Dermpath Diagnosis

The Diagnosis: Spiradenocylindroma

T he biopsy results confirmed the diagnosis of spiradenocylindroma with negative margins. At 6-week follow-up, the patient had no signs of recurrence. Spiradenocylindroma is a benign hybrid neoplasm consisting of histologically intermixed areas representing the spectrum of morphology between spiradenoma and cylindromas.^1,2 Both spiradenoma and cylindroma comprise 2 distinct populations of dark and pale basaloid cells.^2,3 The spiradenomatous areas of the spiradenocylindroma are arranged in large, well-circumscribed collections of small, darkly staining cells with interspersed lymphocytes and a thin basement membrane surrounding spiradenocylindroma component.^2,3 The spiradenocylindroma regions also may contain tubular structures dilated by hemorrhage.² In contrast, the cylindromatous regions have a jigsaw-puzzle configuration of polygonal tumor nests containing peripherally palisading dark cells and central pale cells, surrounded by a thick basement membrane (top quiz image).^2,3 

Clinically, sporadic spiradenocylindromas may resemble other lesions, manifesting as a papule or nodule with coloration ranging from gray-blue to salmon pink along with arborizing telangiectasias.^4,5 Although spiradenocylindromas typically are found on the head, neck, and trunk, they also have been reported in the kidney, vulva, anus, and rectum.^2,6,7 Not only are spiradenocylindromas clinically indistinct from other adnexal growths, but they also share some features with basal cell carcinomas (BCCs) and amelanotic melanomas.⁸ Features of arborizing telangiectasias on a papule may resemble BCC, requiring histopathology for a definitive diagnosis. 

Spiradenocylindromas classically are associated with Brooke-Spiegler syndrome, a rare, autosomal-dominant genodermatosis caused by a germline mutation in the cylindromatosis lysine 63 deubiquitinase tumor-suppressor gene.⁵ Patients develop adnexal neoplasms of the folliculosebaceous-apocrine unit, including spiradenomas, cylindromas, and trichoepitheliomas.⁵ Rarely, malignant transformation to spiradenocylindrocarcinoma has been reported.⁹ Features of malignant transformation include loss of the 2-cell population, cytologic atypia, increased mitotic activity, and loss of intratumoral lymphocytes.¹⁰ 

Trichoepitheliomas are benign, firm, flesh-colored papules to nodules that commonly are found on the mid face but may appear on the scalp, neck, and upper trunk.^5-11 Trichoepitheliomas are closely related to spiradenomas and cylindromas; the familial form, multiple familial trichoepitheliomas, exists on a spectrum with Brooke-Spiegler syndrome.^3,11 Multiple familial trichoepithelioma is characterized by multiple trichoepitheliomas without accompanying spiradenomas, cylindromas, or spiradenocylindromas.3 On histopathology, trichoepitheliomas are distinguished by cribriform clusters or nests of basaloid follicular germinative cells with bulbar differentiation, known as papillary mesenchymal bodies, surrounded by an adherent stroma (eFigure 1).^3,5,11 In addition to follicular bulbar differentiation, trichoepitheliomas are surrounded by an adherent cellular stroma without the retraction artifact around tumor islands seen in BCC, although artifactual clefts may occur within the stroma.¹¹ In contrast, spiradenocylindromas do not demonstrate keratin cysts or artifactual clefts within the stroma.

Trichilemmal cysts, or pilar cysts, are benign adnexal neoplasms derived from the outer root sheath at the isthmus.^12-14 Approximately 90% of pilar cysts are found on the scalp and 2% of trichilemmal cysts may progress to a proliferating trichilemmal cyst, which is locally aggressive and contains an expanding buckled epithelium within the cyst space.^12,14 Clinically, trichilemmal cysts are slow-growing, smooth, round, mobile nodules without a central punctum.^12,13 On histopathology, the cyst wall contains peripherally palisading basal cells and maturing cells showing no intercellular bridging (eFigure 2). As the cells mature, they swell with pale cytoplasm and abruptly keratinize without a granular layer, a process known as trichilemmal keratinization.^12-14 Additionally, cholesterol clefts are common in the keratinous lumen, and about 25% of cysts contain calcifications.^13,14 The broadly basophilic spiradenocylindromas sharply contrast the abundant eosinophilic keratin of trichilemmal cysts. 

Basal cell carcinoma is a slow-growing, locally destructive neoplasm that develops due to chronic sun exposure; thus, BCCs commonly arise on exposed areas of the face, head, neck, arms, and legs.¹⁵ Nodular BCC is the most common subtype and typically manifests as a shiny pearly papule or nodule with a smooth surface, rolled borders, and arborizing telangiectasias.¹⁶ On histopathology, nodular BCCs demonstrate nests or nodules of basaloid keratinocytes with peripheral palisading and retraction artifact between the tumor and stroma (eFigure 3).^15,16 A lack of retraction artifact, cystic dilation of tubular structures, jigsaw molding of nests, and a distinct 2-cell population distinguish spiradenocylindroma from BCC. Of note, in rare instances BCCs also may display a thick fibrous stroma, similar to the stroma of cylindromas.¹⁵ 

Amelanotic melanoma is a variant of melanoma characterized by little to no pigment. Any of the 4 classic subtypes of melanoma (nodular, superficial spreading, lentigo maligna, acral lentiginous) can be amelanotic.¹⁷ Clinically, amelanotic melanomas can vary greatly, manifesting as erythematous macules, dermal plaques, or papulonodular lesions, often with scaling.¹⁸ On histopathology, findings common to all melanomas include cellular atypia, mitoses, pagetoid spread, and pleomorphism (eFigure 4).^18,19 Immunohistochemistry is an important method to distinguish melanoma from other melanocytic proliferations and to aid in the assessment of Breslow depth. Markers include SOX10 (sex-determining region Y-box transcription factor 10), S100, and MART-1 (melanoma antigen recognized by T cells 1/melan-A).^19,20 Expression of PRAME (preferentially expressed antigen in melanoma) often is positive but is not necessary for diagnosis.²¹ Histologically, the atypical pleomorphic cells of melanoma are markedly distinct from both spiradenomas and cylindromas.

The Diagnosis: Spiradenocylindroma

T he biopsy results confirmed the diagnosis of spiradenocylindroma with negative margins. At 6-week follow-up, the patient had no signs of recurrence. Spiradenocylindroma is a benign hybrid neoplasm consisting of histologically intermixed areas representing the spectrum of morphology between spiradenoma and cylindromas.^1,2 Both spiradenoma and cylindroma comprise 2 distinct populations of dark and pale basaloid cells.^2,3 The spiradenomatous areas of the spiradenocylindroma are arranged in large, well-circumscribed collections of small, darkly staining cells with interspersed lymphocytes and a thin basement membrane surrounding spiradenocylindroma component.^2,3 The spiradenocylindroma regions also may contain tubular structures dilated by hemorrhage.² In contrast, the cylindromatous regions have a jigsaw-puzzle configuration of polygonal tumor nests containing peripherally palisading dark cells and central pale cells, surrounded by a thick basement membrane (top quiz image).^2,3 

Clinically, sporadic spiradenocylindromas may resemble other lesions, manifesting as a papule or nodule with coloration ranging from gray-blue to salmon pink along with arborizing telangiectasias.^4,5 Although spiradenocylindromas typically are found on the head, neck, and trunk, they also have been reported in the kidney, vulva, anus, and rectum.^2,6,7 Not only are spiradenocylindromas clinically indistinct from other adnexal growths, but they also share some features with basal cell carcinomas (BCCs) and amelanotic melanomas.⁸ Features of arborizing telangiectasias on a papule may resemble BCC, requiring histopathology for a definitive diagnosis. 

Spiradenocylindromas classically are associated with Brooke-Spiegler syndrome, a rare, autosomal-dominant genodermatosis caused by a germline mutation in the cylindromatosis lysine 63 deubiquitinase tumor-suppressor gene.⁵ Patients develop adnexal neoplasms of the folliculosebaceous-apocrine unit, including spiradenomas, cylindromas, and trichoepitheliomas.⁵ Rarely, malignant transformation to spiradenocylindrocarcinoma has been reported.⁹ Features of malignant transformation include loss of the 2-cell population, cytologic atypia, increased mitotic activity, and loss of intratumoral lymphocytes.¹⁰ 

Trichoepitheliomas are benign, firm, flesh-colored papules to nodules that commonly are found on the mid face but may appear on the scalp, neck, and upper trunk.^5-11 Trichoepitheliomas are closely related to spiradenomas and cylindromas; the familial form, multiple familial trichoepitheliomas, exists on a spectrum with Brooke-Spiegler syndrome.^3,11 Multiple familial trichoepithelioma is characterized by multiple trichoepitheliomas without accompanying spiradenomas, cylindromas, or spiradenocylindromas.3 On histopathology, trichoepitheliomas are distinguished by cribriform clusters or nests of basaloid follicular germinative cells with bulbar differentiation, known as papillary mesenchymal bodies, surrounded by an adherent stroma (eFigure 1).^3,5,11 In addition to follicular bulbar differentiation, trichoepitheliomas are surrounded by an adherent cellular stroma without the retraction artifact around tumor islands seen in BCC, although artifactual clefts may occur within the stroma.¹¹ In contrast, spiradenocylindromas do not demonstrate keratin cysts or artifactual clefts within the stroma.

Trichilemmal cysts, or pilar cysts, are benign adnexal neoplasms derived from the outer root sheath at the isthmus.^12-14 Approximately 90% of pilar cysts are found on the scalp and 2% of trichilemmal cysts may progress to a proliferating trichilemmal cyst, which is locally aggressive and contains an expanding buckled epithelium within the cyst space.^12,14 Clinically, trichilemmal cysts are slow-growing, smooth, round, mobile nodules without a central punctum.^12,13 On histopathology, the cyst wall contains peripherally palisading basal cells and maturing cells showing no intercellular bridging (eFigure 2). As the cells mature, they swell with pale cytoplasm and abruptly keratinize without a granular layer, a process known as trichilemmal keratinization.^12-14 Additionally, cholesterol clefts are common in the keratinous lumen, and about 25% of cysts contain calcifications.^13,14 The broadly basophilic spiradenocylindromas sharply contrast the abundant eosinophilic keratin of trichilemmal cysts. 

Basal cell carcinoma is a slow-growing, locally destructive neoplasm that develops due to chronic sun exposure; thus, BCCs commonly arise on exposed areas of the face, head, neck, arms, and legs.¹⁵ Nodular BCC is the most common subtype and typically manifests as a shiny pearly papule or nodule with a smooth surface, rolled borders, and arborizing telangiectasias.¹⁶ On histopathology, nodular BCCs demonstrate nests or nodules of basaloid keratinocytes with peripheral palisading and retraction artifact between the tumor and stroma (eFigure 3).^15,16 A lack of retraction artifact, cystic dilation of tubular structures, jigsaw molding of nests, and a distinct 2-cell population distinguish spiradenocylindroma from BCC. Of note, in rare instances BCCs also may display a thick fibrous stroma, similar to the stroma of cylindromas.¹⁵ 

Amelanotic melanoma is a variant of melanoma characterized by little to no pigment. Any of the 4 classic subtypes of melanoma (nodular, superficial spreading, lentigo maligna, acral lentiginous) can be amelanotic.¹⁷ Clinically, amelanotic melanomas can vary greatly, manifesting as erythematous macules, dermal plaques, or papulonodular lesions, often with scaling.¹⁸ On histopathology, findings common to all melanomas include cellular atypia, mitoses, pagetoid spread, and pleomorphism (eFigure 4).^18,19 Immunohistochemistry is an important method to distinguish melanoma from other melanocytic proliferations and to aid in the assessment of Breslow depth. Markers include SOX10 (sex-determining region Y-box transcription factor 10), S100, and MART-1 (melanoma antigen recognized by T cells 1/melan-A).^19,20 Expression of PRAME (preferentially expressed antigen in melanoma) often is positive but is not necessary for diagnosis.²¹ Histologically, the atypical pleomorphic cells of melanoma are markedly distinct from both spiradenomas and cylindromas.

The Diagnosis: Spiradenocylindroma

T he biopsy results confirmed the diagnosis of spiradenocylindroma with negative margins. At 6-week follow-up, the patient had no signs of recurrence. Spiradenocylindroma is a benign hybrid neoplasm consisting of histologically intermixed areas representing the spectrum of morphology between spiradenoma and cylindromas.^1,2 Both spiradenoma and cylindroma comprise 2 distinct populations of dark and pale basaloid cells.^2,3 The spiradenomatous areas of the spiradenocylindroma are arranged in large, well-circumscribed collections of small, darkly staining cells with interspersed lymphocytes and a thin basement membrane surrounding spiradenocylindroma component.^2,3 The spiradenocylindroma regions also may contain tubular structures dilated by hemorrhage.² In contrast, the cylindromatous regions have a jigsaw-puzzle configuration of polygonal tumor nests containing peripherally palisading dark cells and central pale cells, surrounded by a thick basement membrane (top quiz image).^2,3 

Clinically, sporadic spiradenocylindromas may resemble other lesions, manifesting as a papule or nodule with coloration ranging from gray-blue to salmon pink along with arborizing telangiectasias.^4,5 Although spiradenocylindromas typically are found on the head, neck, and trunk, they also have been reported in the kidney, vulva, anus, and rectum.^2,6,7 Not only are spiradenocylindromas clinically indistinct from other adnexal growths, but they also share some features with basal cell carcinomas (BCCs) and amelanotic melanomas.⁸ Features of arborizing telangiectasias on a papule may resemble BCC, requiring histopathology for a definitive diagnosis. 

Spiradenocylindromas classically are associated with Brooke-Spiegler syndrome, a rare, autosomal-dominant genodermatosis caused by a germline mutation in the cylindromatosis lysine 63 deubiquitinase tumor-suppressor gene.⁵ Patients develop adnexal neoplasms of the folliculosebaceous-apocrine unit, including spiradenomas, cylindromas, and trichoepitheliomas.⁵ Rarely, malignant transformation to spiradenocylindrocarcinoma has been reported.⁹ Features of malignant transformation include loss of the 2-cell population, cytologic atypia, increased mitotic activity, and loss of intratumoral lymphocytes.¹⁰ 

Trichoepitheliomas are benign, firm, flesh-colored papules to nodules that commonly are found on the mid face but may appear on the scalp, neck, and upper trunk.^5-11 Trichoepitheliomas are closely related to spiradenomas and cylindromas; the familial form, multiple familial trichoepitheliomas, exists on a spectrum with Brooke-Spiegler syndrome.^3,11 Multiple familial trichoepithelioma is characterized by multiple trichoepitheliomas without accompanying spiradenomas, cylindromas, or spiradenocylindromas.3 On histopathology, trichoepitheliomas are distinguished by cribriform clusters or nests of basaloid follicular germinative cells with bulbar differentiation, known as papillary mesenchymal bodies, surrounded by an adherent stroma (eFigure 1).^3,5,11 In addition to follicular bulbar differentiation, trichoepitheliomas are surrounded by an adherent cellular stroma without the retraction artifact around tumor islands seen in BCC, although artifactual clefts may occur within the stroma.¹¹ In contrast, spiradenocylindromas do not demonstrate keratin cysts or artifactual clefts within the stroma.

Trichilemmal cysts, or pilar cysts, are benign adnexal neoplasms derived from the outer root sheath at the isthmus.^12-14 Approximately 90% of pilar cysts are found on the scalp and 2% of trichilemmal cysts may progress to a proliferating trichilemmal cyst, which is locally aggressive and contains an expanding buckled epithelium within the cyst space.^12,14 Clinically, trichilemmal cysts are slow-growing, smooth, round, mobile nodules without a central punctum.^12,13 On histopathology, the cyst wall contains peripherally palisading basal cells and maturing cells showing no intercellular bridging (eFigure 2). As the cells mature, they swell with pale cytoplasm and abruptly keratinize without a granular layer, a process known as trichilemmal keratinization.^12-14 Additionally, cholesterol clefts are common in the keratinous lumen, and about 25% of cysts contain calcifications.^13,14 The broadly basophilic spiradenocylindromas sharply contrast the abundant eosinophilic keratin of trichilemmal cysts. 

Basal cell carcinoma is a slow-growing, locally destructive neoplasm that develops due to chronic sun exposure; thus, BCCs commonly arise on exposed areas of the face, head, neck, arms, and legs.¹⁵ Nodular BCC is the most common subtype and typically manifests as a shiny pearly papule or nodule with a smooth surface, rolled borders, and arborizing telangiectasias.¹⁶ On histopathology, nodular BCCs demonstrate nests or nodules of basaloid keratinocytes with peripheral palisading and retraction artifact between the tumor and stroma (eFigure 3).^15,16 A lack of retraction artifact, cystic dilation of tubular structures, jigsaw molding of nests, and a distinct 2-cell population distinguish spiradenocylindroma from BCC. Of note, in rare instances BCCs also may display a thick fibrous stroma, similar to the stroma of cylindromas.¹⁵ 

Amelanotic melanoma is a variant of melanoma characterized by little to no pigment. Any of the 4 classic subtypes of melanoma (nodular, superficial spreading, lentigo maligna, acral lentiginous) can be amelanotic.¹⁷ Clinically, amelanotic melanomas can vary greatly, manifesting as erythematous macules, dermal plaques, or papulonodular lesions, often with scaling.¹⁸ On histopathology, findings common to all melanomas include cellular atypia, mitoses, pagetoid spread, and pleomorphism (eFigure 4).^18,19 Immunohistochemistry is an important method to distinguish melanoma from other melanocytic proliferations and to aid in the assessment of Breslow depth. Markers include SOX10 (sex-determining region Y-box transcription factor 10), S100, and MART-1 (melanoma antigen recognized by T cells 1/melan-A).^19,20 Expression of PRAME (preferentially expressed antigen in melanoma) often is positive but is not necessary for diagnosis.²¹ Histologically, the atypical pleomorphic cells of melanoma are markedly distinct from both spiradenomas and cylindromas.

THE DIAGNOSIS: Malignant Proliferating Trichilemmal Tumor

Biopsy revealed a squamous epithelium with cystic changes, trichilemmal differentiation, squamous eddy formation, keratinocyte atypia, focal necrotic changes, and a focus of atypical keratinocytes invading the dermis (Figure 1). Based on these findings, a diagnosis of malignant proliferating trichilemmal tumor (MPTT) was made.

Malignant proliferating trichilemmal tumor is a rare adnexal tumor that develops from the outer root sheath of the hair follicle. It often arises due to malignant transformation of pre-existing trichilemmal cysts, but some cases occur de novo.¹ Malignant transformation is thought to start from a trichilemmal cyst in an adenomatous histologic stage, progressing to a proliferating trichilemmal cyst (PTC) in an epitheliomatous phase, ultimately becoming carcinomatous with MPTT.^2-4 This transformation has been categorized into 3 morphologic groups to predict tumor behavior, including benign PTCs (curable by excision), low-grade malignant PTCs (minor risk for local recurrence), and high-grade malignant PTCs (risk for regional spread and metastasis with cytologic atypical features and potential for aggressive growth).¹

More commonly observed in women in the fourth to eighth decades of life, MPTT may manifest as a fast- growing, painless, solitary nodule or as a progressively enlarging nodule at the site of a previously stable, long-standing lesion. Malignant proliferating trichilemmal tumor manifests frequently on the scalp, face, or neck, but there are reports of MPTT manifesting on the trunk and even as multiple concurrent lesions.^1-4 The variability in clinical presentation and the potential to be mistaken for benign conditions makes excisional biopsy essential for diagnosis of MPTT. Histopathology classically demonstrates trichilemmal keratinization, a high mitotic index, and cellular atypia with invasion into the dermis.⁴ Malignant transformation frequently follows a prior history of trauma to the area or local inflammation.

Given the locally aggressive nature of MPTT, our patient was referred to a Mohs micrographic surgeon. While both wide excision with tumor-free margins and Mohs micrographic surgery are accepted surgical procedures for MPTT, there is no consensus in the literature on a standard treatment recommendation. Following surgery, close monitoring is needed for potential recurrence and metastases intracranially to the dura and muscles,⁵ as well as to the lungs.⁶ Further imaging using computed tomography or positron emission tomography can be ordered to rule out metastatic disease.⁴

Pilomatrixomas are benign neoplasms that arise from hair matrix cells and have been associated with catenin beta-1 gene mutations, as well as genetic syndromes and trauma.⁷ Clinically, pilomatrixomas manifest as solitary, firm, painless, slow-growing nodules that commonly are found in the head and neck region. This tumor has a slight predominance in women and occurs frequently in adolescent years. The overlying skin may appear normal or show grey-bluish discoloration.⁸ Histopathology shows basaloid cells resembling primitive hair matrix cells with an abrupt transition to shadow cells composed of transformed keratinocytes without nuclei and calcification.^7-8 This tumor can be differentiated by the presence of basaloid and shadow cells with calcification on histopathology, while MPTT will show atypical, mitotically active squamous cells with trichilemmal keratinization (Figure 2).

Proliferating trichilemmal cyst is a variant of trichilemmal cyst (TC) arising from the outer root sheath cells of the hair follicle. While TCs usually are slow growing and benign, the proliferating variant can be more aggressive with malignant potential. Patients often present with a solitary, well-circumscribed, rapidly growing nodule on the scalp. The lesion may be painful, and ulceration can occur, exposing the cystic contents. Histopathologically, PTCs resemble TCs with trichilemmal keratinization but also exhibit notable epithelial proliferation within the cystic space.⁹ While there can be considerable histopathologic overlap between PTC and MPTT—including extensive trichilemmal keratinization, variable atypia, and mitotic activity—PTC typically should not demonstrate invasion into the surrounding soft tissue or the degree of high-grade atypia, brisk mitoses, or necrosis seen in MPTT (eFigure 1).¹ Immunohistochemistry may help distinguish PTC from MPTT and squamous cell carcinoma (SCC).^10-11 The pattern of Ki-67 and p53 expression may be helpful with classification of PTC/MPTT into the 3 groups (benign, low-grade malignant, and high-grade malignant) proposed by Ye et al.¹ Other investigators have suggested that Ki-67 expression may correlate potential for recurrence and clinical prognosis.¹² Expression of CD34 (a marker that supports outer root sheath origin) might favor PTC/MPTT over SCC; however, cases of CD34- negative MPTT have been reported, particularly those with poorly differentiated histopathology.

Squamous cell carcinoma with cystic features is a histologic variant of SCC characterized by cystlike spaces containing malignant squamous epithelial cells.¹³ Squamous cell carcinoma with cystic features can manifest as a firm nodule with ulceration similar to MPTT or PTC but also can mimic a benign cyst.¹⁴ The diagnosis of invasive SCC with cystic features typically is straightforward and characterized by cords and nests of atypical keratinocytes extending into the dermis with areas of cystic architecture (eFigure 2). While both SCC with cystic features and MPTT may show cystic histopathologic architecture, MPTT typically shows areas of PTC, whereas SCC with cystic features lacks such areas.

Verrucous cysts refer to infundibular cysts or less commonly pilar cysts or hybrid pilar-epidermoid cysts that exhibit superimposed human papillomavirus (HPV) cytopathic changes. Clinically, a verrucous cyst manifests as a single, asymptomatic, slow-growing, firm lesion most commonly manifesting on the face and back. Histopathologically, the cyst wall may show acanthosis, papillomatosis, hypergranulosis with coarse keratohyalin granules, and koilocytic changes (eFigure 3). These histopathologic features are believed to be induced by secondary HPV infection. While HPV-related change, characterized by koilocytic alteration, papillomatosis, and verruciform hyperplasia, more commonly affects epidermal cysts, occasionally trichilemmal (pilar) cysts are involved. In these cases, verrucous cysts should be distinguished from MPTT. Verrucous cysts may contain rare normal mitotic figures, but do not contain atypical mitosis, marked cellular pleomorphism, or an infiltrating pattern similar to MPTT.¹⁵

THE DIAGNOSIS: Malignant Proliferating Trichilemmal Tumor

Biopsy revealed a squamous epithelium with cystic changes, trichilemmal differentiation, squamous eddy formation, keratinocyte atypia, focal necrotic changes, and a focus of atypical keratinocytes invading the dermis (Figure 1). Based on these findings, a diagnosis of malignant proliferating trichilemmal tumor (MPTT) was made.

Malignant proliferating trichilemmal tumor is a rare adnexal tumor that develops from the outer root sheath of the hair follicle. It often arises due to malignant transformation of pre-existing trichilemmal cysts, but some cases occur de novo.¹ Malignant transformation is thought to start from a trichilemmal cyst in an adenomatous histologic stage, progressing to a proliferating trichilemmal cyst (PTC) in an epitheliomatous phase, ultimately becoming carcinomatous with MPTT.^2-4 This transformation has been categorized into 3 morphologic groups to predict tumor behavior, including benign PTCs (curable by excision), low-grade malignant PTCs (minor risk for local recurrence), and high-grade malignant PTCs (risk for regional spread and metastasis with cytologic atypical features and potential for aggressive growth).¹

More commonly observed in women in the fourth to eighth decades of life, MPTT may manifest as a fast- growing, painless, solitary nodule or as a progressively enlarging nodule at the site of a previously stable, long-standing lesion. Malignant proliferating trichilemmal tumor manifests frequently on the scalp, face, or neck, but there are reports of MPTT manifesting on the trunk and even as multiple concurrent lesions.^1-4 The variability in clinical presentation and the potential to be mistaken for benign conditions makes excisional biopsy essential for diagnosis of MPTT. Histopathology classically demonstrates trichilemmal keratinization, a high mitotic index, and cellular atypia with invasion into the dermis.⁴ Malignant transformation frequently follows a prior history of trauma to the area or local inflammation.

Given the locally aggressive nature of MPTT, our patient was referred to a Mohs micrographic surgeon. While both wide excision with tumor-free margins and Mohs micrographic surgery are accepted surgical procedures for MPTT, there is no consensus in the literature on a standard treatment recommendation. Following surgery, close monitoring is needed for potential recurrence and metastases intracranially to the dura and muscles,⁵ as well as to the lungs.⁶ Further imaging using computed tomography or positron emission tomography can be ordered to rule out metastatic disease.⁴

Pilomatrixomas are benign neoplasms that arise from hair matrix cells and have been associated with catenin beta-1 gene mutations, as well as genetic syndromes and trauma.⁷ Clinically, pilomatrixomas manifest as solitary, firm, painless, slow-growing nodules that commonly are found in the head and neck region. This tumor has a slight predominance in women and occurs frequently in adolescent years. The overlying skin may appear normal or show grey-bluish discoloration.⁸ Histopathology shows basaloid cells resembling primitive hair matrix cells with an abrupt transition to shadow cells composed of transformed keratinocytes without nuclei and calcification.^7-8 This tumor can be differentiated by the presence of basaloid and shadow cells with calcification on histopathology, while MPTT will show atypical, mitotically active squamous cells with trichilemmal keratinization (Figure 2).

Proliferating trichilemmal cyst is a variant of trichilemmal cyst (TC) arising from the outer root sheath cells of the hair follicle. While TCs usually are slow growing and benign, the proliferating variant can be more aggressive with malignant potential. Patients often present with a solitary, well-circumscribed, rapidly growing nodule on the scalp. The lesion may be painful, and ulceration can occur, exposing the cystic contents. Histopathologically, PTCs resemble TCs with trichilemmal keratinization but also exhibit notable epithelial proliferation within the cystic space.⁹ While there can be considerable histopathologic overlap between PTC and MPTT—including extensive trichilemmal keratinization, variable atypia, and mitotic activity—PTC typically should not demonstrate invasion into the surrounding soft tissue or the degree of high-grade atypia, brisk mitoses, or necrosis seen in MPTT (eFigure 1).¹ Immunohistochemistry may help distinguish PTC from MPTT and squamous cell carcinoma (SCC).^10-11 The pattern of Ki-67 and p53 expression may be helpful with classification of PTC/MPTT into the 3 groups (benign, low-grade malignant, and high-grade malignant) proposed by Ye et al.¹ Other investigators have suggested that Ki-67 expression may correlate potential for recurrence and clinical prognosis.¹² Expression of CD34 (a marker that supports outer root sheath origin) might favor PTC/MPTT over SCC; however, cases of CD34- negative MPTT have been reported, particularly those with poorly differentiated histopathology.

Squamous cell carcinoma with cystic features is a histologic variant of SCC characterized by cystlike spaces containing malignant squamous epithelial cells.¹³ Squamous cell carcinoma with cystic features can manifest as a firm nodule with ulceration similar to MPTT or PTC but also can mimic a benign cyst.¹⁴ The diagnosis of invasive SCC with cystic features typically is straightforward and characterized by cords and nests of atypical keratinocytes extending into the dermis with areas of cystic architecture (eFigure 2). While both SCC with cystic features and MPTT may show cystic histopathologic architecture, MPTT typically shows areas of PTC, whereas SCC with cystic features lacks such areas.

Verrucous cysts refer to infundibular cysts or less commonly pilar cysts or hybrid pilar-epidermoid cysts that exhibit superimposed human papillomavirus (HPV) cytopathic changes. Clinically, a verrucous cyst manifests as a single, asymptomatic, slow-growing, firm lesion most commonly manifesting on the face and back. Histopathologically, the cyst wall may show acanthosis, papillomatosis, hypergranulosis with coarse keratohyalin granules, and koilocytic changes (eFigure 3). These histopathologic features are believed to be induced by secondary HPV infection. While HPV-related change, characterized by koilocytic alteration, papillomatosis, and verruciform hyperplasia, more commonly affects epidermal cysts, occasionally trichilemmal (pilar) cysts are involved. In these cases, verrucous cysts should be distinguished from MPTT. Verrucous cysts may contain rare normal mitotic figures, but do not contain atypical mitosis, marked cellular pleomorphism, or an infiltrating pattern similar to MPTT.¹⁵

THE DIAGNOSIS: Malignant Proliferating Trichilemmal Tumor

Biopsy revealed a squamous epithelium with cystic changes, trichilemmal differentiation, squamous eddy formation, keratinocyte atypia, focal necrotic changes, and a focus of atypical keratinocytes invading the dermis (Figure 1). Based on these findings, a diagnosis of malignant proliferating trichilemmal tumor (MPTT) was made.

Malignant proliferating trichilemmal tumor is a rare adnexal tumor that develops from the outer root sheath of the hair follicle. It often arises due to malignant transformation of pre-existing trichilemmal cysts, but some cases occur de novo.¹ Malignant transformation is thought to start from a trichilemmal cyst in an adenomatous histologic stage, progressing to a proliferating trichilemmal cyst (PTC) in an epitheliomatous phase, ultimately becoming carcinomatous with MPTT.^2-4 This transformation has been categorized into 3 morphologic groups to predict tumor behavior, including benign PTCs (curable by excision), low-grade malignant PTCs (minor risk for local recurrence), and high-grade malignant PTCs (risk for regional spread and metastasis with cytologic atypical features and potential for aggressive growth).¹

More commonly observed in women in the fourth to eighth decades of life, MPTT may manifest as a fast- growing, painless, solitary nodule or as a progressively enlarging nodule at the site of a previously stable, long-standing lesion. Malignant proliferating trichilemmal tumor manifests frequently on the scalp, face, or neck, but there are reports of MPTT manifesting on the trunk and even as multiple concurrent lesions.^1-4 The variability in clinical presentation and the potential to be mistaken for benign conditions makes excisional biopsy essential for diagnosis of MPTT. Histopathology classically demonstrates trichilemmal keratinization, a high mitotic index, and cellular atypia with invasion into the dermis.⁴ Malignant transformation frequently follows a prior history of trauma to the area or local inflammation.

Given the locally aggressive nature of MPTT, our patient was referred to a Mohs micrographic surgeon. While both wide excision with tumor-free margins and Mohs micrographic surgery are accepted surgical procedures for MPTT, there is no consensus in the literature on a standard treatment recommendation. Following surgery, close monitoring is needed for potential recurrence and metastases intracranially to the dura and muscles,⁵ as well as to the lungs.⁶ Further imaging using computed tomography or positron emission tomography can be ordered to rule out metastatic disease.⁴

Pilomatrixomas are benign neoplasms that arise from hair matrix cells and have been associated with catenin beta-1 gene mutations, as well as genetic syndromes and trauma.⁷ Clinically, pilomatrixomas manifest as solitary, firm, painless, slow-growing nodules that commonly are found in the head and neck region. This tumor has a slight predominance in women and occurs frequently in adolescent years. The overlying skin may appear normal or show grey-bluish discoloration.⁸ Histopathology shows basaloid cells resembling primitive hair matrix cells with an abrupt transition to shadow cells composed of transformed keratinocytes without nuclei and calcification.^7-8 This tumor can be differentiated by the presence of basaloid and shadow cells with calcification on histopathology, while MPTT will show atypical, mitotically active squamous cells with trichilemmal keratinization (Figure 2).

Proliferating trichilemmal cyst is a variant of trichilemmal cyst (TC) arising from the outer root sheath cells of the hair follicle. While TCs usually are slow growing and benign, the proliferating variant can be more aggressive with malignant potential. Patients often present with a solitary, well-circumscribed, rapidly growing nodule on the scalp. The lesion may be painful, and ulceration can occur, exposing the cystic contents. Histopathologically, PTCs resemble TCs with trichilemmal keratinization but also exhibit notable epithelial proliferation within the cystic space.⁹ While there can be considerable histopathologic overlap between PTC and MPTT—including extensive trichilemmal keratinization, variable atypia, and mitotic activity—PTC typically should not demonstrate invasion into the surrounding soft tissue or the degree of high-grade atypia, brisk mitoses, or necrosis seen in MPTT (eFigure 1).¹ Immunohistochemistry may help distinguish PTC from MPTT and squamous cell carcinoma (SCC).^10-11 The pattern of Ki-67 and p53 expression may be helpful with classification of PTC/MPTT into the 3 groups (benign, low-grade malignant, and high-grade malignant) proposed by Ye et al.¹ Other investigators have suggested that Ki-67 expression may correlate potential for recurrence and clinical prognosis.¹² Expression of CD34 (a marker that supports outer root sheath origin) might favor PTC/MPTT over SCC; however, cases of CD34- negative MPTT have been reported, particularly those with poorly differentiated histopathology.

Squamous cell carcinoma with cystic features is a histologic variant of SCC characterized by cystlike spaces containing malignant squamous epithelial cells.¹³ Squamous cell carcinoma with cystic features can manifest as a firm nodule with ulceration similar to MPTT or PTC but also can mimic a benign cyst.¹⁴ The diagnosis of invasive SCC with cystic features typically is straightforward and characterized by cords and nests of atypical keratinocytes extending into the dermis with areas of cystic architecture (eFigure 2). While both SCC with cystic features and MPTT may show cystic histopathologic architecture, MPTT typically shows areas of PTC, whereas SCC with cystic features lacks such areas.

Verrucous cysts refer to infundibular cysts or less commonly pilar cysts or hybrid pilar-epidermoid cysts that exhibit superimposed human papillomavirus (HPV) cytopathic changes. Clinically, a verrucous cyst manifests as a single, asymptomatic, slow-growing, firm lesion most commonly manifesting on the face and back. Histopathologically, the cyst wall may show acanthosis, papillomatosis, hypergranulosis with coarse keratohyalin granules, and koilocytic changes (eFigure 3). These histopathologic features are believed to be induced by secondary HPV infection. While HPV-related change, characterized by koilocytic alteration, papillomatosis, and verruciform hyperplasia, more commonly affects epidermal cysts, occasionally trichilemmal (pilar) cysts are involved. In these cases, verrucous cysts should be distinguished from MPTT. Verrucous cysts may contain rare normal mitotic figures, but do not contain atypical mitosis, marked cellular pleomorphism, or an infiltrating pattern similar to MPTT.¹⁵

THE DIAGNOSIS: Lepromatous Leprosy

Histopathology showed collections of epithelioid to sarcoidal granulomas throughout the dermis and clustered around nerve bundles with a grenz zone at the dermoepidermal junction. Fite stain was positive for acid-fast bacteria, which were confirmed to be Mycobacterium leprae by by the National Hansen’s Disease program. Based on these findings, a diagnosis of lepromatous leprosy (LL) was made. The patient was treated by the infectious disease department with multidrug therapy that included monthly rifampin, moxifloxacin, and minocycline; weekly methotrexate with daily folic acid; and an extended prednisone taper with prophylactic cholecalciferol.

Lepromatous leprosy is characterized by high antibody titers to the acid-fast, gram-positive bacillus Mycobacterium leprae as well as a high bacillary load.¹ Patients typically present with muscle weakness, anesthetic skin patches, and claw hands. Patients also may present with foot drop, ulcerations of the hands and feet, autonomic dysfunction with anhidrosis or impaired sweating, and localized alopecia.² Over months to years, LL may progress to extensive sensory loss and indurated lesions that infiltrate the skin and cause thickening, especially on the face (known as leonine facies). Furthermore, LL is characterized by extensive bilaterally symmetric cutaneous lesions with poorly defined borders and raised indurated centers.³

Lepromatous leprosy transmission is not fully understood but is thought to occur via airborne droplets from coughing/sneezing and nasal secretions.² Histopathology generally shows a dense and diffuse granulomatous infiltrate that involves the dermis but is separated from the epidermis by a zone of collagen (grenz zone).³ Histology is characterized by the presence of lymphocytes and numerous foamy macrophages (lepra or Virchow cells) containing M leprae organisms. In persistent lesions, the high density of uncleared bacilli forms spherical cytoplasmic clumps known as globi within enlarged foamy histiocytes (Figure 1).⁴ The macrophages form granulomatous lesions in the skin and around nerve bundles, resulting in tissue damage and decreased sensation. The current standard of care for LL is a multidrug combination of dapsone, rifampin, and clofazimine. Early diagnosis and complete treatment of LL is crucial, as this approach typically leads to complete cure of the disease.

The differential diagnosis for LL includes granuloma annulare (GA), mycosis fungoides (MF), sarcoidosis, and subacute cutaneous lupus erythematosus (SCLE). Granuloma annulare is a noninfectious inflammatory granulomatous skin disease that manifests in a localized, generalized, or subcutaneous pattern. Localized GA is the most common form and manifests as self-resolving, flesh-colored or erythematous papules or plaques limited to the extremities.^5,6 Generalized GA is defined by more than 10 widespread annular plaques involving the trunk and extremities and can persist for decades.⁶ This form can be associated with hyperlipidemia, diabetes, autoimmune disease and immunodeficiency (eg, HIV), and rarely with lymphoma or solid tumors. On histology, GA shows necrobiosis surrounded by palisading histiocytes and mucin (palisading GA) or patchy interstitial histiocytes and lymphocytes (interstitial GA)(Figure 2).⁶ This palisading pattern differs from the histiocytes in LL, which contain numerous acid-fast bacilli and bacterial clumps. Topical and intralesional corticosteroids are first-line therapies for GA.

Mycosis fungoides is a cutaneous T-cell lymphoma characterized by proliferation of CD4+ T cells.⁷ In the early stages of MF, patients may present with multiple erythematous and scaly patches, plaques, or nodules that most commonly develop on unexposed areas of the skin, but specific variants frequently may cause lesions on the face or scalp.⁸ Tumors may be solitary, localized, or generalized and may be observed alongside patches and plaques or in the absence of cutaneous lesions.⁷ The pathologic features of MF include fibrosis of the papillary dermis, individual haloed atypical lymphocytes in the epidermis, and atypical lymphoid cells with cerebriform nuclei (Figure 3).⁹ Granulomatous MF is characterized by diffuse nodular and perivascular infiltrates of histiocytes with small lymphocytes without atypia, eosinophils, and plasma cells. Small lymphocytes with cerebriform nuclei and larger lymphocytes with hyperconvoluted nuclei also may be seen, in addition to multinucleated histiocytic giant cells. Although MF commonly manifests with epidermotropism, it typically is absent in granulomatous MF (GMF).¹⁰ Granulomatous MF may manifest similarly to LL. Noduloulcerative lesions and infiltration of atypical lymphocytes into the epidermis (epidermotropism) are much more common in GMF than in LL; however, although ulcerative nodules are not a common feature in patients with leprosy (except during reactional states [ie, Lucio phenomenon]) or secondary to neuropathies, they also can occur in LL.¹¹ In GMF, the infiltrate does not follow a specific pattern, whereas LL infiltrates tend to follow a nerve distribution. Treatment for MF is determined by disease severity.¹² First-line therapy includes local corticosteroids and phototherapy with UVB irradiation.

Sarcoidosis is a multisystem disease that demonstrates nonspecific clinical manifestations affecting the lungs, eyes, liver, and skin.¹³ Environmental exposures to silica and inorganic matter have been linked to an increased risk for sarcoidosis, with patients presenting with fatigue, fever, and arthralgia.¹³ Skin manifestations include subcutaneous nodules, polymorphous plaques, and erythema nodosum—nodosum—the most common cutaneous presentation of sarcoidosis. Erythema nodosum manifests as symmetrically distributed, nonulcerative, painful red nodules on the skin, especially the lower legs. The histopathology of sarcoidosis shows noncaseating granulomas with activated T-lymphocytes, epithelioid cells, and multinucleated giant cells (Figure 4). Although granulomas occur in both LL and sarcoidosis, those in sarcoidosis typically consist of epithelioid cells surrounded by a rim of lymphocytes, whereas LL granulomas contain foamy histiocytes and multinucleated giant cells. Treatment of sarcoidosis depends on disease progression and generally involves oral corticosteroids, followed by corticosteroid-sparing regimens.

Subacute cutaneous lupus erythematosus is a chronic autoimmune disease that predominantly affects younger women. Common findings in SCLE include red scaly plaques and ring-shaped lesions on sun-exposed areas of the skin.¹⁴ Subacute cutaneous lupus erythematosus primarily is characterized by a photosensitive rash, often with arthralgia, myalgia, and/or oral ulcers; less commonly, a small percentage of patients can experience central nervous system involvement, vasculitis, or nephritis. The histologic findings of SCLE include hydropic degeneration of the basal cell layer and periadnexal infiltrates (Figure 5). The incidence of SCLE often is associated with anti-Ro (SSA) and anti-La (SSB) antibodies.¹⁵ Treatment of SCLE focuses on managing skin symptoms with corticosteroids, antimalarials, and sun protection.

THE DIAGNOSIS: Lepromatous Leprosy

Histopathology showed collections of epithelioid to sarcoidal granulomas throughout the dermis and clustered around nerve bundles with a grenz zone at the dermoepidermal junction. Fite stain was positive for acid-fast bacteria, which were confirmed to be Mycobacterium leprae by by the National Hansen’s Disease program. Based on these findings, a diagnosis of lepromatous leprosy (LL) was made. The patient was treated by the infectious disease department with multidrug therapy that included monthly rifampin, moxifloxacin, and minocycline; weekly methotrexate with daily folic acid; and an extended prednisone taper with prophylactic cholecalciferol.

Lepromatous leprosy is characterized by high antibody titers to the acid-fast, gram-positive bacillus Mycobacterium leprae as well as a high bacillary load.¹ Patients typically present with muscle weakness, anesthetic skin patches, and claw hands. Patients also may present with foot drop, ulcerations of the hands and feet, autonomic dysfunction with anhidrosis or impaired sweating, and localized alopecia.² Over months to years, LL may progress to extensive sensory loss and indurated lesions that infiltrate the skin and cause thickening, especially on the face (known as leonine facies). Furthermore, LL is characterized by extensive bilaterally symmetric cutaneous lesions with poorly defined borders and raised indurated centers.³

Lepromatous leprosy transmission is not fully understood but is thought to occur via airborne droplets from coughing/sneezing and nasal secretions.² Histopathology generally shows a dense and diffuse granulomatous infiltrate that involves the dermis but is separated from the epidermis by a zone of collagen (grenz zone).³ Histology is characterized by the presence of lymphocytes and numerous foamy macrophages (lepra or Virchow cells) containing M leprae organisms. In persistent lesions, the high density of uncleared bacilli forms spherical cytoplasmic clumps known as globi within enlarged foamy histiocytes (Figure 1).⁴ The macrophages form granulomatous lesions in the skin and around nerve bundles, resulting in tissue damage and decreased sensation. The current standard of care for LL is a multidrug combination of dapsone, rifampin, and clofazimine. Early diagnosis and complete treatment of LL is crucial, as this approach typically leads to complete cure of the disease.

The differential diagnosis for LL includes granuloma annulare (GA), mycosis fungoides (MF), sarcoidosis, and subacute cutaneous lupus erythematosus (SCLE). Granuloma annulare is a noninfectious inflammatory granulomatous skin disease that manifests in a localized, generalized, or subcutaneous pattern. Localized GA is the most common form and manifests as self-resolving, flesh-colored or erythematous papules or plaques limited to the extremities.^5,6 Generalized GA is defined by more than 10 widespread annular plaques involving the trunk and extremities and can persist for decades.⁶ This form can be associated with hyperlipidemia, diabetes, autoimmune disease and immunodeficiency (eg, HIV), and rarely with lymphoma or solid tumors. On histology, GA shows necrobiosis surrounded by palisading histiocytes and mucin (palisading GA) or patchy interstitial histiocytes and lymphocytes (interstitial GA)(Figure 2).⁶ This palisading pattern differs from the histiocytes in LL, which contain numerous acid-fast bacilli and bacterial clumps. Topical and intralesional corticosteroids are first-line therapies for GA.

Mycosis fungoides is a cutaneous T-cell lymphoma characterized by proliferation of CD4+ T cells.⁷ In the early stages of MF, patients may present with multiple erythematous and scaly patches, plaques, or nodules that most commonly develop on unexposed areas of the skin, but specific variants frequently may cause lesions on the face or scalp.⁸ Tumors may be solitary, localized, or generalized and may be observed alongside patches and plaques or in the absence of cutaneous lesions.⁷ The pathologic features of MF include fibrosis of the papillary dermis, individual haloed atypical lymphocytes in the epidermis, and atypical lymphoid cells with cerebriform nuclei (Figure 3).⁹ Granulomatous MF is characterized by diffuse nodular and perivascular infiltrates of histiocytes with small lymphocytes without atypia, eosinophils, and plasma cells. Small lymphocytes with cerebriform nuclei and larger lymphocytes with hyperconvoluted nuclei also may be seen, in addition to multinucleated histiocytic giant cells. Although MF commonly manifests with epidermotropism, it typically is absent in granulomatous MF (GMF).¹⁰ Granulomatous MF may manifest similarly to LL. Noduloulcerative lesions and infiltration of atypical lymphocytes into the epidermis (epidermotropism) are much more common in GMF than in LL; however, although ulcerative nodules are not a common feature in patients with leprosy (except during reactional states [ie, Lucio phenomenon]) or secondary to neuropathies, they also can occur in LL.¹¹ In GMF, the infiltrate does not follow a specific pattern, whereas LL infiltrates tend to follow a nerve distribution. Treatment for MF is determined by disease severity.¹² First-line therapy includes local corticosteroids and phototherapy with UVB irradiation.

Sarcoidosis is a multisystem disease that demonstrates nonspecific clinical manifestations affecting the lungs, eyes, liver, and skin.¹³ Environmental exposures to silica and inorganic matter have been linked to an increased risk for sarcoidosis, with patients presenting with fatigue, fever, and arthralgia.¹³ Skin manifestations include subcutaneous nodules, polymorphous plaques, and erythema nodosum—nodosum—the most common cutaneous presentation of sarcoidosis. Erythema nodosum manifests as symmetrically distributed, nonulcerative, painful red nodules on the skin, especially the lower legs. The histopathology of sarcoidosis shows noncaseating granulomas with activated T-lymphocytes, epithelioid cells, and multinucleated giant cells (Figure 4). Although granulomas occur in both LL and sarcoidosis, those in sarcoidosis typically consist of epithelioid cells surrounded by a rim of lymphocytes, whereas LL granulomas contain foamy histiocytes and multinucleated giant cells. Treatment of sarcoidosis depends on disease progression and generally involves oral corticosteroids, followed by corticosteroid-sparing regimens.

Subacute cutaneous lupus erythematosus is a chronic autoimmune disease that predominantly affects younger women. Common findings in SCLE include red scaly plaques and ring-shaped lesions on sun-exposed areas of the skin.¹⁴ Subacute cutaneous lupus erythematosus primarily is characterized by a photosensitive rash, often with arthralgia, myalgia, and/or oral ulcers; less commonly, a small percentage of patients can experience central nervous system involvement, vasculitis, or nephritis. The histologic findings of SCLE include hydropic degeneration of the basal cell layer and periadnexal infiltrates (Figure 5). The incidence of SCLE often is associated with anti-Ro (SSA) and anti-La (SSB) antibodies.¹⁵ Treatment of SCLE focuses on managing skin symptoms with corticosteroids, antimalarials, and sun protection.

THE DIAGNOSIS: Lepromatous Leprosy

Histopathology showed collections of epithelioid to sarcoidal granulomas throughout the dermis and clustered around nerve bundles with a grenz zone at the dermoepidermal junction. Fite stain was positive for acid-fast bacteria, which were confirmed to be Mycobacterium leprae by by the National Hansen’s Disease program. Based on these findings, a diagnosis of lepromatous leprosy (LL) was made. The patient was treated by the infectious disease department with multidrug therapy that included monthly rifampin, moxifloxacin, and minocycline; weekly methotrexate with daily folic acid; and an extended prednisone taper with prophylactic cholecalciferol.

Lepromatous leprosy is characterized by high antibody titers to the acid-fast, gram-positive bacillus Mycobacterium leprae as well as a high bacillary load.¹ Patients typically present with muscle weakness, anesthetic skin patches, and claw hands. Patients also may present with foot drop, ulcerations of the hands and feet, autonomic dysfunction with anhidrosis or impaired sweating, and localized alopecia.² Over months to years, LL may progress to extensive sensory loss and indurated lesions that infiltrate the skin and cause thickening, especially on the face (known as leonine facies). Furthermore, LL is characterized by extensive bilaterally symmetric cutaneous lesions with poorly defined borders and raised indurated centers.³

Lepromatous leprosy transmission is not fully understood but is thought to occur via airborne droplets from coughing/sneezing and nasal secretions.² Histopathology generally shows a dense and diffuse granulomatous infiltrate that involves the dermis but is separated from the epidermis by a zone of collagen (grenz zone).³ Histology is characterized by the presence of lymphocytes and numerous foamy macrophages (lepra or Virchow cells) containing M leprae organisms. In persistent lesions, the high density of uncleared bacilli forms spherical cytoplasmic clumps known as globi within enlarged foamy histiocytes (Figure 1).⁴ The macrophages form granulomatous lesions in the skin and around nerve bundles, resulting in tissue damage and decreased sensation. The current standard of care for LL is a multidrug combination of dapsone, rifampin, and clofazimine. Early diagnosis and complete treatment of LL is crucial, as this approach typically leads to complete cure of the disease.

The differential diagnosis for LL includes granuloma annulare (GA), mycosis fungoides (MF), sarcoidosis, and subacute cutaneous lupus erythematosus (SCLE). Granuloma annulare is a noninfectious inflammatory granulomatous skin disease that manifests in a localized, generalized, or subcutaneous pattern. Localized GA is the most common form and manifests as self-resolving, flesh-colored or erythematous papules or plaques limited to the extremities.^5,6 Generalized GA is defined by more than 10 widespread annular plaques involving the trunk and extremities and can persist for decades.⁶ This form can be associated with hyperlipidemia, diabetes, autoimmune disease and immunodeficiency (eg, HIV), and rarely with lymphoma or solid tumors. On histology, GA shows necrobiosis surrounded by palisading histiocytes and mucin (palisading GA) or patchy interstitial histiocytes and lymphocytes (interstitial GA)(Figure 2).⁶ This palisading pattern differs from the histiocytes in LL, which contain numerous acid-fast bacilli and bacterial clumps. Topical and intralesional corticosteroids are first-line therapies for GA.

Mycosis fungoides is a cutaneous T-cell lymphoma characterized by proliferation of CD4+ T cells.⁷ In the early stages of MF, patients may present with multiple erythematous and scaly patches, plaques, or nodules that most commonly develop on unexposed areas of the skin, but specific variants frequently may cause lesions on the face or scalp.⁸ Tumors may be solitary, localized, or generalized and may be observed alongside patches and plaques or in the absence of cutaneous lesions.⁷ The pathologic features of MF include fibrosis of the papillary dermis, individual haloed atypical lymphocytes in the epidermis, and atypical lymphoid cells with cerebriform nuclei (Figure 3).⁹ Granulomatous MF is characterized by diffuse nodular and perivascular infiltrates of histiocytes with small lymphocytes without atypia, eosinophils, and plasma cells. Small lymphocytes with cerebriform nuclei and larger lymphocytes with hyperconvoluted nuclei also may be seen, in addition to multinucleated histiocytic giant cells. Although MF commonly manifests with epidermotropism, it typically is absent in granulomatous MF (GMF).¹⁰ Granulomatous MF may manifest similarly to LL. Noduloulcerative lesions and infiltration of atypical lymphocytes into the epidermis (epidermotropism) are much more common in GMF than in LL; however, although ulcerative nodules are not a common feature in patients with leprosy (except during reactional states [ie, Lucio phenomenon]) or secondary to neuropathies, they also can occur in LL.¹¹ In GMF, the infiltrate does not follow a specific pattern, whereas LL infiltrates tend to follow a nerve distribution. Treatment for MF is determined by disease severity.¹² First-line therapy includes local corticosteroids and phototherapy with UVB irradiation.

Sarcoidosis is a multisystem disease that demonstrates nonspecific clinical manifestations affecting the lungs, eyes, liver, and skin.¹³ Environmental exposures to silica and inorganic matter have been linked to an increased risk for sarcoidosis, with patients presenting with fatigue, fever, and arthralgia.¹³ Skin manifestations include subcutaneous nodules, polymorphous plaques, and erythema nodosum—nodosum—the most common cutaneous presentation of sarcoidosis. Erythema nodosum manifests as symmetrically distributed, nonulcerative, painful red nodules on the skin, especially the lower legs. The histopathology of sarcoidosis shows noncaseating granulomas with activated T-lymphocytes, epithelioid cells, and multinucleated giant cells (Figure 4). Although granulomas occur in both LL and sarcoidosis, those in sarcoidosis typically consist of epithelioid cells surrounded by a rim of lymphocytes, whereas LL granulomas contain foamy histiocytes and multinucleated giant cells. Treatment of sarcoidosis depends on disease progression and generally involves oral corticosteroids, followed by corticosteroid-sparing regimens.

Subacute cutaneous lupus erythematosus is a chronic autoimmune disease that predominantly affects younger women. Common findings in SCLE include red scaly plaques and ring-shaped lesions on sun-exposed areas of the skin.¹⁴ Subacute cutaneous lupus erythematosus primarily is characterized by a photosensitive rash, often with arthralgia, myalgia, and/or oral ulcers; less commonly, a small percentage of patients can experience central nervous system involvement, vasculitis, or nephritis. The histologic findings of SCLE include hydropic degeneration of the basal cell layer and periadnexal infiltrates (Figure 5). The incidence of SCLE often is associated with anti-Ro (SSA) and anti-La (SSB) antibodies.¹⁵ Treatment of SCLE focuses on managing skin symptoms with corticosteroids, antimalarials, and sun protection.

THE DIAGNOSIS: Squamoid Eccrine Ductal Carcinoma

Immunohistochemical staining of the biopsy specimen showed neoplastic aggregates that were diffusely positive for pancytokeratin and strongly positive for cytokeratin (CK) 5/6. Epithelial membrane antigen (EMA) and CK7 also were positive, CAM 5.2 was partially positive, and carcinoembryonic antigen (CEA) was focally positive (periluminal); S100 was negative. Given the histologic findings of irregular infiltrative cords and stranding exhibiting ductal differentiation in a fibrotic stroma in combination with the staining pattern, a diagnosis of squamous eccrine ductal carcinoma (SEDC) was made.

Squamoid eccrine ductal carcinoma is a rare primary cutaneous tumor with aggressive features that can be confused both clinically and histologically with squamous cell carcinoma (SCC). Histologically, SEDC is a biphasic tumor. If a shallow histologic specimen is obtained, it may be indistinguishable from a well-differentiated SCC (Figure 1). A deeper biopsy reveals irregular infiltrative cords and strands exhibiting ductal differentiation in a fibrotic stroma.¹

The immunohistochemical staining pattern of SEDC is similar to that of SCC, showing diffuse staining with pancytokeratin (AE1/AE3), CK 5/6, CK7, p63, and EMA. What distinguishes SEDC from SCC is that CEA highlights areas of glandular differentiation. An additional histologic feature seen commonly with SEDC is perineural invasion.

The etiology of SEDC remains controversial; although it originally was considered an aggressive variant of SCC along the same continuum as adenosquamous carcinoma, the fifth edition of the WHO Classification of Skin Tumors² has categorized SEDC as an adnexal neoplasm. Our patient demonstrated an atypical presentation of this tumor, which has been most commonly described in the literature as manifesting on the head, neck, or upper extremities in older adults.³ Mohs micrographic surgery is the recommended treatment for this aggressive tumor.³

The differential diagnosis for SEDC includes microcystic adnexal carcinoma, porocarcinoma, and eccrine syringofibroadenoma. Microcystic adnexal carcinoma is a rare, low-grade tumor of the sweat glands that typically manifests as a firm pink papule or plaque in the head and neck region. Microscopically, it demonstrates cords of basaloid cells in a paisley-tie tadpole pattern with a dense pink to red stroma and horn cysts (Figure 2). Histologic differential diagnoses include syringoma, morpheaform basal cell carcinoma, desmoplastic trichoepithelioma, and trichoadenoma. Carcinoembryonic antigen stains positive in microcystic adnexal carcinoma, which helps distinguish it from basal cell carcinoma and SCC. Surgical excision or Mohs surgery are recommended for management.⁴

Porocarcinoma is a malignant skin tumor that originates from the intraepidermal sweat gland ducts. It also has been proposed that porocarcinoma develops from benign eccrine poroma. Porocarcinoma often is seen in elderly individuals, with a predilection for the lower extremities. Porocarcinoma demonstrates diverse clinical and histopathologic features, which can make diagnosis challenging. Histopathologically, porocarcinoma has an infiltrative growth pattern, with large basaloid epithelial cells that demonstrate ductal differentiation, cytologic atypia, increased mitotic activity, and tumor necrosis (Figure 3). Some porocarcinomas may exhibit squamous-cell, spindle-cell, or clear-cell differentiation. Neoplastic cells stain positive for CEA, EMA, and CD117, which can assist in distinguishing porocarcinoma from cutaneous SCC.⁵

Eccrine syringofibroadenoma is an unusual benign cutaneous adnexal tumor that manifests mostly in individuals aged 40 years or older. It develops as single or multiple lesions that usually affect the lower extremities. Histologically, eccrine syringofibroadenoma demonstrates unique findings of anastomosing ducts and monomorphous epithelial cells within a fibrovascular stroma (Figure 4). On immunohistochemistry, it stains positive for EMA, CEA, high-molecular-weight kininogen, and filaggrin.⁶ Periodic acid–Schiff staining also is positive.

THE DIAGNOSIS: Squamoid Eccrine Ductal Carcinoma

Immunohistochemical staining of the biopsy specimen showed neoplastic aggregates that were diffusely positive for pancytokeratin and strongly positive for cytokeratin (CK) 5/6. Epithelial membrane antigen (EMA) and CK7 also were positive, CAM 5.2 was partially positive, and carcinoembryonic antigen (CEA) was focally positive (periluminal); S100 was negative. Given the histologic findings of irregular infiltrative cords and stranding exhibiting ductal differentiation in a fibrotic stroma in combination with the staining pattern, a diagnosis of squamous eccrine ductal carcinoma (SEDC) was made.

Squamoid eccrine ductal carcinoma is a rare primary cutaneous tumor with aggressive features that can be confused both clinically and histologically with squamous cell carcinoma (SCC). Histologically, SEDC is a biphasic tumor. If a shallow histologic specimen is obtained, it may be indistinguishable from a well-differentiated SCC (Figure 1). A deeper biopsy reveals irregular infiltrative cords and strands exhibiting ductal differentiation in a fibrotic stroma.¹

The immunohistochemical staining pattern of SEDC is similar to that of SCC, showing diffuse staining with pancytokeratin (AE1/AE3), CK 5/6, CK7, p63, and EMA. What distinguishes SEDC from SCC is that CEA highlights areas of glandular differentiation. An additional histologic feature seen commonly with SEDC is perineural invasion.

The etiology of SEDC remains controversial; although it originally was considered an aggressive variant of SCC along the same continuum as adenosquamous carcinoma, the fifth edition of the WHO Classification of Skin Tumors² has categorized SEDC as an adnexal neoplasm. Our patient demonstrated an atypical presentation of this tumor, which has been most commonly described in the literature as manifesting on the head, neck, or upper extremities in older adults.³ Mohs micrographic surgery is the recommended treatment for this aggressive tumor.³

The differential diagnosis for SEDC includes microcystic adnexal carcinoma, porocarcinoma, and eccrine syringofibroadenoma. Microcystic adnexal carcinoma is a rare, low-grade tumor of the sweat glands that typically manifests as a firm pink papule or plaque in the head and neck region. Microscopically, it demonstrates cords of basaloid cells in a paisley-tie tadpole pattern with a dense pink to red stroma and horn cysts (Figure 2). Histologic differential diagnoses include syringoma, morpheaform basal cell carcinoma, desmoplastic trichoepithelioma, and trichoadenoma. Carcinoembryonic antigen stains positive in microcystic adnexal carcinoma, which helps distinguish it from basal cell carcinoma and SCC. Surgical excision or Mohs surgery are recommended for management.⁴

Porocarcinoma is a malignant skin tumor that originates from the intraepidermal sweat gland ducts. It also has been proposed that porocarcinoma develops from benign eccrine poroma. Porocarcinoma often is seen in elderly individuals, with a predilection for the lower extremities. Porocarcinoma demonstrates diverse clinical and histopathologic features, which can make diagnosis challenging. Histopathologically, porocarcinoma has an infiltrative growth pattern, with large basaloid epithelial cells that demonstrate ductal differentiation, cytologic atypia, increased mitotic activity, and tumor necrosis (Figure 3). Some porocarcinomas may exhibit squamous-cell, spindle-cell, or clear-cell differentiation. Neoplastic cells stain positive for CEA, EMA, and CD117, which can assist in distinguishing porocarcinoma from cutaneous SCC.⁵

Eccrine syringofibroadenoma is an unusual benign cutaneous adnexal tumor that manifests mostly in individuals aged 40 years or older. It develops as single or multiple lesions that usually affect the lower extremities. Histologically, eccrine syringofibroadenoma demonstrates unique findings of anastomosing ducts and monomorphous epithelial cells within a fibrovascular stroma (Figure 4). On immunohistochemistry, it stains positive for EMA, CEA, high-molecular-weight kininogen, and filaggrin.⁶ Periodic acid–Schiff staining also is positive.

THE DIAGNOSIS: Squamoid Eccrine Ductal Carcinoma

Immunohistochemical staining of the biopsy specimen showed neoplastic aggregates that were diffusely positive for pancytokeratin and strongly positive for cytokeratin (CK) 5/6. Epithelial membrane antigen (EMA) and CK7 also were positive, CAM 5.2 was partially positive, and carcinoembryonic antigen (CEA) was focally positive (periluminal); S100 was negative. Given the histologic findings of irregular infiltrative cords and stranding exhibiting ductal differentiation in a fibrotic stroma in combination with the staining pattern, a diagnosis of squamous eccrine ductal carcinoma (SEDC) was made.

Squamoid eccrine ductal carcinoma is a rare primary cutaneous tumor with aggressive features that can be confused both clinically and histologically with squamous cell carcinoma (SCC). Histologically, SEDC is a biphasic tumor. If a shallow histologic specimen is obtained, it may be indistinguishable from a well-differentiated SCC (Figure 1). A deeper biopsy reveals irregular infiltrative cords and strands exhibiting ductal differentiation in a fibrotic stroma.¹

The immunohistochemical staining pattern of SEDC is similar to that of SCC, showing diffuse staining with pancytokeratin (AE1/AE3), CK 5/6, CK7, p63, and EMA. What distinguishes SEDC from SCC is that CEA highlights areas of glandular differentiation. An additional histologic feature seen commonly with SEDC is perineural invasion.

The etiology of SEDC remains controversial; although it originally was considered an aggressive variant of SCC along the same continuum as adenosquamous carcinoma, the fifth edition of the WHO Classification of Skin Tumors² has categorized SEDC as an adnexal neoplasm. Our patient demonstrated an atypical presentation of this tumor, which has been most commonly described in the literature as manifesting on the head, neck, or upper extremities in older adults.³ Mohs micrographic surgery is the recommended treatment for this aggressive tumor.³

The differential diagnosis for SEDC includes microcystic adnexal carcinoma, porocarcinoma, and eccrine syringofibroadenoma. Microcystic adnexal carcinoma is a rare, low-grade tumor of the sweat glands that typically manifests as a firm pink papule or plaque in the head and neck region. Microscopically, it demonstrates cords of basaloid cells in a paisley-tie tadpole pattern with a dense pink to red stroma and horn cysts (Figure 2). Histologic differential diagnoses include syringoma, morpheaform basal cell carcinoma, desmoplastic trichoepithelioma, and trichoadenoma. Carcinoembryonic antigen stains positive in microcystic adnexal carcinoma, which helps distinguish it from basal cell carcinoma and SCC. Surgical excision or Mohs surgery are recommended for management.⁴

Porocarcinoma is a malignant skin tumor that originates from the intraepidermal sweat gland ducts. It also has been proposed that porocarcinoma develops from benign eccrine poroma. Porocarcinoma often is seen in elderly individuals, with a predilection for the lower extremities. Porocarcinoma demonstrates diverse clinical and histopathologic features, which can make diagnosis challenging. Histopathologically, porocarcinoma has an infiltrative growth pattern, with large basaloid epithelial cells that demonstrate ductal differentiation, cytologic atypia, increased mitotic activity, and tumor necrosis (Figure 3). Some porocarcinomas may exhibit squamous-cell, spindle-cell, or clear-cell differentiation. Neoplastic cells stain positive for CEA, EMA, and CD117, which can assist in distinguishing porocarcinoma from cutaneous SCC.⁵

Eccrine syringofibroadenoma is an unusual benign cutaneous adnexal tumor that manifests mostly in individuals aged 40 years or older. It develops as single or multiple lesions that usually affect the lower extremities. Histologically, eccrine syringofibroadenoma demonstrates unique findings of anastomosing ducts and monomorphous epithelial cells within a fibrovascular stroma (Figure 4). On immunohistochemistry, it stains positive for EMA, CEA, high-molecular-weight kininogen, and filaggrin.⁶ Periodic acid–Schiff staining also is positive.

THE DIAGNOSIS: Mpox Virus

The histopathologic features of mpox virus infection may vary depending on the stage of evolution; findings include ballooning degeneration with multinucleated keratinocytes, acanthosis, spongiosis, a neutrophil-rich inflammatory infiltrate, and eosinophilic intracytoplasmic (Guarnieri) inclusion bodies (quiz image inset [arrows]). Prominent neutrophil exocytosis also has been described and may be a characteristic feature in the pustular stage.^1,2 A pattern of interface dermatitis also has been observed on histopathology.³ In our patient, the diagnosis of mpox initially was made by clinical and histopathologic correlation and exclusion of other entities in the differential diagnosis. The diagnosis subsequently was confirmed by real-time polymerase chain reaction. The patient received treatment with tecovirimat, but lesions progressed over the following 6 weeks. He subsequently died due to sepsis and multiorgan failure secondary to AIDS.

Mpox is a zoonotic, double-stranded DNA virus of the genus Orthopoxvirus in the family Poxviridae.⁴ It is transmitted to humans via direct contact with infected animals, most commonly small mammals such as monkeys, squirrels, and rodents. Mpox also may be transmitted between humans through direct contact with bodily fluids, skin and mucosal lesions, respiratory droplets, or fomites. Mpox infection typically begins with a nonspecific flulike prodrome after a 5- to 21-day incubation period, followed by skin lesions of variable morphology affecting any region of the body. Clinically, mpox lesions have been reported to evolve through macular, papular, and vesiculopustular phases, followed by resolution with crusting. Lesions may occur anywhere on the body but frequently manifest on the face then spread centrifugally across the body, with various phases observed simultaneously.⁵ A worldwide outbreak in 2022 involved larger numbers of cases in nonendemic areas, primarily due to skin-to-skin contact, with predominant anal and genital localization of the lesions as well as fewer prodromal symptoms.⁶

The differential diagnosis of crusted and umbilicated papules includes disseminated herpesvirus infection, molluscum contagiosum, disseminated cryptococcosis, and histoplasmosis. Additional causative organisms to consider include Penicillium, Mycobacterium tuberculosis and nontuberculous mycobacteria, as well as Sporothrix schenckii.

Herpesvirus infections may have similar clinical and histopathologic findings to mpox. Histopathologically, herpes simplex virus (HSV) and varicella zoster virus (VZV) are essentially identical; both demonstrate ballooning and reticular epidermal degeneration, chromatin condensation, nuclear degeneration, multinucleated keratinocytes with steel-gray nuclei, and prominent epidermal acantholysis with an inflammatory infiltrate (Figure 1). However, involvement of folliculosebaceous units may favor a diagnosis of VZV. Immunohistochemical staining can further differentiate between HSV and VZV.⁷ While mpox may have features that overlap with both HSV and VZV, including ballooning degeneration and multinucleated keratinocytes with nuclear degeneration, acantholysis is a less commonly reported feature of mpox, and mpox virus infection is characterized by intracytoplasmic (Guarnieri) inclusion bodies rather than the intranuclear inclusion bodies of HSV and VZV.^2,5 The presence of Guarnieri bodies in mpox may further help to distinguish mpox from HSV infection on routine histology.

Molluscum contagiosum infection typically manifests as multiple umbilicated papules at sites of inoculation. Large lesions may be seen in the setting of immunosuppression; however, they usually do not progress to vesicular, pustular, or crusted morphologies. Histopathology demonstrates a cup-shaped invagination of the epidermis into the dermis and proliferative rete ridges that descend downward and encircle the dermis with large eosinophilic intracytoplasmic inclusion (Henderson-Patterson) bodies (Figure 2).⁸

Disseminated cryptococcus infection is caused by the invasive fungus Cryptococcus neoformans and is characterized by meningitis along with fever, malaise, headache, neck stiffness, photophobia, nausea, vomiting, pneumonia with cough and dyspnea, and skin rash, most commonly in immunocompromised individuals.⁹ Skin lesions are a sign of disseminated infection and can manifest as umbilicated or molluscumlike lesions. Histopathology of cryptococcosis demonstrates a granulomatous dermal infiltrate with neutrophils and pleomorphic yeasts measuring 4 µm to 6 µm with refringent capsules.¹⁰ Staining with Grocott methenamine silver and/or mucicarmine for yeast capsules can help to identify organisms (Figure 3).

Cutaneous histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus that can lead to pulmonary, cutaneous, and disseminated disease, often in immunocompromised patients.¹¹ Cutaneous disease may manifest with molluscumlike or verrucous papules and plaques. Histopathologic examination reveals diffuse suppurative and granulomatous infiltrates with foamy histiocytes and multinucleated giant cells, containing intracellular and extracellular yeasts measuring 1µm to 5µm, surrounded by a clear halo visible with Grocott methenamine silver stain (Figure 4).

Spreading cutaneous lesions in an immunocompromised individual may be the presentation of multiple infectious etiologies. With the recent rise in mpox cases occurring in nonendemic areas, clinicians should be aware of the spectrum of clinical findings that may occur. Notably, more than one infection may be present in severely immunocompromised individuals, as seen in our patient with chronic orolabial HSV-2 and acute mpox infection. Thorough clinical, histopathologic, and laboratory investigations are necessary for timely diagnosis, appropriate treatment, and exclusion of other life-threatening conditions.

THE DIAGNOSIS: Mpox Virus

The histopathologic features of mpox virus infection may vary depending on the stage of evolution; findings include ballooning degeneration with multinucleated keratinocytes, acanthosis, spongiosis, a neutrophil-rich inflammatory infiltrate, and eosinophilic intracytoplasmic (Guarnieri) inclusion bodies (quiz image inset [arrows]). Prominent neutrophil exocytosis also has been described and may be a characteristic feature in the pustular stage.^1,2 A pattern of interface dermatitis also has been observed on histopathology.³ In our patient, the diagnosis of mpox initially was made by clinical and histopathologic correlation and exclusion of other entities in the differential diagnosis. The diagnosis subsequently was confirmed by real-time polymerase chain reaction. The patient received treatment with tecovirimat, but lesions progressed over the following 6 weeks. He subsequently died due to sepsis and multiorgan failure secondary to AIDS.

Mpox is a zoonotic, double-stranded DNA virus of the genus Orthopoxvirus in the family Poxviridae.⁴ It is transmitted to humans via direct contact with infected animals, most commonly small mammals such as monkeys, squirrels, and rodents. Mpox also may be transmitted between humans through direct contact with bodily fluids, skin and mucosal lesions, respiratory droplets, or fomites. Mpox infection typically begins with a nonspecific flulike prodrome after a 5- to 21-day incubation period, followed by skin lesions of variable morphology affecting any region of the body. Clinically, mpox lesions have been reported to evolve through macular, papular, and vesiculopustular phases, followed by resolution with crusting. Lesions may occur anywhere on the body but frequently manifest on the face then spread centrifugally across the body, with various phases observed simultaneously.⁵ A worldwide outbreak in 2022 involved larger numbers of cases in nonendemic areas, primarily due to skin-to-skin contact, with predominant anal and genital localization of the lesions as well as fewer prodromal symptoms.⁶

The differential diagnosis of crusted and umbilicated papules includes disseminated herpesvirus infection, molluscum contagiosum, disseminated cryptococcosis, and histoplasmosis. Additional causative organisms to consider include Penicillium, Mycobacterium tuberculosis and nontuberculous mycobacteria, as well as Sporothrix schenckii.

Herpesvirus infections may have similar clinical and histopathologic findings to mpox. Histopathologically, herpes simplex virus (HSV) and varicella zoster virus (VZV) are essentially identical; both demonstrate ballooning and reticular epidermal degeneration, chromatin condensation, nuclear degeneration, multinucleated keratinocytes with steel-gray nuclei, and prominent epidermal acantholysis with an inflammatory infiltrate (Figure 1). However, involvement of folliculosebaceous units may favor a diagnosis of VZV. Immunohistochemical staining can further differentiate between HSV and VZV.⁷ While mpox may have features that overlap with both HSV and VZV, including ballooning degeneration and multinucleated keratinocytes with nuclear degeneration, acantholysis is a less commonly reported feature of mpox, and mpox virus infection is characterized by intracytoplasmic (Guarnieri) inclusion bodies rather than the intranuclear inclusion bodies of HSV and VZV.^2,5 The presence of Guarnieri bodies in mpox may further help to distinguish mpox from HSV infection on routine histology.

Molluscum contagiosum infection typically manifests as multiple umbilicated papules at sites of inoculation. Large lesions may be seen in the setting of immunosuppression; however, they usually do not progress to vesicular, pustular, or crusted morphologies. Histopathology demonstrates a cup-shaped invagination of the epidermis into the dermis and proliferative rete ridges that descend downward and encircle the dermis with large eosinophilic intracytoplasmic inclusion (Henderson-Patterson) bodies (Figure 2).⁸

Disseminated cryptococcus infection is caused by the invasive fungus Cryptococcus neoformans and is characterized by meningitis along with fever, malaise, headache, neck stiffness, photophobia, nausea, vomiting, pneumonia with cough and dyspnea, and skin rash, most commonly in immunocompromised individuals.⁹ Skin lesions are a sign of disseminated infection and can manifest as umbilicated or molluscumlike lesions. Histopathology of cryptococcosis demonstrates a granulomatous dermal infiltrate with neutrophils and pleomorphic yeasts measuring 4 µm to 6 µm with refringent capsules.¹⁰ Staining with Grocott methenamine silver and/or mucicarmine for yeast capsules can help to identify organisms (Figure 3).

Cutaneous histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus that can lead to pulmonary, cutaneous, and disseminated disease, often in immunocompromised patients.¹¹ Cutaneous disease may manifest with molluscumlike or verrucous papules and plaques. Histopathologic examination reveals diffuse suppurative and granulomatous infiltrates with foamy histiocytes and multinucleated giant cells, containing intracellular and extracellular yeasts measuring 1µm to 5µm, surrounded by a clear halo visible with Grocott methenamine silver stain (Figure 4).

Spreading cutaneous lesions in an immunocompromised individual may be the presentation of multiple infectious etiologies. With the recent rise in mpox cases occurring in nonendemic areas, clinicians should be aware of the spectrum of clinical findings that may occur. Notably, more than one infection may be present in severely immunocompromised individuals, as seen in our patient with chronic orolabial HSV-2 and acute mpox infection. Thorough clinical, histopathologic, and laboratory investigations are necessary for timely diagnosis, appropriate treatment, and exclusion of other life-threatening conditions.

THE DIAGNOSIS: Mpox Virus

The histopathologic features of mpox virus infection may vary depending on the stage of evolution; findings include ballooning degeneration with multinucleated keratinocytes, acanthosis, spongiosis, a neutrophil-rich inflammatory infiltrate, and eosinophilic intracytoplasmic (Guarnieri) inclusion bodies (quiz image inset [arrows]). Prominent neutrophil exocytosis also has been described and may be a characteristic feature in the pustular stage.^1,2 A pattern of interface dermatitis also has been observed on histopathology.³ In our patient, the diagnosis of mpox initially was made by clinical and histopathologic correlation and exclusion of other entities in the differential diagnosis. The diagnosis subsequently was confirmed by real-time polymerase chain reaction. The patient received treatment with tecovirimat, but lesions progressed over the following 6 weeks. He subsequently died due to sepsis and multiorgan failure secondary to AIDS.

Mpox is a zoonotic, double-stranded DNA virus of the genus Orthopoxvirus in the family Poxviridae.⁴ It is transmitted to humans via direct contact with infected animals, most commonly small mammals such as monkeys, squirrels, and rodents. Mpox also may be transmitted between humans through direct contact with bodily fluids, skin and mucosal lesions, respiratory droplets, or fomites. Mpox infection typically begins with a nonspecific flulike prodrome after a 5- to 21-day incubation period, followed by skin lesions of variable morphology affecting any region of the body. Clinically, mpox lesions have been reported to evolve through macular, papular, and vesiculopustular phases, followed by resolution with crusting. Lesions may occur anywhere on the body but frequently manifest on the face then spread centrifugally across the body, with various phases observed simultaneously.⁵ A worldwide outbreak in 2022 involved larger numbers of cases in nonendemic areas, primarily due to skin-to-skin contact, with predominant anal and genital localization of the lesions as well as fewer prodromal symptoms.⁶

The differential diagnosis of crusted and umbilicated papules includes disseminated herpesvirus infection, molluscum contagiosum, disseminated cryptococcosis, and histoplasmosis. Additional causative organisms to consider include Penicillium, Mycobacterium tuberculosis and nontuberculous mycobacteria, as well as Sporothrix schenckii.

Herpesvirus infections may have similar clinical and histopathologic findings to mpox. Histopathologically, herpes simplex virus (HSV) and varicella zoster virus (VZV) are essentially identical; both demonstrate ballooning and reticular epidermal degeneration, chromatin condensation, nuclear degeneration, multinucleated keratinocytes with steel-gray nuclei, and prominent epidermal acantholysis with an inflammatory infiltrate (Figure 1). However, involvement of folliculosebaceous units may favor a diagnosis of VZV. Immunohistochemical staining can further differentiate between HSV and VZV.⁷ While mpox may have features that overlap with both HSV and VZV, including ballooning degeneration and multinucleated keratinocytes with nuclear degeneration, acantholysis is a less commonly reported feature of mpox, and mpox virus infection is characterized by intracytoplasmic (Guarnieri) inclusion bodies rather than the intranuclear inclusion bodies of HSV and VZV.^2,5 The presence of Guarnieri bodies in mpox may further help to distinguish mpox from HSV infection on routine histology.

Molluscum contagiosum infection typically manifests as multiple umbilicated papules at sites of inoculation. Large lesions may be seen in the setting of immunosuppression; however, they usually do not progress to vesicular, pustular, or crusted morphologies. Histopathology demonstrates a cup-shaped invagination of the epidermis into the dermis and proliferative rete ridges that descend downward and encircle the dermis with large eosinophilic intracytoplasmic inclusion (Henderson-Patterson) bodies (Figure 2).⁸

Disseminated cryptococcus infection is caused by the invasive fungus Cryptococcus neoformans and is characterized by meningitis along with fever, malaise, headache, neck stiffness, photophobia, nausea, vomiting, pneumonia with cough and dyspnea, and skin rash, most commonly in immunocompromised individuals.⁹ Skin lesions are a sign of disseminated infection and can manifest as umbilicated or molluscumlike lesions. Histopathology of cryptococcosis demonstrates a granulomatous dermal infiltrate with neutrophils and pleomorphic yeasts measuring 4 µm to 6 µm with refringent capsules.¹⁰ Staining with Grocott methenamine silver and/or mucicarmine for yeast capsules can help to identify organisms (Figure 3).

Cutaneous histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fungus that can lead to pulmonary, cutaneous, and disseminated disease, often in immunocompromised patients.¹¹ Cutaneous disease may manifest with molluscumlike or verrucous papules and plaques. Histopathologic examination reveals diffuse suppurative and granulomatous infiltrates with foamy histiocytes and multinucleated giant cells, containing intracellular and extracellular yeasts measuring 1µm to 5µm, surrounded by a clear halo visible with Grocott methenamine silver stain (Figure 4).

Spreading cutaneous lesions in an immunocompromised individual may be the presentation of multiple infectious etiologies. With the recent rise in mpox cases occurring in nonendemic areas, clinicians should be aware of the spectrum of clinical findings that may occur. Notably, more than one infection may be present in severely immunocompromised individuals, as seen in our patient with chronic orolabial HSV-2 and acute mpox infection. Thorough clinical, histopathologic, and laboratory investigations are necessary for timely diagnosis, appropriate treatment, and exclusion of other life-threatening conditions.

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

THE DIAGNOSIS: Rhabdomyomatous Mesenchymal Hamartoma

Histopathologic examination of the excised tissue revealed haphazardly arranged bundles of mature striated muscle within the dermis and subcutaneous tissue admixed with adipose tissue, adnexal structures, blood vessels, and nerves. The presence of the lesion since birth, midline clinical presentation, and histologic findings were consistent with a diagnosis of rhabdomyomatous mesenchymal hamartoma (RMH).

Also referred to as striated muscle hamartoma, RMH is a rare benign lesion thought to have embryonic origin due to its midline presentation.¹ The etiology of RMH is unknown but is hypothesized to be due to abnormal migration or growth of embryonic mesenchymal tissue. Rhabdomyomatous mesenchymal hamartoma typically manifests in infancy or early childhood as a solitary midline papule on the head or neck, although there have been rare reports of development in adulthood.^2-4 Lesions often are polypoid or exophytic but may manifest as smooth papules or subcutaneous nodules.² Although benign, RMH may be associated with other congenital abnormalities and conditions, such as Delleman syndrome, which is caused by a sporadic genetic abnormality and results in defects of the eye, central nervous system, and skin.⁵ Treatment for RMH is not needed, but surgical excision for cosmetic purposes can be performed with low risk for recurrence. Histologically, RMH demonstrates a normal epidermis overlying disorganized bundles of skeletal muscle accompanied by varying amounts of other mature dermal and subcutaneous tissues including nerves, blood vessels, adipose tissue, and other adnexal structures.^2,6 Myoglobin and desmin are positive within the skeletal muscle bundles.⁷

Fibrous hamartoma of infancy (FHI) often manifests as a movable, ill-defined nodule within the subcutaneous tissue. While also occurring in young children—typically within the first 2 years of life—FHI primarily is found on the upper arms, back, and axillae, in contrast to FHI.⁸ The classic histopathologic presentation of FHI consists of a triphasic morphology consisting of undifferentiated mesenchymal cells and dense fibroblastic/myofibroblastic tissue with mature adipose tissue woven throughout in islands (Figure 1).⁹ Skeletal muscle is not a component of this tumor.

Neurofibromas also may manifest clinically as papules or nodules and arise from the peripheral nerve sheath. There are 3 major subtypes of neurofibromas—localized, diffuse, and plexiform—with the last being strongly associated with neurofibromatosis type 1.¹⁰ The plexiform type has a rare risk for malignant transformation. The typical histopathologic finding of a localized cutaneous neurofibroma is a dermal proliferation of spindle cells with wavy nuclei within a variably myxoid stroma (Figure 2).¹¹ Interspersed mast cells also can be seen. A plexiform neurofibroma typically involves multiple nerve fascicles and comprises multinodular or tortuous bundles of cytologically bland spindle cells. Compared to RMH, skeletal muscle is not a component of this tumor.

Nevus lipomatosus superficialis is a benign hamartoma that can manifest as a pedunculated or exophytic papule. The lesions may be solitary or multiple and, unlike RMH, are most common on the buttocks, upper thighs, and trunk.¹² The histopathologic features of nevus lipomatosus superficialis include clusters of mature adipose tissue in the superficial dermis admixed with collagen fibers and variably increased vasculature (Figure 3).¹³ Nevus lipomatosus superficialis does not contain skeletal muscle within the tumor in comparison to RMH.

It is important to distinguish rhabdomyosarcoma (RMS) from RMH, as it is associated with increased mortality and morbidity. Rhabdomyosarcoma is the most common soft-tissue sarcoma in children and is derived from mesenchyme with variable degrees of skeletal muscle differentiation.¹⁴ Due to its mesenchymal origin, these tumors can manifest in a variety of places but most commonly on the head and neck and in the genital region.¹⁵ The most common subtype is embryonal rhabdomyosarcoma. Histologically, embryonal RMS shows a moderately cellular tumor composed of sheets of spindle-shaped or round cells with scant or eosinophilic cytoplasm (Figure 4). The absence of genetic translocation in the paired box-forkhead box protein 01 (PAX-FOXO1) gene helps distinguish it from solid alveolar RMS, the second most common and more aggressive subtype.¹² Positive immunohistochemical staining for desmin, myoblast determination protein 1 (MyoD1), and myogenin supports myogenic differentiation.¹⁴

THE DIAGNOSIS: Epithelioid Fibrous Histiocytoma

In our patient, immunohistochemical stains for Factor XIIIa, CD68, and anaplastic lymphoma kinase (ALK) 1 confirmed the diagnosis of epithelioid fibrous histiocytoma (EFH). The location and relatively large size of the lesion led to a joint decision by the patient and physician to perform a complete excision, which was done with no complications.

Once considered a rare variant of dermatofibroma, EFH most commonly manifests as a solitary, vascular-appearing or flesh-colored papule or nodule on the legs. It often develops in the fifth decade of life with greater prevalence in men.^1-5 Our patient is one of the few known cases of EFH in children that have been reported in the literature.^3,6 Although EFH is benign, complete excision typically is performed due to the rarity of the lesion.³

The overexpression of ALK distinguishes EFH from other fibrohistiocytic lesions (Figure 1).⁵ The most common fusion partners are sequestosome 1 and vinculin (VCL), which account for more than 70% of cases.^3,5,7 Interestingly, VCL-ALK fusions have been reported to occur in a subset of pediatric renal cell carcinomas and recently in an ovoid spindle cell neoplasm considered to be a low-grade sarcoma.^3,7-9 Further studies have identified less common fusion partners, including the dynactin subunit 1, ETS variant transcription factor 6, protein-tyrosine phosphatase, receptor-type, F polypeptide-interacting protein-binding protein 1, sperm antigen with calponin homology and coiled-coil domains 1, tropomyosin 3, protein kinase cAMP-dependent type II regulatory subunit alpha, melanophilin, and Echinoderm microtubule-associated protein-like 4 genes.^3,8

In contrast to benign fibrous histiocytomas, EFHs primarily consist of epithelioid cells, have well-defined borders, exhibit prominent vascularity, usually are situated close to the epidermis, and lack multinucleated cells or histiocytes laden with lipids or hemosiderin.² The characteristic histopathologic finding is rounded or angulated epithelioid cells, with eosinophilic cytoplasm accounting for more than 50% of the tumor cell population.^1-3,5 The nuclei of the epithelioid cells are rounded and vesicular with small eosinophilic nucleoli and low mitotic activity. Common clinical features include an exophytic nodule with a classic epidermal collarette and an epidermis that exhibits variable degrees of hyperplasia.^1-3,5 Epithelioid fibrous histiocytomas often are confined to the superficial dermis and rarely extend to the subcutaneous layer. The stroma is collagenous with prominent vascularity, although older lesions can become more hyalinized and sclerotic.³ Histopathologically, these tumors can be a diagnostic challenge, as they often are mistaken for other fibrohistiocytic or melanocytic lesions.

Atypical fibroxanthoma (AFX) manifests as a dome-shaped exophytic nodule that can rapidly grow to 1 to 2 cm. Historically, it was thought to be a pseudomalignancy, but most investigators consider it within the spectrum of pleomorphic dermal sarcoma and undifferentiated pleomorphic sarcoma. Atypical fibroxanthoma usually occurs on the head and neck in elderly patients with sun-damaged skin. Histopathologically, the neoplastic cells of AFX range from atypical spindle cells and pleomorphic round to polygonal epithelioid cells to large, irregularly shaped multinucleated cells, some with foamy cytoplasm (Figure 2). The atypical spindle cells stain diffusely positive for CD10 and vimentin, while small subpopulations stain positively for CD68 or CD163 and procollagen 1. Smooth muscle actin inconsistently stains the tumor, and when it does, the staining typically is faint and patchy. Atypical fibroxanthomas usually do not stain positively for melanocytic, skeletal muscle, or keratinocytic markers.

Cellular dermatofibroma typically manifests as small, dome-shaped papules on the arms and legs that normally range from a few millimeters to 1 cm but occasionally measure up to 2 cm. Histopathologically, there are interweaving fascicles of spindle cells with hyperchromatic nuclei and peripheral splaying of the plump spindle cells that wrap around collagen bundles, known as collagen trapping (Figure 3). Unlike EFH, multinucleated cells and histiocytes with abundant lipids and hemosiderin often accompany the spindle cells in cellular dermatofibromas, which stain strongly positive for CD10 and vimentin, similar to AFX and EFH. The smooth muscle actin–staining pattern usually is faint and patchy, and in some cases, cellular dermatofibroma may not stain at all. Factor XIIIa and CD68 highlight the 2 populations of cells—fibroblasts and histiocytes—that make up the lesion.⁴

Epithelioid sarcoma comprises 2 types: distal (or conventional) type occurring on the distal arms and legs, particularly the hands and fingers of young adults, and proximal type occurring on the trunk and proximal extremities, including the upper arms and thighs.¹⁰ Epithelioid sarcoma is a rare aggressive malignancy that usually manifests as a firm nodule, sometimes with ulceration depending on the size. Histopathologically, diffuse dermal proliferation of ovoid to polygonal epithelioid cells arranged in short fascicles and nodular aggregations is observed (Figure 4). Spindle cells may be observed at the periphery of the lesion. Areas of necrosis are a frequent finding and a helpful diagnostic clue. Nearly all cases stain positively for pancytokeratin, CAM5.2, epithelial membrane antigen, and vimentin, and approximately half stain positively for CD34; there are variable expressions of ERG and smooth muscle actin.¹⁰ In most cases, epithelioid sarcoma does not stain positively for S100 or CD68. The majority (90%) of cases harbor a mutation in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene, resulting in the loss of INI1 protein expression, which can be demonstrated by immunohistochemistry. ¹⁰ As the cytologic atypia usually is minimal, epithelioid sarcoma may be misdiagnosed as a necrotizing granuloma and benign fibrous lesions, particularly when superficial or small partial biopsies are performed.

Intradermal Spitz nevi can measure from a few millimeters to more than 2 cm and can range from pink to brown to black. The most common locations are the lower extremities as well as the head and neck. Histopathologically, intradermal Spitz nevi have nests of large epithelioid melanocytes with large nuclei and abundant cytoplasm (eFigure). Nuclear pseudo-inclusions, which are cytoplasmic invaginations into the nucleus, are frequent. Unlike the other conditions in the differential, these entities stain positively for melanocytic markers—S100, SOX10, and Melan-A—but not CD68 or CD163.11 A variety of kinase fusions are observed in Spitz nevi, including the ALK gene, neurotrophic tyrosine receptor kinase, ROS proto-oncogene 1, megakaryocyte-erythroid progenitor, and v-raf murine sarcoma viral oncogene homolog B1 genes.¹²

THE DIAGNOSIS: Epithelioid Fibrous Histiocytoma

In our patient, immunohistochemical stains for Factor XIIIa, CD68, and anaplastic lymphoma kinase (ALK) 1 confirmed the diagnosis of epithelioid fibrous histiocytoma (EFH). The location and relatively large size of the lesion led to a joint decision by the patient and physician to perform a complete excision, which was done with no complications.

Once considered a rare variant of dermatofibroma, EFH most commonly manifests as a solitary, vascular-appearing or flesh-colored papule or nodule on the legs. It often develops in the fifth decade of life with greater prevalence in men.^1-5 Our patient is one of the few known cases of EFH in children that have been reported in the literature.^3,6 Although EFH is benign, complete excision typically is performed due to the rarity of the lesion.³

The overexpression of ALK distinguishes EFH from other fibrohistiocytic lesions (Figure 1).⁵ The most common fusion partners are sequestosome 1 and vinculin (VCL), which account for more than 70% of cases.^3,5,7 Interestingly, VCL-ALK fusions have been reported to occur in a subset of pediatric renal cell carcinomas and recently in an ovoid spindle cell neoplasm considered to be a low-grade sarcoma.^3,7-9 Further studies have identified less common fusion partners, including the dynactin subunit 1, ETS variant transcription factor 6, protein-tyrosine phosphatase, receptor-type, F polypeptide-interacting protein-binding protein 1, sperm antigen with calponin homology and coiled-coil domains 1, tropomyosin 3, protein kinase cAMP-dependent type II regulatory subunit alpha, melanophilin, and Echinoderm microtubule-associated protein-like 4 genes.^3,8

In contrast to benign fibrous histiocytomas, EFHs primarily consist of epithelioid cells, have well-defined borders, exhibit prominent vascularity, usually are situated close to the epidermis, and lack multinucleated cells or histiocytes laden with lipids or hemosiderin.² The characteristic histopathologic finding is rounded or angulated epithelioid cells, with eosinophilic cytoplasm accounting for more than 50% of the tumor cell population.^1-3,5 The nuclei of the epithelioid cells are rounded and vesicular with small eosinophilic nucleoli and low mitotic activity. Common clinical features include an exophytic nodule with a classic epidermal collarette and an epidermis that exhibits variable degrees of hyperplasia.^1-3,5 Epithelioid fibrous histiocytomas often are confined to the superficial dermis and rarely extend to the subcutaneous layer. The stroma is collagenous with prominent vascularity, although older lesions can become more hyalinized and sclerotic.³ Histopathologically, these tumors can be a diagnostic challenge, as they often are mistaken for other fibrohistiocytic or melanocytic lesions.

Atypical fibroxanthoma (AFX) manifests as a dome-shaped exophytic nodule that can rapidly grow to 1 to 2 cm. Historically, it was thought to be a pseudomalignancy, but most investigators consider it within the spectrum of pleomorphic dermal sarcoma and undifferentiated pleomorphic sarcoma. Atypical fibroxanthoma usually occurs on the head and neck in elderly patients with sun-damaged skin. Histopathologically, the neoplastic cells of AFX range from atypical spindle cells and pleomorphic round to polygonal epithelioid cells to large, irregularly shaped multinucleated cells, some with foamy cytoplasm (Figure 2). The atypical spindle cells stain diffusely positive for CD10 and vimentin, while small subpopulations stain positively for CD68 or CD163 and procollagen 1. Smooth muscle actin inconsistently stains the tumor, and when it does, the staining typically is faint and patchy. Atypical fibroxanthomas usually do not stain positively for melanocytic, skeletal muscle, or keratinocytic markers.

Cellular dermatofibroma typically manifests as small, dome-shaped papules on the arms and legs that normally range from a few millimeters to 1 cm but occasionally measure up to 2 cm. Histopathologically, there are interweaving fascicles of spindle cells with hyperchromatic nuclei and peripheral splaying of the plump spindle cells that wrap around collagen bundles, known as collagen trapping (Figure 3). Unlike EFH, multinucleated cells and histiocytes with abundant lipids and hemosiderin often accompany the spindle cells in cellular dermatofibromas, which stain strongly positive for CD10 and vimentin, similar to AFX and EFH. The smooth muscle actin–staining pattern usually is faint and patchy, and in some cases, cellular dermatofibroma may not stain at all. Factor XIIIa and CD68 highlight the 2 populations of cells—fibroblasts and histiocytes—that make up the lesion.⁴

Epithelioid sarcoma comprises 2 types: distal (or conventional) type occurring on the distal arms and legs, particularly the hands and fingers of young adults, and proximal type occurring on the trunk and proximal extremities, including the upper arms and thighs.¹⁰ Epithelioid sarcoma is a rare aggressive malignancy that usually manifests as a firm nodule, sometimes with ulceration depending on the size. Histopathologically, diffuse dermal proliferation of ovoid to polygonal epithelioid cells arranged in short fascicles and nodular aggregations is observed (Figure 4). Spindle cells may be observed at the periphery of the lesion. Areas of necrosis are a frequent finding and a helpful diagnostic clue. Nearly all cases stain positively for pancytokeratin, CAM5.2, epithelial membrane antigen, and vimentin, and approximately half stain positively for CD34; there are variable expressions of ERG and smooth muscle actin.¹⁰ In most cases, epithelioid sarcoma does not stain positively for S100 or CD68. The majority (90%) of cases harbor a mutation in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene, resulting in the loss of INI1 protein expression, which can be demonstrated by immunohistochemistry. ¹⁰ As the cytologic atypia usually is minimal, epithelioid sarcoma may be misdiagnosed as a necrotizing granuloma and benign fibrous lesions, particularly when superficial or small partial biopsies are performed.

Intradermal Spitz nevi can measure from a few millimeters to more than 2 cm and can range from pink to brown to black. The most common locations are the lower extremities as well as the head and neck. Histopathologically, intradermal Spitz nevi have nests of large epithelioid melanocytes with large nuclei and abundant cytoplasm (eFigure). Nuclear pseudo-inclusions, which are cytoplasmic invaginations into the nucleus, are frequent. Unlike the other conditions in the differential, these entities stain positively for melanocytic markers—S100, SOX10, and Melan-A—but not CD68 or CD163.11 A variety of kinase fusions are observed in Spitz nevi, including the ALK gene, neurotrophic tyrosine receptor kinase, ROS proto-oncogene 1, megakaryocyte-erythroid progenitor, and v-raf murine sarcoma viral oncogene homolog B1 genes.¹²

THE DIAGNOSIS: Epithelioid Fibrous Histiocytoma

In our patient, immunohistochemical stains for Factor XIIIa, CD68, and anaplastic lymphoma kinase (ALK) 1 confirmed the diagnosis of epithelioid fibrous histiocytoma (EFH). The location and relatively large size of the lesion led to a joint decision by the patient and physician to perform a complete excision, which was done with no complications.

Once considered a rare variant of dermatofibroma, EFH most commonly manifests as a solitary, vascular-appearing or flesh-colored papule or nodule on the legs. It often develops in the fifth decade of life with greater prevalence in men.^1-5 Our patient is one of the few known cases of EFH in children that have been reported in the literature.^3,6 Although EFH is benign, complete excision typically is performed due to the rarity of the lesion.³

The overexpression of ALK distinguishes EFH from other fibrohistiocytic lesions (Figure 1).⁵ The most common fusion partners are sequestosome 1 and vinculin (VCL), which account for more than 70% of cases.^3,5,7 Interestingly, VCL-ALK fusions have been reported to occur in a subset of pediatric renal cell carcinomas and recently in an ovoid spindle cell neoplasm considered to be a low-grade sarcoma.^3,7-9 Further studies have identified less common fusion partners, including the dynactin subunit 1, ETS variant transcription factor 6, protein-tyrosine phosphatase, receptor-type, F polypeptide-interacting protein-binding protein 1, sperm antigen with calponin homology and coiled-coil domains 1, tropomyosin 3, protein kinase cAMP-dependent type II regulatory subunit alpha, melanophilin, and Echinoderm microtubule-associated protein-like 4 genes.^3,8

In contrast to benign fibrous histiocytomas, EFHs primarily consist of epithelioid cells, have well-defined borders, exhibit prominent vascularity, usually are situated close to the epidermis, and lack multinucleated cells or histiocytes laden with lipids or hemosiderin.² The characteristic histopathologic finding is rounded or angulated epithelioid cells, with eosinophilic cytoplasm accounting for more than 50% of the tumor cell population.^1-3,5 The nuclei of the epithelioid cells are rounded and vesicular with small eosinophilic nucleoli and low mitotic activity. Common clinical features include an exophytic nodule with a classic epidermal collarette and an epidermis that exhibits variable degrees of hyperplasia.^1-3,5 Epithelioid fibrous histiocytomas often are confined to the superficial dermis and rarely extend to the subcutaneous layer. The stroma is collagenous with prominent vascularity, although older lesions can become more hyalinized and sclerotic.³ Histopathologically, these tumors can be a diagnostic challenge, as they often are mistaken for other fibrohistiocytic or melanocytic lesions.

Atypical fibroxanthoma (AFX) manifests as a dome-shaped exophytic nodule that can rapidly grow to 1 to 2 cm. Historically, it was thought to be a pseudomalignancy, but most investigators consider it within the spectrum of pleomorphic dermal sarcoma and undifferentiated pleomorphic sarcoma. Atypical fibroxanthoma usually occurs on the head and neck in elderly patients with sun-damaged skin. Histopathologically, the neoplastic cells of AFX range from atypical spindle cells and pleomorphic round to polygonal epithelioid cells to large, irregularly shaped multinucleated cells, some with foamy cytoplasm (Figure 2). The atypical spindle cells stain diffusely positive for CD10 and vimentin, while small subpopulations stain positively for CD68 or CD163 and procollagen 1. Smooth muscle actin inconsistently stains the tumor, and when it does, the staining typically is faint and patchy. Atypical fibroxanthomas usually do not stain positively for melanocytic, skeletal muscle, or keratinocytic markers.

Cellular dermatofibroma typically manifests as small, dome-shaped papules on the arms and legs that normally range from a few millimeters to 1 cm but occasionally measure up to 2 cm. Histopathologically, there are interweaving fascicles of spindle cells with hyperchromatic nuclei and peripheral splaying of the plump spindle cells that wrap around collagen bundles, known as collagen trapping (Figure 3). Unlike EFH, multinucleated cells and histiocytes with abundant lipids and hemosiderin often accompany the spindle cells in cellular dermatofibromas, which stain strongly positive for CD10 and vimentin, similar to AFX and EFH. The smooth muscle actin–staining pattern usually is faint and patchy, and in some cases, cellular dermatofibroma may not stain at all. Factor XIIIa and CD68 highlight the 2 populations of cells—fibroblasts and histiocytes—that make up the lesion.⁴

Epithelioid sarcoma comprises 2 types: distal (or conventional) type occurring on the distal arms and legs, particularly the hands and fingers of young adults, and proximal type occurring on the trunk and proximal extremities, including the upper arms and thighs.¹⁰ Epithelioid sarcoma is a rare aggressive malignancy that usually manifests as a firm nodule, sometimes with ulceration depending on the size. Histopathologically, diffuse dermal proliferation of ovoid to polygonal epithelioid cells arranged in short fascicles and nodular aggregations is observed (Figure 4). Spindle cells may be observed at the periphery of the lesion. Areas of necrosis are a frequent finding and a helpful diagnostic clue. Nearly all cases stain positively for pancytokeratin, CAM5.2, epithelial membrane antigen, and vimentin, and approximately half stain positively for CD34; there are variable expressions of ERG and smooth muscle actin.¹⁰ In most cases, epithelioid sarcoma does not stain positively for S100 or CD68. The majority (90%) of cases harbor a mutation in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene, resulting in the loss of INI1 protein expression, which can be demonstrated by immunohistochemistry. ¹⁰ As the cytologic atypia usually is minimal, epithelioid sarcoma may be misdiagnosed as a necrotizing granuloma and benign fibrous lesions, particularly when superficial or small partial biopsies are performed.

Intradermal Spitz nevi can measure from a few millimeters to more than 2 cm and can range from pink to brown to black. The most common locations are the lower extremities as well as the head and neck. Histopathologically, intradermal Spitz nevi have nests of large epithelioid melanocytes with large nuclei and abundant cytoplasm (eFigure). Nuclear pseudo-inclusions, which are cytoplasmic invaginations into the nucleus, are frequent. Unlike the other conditions in the differential, these entities stain positively for melanocytic markers—S100, SOX10, and Melan-A—but not CD68 or CD163.11 A variety of kinase fusions are observed in Spitz nevi, including the ALK gene, neurotrophic tyrosine receptor kinase, ROS proto-oncogene 1, megakaryocyte-erythroid progenitor, and v-raf murine sarcoma viral oncogene homolog B1 genes.¹²

THE DIAGNOSIS: Dermatofibrosarcoma Protuberans

The histologic findings showed fascicular proliferation of relatively monomorphic spindle cells with extensive entrapment of collagen and adipocytes. Immunohistochemical staining showed that the lesional cells were diffusely positive for CD34 and negative for SOX10, S100, desmin, and factor XIIIa. The decision was made to perform cytogenetic testing with fluorescence in situ hybridization to evaluate for the presence of platelet-derived growth factor receptor beta (PDGFB) polypeptide rearrangement, a key biomarker known to be positive in most patients with dermatofibrosarcoma protuberans (DFSP).¹ This rearrangement results in overproduction of PDGFB, continuous activation of platelet-derived growth factor receptor beta, cellular proliferation, and tumor formation.² In our patient, results were positive for the PDGFB polypeptide rearrangement, which confirmed suspected diagnosis of DFSP with fibrous histiocytoma like morphology. The patient was referred for Mohs micrographic surgery for proper management.

Dermatofibrosarcoma protuberans is a rare soft-tissue tumor that involves the dermis, subcutaneous fat, and sometimes muscle and fascia.² Dermatofibrosarcoma protuberans primarily affects young to middle-aged adults, with a slight predilection for individuals in the third to fifth decades of life.³ Lesions preferentially involve the trunk, particularly the shoulder and chest regions, and manifest as poorly circumscribed, locally aggressive mesenchymal neoplasms with a high local recurrence rate but low metastatic potential.^4,5 Clinically, the lesions appear as flesh-colored, rubbery plaques or nodules. A diagnosis of DFSP requires a high index of clinical suspicion, and histologic, immunohistochemical, and molecular testing usually are required for confirmation.

On histopathologic examination, DFSP classically demonstrates uniform, spindle-shaped cells that traditionally are arranged in an intersecting pattern and primarily are based in the dermis (Figure 1).⁵ Infiltration into the underlying tissue is a common feature, with neoplastic extensions causing a classic honeycomb pattern6 that also can be seen in diffuse neurofibroma and may cause diagnostic challenges; however, the immunohistology staining of neurofibroma differs from DFSP in that it stains positive for CD34, SOX-100, and S100, while DFSP has strong and diffuse CD34 immunoreactivity with negative immunostaining for SOX10, S100, desmin, and factor XIIIa.^2,6

Dermatofibrosarcoma protuberans can cause considerable fat infiltration compared to other soft-tissue neoplasms, making this finding suspicious for—if not characteristic of—DFSP. Collagen trapping also can be observed; however, this is more pathognomonic in cellular fibrous histiocytoma, which is a distinct clinical variant of dermatofibromas. Due to its similarity to other lesions, histopathologic examination along with immunostaining can assist in differentiating and accurately diagnosing DFSP.⁶

Cellular fibrous histiocytoma (CFH), a distinct clinical variant of dermatofibromas, is a benign tumor of mesenchymal origin that occurs more commonly on the trunk, arms, and legs. On histologic examination, CFH is composed of spindle-shaped cells with variable amounts of eosinophilic cytoplasm and small, oval-shaped eosinophilic nuclei and collagen trapping (Figure 2).^7,8 Most CFHs occupy the superficial dermis but can extend into the deep reticular dermis, thus mimicking the honeycomb pattern seen in DFSP. This neoplasm can show a similar architecture to DFSP, which is why further investigation including cytogenetics and immunohistochemical staining can help differentiate the two conditions. Cellular fibrous histiocytoma typically stains negative for CD34 and positive for factor XIIIa.⁹ However, CD34 can be positive in a subset of CFHs, with a considerable subset showing peripheral CD34 positivity and a smaller subset showing central CD34 the positivity.¹⁰ This suggests that CD34 cannot be the only factor differentiating these 2 lesions in making a proper dermatopathologic diagnosis.

Solitary fibrous tumor (SFT) is a rare mesenchymal tumor that can occur anywhere on the body and typically manifests as a deep, painless, enlarging mass in adults aged 50 to 60 years.¹¹ On histologic examination, SFT consists of randomly arranged cells with a spindle or ovoid shape within a collagenous stroma intermixed with blood vessels with a characteristic staghorn shape (Figure 3).¹¹ Low-grade SFT shows a patternless arrangement with spindle cells, a low number of mitotic figures, and vessels with a staghorn appearance compared to high-grade SFT, which shows hypercellularity with nuclear pleomorphism and a high number of mitotic figures.¹¹ Solitary fibrous tumors are positive for CD34 and STAT-6 and negative for CD31 and typically demonstrate NGFI-A binding protein 2 (NAB2)—signal transducer and activator of transcription 6 (STAT 6) gene fusion.¹¹

Spindle-cell lipomas are rare, benign, slow-growing, lipomatous tumors that typically manifest in men aged 40 to 70 years.¹² These lesions originate most frequently in the subcutaneous tissue of the upper back, posterior neck, and shoulders. The histologic growth pattern of spindle-cell lipomas can mimic other spindle-cell and myxoid tumors, which is why cytogenetic analysis is crucial for differentiating these lesions. On histologic examination, spindle-cell lipomas exhibit a mixture of mature adipocytes, uniform spindle cells, and collagen bundles (eFigure). Spindle-cell lipoma stains positive for CD34 but negative for S100.¹³ In addition, spindle-cell lipomas tend to show structural rearrangements (mainly deletions) of the long arm of chromosome 13 or even losses of whole chromosome 13, which contains the retinoblastoma (RB1) gene.¹³

Pleomorphic dermal sarcoma is a rare mesenchymal tumor that can appear clinically and histologically similar to atypical fibroxanthoma.¹⁴ This lesion often manifests in elderly patients and is strongly associated with chronic sun exposure.¹⁵ Pleomorphic dermal sarcoma is a locally aggressive tumor with metastatic potential to the skin or lymph nodes. On histologic examination, these tumors exhibit pleomorphic atypical epithelioid or spindle cells as well as multinucleated tumor giant cells with possible tumor necrosis, lymphovascular invasion, or perineural infiltration (Figure 4). Pleomorphic dermal sarcoma, typically a diagnosis of exclusion, requires immunohistochemistry to aid in proper identification.¹⁶ These lesions stain positive for CD10 and negative for cytokeratins, desmin, HMB45, CD34, p63, p40, SOX10, and S100.^15,16

THE DIAGNOSIS: Dermatofibrosarcoma Protuberans

The histologic findings showed fascicular proliferation of relatively monomorphic spindle cells with extensive entrapment of collagen and adipocytes. Immunohistochemical staining showed that the lesional cells were diffusely positive for CD34 and negative for SOX10, S100, desmin, and factor XIIIa. The decision was made to perform cytogenetic testing with fluorescence in situ hybridization to evaluate for the presence of platelet-derived growth factor receptor beta (PDGFB) polypeptide rearrangement, a key biomarker known to be positive in most patients with dermatofibrosarcoma protuberans (DFSP).¹ This rearrangement results in overproduction of PDGFB, continuous activation of platelet-derived growth factor receptor beta, cellular proliferation, and tumor formation.² In our patient, results were positive for the PDGFB polypeptide rearrangement, which confirmed suspected diagnosis of DFSP with fibrous histiocytoma like morphology. The patient was referred for Mohs micrographic surgery for proper management.

Dermatofibrosarcoma protuberans is a rare soft-tissue tumor that involves the dermis, subcutaneous fat, and sometimes muscle and fascia.² Dermatofibrosarcoma protuberans primarily affects young to middle-aged adults, with a slight predilection for individuals in the third to fifth decades of life.³ Lesions preferentially involve the trunk, particularly the shoulder and chest regions, and manifest as poorly circumscribed, locally aggressive mesenchymal neoplasms with a high local recurrence rate but low metastatic potential.^4,5 Clinically, the lesions appear as flesh-colored, rubbery plaques or nodules. A diagnosis of DFSP requires a high index of clinical suspicion, and histologic, immunohistochemical, and molecular testing usually are required for confirmation.

On histopathologic examination, DFSP classically demonstrates uniform, spindle-shaped cells that traditionally are arranged in an intersecting pattern and primarily are based in the dermis (Figure 1).⁵ Infiltration into the underlying tissue is a common feature, with neoplastic extensions causing a classic honeycomb pattern6 that also can be seen in diffuse neurofibroma and may cause diagnostic challenges; however, the immunohistology staining of neurofibroma differs from DFSP in that it stains positive for CD34, SOX-100, and S100, while DFSP has strong and diffuse CD34 immunoreactivity with negative immunostaining for SOX10, S100, desmin, and factor XIIIa.^2,6

Dermatofibrosarcoma protuberans can cause considerable fat infiltration compared to other soft-tissue neoplasms, making this finding suspicious for—if not characteristic of—DFSP. Collagen trapping also can be observed; however, this is more pathognomonic in cellular fibrous histiocytoma, which is a distinct clinical variant of dermatofibromas. Due to its similarity to other lesions, histopathologic examination along with immunostaining can assist in differentiating and accurately diagnosing DFSP.⁶

Cellular fibrous histiocytoma (CFH), a distinct clinical variant of dermatofibromas, is a benign tumor of mesenchymal origin that occurs more commonly on the trunk, arms, and legs. On histologic examination, CFH is composed of spindle-shaped cells with variable amounts of eosinophilic cytoplasm and small, oval-shaped eosinophilic nuclei and collagen trapping (Figure 2).^7,8 Most CFHs occupy the superficial dermis but can extend into the deep reticular dermis, thus mimicking the honeycomb pattern seen in DFSP. This neoplasm can show a similar architecture to DFSP, which is why further investigation including cytogenetics and immunohistochemical staining can help differentiate the two conditions. Cellular fibrous histiocytoma typically stains negative for CD34 and positive for factor XIIIa.⁹ However, CD34 can be positive in a subset of CFHs, with a considerable subset showing peripheral CD34 positivity and a smaller subset showing central CD34 the positivity.¹⁰ This suggests that CD34 cannot be the only factor differentiating these 2 lesions in making a proper dermatopathologic diagnosis.

Solitary fibrous tumor (SFT) is a rare mesenchymal tumor that can occur anywhere on the body and typically manifests as a deep, painless, enlarging mass in adults aged 50 to 60 years.¹¹ On histologic examination, SFT consists of randomly arranged cells with a spindle or ovoid shape within a collagenous stroma intermixed with blood vessels with a characteristic staghorn shape (Figure 3).¹¹ Low-grade SFT shows a patternless arrangement with spindle cells, a low number of mitotic figures, and vessels with a staghorn appearance compared to high-grade SFT, which shows hypercellularity with nuclear pleomorphism and a high number of mitotic figures.¹¹ Solitary fibrous tumors are positive for CD34 and STAT-6 and negative for CD31 and typically demonstrate NGFI-A binding protein 2 (NAB2)—signal transducer and activator of transcription 6 (STAT 6) gene fusion.¹¹

Spindle-cell lipomas are rare, benign, slow-growing, lipomatous tumors that typically manifest in men aged 40 to 70 years.¹² These lesions originate most frequently in the subcutaneous tissue of the upper back, posterior neck, and shoulders. The histologic growth pattern of spindle-cell lipomas can mimic other spindle-cell and myxoid tumors, which is why cytogenetic analysis is crucial for differentiating these lesions. On histologic examination, spindle-cell lipomas exhibit a mixture of mature adipocytes, uniform spindle cells, and collagen bundles (eFigure). Spindle-cell lipoma stains positive for CD34 but negative for S100.¹³ In addition, spindle-cell lipomas tend to show structural rearrangements (mainly deletions) of the long arm of chromosome 13 or even losses of whole chromosome 13, which contains the retinoblastoma (RB1) gene.¹³

Pleomorphic dermal sarcoma is a rare mesenchymal tumor that can appear clinically and histologically similar to atypical fibroxanthoma.¹⁴ This lesion often manifests in elderly patients and is strongly associated with chronic sun exposure.¹⁵ Pleomorphic dermal sarcoma is a locally aggressive tumor with metastatic potential to the skin or lymph nodes. On histologic examination, these tumors exhibit pleomorphic atypical epithelioid or spindle cells as well as multinucleated tumor giant cells with possible tumor necrosis, lymphovascular invasion, or perineural infiltration (Figure 4). Pleomorphic dermal sarcoma, typically a diagnosis of exclusion, requires immunohistochemistry to aid in proper identification.¹⁶ These lesions stain positive for CD10 and negative for cytokeratins, desmin, HMB45, CD34, p63, p40, SOX10, and S100.^15,16

THE DIAGNOSIS: Dermatofibrosarcoma Protuberans

The histologic findings showed fascicular proliferation of relatively monomorphic spindle cells with extensive entrapment of collagen and adipocytes. Immunohistochemical staining showed that the lesional cells were diffusely positive for CD34 and negative for SOX10, S100, desmin, and factor XIIIa. The decision was made to perform cytogenetic testing with fluorescence in situ hybridization to evaluate for the presence of platelet-derived growth factor receptor beta (PDGFB) polypeptide rearrangement, a key biomarker known to be positive in most patients with dermatofibrosarcoma protuberans (DFSP).¹ This rearrangement results in overproduction of PDGFB, continuous activation of platelet-derived growth factor receptor beta, cellular proliferation, and tumor formation.² In our patient, results were positive for the PDGFB polypeptide rearrangement, which confirmed suspected diagnosis of DFSP with fibrous histiocytoma like morphology. The patient was referred for Mohs micrographic surgery for proper management.

Dermatofibrosarcoma protuberans is a rare soft-tissue tumor that involves the dermis, subcutaneous fat, and sometimes muscle and fascia.² Dermatofibrosarcoma protuberans primarily affects young to middle-aged adults, with a slight predilection for individuals in the third to fifth decades of life.³ Lesions preferentially involve the trunk, particularly the shoulder and chest regions, and manifest as poorly circumscribed, locally aggressive mesenchymal neoplasms with a high local recurrence rate but low metastatic potential.^4,5 Clinically, the lesions appear as flesh-colored, rubbery plaques or nodules. A diagnosis of DFSP requires a high index of clinical suspicion, and histologic, immunohistochemical, and molecular testing usually are required for confirmation.

On histopathologic examination, DFSP classically demonstrates uniform, spindle-shaped cells that traditionally are arranged in an intersecting pattern and primarily are based in the dermis (Figure 1).⁵ Infiltration into the underlying tissue is a common feature, with neoplastic extensions causing a classic honeycomb pattern6 that also can be seen in diffuse neurofibroma and may cause diagnostic challenges; however, the immunohistology staining of neurofibroma differs from DFSP in that it stains positive for CD34, SOX-100, and S100, while DFSP has strong and diffuse CD34 immunoreactivity with negative immunostaining for SOX10, S100, desmin, and factor XIIIa.^2,6

Dermatofibrosarcoma protuberans can cause considerable fat infiltration compared to other soft-tissue neoplasms, making this finding suspicious for—if not characteristic of—DFSP. Collagen trapping also can be observed; however, this is more pathognomonic in cellular fibrous histiocytoma, which is a distinct clinical variant of dermatofibromas. Due to its similarity to other lesions, histopathologic examination along with immunostaining can assist in differentiating and accurately diagnosing DFSP.⁶

Cellular fibrous histiocytoma (CFH), a distinct clinical variant of dermatofibromas, is a benign tumor of mesenchymal origin that occurs more commonly on the trunk, arms, and legs. On histologic examination, CFH is composed of spindle-shaped cells with variable amounts of eosinophilic cytoplasm and small, oval-shaped eosinophilic nuclei and collagen trapping (Figure 2).^7,8 Most CFHs occupy the superficial dermis but can extend into the deep reticular dermis, thus mimicking the honeycomb pattern seen in DFSP. This neoplasm can show a similar architecture to DFSP, which is why further investigation including cytogenetics and immunohistochemical staining can help differentiate the two conditions. Cellular fibrous histiocytoma typically stains negative for CD34 and positive for factor XIIIa.⁹ However, CD34 can be positive in a subset of CFHs, with a considerable subset showing peripheral CD34 positivity and a smaller subset showing central CD34 the positivity.¹⁰ This suggests that CD34 cannot be the only factor differentiating these 2 lesions in making a proper dermatopathologic diagnosis.

Solitary fibrous tumor (SFT) is a rare mesenchymal tumor that can occur anywhere on the body and typically manifests as a deep, painless, enlarging mass in adults aged 50 to 60 years.¹¹ On histologic examination, SFT consists of randomly arranged cells with a spindle or ovoid shape within a collagenous stroma intermixed with blood vessels with a characteristic staghorn shape (Figure 3).¹¹ Low-grade SFT shows a patternless arrangement with spindle cells, a low number of mitotic figures, and vessels with a staghorn appearance compared to high-grade SFT, which shows hypercellularity with nuclear pleomorphism and a high number of mitotic figures.¹¹ Solitary fibrous tumors are positive for CD34 and STAT-6 and negative for CD31 and typically demonstrate NGFI-A binding protein 2 (NAB2)—signal transducer and activator of transcription 6 (STAT 6) gene fusion.¹¹

Spindle-cell lipomas are rare, benign, slow-growing, lipomatous tumors that typically manifest in men aged 40 to 70 years.¹² These lesions originate most frequently in the subcutaneous tissue of the upper back, posterior neck, and shoulders. The histologic growth pattern of spindle-cell lipomas can mimic other spindle-cell and myxoid tumors, which is why cytogenetic analysis is crucial for differentiating these lesions. On histologic examination, spindle-cell lipomas exhibit a mixture of mature adipocytes, uniform spindle cells, and collagen bundles (eFigure). Spindle-cell lipoma stains positive for CD34 but negative for S100.¹³ In addition, spindle-cell lipomas tend to show structural rearrangements (mainly deletions) of the long arm of chromosome 13 or even losses of whole chromosome 13, which contains the retinoblastoma (RB1) gene.¹³

Pleomorphic dermal sarcoma is a rare mesenchymal tumor that can appear clinically and histologically similar to atypical fibroxanthoma.¹⁴ This lesion often manifests in elderly patients and is strongly associated with chronic sun exposure.¹⁵ Pleomorphic dermal sarcoma is a locally aggressive tumor with metastatic potential to the skin or lymph nodes. On histologic examination, these tumors exhibit pleomorphic atypical epithelioid or spindle cells as well as multinucleated tumor giant cells with possible tumor necrosis, lymphovascular invasion, or perineural infiltration (Figure 4). Pleomorphic dermal sarcoma, typically a diagnosis of exclusion, requires immunohistochemistry to aid in proper identification.¹⁶ These lesions stain positive for CD10 and negative for cytokeratins, desmin, HMB45, CD34, p63, p40, SOX10, and S100.^15,16

THE DIAGNOSIS: Acral Persistent Papular Mucinosis

Histopathologic analysis revealed conspicuous interstitial mucin deposition throughout the upper to mid reticular dermis in the absence of a cellular infiltrate or fibroplasia. Colloidal iron staining confirmed the presence of mucin. In correlation with the clinical presentation, a diagnosis of acral persistent papular mucinosis (APPM) was made. The patient was counseled on the benign disease course and lack of associated comorbidities, and additional treatment was not pursued.

Acral persistent papular mucinosis is a rare distinct subtype of cutaneous mucinosis that initially was described by Rongioletti et al¹ in 1986. As a localized form of lichen myxedematosus, APPM is characterized by mucin deposition in the dermis with no systemic involvement. The precise pathogenesis remains unclear, although some investigators have suggested that cytokine-mediated stimulation of glycosaminoglycan production may contribute to increased mucin accumulation in the dermis.² Acral persistent papular mucinosis predominantly affects middle-aged women with a 5:1 female-to-male predominance.³ Clinically, patients present with discrete, nonfollicular, waxy papules that typically measure 2 to 5 mm and are distributed symmetrically on the extensor surfaces of the wrists and forearms. While the lesions generally are asymptomatic, some patients may report mild pruritus. The condition is chronic, with lesions seldom resolving and often increasing in number over time.³

Histologically, APPM is characterized by focal deposits of mucin in the upper reticular dermis with no evidence of increased fibroblast proliferation or fibrosis.⁴ This feature is pivotal in differentiating APPM from other subtypes of localized lichen myxedematosus and similar dermatoses. Diagnosis of APPM requires exclusion of systemic involvement, including thyroid abnormalities and monoclonal gammopathy, aligning with its classification as a purely cutaneous condition.⁵ Management of APPM is unclear due to its rarity. Reassurance for patients of its benign nature as well as clinical observation are recommended, though some reports cite benefits of treatment with topical corticosteroids or calcineurin inhibitors.^6,7 The long-term prognosis for patients with APPM is favorable, although the persistence of and potential increase in lesions over time can be a cosmetic concern.

The differential diagnoses for APPM include scleromyxedema, scleredema, and other cutaneous eruptions that manifest as smooth flesh-colored papules, such as granuloma annulare and lichen nitidus.³ Scleromyxedema is a systemic cutaneous mucinosis that is part of the same disease spectrum as lichen myxedematosus. The papular eruption of scleromyxedema is much more widespread, and coalescing of the lesions may lead to characteristic skin thickening, creating leonine facies and deep furrowing over the trunk.⁸ Extracutaneous manifestations are frequent in scleromyxedema, and up to 90% of patients exhibit evidence of an underlying plasma cell dyscrasia.² Histopathologically, scleromyxedema shows extensive fibroblast proliferation and fibrosis, in contrast to the findings of APPM (Figure 1).

The histopathology of APPM is most similar to scleredema, a rare fibromucinous disorder of the skin associated with diabetes, infection (especially poststreptococcal), or monoclonal gammopathy.⁹ Biopsy evaluation of scleredema reveals a normal epidermis with mucin deposition between collagen bundles predominantly in the deep reticular dermis as well as absent fibroblast proliferation (Figure 2). Unlike APPM, scleredema manifests with diffuse woody induration with erythema and hyperpigmentation on the posterior neck and upper back.⁹ On physical examination, the distinct clinical features of scleredema distinguish this condition from APPM and scleromyxedema.

Papular granuloma annulare also was considered in our patient due to the presence of small flesh-colored papules. Histologically, granuloma annulare is characterized by palisading granulomas and mucin deposition in the dermis.¹⁰ However, the pattern of mucin deposition differs from that seen in APPM. In granuloma annulare, mucin is observed around foci of degenerated collagen (Figure 3), which was not observed in our patient.¹⁰ Additionally, the absence of an inflammatory infiltrate in our patient further ruled out this diagnosis.

Lichen nitidus also could be considered in the differential diagnosis for ACCM. It typically manifests with minute, clustered, monomorphous papules with a predilection for the chest, abdomen, flexural forearms, and genitalia. The histology of lichen nitidus is distinct, showing a well-circumscribed lymphohistiocytic infiltrate in the papillary dermis bordered by epidermal ridges, resembling a ball and clutch appearance (Figure 4).¹¹

Although the clinical differential diagnosis in our patient was broad, histopathologic evaluation played a crucial role in confirming the diagnosis of APPM. This benign condition could be overlooked by patients and physicians; thorough clinical evaluation is necessary to rule out systemic mucinoses, which are associated with higher risks of morbidity and mortality.

THE DIAGNOSIS: Acral Persistent Papular Mucinosis

Histopathologic analysis revealed conspicuous interstitial mucin deposition throughout the upper to mid reticular dermis in the absence of a cellular infiltrate or fibroplasia. Colloidal iron staining confirmed the presence of mucin. In correlation with the clinical presentation, a diagnosis of acral persistent papular mucinosis (APPM) was made. The patient was counseled on the benign disease course and lack of associated comorbidities, and additional treatment was not pursued.

Acral persistent papular mucinosis is a rare distinct subtype of cutaneous mucinosis that initially was described by Rongioletti et al¹ in 1986. As a localized form of lichen myxedematosus, APPM is characterized by mucin deposition in the dermis with no systemic involvement. The precise pathogenesis remains unclear, although some investigators have suggested that cytokine-mediated stimulation of glycosaminoglycan production may contribute to increased mucin accumulation in the dermis.² Acral persistent papular mucinosis predominantly affects middle-aged women with a 5:1 female-to-male predominance.³ Clinically, patients present with discrete, nonfollicular, waxy papules that typically measure 2 to 5 mm and are distributed symmetrically on the extensor surfaces of the wrists and forearms. While the lesions generally are asymptomatic, some patients may report mild pruritus. The condition is chronic, with lesions seldom resolving and often increasing in number over time.³

Histologically, APPM is characterized by focal deposits of mucin in the upper reticular dermis with no evidence of increased fibroblast proliferation or fibrosis.⁴ This feature is pivotal in differentiating APPM from other subtypes of localized lichen myxedematosus and similar dermatoses. Diagnosis of APPM requires exclusion of systemic involvement, including thyroid abnormalities and monoclonal gammopathy, aligning with its classification as a purely cutaneous condition.⁵ Management of APPM is unclear due to its rarity. Reassurance for patients of its benign nature as well as clinical observation are recommended, though some reports cite benefits of treatment with topical corticosteroids or calcineurin inhibitors.^6,7 The long-term prognosis for patients with APPM is favorable, although the persistence of and potential increase in lesions over time can be a cosmetic concern.

The differential diagnoses for APPM include scleromyxedema, scleredema, and other cutaneous eruptions that manifest as smooth flesh-colored papules, such as granuloma annulare and lichen nitidus.³ Scleromyxedema is a systemic cutaneous mucinosis that is part of the same disease spectrum as lichen myxedematosus. The papular eruption of scleromyxedema is much more widespread, and coalescing of the lesions may lead to characteristic skin thickening, creating leonine facies and deep furrowing over the trunk.⁸ Extracutaneous manifestations are frequent in scleromyxedema, and up to 90% of patients exhibit evidence of an underlying plasma cell dyscrasia.² Histopathologically, scleromyxedema shows extensive fibroblast proliferation and fibrosis, in contrast to the findings of APPM (Figure 1).

The histopathology of APPM is most similar to scleredema, a rare fibromucinous disorder of the skin associated with diabetes, infection (especially poststreptococcal), or monoclonal gammopathy.⁹ Biopsy evaluation of scleredema reveals a normal epidermis with mucin deposition between collagen bundles predominantly in the deep reticular dermis as well as absent fibroblast proliferation (Figure 2). Unlike APPM, scleredema manifests with diffuse woody induration with erythema and hyperpigmentation on the posterior neck and upper back.⁹ On physical examination, the distinct clinical features of scleredema distinguish this condition from APPM and scleromyxedema.

Papular granuloma annulare also was considered in our patient due to the presence of small flesh-colored papules. Histologically, granuloma annulare is characterized by palisading granulomas and mucin deposition in the dermis.¹⁰ However, the pattern of mucin deposition differs from that seen in APPM. In granuloma annulare, mucin is observed around foci of degenerated collagen (Figure 3), which was not observed in our patient.¹⁰ Additionally, the absence of an inflammatory infiltrate in our patient further ruled out this diagnosis.

Lichen nitidus also could be considered in the differential diagnosis for ACCM. It typically manifests with minute, clustered, monomorphous papules with a predilection for the chest, abdomen, flexural forearms, and genitalia. The histology of lichen nitidus is distinct, showing a well-circumscribed lymphohistiocytic infiltrate in the papillary dermis bordered by epidermal ridges, resembling a ball and clutch appearance (Figure 4).¹¹

Although the clinical differential diagnosis in our patient was broad, histopathologic evaluation played a crucial role in confirming the diagnosis of APPM. This benign condition could be overlooked by patients and physicians; thorough clinical evaluation is necessary to rule out systemic mucinoses, which are associated with higher risks of morbidity and mortality.

THE DIAGNOSIS: Acral Persistent Papular Mucinosis

Histopathologic analysis revealed conspicuous interstitial mucin deposition throughout the upper to mid reticular dermis in the absence of a cellular infiltrate or fibroplasia. Colloidal iron staining confirmed the presence of mucin. In correlation with the clinical presentation, a diagnosis of acral persistent papular mucinosis (APPM) was made. The patient was counseled on the benign disease course and lack of associated comorbidities, and additional treatment was not pursued.

Acral persistent papular mucinosis is a rare distinct subtype of cutaneous mucinosis that initially was described by Rongioletti et al¹ in 1986. As a localized form of lichen myxedematosus, APPM is characterized by mucin deposition in the dermis with no systemic involvement. The precise pathogenesis remains unclear, although some investigators have suggested that cytokine-mediated stimulation of glycosaminoglycan production may contribute to increased mucin accumulation in the dermis.² Acral persistent papular mucinosis predominantly affects middle-aged women with a 5:1 female-to-male predominance.³ Clinically, patients present with discrete, nonfollicular, waxy papules that typically measure 2 to 5 mm and are distributed symmetrically on the extensor surfaces of the wrists and forearms. While the lesions generally are asymptomatic, some patients may report mild pruritus. The condition is chronic, with lesions seldom resolving and often increasing in number over time.³

Histologically, APPM is characterized by focal deposits of mucin in the upper reticular dermis with no evidence of increased fibroblast proliferation or fibrosis.⁴ This feature is pivotal in differentiating APPM from other subtypes of localized lichen myxedematosus and similar dermatoses. Diagnosis of APPM requires exclusion of systemic involvement, including thyroid abnormalities and monoclonal gammopathy, aligning with its classification as a purely cutaneous condition.⁵ Management of APPM is unclear due to its rarity. Reassurance for patients of its benign nature as well as clinical observation are recommended, though some reports cite benefits of treatment with topical corticosteroids or calcineurin inhibitors.^6,7 The long-term prognosis for patients with APPM is favorable, although the persistence of and potential increase in lesions over time can be a cosmetic concern.

The differential diagnoses for APPM include scleromyxedema, scleredema, and other cutaneous eruptions that manifest as smooth flesh-colored papules, such as granuloma annulare and lichen nitidus.³ Scleromyxedema is a systemic cutaneous mucinosis that is part of the same disease spectrum as lichen myxedematosus. The papular eruption of scleromyxedema is much more widespread, and coalescing of the lesions may lead to characteristic skin thickening, creating leonine facies and deep furrowing over the trunk.⁸ Extracutaneous manifestations are frequent in scleromyxedema, and up to 90% of patients exhibit evidence of an underlying plasma cell dyscrasia.² Histopathologically, scleromyxedema shows extensive fibroblast proliferation and fibrosis, in contrast to the findings of APPM (Figure 1).

The histopathology of APPM is most similar to scleredema, a rare fibromucinous disorder of the skin associated with diabetes, infection (especially poststreptococcal), or monoclonal gammopathy.⁹ Biopsy evaluation of scleredema reveals a normal epidermis with mucin deposition between collagen bundles predominantly in the deep reticular dermis as well as absent fibroblast proliferation (Figure 2). Unlike APPM, scleredema manifests with diffuse woody induration with erythema and hyperpigmentation on the posterior neck and upper back.⁹ On physical examination, the distinct clinical features of scleredema distinguish this condition from APPM and scleromyxedema.

Papular granuloma annulare also was considered in our patient due to the presence of small flesh-colored papules. Histologically, granuloma annulare is characterized by palisading granulomas and mucin deposition in the dermis.¹⁰ However, the pattern of mucin deposition differs from that seen in APPM. In granuloma annulare, mucin is observed around foci of degenerated collagen (Figure 3), which was not observed in our patient.¹⁰ Additionally, the absence of an inflammatory infiltrate in our patient further ruled out this diagnosis.

Lichen nitidus also could be considered in the differential diagnosis for ACCM. It typically manifests with minute, clustered, monomorphous papules with a predilection for the chest, abdomen, flexural forearms, and genitalia. The histology of lichen nitidus is distinct, showing a well-circumscribed lymphohistiocytic infiltrate in the papillary dermis bordered by epidermal ridges, resembling a ball and clutch appearance (Figure 4).¹¹

Although the clinical differential diagnosis in our patient was broad, histopathologic evaluation played a crucial role in confirming the diagnosis of APPM. This benign condition could be overlooked by patients and physicians; thorough clinical evaluation is necessary to rule out systemic mucinoses, which are associated with higher risks of morbidity and mortality.

THE DIAGNOSIS: Cutaneous Cryptococcosis

Biopsy of the ulcerated nodule showed numerous yeastlike organisms within clear mucinous capsules and with some surrounding inflammation. On Grocott methenamine silver staining, the organisms stained black. Workup for disseminated cryptococcus was negative, leading to a diagnosis of primary cutaneous cryptococcosis in the setting of immunosuppression. Notably, cryptococcosis infection has been reported in patients taking fingolimod (a sphingosine-1-phosphate receptor) for multiple sclerosis, which was the case for our patient.¹

The genus Cryptococcus comprises more than 30 species of encapsulated basidiomycetous fungi distributed ubiquitously in nature. Currently, only 2 species are known to cause infectious disease in humans: Cryptococcus neoformans, which affects both immunocompromised and immunocompetent patients and frequently is isolated from pigeon droppings, as well as Cryptococcus gatti, which primarily affects immunocompetent patients and is more commonly isolated from soil and decaying wood.²

Primary cutaneous cryptococcosis (PCC), characterized by direct inoculation of C neoformans or C gatti via skin injury, is rare and typically is seen in patients with decreased cell-mediated immunity, such as those on chronic corticosteroid therapy, solid-organ transplant recipients, and those with HIV.³ Primary cutaneous cryptococcosis typically manifests as a solitary or confined lesion on exposed areas of the skin and often is accompanied by regional lymphadenopathy.^4,5 The most common cutaneous findings associated with PCC include ulceration, cellulitis, and whitlow.⁵ In immunocompetent hosts, frequently affected sites include the arms, fingers, and face, while the trunk and lower extremities are more commonly affected in immunocompromised hosts.³ Secondary cutaneous cryptococcosis occurs through hematologic spread in patients with disseminated cryptococcosis after inhalation of Cryptococcosis spores and differs from PCC in that it typically manifests as multiple lesions scattered on both exposed and covered areas of the skin. Patients also may have signs and symptoms of disseminated cryptococcosis such as pneumonia and/or meningitis at presentation.⁵

Despite the difference between PCC and secondary cutaneous cryptococcosis, almost every type of skin lesion has been observed in cryptococcosis, including pustules, nodules, vesicles, acneform lesions, purpura, ulcers, abscesses, molluscumlike lesions, granulomas, draining sinuses, and cellulitis.^6,7

Cutaneous cryptococcosis generally is associated with 2 types of histologic reactions: gelatinous and granulomatous. The gelatinous reaction shows numerous yeastlike organisms ranging from 4 μm to 12 μm in diameter with large mucinous polysaccharide capsules and scant inflammation. Organisms may be seen in mucoid sheets.⁸ The granulomatous type shows a more pronounced reaction with fewer organisms ranging from 2 μm to 4 μm in diameter found within giant cells, histiocytes, and lymphocytes.^6,9 Areas of necrosis occasionally can be observed.⁸

It is important to consider infection with Blastomyces dermatitidis and Histoplasma capsulatum in the differential Both entities can manifest as necrotizing granulomas on histology (Figures 1 and 2).¹⁰ Microscopic morphology can help differentiate these pathogenic fungi from Cryptococcus diagnosis of cryptococcosis. species which show pleomorphic, narrow-based budding yeast with wide capsules. In contrast, H capsulatum is characterized by small, intracellular, yeastlike cells with microconidia and macroconidia, while B dermatitidis is distinguished by spherical, thick-walled cells with broad-based budding.¹¹ Capsular material also can help distinguish Cryptococcus from other pathogenic fungi. Special stains highlighting the polysaccharide capsule of Cryptococcus can best identify the yeast. The capsule stains red with periodic acid–Schiff, blue with Alcian blue, and black with Grocott methenamine silver. Mucicarmine is especially useful as it can stain the mucinous capsule pinkish red and typically does not stain other pathogenic fungi.¹² Capsule-deficient organisms can lead to considerable difficulties in diagnosis given the organisms can vary in size and may mimic H capsulatum or B dermatitidis. The Fontana-Masson stain is a valuable tool in identifying capsule-deficient organisms, as melanin is found in Cryptococcus cell walls; thus, positive staining excludes H capsulatum and B dermatitidis.¹³

Cutaneous foreign body granuloma, which refers to a granulomatous inflammatory reaction to a foreign body in the skin, is another differential diagnosis that is important to distinguish from cutaneous cryptococcosis. On histology, a collection of histiocytes surround the inert material, forming giant cells without an immune response (Figure 3).¹⁰ In contrast, granulomas caused by infectious etiologies (eg, Cryptococcus species) have an associated adaptive immune response and can be further classified as necrotizing or non-necrotizing. Necrotizing granulomas have a distinct central necrosis with a surrounding lymphohistiocytic reaction with peripheral chronic inflammation.¹⁰

Sweet syndrome is another mimicker of cutaneous cryptococcosis. A histologic variant of Sweet syndrome has been reported that has characteristic cutaneous lesions clinically but shows basophilic bodies with a surrounding halo on pathology that can be mistaken for Cryptococcus yeast. Classic histopathology of Sweet syndrome features papillary dermal edema with neutrophil or histiocytelike inflammatory infiltrate (Figure 4). Identification of Sweet syndrome can be aided by positive myeloperoxidase staining and negative periodic acid–Schiff staining.^14,15

THE DIAGNOSIS: Cutaneous Cryptococcosis

Biopsy of the ulcerated nodule showed numerous yeastlike organisms within clear mucinous capsules and with some surrounding inflammation. On Grocott methenamine silver staining, the organisms stained black. Workup for disseminated cryptococcus was negative, leading to a diagnosis of primary cutaneous cryptococcosis in the setting of immunosuppression. Notably, cryptococcosis infection has been reported in patients taking fingolimod (a sphingosine-1-phosphate receptor) for multiple sclerosis, which was the case for our patient.¹

The genus Cryptococcus comprises more than 30 species of encapsulated basidiomycetous fungi distributed ubiquitously in nature. Currently, only 2 species are known to cause infectious disease in humans: Cryptococcus neoformans, which affects both immunocompromised and immunocompetent patients and frequently is isolated from pigeon droppings, as well as Cryptococcus gatti, which primarily affects immunocompetent patients and is more commonly isolated from soil and decaying wood.²

Primary cutaneous cryptococcosis (PCC), characterized by direct inoculation of C neoformans or C gatti via skin injury, is rare and typically is seen in patients with decreased cell-mediated immunity, such as those on chronic corticosteroid therapy, solid-organ transplant recipients, and those with HIV.³ Primary cutaneous cryptococcosis typically manifests as a solitary or confined lesion on exposed areas of the skin and often is accompanied by regional lymphadenopathy.^4,5 The most common cutaneous findings associated with PCC include ulceration, cellulitis, and whitlow.⁵ In immunocompetent hosts, frequently affected sites include the arms, fingers, and face, while the trunk and lower extremities are more commonly affected in immunocompromised hosts.³ Secondary cutaneous cryptococcosis occurs through hematologic spread in patients with disseminated cryptococcosis after inhalation of Cryptococcosis spores and differs from PCC in that it typically manifests as multiple lesions scattered on both exposed and covered areas of the skin. Patients also may have signs and symptoms of disseminated cryptococcosis such as pneumonia and/or meningitis at presentation.⁵

Despite the difference between PCC and secondary cutaneous cryptococcosis, almost every type of skin lesion has been observed in cryptococcosis, including pustules, nodules, vesicles, acneform lesions, purpura, ulcers, abscesses, molluscumlike lesions, granulomas, draining sinuses, and cellulitis.^6,7

Cutaneous cryptococcosis generally is associated with 2 types of histologic reactions: gelatinous and granulomatous. The gelatinous reaction shows numerous yeastlike organisms ranging from 4 μm to 12 μm in diameter with large mucinous polysaccharide capsules and scant inflammation. Organisms may be seen in mucoid sheets.⁸ The granulomatous type shows a more pronounced reaction with fewer organisms ranging from 2 μm to 4 μm in diameter found within giant cells, histiocytes, and lymphocytes.^6,9 Areas of necrosis occasionally can be observed.⁸

It is important to consider infection with Blastomyces dermatitidis and Histoplasma capsulatum in the differential Both entities can manifest as necrotizing granulomas on histology (Figures 1 and 2).¹⁰ Microscopic morphology can help differentiate these pathogenic fungi from Cryptococcus diagnosis of cryptococcosis. species which show pleomorphic, narrow-based budding yeast with wide capsules. In contrast, H capsulatum is characterized by small, intracellular, yeastlike cells with microconidia and macroconidia, while B dermatitidis is distinguished by spherical, thick-walled cells with broad-based budding.¹¹ Capsular material also can help distinguish Cryptococcus from other pathogenic fungi. Special stains highlighting the polysaccharide capsule of Cryptococcus can best identify the yeast. The capsule stains red with periodic acid–Schiff, blue with Alcian blue, and black with Grocott methenamine silver. Mucicarmine is especially useful as it can stain the mucinous capsule pinkish red and typically does not stain other pathogenic fungi.¹² Capsule-deficient organisms can lead to considerable difficulties in diagnosis given the organisms can vary in size and may mimic H capsulatum or B dermatitidis. The Fontana-Masson stain is a valuable tool in identifying capsule-deficient organisms, as melanin is found in Cryptococcus cell walls; thus, positive staining excludes H capsulatum and B dermatitidis.¹³

Cutaneous foreign body granuloma, which refers to a granulomatous inflammatory reaction to a foreign body in the skin, is another differential diagnosis that is important to distinguish from cutaneous cryptococcosis. On histology, a collection of histiocytes surround the inert material, forming giant cells without an immune response (Figure 3).¹⁰ In contrast, granulomas caused by infectious etiologies (eg, Cryptococcus species) have an associated adaptive immune response and can be further classified as necrotizing or non-necrotizing. Necrotizing granulomas have a distinct central necrosis with a surrounding lymphohistiocytic reaction with peripheral chronic inflammation.¹⁰

Sweet syndrome is another mimicker of cutaneous cryptococcosis. A histologic variant of Sweet syndrome has been reported that has characteristic cutaneous lesions clinically but shows basophilic bodies with a surrounding halo on pathology that can be mistaken for Cryptococcus yeast. Classic histopathology of Sweet syndrome features papillary dermal edema with neutrophil or histiocytelike inflammatory infiltrate (Figure 4). Identification of Sweet syndrome can be aided by positive myeloperoxidase staining and negative periodic acid–Schiff staining.^14,15

THE DIAGNOSIS: Cutaneous Cryptococcosis

Biopsy of the ulcerated nodule showed numerous yeastlike organisms within clear mucinous capsules and with some surrounding inflammation. On Grocott methenamine silver staining, the organisms stained black. Workup for disseminated cryptococcus was negative, leading to a diagnosis of primary cutaneous cryptococcosis in the setting of immunosuppression. Notably, cryptococcosis infection has been reported in patients taking fingolimod (a sphingosine-1-phosphate receptor) for multiple sclerosis, which was the case for our patient.¹

The genus Cryptococcus comprises more than 30 species of encapsulated basidiomycetous fungi distributed ubiquitously in nature. Currently, only 2 species are known to cause infectious disease in humans: Cryptococcus neoformans, which affects both immunocompromised and immunocompetent patients and frequently is isolated from pigeon droppings, as well as Cryptococcus gatti, which primarily affects immunocompetent patients and is more commonly isolated from soil and decaying wood.²

Primary cutaneous cryptococcosis (PCC), characterized by direct inoculation of C neoformans or C gatti via skin injury, is rare and typically is seen in patients with decreased cell-mediated immunity, such as those on chronic corticosteroid therapy, solid-organ transplant recipients, and those with HIV.³ Primary cutaneous cryptococcosis typically manifests as a solitary or confined lesion on exposed areas of the skin and often is accompanied by regional lymphadenopathy.^4,5 The most common cutaneous findings associated with PCC include ulceration, cellulitis, and whitlow.⁵ In immunocompetent hosts, frequently affected sites include the arms, fingers, and face, while the trunk and lower extremities are more commonly affected in immunocompromised hosts.³ Secondary cutaneous cryptococcosis occurs through hematologic spread in patients with disseminated cryptococcosis after inhalation of Cryptococcosis spores and differs from PCC in that it typically manifests as multiple lesions scattered on both exposed and covered areas of the skin. Patients also may have signs and symptoms of disseminated cryptococcosis such as pneumonia and/or meningitis at presentation.⁵

Despite the difference between PCC and secondary cutaneous cryptococcosis, almost every type of skin lesion has been observed in cryptococcosis, including pustules, nodules, vesicles, acneform lesions, purpura, ulcers, abscesses, molluscumlike lesions, granulomas, draining sinuses, and cellulitis.^6,7

Cutaneous cryptococcosis generally is associated with 2 types of histologic reactions: gelatinous and granulomatous. The gelatinous reaction shows numerous yeastlike organisms ranging from 4 μm to 12 μm in diameter with large mucinous polysaccharide capsules and scant inflammation. Organisms may be seen in mucoid sheets.⁸ The granulomatous type shows a more pronounced reaction with fewer organisms ranging from 2 μm to 4 μm in diameter found within giant cells, histiocytes, and lymphocytes.^6,9 Areas of necrosis occasionally can be observed.⁸

It is important to consider infection with Blastomyces dermatitidis and Histoplasma capsulatum in the differential Both entities can manifest as necrotizing granulomas on histology (Figures 1 and 2).¹⁰ Microscopic morphology can help differentiate these pathogenic fungi from Cryptococcus diagnosis of cryptococcosis. species which show pleomorphic, narrow-based budding yeast with wide capsules. In contrast, H capsulatum is characterized by small, intracellular, yeastlike cells with microconidia and macroconidia, while B dermatitidis is distinguished by spherical, thick-walled cells with broad-based budding.¹¹ Capsular material also can help distinguish Cryptococcus from other pathogenic fungi. Special stains highlighting the polysaccharide capsule of Cryptococcus can best identify the yeast. The capsule stains red with periodic acid–Schiff, blue with Alcian blue, and black with Grocott methenamine silver. Mucicarmine is especially useful as it can stain the mucinous capsule pinkish red and typically does not stain other pathogenic fungi.¹² Capsule-deficient organisms can lead to considerable difficulties in diagnosis given the organisms can vary in size and may mimic H capsulatum or B dermatitidis. The Fontana-Masson stain is a valuable tool in identifying capsule-deficient organisms, as melanin is found in Cryptococcus cell walls; thus, positive staining excludes H capsulatum and B dermatitidis.¹³

Cutaneous foreign body granuloma, which refers to a granulomatous inflammatory reaction to a foreign body in the skin, is another differential diagnosis that is important to distinguish from cutaneous cryptococcosis. On histology, a collection of histiocytes surround the inert material, forming giant cells without an immune response (Figure 3).¹⁰ In contrast, granulomas caused by infectious etiologies (eg, Cryptococcus species) have an associated adaptive immune response and can be further classified as necrotizing or non-necrotizing. Necrotizing granulomas have a distinct central necrosis with a surrounding lymphohistiocytic reaction with peripheral chronic inflammation.¹⁰

Sweet syndrome is another mimicker of cutaneous cryptococcosis. A histologic variant of Sweet syndrome has been reported that has characteristic cutaneous lesions clinically but shows basophilic bodies with a surrounding halo on pathology that can be mistaken for Cryptococcus yeast. Classic histopathology of Sweet syndrome features papillary dermal edema with neutrophil or histiocytelike inflammatory infiltrate (Figure 4). Identification of Sweet syndrome can be aided by positive myeloperoxidase staining and negative periodic acid–Schiff staining.^14,15