnosis on the differential when evaluating a soft tissue mass that appears in the axillary region.

The Diagnosis: Accessory Breast

A diagnosis of accessory breast was confirmed on histopathology, which demonstrated a slightly hyperplastic and hyperpigmented epidermis. The dermis contained an increased number of smooth muscle bundles with the presence of apocrine glands and mammary lobules (Figure). Tenderness of the mass fluctuated according to the patient’s menstrual cycle, which supported a diagnosis of accessory breast over lipoma. The patient had no signs of infection or other systemic symptoms that were suggestive of lymphadenopathy. Unlike an epidermoid inclusion cyst, our patient’s mass presented as poorly defined and boggy in texture. Biopsy results were not consistent with malignancy, ruling out soft tissue sarcoma. 

Accessory breasts are characterized by the presence of breast tissue outside the breast and can be found anywhere along the milk line from the axillae to the vulva.¹ The prevalence of accessory breasts is 2% to 6% of women, with an average age of presentation for treatment of 42 years.² Ninety percent of accessory breasts are found in the thorax, 5% are found in the abdomen, and 5% are found in the axillae.³ Incidence is uncommon in adolescents; however, in addition to our patient, there are several cases in the literature of adolescents with accessory breasts in the axillae.^4,5 

Ectopic mammary tissue is divided into 8 classes based on the Kajava classification system (Table). In a retrospective study of adolescent females with accessory breasts, 91% (10/11) of patients were classified as class IV, and 1 was class II.⁶ Similarly, our patient was classified as class IV since her accessory breast was composed entirely of glandular tissue and did not include an areola and nipple. 

Supernumerary breast structures such as areolas and nipples typically are diagnosed at birth, whereas supernumerary breast tissue is not diagnosed until after hormonal stimulation typically seen during puberty, pregnancy, or breastfeeding. Common symptoms include cyclic pain with menstruation, fluctuation in the size of the mass, and tenderness of the ectopic tissue. There also can be restricted range of motion and increased irritation from clothing. Ultrasonography generally shows a hypoechoic septate indicative of mammary tissue.⁶ Diagnosis is confirmed by histopathologic studies that show mammary lobules in the dermis with smooth muscle, mammary ducts connected to the nipple, and connective stroma.⁶ 

If bothersome, ectopic breast tissue can be surgically removed, either by direct excision or suction lipectomy depending on the size of the mass.² Postoperative complications are low but can include seroma, bleeding, infection, remnant tissue, or undesired cosmetic results. As with normal breast tissue, ectopic breast tissue can manifest with benign and malignant pathologies. 

In conclusion, accessory breast is a benign condition that can cause cyclical pain with menstruation, restricted range of motion, discomfort, anxiety, and cosmetic problems. It is important to keep this diagnosis on the differential when evaluating a soft tissue mass that appears in the axillary region.

The Diagnosis: Accessory Breast

A diagnosis of accessory breast was confirmed on histopathology, which demonstrated a slightly hyperplastic and hyperpigmented epidermis. The dermis contained an increased number of smooth muscle bundles with the presence of apocrine glands and mammary lobules (Figure). Tenderness of the mass fluctuated according to the patient’s menstrual cycle, which supported a diagnosis of accessory breast over lipoma. The patient had no signs of infection or other systemic symptoms that were suggestive of lymphadenopathy. Unlike an epidermoid inclusion cyst, our patient’s mass presented as poorly defined and boggy in texture. Biopsy results were not consistent with malignancy, ruling out soft tissue sarcoma. 

Accessory breasts are characterized by the presence of breast tissue outside the breast and can be found anywhere along the milk line from the axillae to the vulva.¹ The prevalence of accessory breasts is 2% to 6% of women, with an average age of presentation for treatment of 42 years.² Ninety percent of accessory breasts are found in the thorax, 5% are found in the abdomen, and 5% are found in the axillae.³ Incidence is uncommon in adolescents; however, in addition to our patient, there are several cases in the literature of adolescents with accessory breasts in the axillae.^4,5 

Ectopic mammary tissue is divided into 8 classes based on the Kajava classification system (Table). In a retrospective study of adolescent females with accessory breasts, 91% (10/11) of patients were classified as class IV, and 1 was class II.⁶ Similarly, our patient was classified as class IV since her accessory breast was composed entirely of glandular tissue and did not include an areola and nipple. 

Supernumerary breast structures such as areolas and nipples typically are diagnosed at birth, whereas supernumerary breast tissue is not diagnosed until after hormonal stimulation typically seen during puberty, pregnancy, or breastfeeding. Common symptoms include cyclic pain with menstruation, fluctuation in the size of the mass, and tenderness of the ectopic tissue. There also can be restricted range of motion and increased irritation from clothing. Ultrasonography generally shows a hypoechoic septate indicative of mammary tissue.⁶ Diagnosis is confirmed by histopathologic studies that show mammary lobules in the dermis with smooth muscle, mammary ducts connected to the nipple, and connective stroma.⁶ 

If bothersome, ectopic breast tissue can be surgically removed, either by direct excision or suction lipectomy depending on the size of the mass.² Postoperative complications are low but can include seroma, bleeding, infection, remnant tissue, or undesired cosmetic results. As with normal breast tissue, ectopic breast tissue can manifest with benign and malignant pathologies. 

In conclusion, accessory breast is a benign condition that can cause cyclical pain with menstruation, restricted range of motion, discomfort, anxiety, and cosmetic problems. It is important to keep this diagnosis on the differential when evaluating a soft tissue mass that appears in the axillary region.