Dermpath Diagnosis

The Diagnosis: Pleomorphic Lipoma

Pleomorphic lipoma is a rare, benign, adipocytic neoplasm that presents in the subcutaneous tissues of the upper shoulder, back, or neck. It predominantly affects men aged 50 to 70 years. Most lesions are situated in the subcutaneous tissues; few cases of intramuscular and retroperitoneal tumors have been reported.¹ Clinically, pleomorphic lipomas present as painless, well-circumscribed lesions of the subcutaneous tissue that often resemble a lipoma or occasionally may be mistaken for liposarcoma. Histopathologic examination of ordinary lipomas reveals uniform mature adipocytes. However, pleomorphic lipomas consist of a mixture of multinucleated floretlike giant cells, variable-sized adipocytes, and fibrous tissue (ropy collagen bundles) with some myxoid and spindled areas.^1,2 The most characteristic histologic feature of pleomorphic lipoma is multinucleated floretlike giant cells. The nuclei of these giant cells appear hyperchromatic, enlarged, and disposed to the periphery of the cell in a circular pattern. Additionally, tumors frequently contain excess mature dense collagen bundles that are strongly refractile in polarized light. Numerous mast cells are present. Atypical lipoblasts and capillary networks commonly are not visible in pleomorphic lipoma.³ The spindle cells express CD34 on immunohistochemistry. Loss of Rb-1 expression is typical.⁴

Dermatofibrosarcoma protuberans is a slow-growing soft tissue sarcoma that commonly begins as a pink or violet plaque on the trunk or upper limbs. Involvement of the head or neck accounts for only 10% to 15% of cases.⁵ This tumor has low metastatic potential but is highly infiltrative of surrounding tissues. It is associated with a translocation between chromosomes 22 and 17, leading to the fusion of the platelet-derived growth factor subunit β, PDGFB, and collagen type 1α1, COL1A1, genes.⁵ Clinically, patients often report that the lesion was present for several years prior to presentation with general stability in size and shape. Eventually, untreated lesions progress to become nodules or tumors and may even bleed or ulcerate. Histology reveals a storiform spindle cell proliferation throughout the dermis with infiltration into subcutaneous fat, commonly appearing in a honeycomblike pattern (Figure 1). Numerous histologic variants exist, including myxoid, sclerosing, pigmented (Bednar tumor), myoid, atrophic, or fibrosarcomatous dermatofibrosarcoma protuberans, as well as a giant cell fibroblastoma variant.⁶ These tumor subtypes can exist independently or in association with one another, creating hybrid lesions that can closely mimic other entities such as pleomorphic lipoma. The spindle cells stain positively for CD34. Treatment of these tumors involves complete surgical excision or Mohs micrographic surgery; however, recurrence is common for tumors involving the head or neck.⁵

Superficial angiomyxoma is a slow-growing papule that most commonly appears on the trunk, head, or neck in middle-aged adults. Occasionally, patients with Carney complex also can develop lesions on the external ear or breast.⁷ Histologically, superficial angiomyxoma is a hypocellular tumor characterized by abundant myxoid stroma, thin blood vessels, and small spindled and stellate cells with minimal cytoplasm (Figure 2).⁸ Superficial angiomyxoma and pleomorphic lipoma present differently on histology; superficial angiomyxoma is not associated with nuclear atypia or pleomorphism, whereas pleomorphic lipoma characteristically contains multinucleated floretlike giant cells and pleomorphism. Frequently, there also is loss of normal PRKAR1A gene expression, which is responsible for protein kinase A regulatory subunit 1-alpha expression.⁸

Multinucleate cell angiohistiocytoma is a rare benign proliferation that presents with numerous red-violet asymptomatic papules that commonly appear on the upper and lower extremities of women aged 40 to 70 years. Lesions feature both a fibrohistiocytic and vascular component.9 Histologic examination commonly shows multinucleated cells with angular outlining in the superficial dermis accompanied by fibrosis and ectatic small-caliber vessels (Figure 3). Although both pleomorphic lipoma and multinucleate cell angiohistiocytoma have similar-appearing multinucleated giant cells, the latter has a proliferation of narrow vessels in thick collagen bundles and lacks an adipocytic component, which distinguishes it from the former.¹⁰ Multinucleate cell angiohistiocytoma also is characterized by a substantial number of factor XIIIa–positive fibrohistiocytic interstitial cells and vascular hyperplasia.⁹

Nodular fasciitis is a benign lesion involving the rapid proliferation of myofibroblasts and fibroblasts in the subcutaneous tissue and most commonly is encountered on the extremities or head and neck regions. Many cases appear at sites of prior trauma, especially in patients aged 20 to 40 years. However, in infants and children the lesions typically are found in the head and neck regions.¹¹ Clinically, lesions present as subcutaneous nodules. Histology reveals an infiltrative and poorly circumscribed proliferation of spindled myofibroblasts associated with myxoid stroma and dense collagen depositions. The spindled cells are loosely associated, rendering a tissue culture–like appearance (Figure 4). It also is common to see erythrocyte extravasation adjacent to myxoid stroma.¹¹ Positive stains include vimentin, smooth muscle actin, and CD68, though immunohistochemistry often is not necessary for diagnosis.¹² There often is abundant mitotic activity in nodular fasciitis, especially in early lesions, and the differential diagnosis includes sarcoma. Although nodular fasciitis is mitotically active, it does not show atypical mitotic figures. Nodular fasciitis commonly harbors a gene translocation of the MYH9 gene’s promoter region to the USP6 gene’s coding region.¹³

The Diagnosis: Pleomorphic Lipoma

Pleomorphic lipoma is a rare, benign, adipocytic neoplasm that presents in the subcutaneous tissues of the upper shoulder, back, or neck. It predominantly affects men aged 50 to 70 years. Most lesions are situated in the subcutaneous tissues; few cases of intramuscular and retroperitoneal tumors have been reported.¹ Clinically, pleomorphic lipomas present as painless, well-circumscribed lesions of the subcutaneous tissue that often resemble a lipoma or occasionally may be mistaken for liposarcoma. Histopathologic examination of ordinary lipomas reveals uniform mature adipocytes. However, pleomorphic lipomas consist of a mixture of multinucleated floretlike giant cells, variable-sized adipocytes, and fibrous tissue (ropy collagen bundles) with some myxoid and spindled areas.^1,2 The most characteristic histologic feature of pleomorphic lipoma is multinucleated floretlike giant cells. The nuclei of these giant cells appear hyperchromatic, enlarged, and disposed to the periphery of the cell in a circular pattern. Additionally, tumors frequently contain excess mature dense collagen bundles that are strongly refractile in polarized light. Numerous mast cells are present. Atypical lipoblasts and capillary networks commonly are not visible in pleomorphic lipoma.³ The spindle cells express CD34 on immunohistochemistry. Loss of Rb-1 expression is typical.⁴

Dermatofibrosarcoma protuberans is a slow-growing soft tissue sarcoma that commonly begins as a pink or violet plaque on the trunk or upper limbs. Involvement of the head or neck accounts for only 10% to 15% of cases.⁵ This tumor has low metastatic potential but is highly infiltrative of surrounding tissues. It is associated with a translocation between chromosomes 22 and 17, leading to the fusion of the platelet-derived growth factor subunit β, PDGFB, and collagen type 1α1, COL1A1, genes.⁵ Clinically, patients often report that the lesion was present for several years prior to presentation with general stability in size and shape. Eventually, untreated lesions progress to become nodules or tumors and may even bleed or ulcerate. Histology reveals a storiform spindle cell proliferation throughout the dermis with infiltration into subcutaneous fat, commonly appearing in a honeycomblike pattern (Figure 1). Numerous histologic variants exist, including myxoid, sclerosing, pigmented (Bednar tumor), myoid, atrophic, or fibrosarcomatous dermatofibrosarcoma protuberans, as well as a giant cell fibroblastoma variant.⁶ These tumor subtypes can exist independently or in association with one another, creating hybrid lesions that can closely mimic other entities such as pleomorphic lipoma. The spindle cells stain positively for CD34. Treatment of these tumors involves complete surgical excision or Mohs micrographic surgery; however, recurrence is common for tumors involving the head or neck.⁵

Superficial angiomyxoma is a slow-growing papule that most commonly appears on the trunk, head, or neck in middle-aged adults. Occasionally, patients with Carney complex also can develop lesions on the external ear or breast.⁷ Histologically, superficial angiomyxoma is a hypocellular tumor characterized by abundant myxoid stroma, thin blood vessels, and small spindled and stellate cells with minimal cytoplasm (Figure 2).⁸ Superficial angiomyxoma and pleomorphic lipoma present differently on histology; superficial angiomyxoma is not associated with nuclear atypia or pleomorphism, whereas pleomorphic lipoma characteristically contains multinucleated floretlike giant cells and pleomorphism. Frequently, there also is loss of normal PRKAR1A gene expression, which is responsible for protein kinase A regulatory subunit 1-alpha expression.⁸

Multinucleate cell angiohistiocytoma is a rare benign proliferation that presents with numerous red-violet asymptomatic papules that commonly appear on the upper and lower extremities of women aged 40 to 70 years. Lesions feature both a fibrohistiocytic and vascular component.9 Histologic examination commonly shows multinucleated cells with angular outlining in the superficial dermis accompanied by fibrosis and ectatic small-caliber vessels (Figure 3). Although both pleomorphic lipoma and multinucleate cell angiohistiocytoma have similar-appearing multinucleated giant cells, the latter has a proliferation of narrow vessels in thick collagen bundles and lacks an adipocytic component, which distinguishes it from the former.¹⁰ Multinucleate cell angiohistiocytoma also is characterized by a substantial number of factor XIIIa–positive fibrohistiocytic interstitial cells and vascular hyperplasia.⁹

Nodular fasciitis is a benign lesion involving the rapid proliferation of myofibroblasts and fibroblasts in the subcutaneous tissue and most commonly is encountered on the extremities or head and neck regions. Many cases appear at sites of prior trauma, especially in patients aged 20 to 40 years. However, in infants and children the lesions typically are found in the head and neck regions.¹¹ Clinically, lesions present as subcutaneous nodules. Histology reveals an infiltrative and poorly circumscribed proliferation of spindled myofibroblasts associated with myxoid stroma and dense collagen depositions. The spindled cells are loosely associated, rendering a tissue culture–like appearance (Figure 4). It also is common to see erythrocyte extravasation adjacent to myxoid stroma.¹¹ Positive stains include vimentin, smooth muscle actin, and CD68, though immunohistochemistry often is not necessary for diagnosis.¹² There often is abundant mitotic activity in nodular fasciitis, especially in early lesions, and the differential diagnosis includes sarcoma. Although nodular fasciitis is mitotically active, it does not show atypical mitotic figures. Nodular fasciitis commonly harbors a gene translocation of the MYH9 gene’s promoter region to the USP6 gene’s coding region.¹³

The Diagnosis: Pleomorphic Lipoma

Pleomorphic lipoma is a rare, benign, adipocytic neoplasm that presents in the subcutaneous tissues of the upper shoulder, back, or neck. It predominantly affects men aged 50 to 70 years. Most lesions are situated in the subcutaneous tissues; few cases of intramuscular and retroperitoneal tumors have been reported.¹ Clinically, pleomorphic lipomas present as painless, well-circumscribed lesions of the subcutaneous tissue that often resemble a lipoma or occasionally may be mistaken for liposarcoma. Histopathologic examination of ordinary lipomas reveals uniform mature adipocytes. However, pleomorphic lipomas consist of a mixture of multinucleated floretlike giant cells, variable-sized adipocytes, and fibrous tissue (ropy collagen bundles) with some myxoid and spindled areas.^1,2 The most characteristic histologic feature of pleomorphic lipoma is multinucleated floretlike giant cells. The nuclei of these giant cells appear hyperchromatic, enlarged, and disposed to the periphery of the cell in a circular pattern. Additionally, tumors frequently contain excess mature dense collagen bundles that are strongly refractile in polarized light. Numerous mast cells are present. Atypical lipoblasts and capillary networks commonly are not visible in pleomorphic lipoma.³ The spindle cells express CD34 on immunohistochemistry. Loss of Rb-1 expression is typical.⁴

Dermatofibrosarcoma protuberans is a slow-growing soft tissue sarcoma that commonly begins as a pink or violet plaque on the trunk or upper limbs. Involvement of the head or neck accounts for only 10% to 15% of cases.⁵ This tumor has low metastatic potential but is highly infiltrative of surrounding tissues. It is associated with a translocation between chromosomes 22 and 17, leading to the fusion of the platelet-derived growth factor subunit β, PDGFB, and collagen type 1α1, COL1A1, genes.⁵ Clinically, patients often report that the lesion was present for several years prior to presentation with general stability in size and shape. Eventually, untreated lesions progress to become nodules or tumors and may even bleed or ulcerate. Histology reveals a storiform spindle cell proliferation throughout the dermis with infiltration into subcutaneous fat, commonly appearing in a honeycomblike pattern (Figure 1). Numerous histologic variants exist, including myxoid, sclerosing, pigmented (Bednar tumor), myoid, atrophic, or fibrosarcomatous dermatofibrosarcoma protuberans, as well as a giant cell fibroblastoma variant.⁶ These tumor subtypes can exist independently or in association with one another, creating hybrid lesions that can closely mimic other entities such as pleomorphic lipoma. The spindle cells stain positively for CD34. Treatment of these tumors involves complete surgical excision or Mohs micrographic surgery; however, recurrence is common for tumors involving the head or neck.⁵

Superficial angiomyxoma is a slow-growing papule that most commonly appears on the trunk, head, or neck in middle-aged adults. Occasionally, patients with Carney complex also can develop lesions on the external ear or breast.⁷ Histologically, superficial angiomyxoma is a hypocellular tumor characterized by abundant myxoid stroma, thin blood vessels, and small spindled and stellate cells with minimal cytoplasm (Figure 2).⁸ Superficial angiomyxoma and pleomorphic lipoma present differently on histology; superficial angiomyxoma is not associated with nuclear atypia or pleomorphism, whereas pleomorphic lipoma characteristically contains multinucleated floretlike giant cells and pleomorphism. Frequently, there also is loss of normal PRKAR1A gene expression, which is responsible for protein kinase A regulatory subunit 1-alpha expression.⁸

Multinucleate cell angiohistiocytoma is a rare benign proliferation that presents with numerous red-violet asymptomatic papules that commonly appear on the upper and lower extremities of women aged 40 to 70 years. Lesions feature both a fibrohistiocytic and vascular component.9 Histologic examination commonly shows multinucleated cells with angular outlining in the superficial dermis accompanied by fibrosis and ectatic small-caliber vessels (Figure 3). Although both pleomorphic lipoma and multinucleate cell angiohistiocytoma have similar-appearing multinucleated giant cells, the latter has a proliferation of narrow vessels in thick collagen bundles and lacks an adipocytic component, which distinguishes it from the former.¹⁰ Multinucleate cell angiohistiocytoma also is characterized by a substantial number of factor XIIIa–positive fibrohistiocytic interstitial cells and vascular hyperplasia.⁹

Nodular fasciitis is a benign lesion involving the rapid proliferation of myofibroblasts and fibroblasts in the subcutaneous tissue and most commonly is encountered on the extremities or head and neck regions. Many cases appear at sites of prior trauma, especially in patients aged 20 to 40 years. However, in infants and children the lesions typically are found in the head and neck regions.¹¹ Clinically, lesions present as subcutaneous nodules. Histology reveals an infiltrative and poorly circumscribed proliferation of spindled myofibroblasts associated with myxoid stroma and dense collagen depositions. The spindled cells are loosely associated, rendering a tissue culture–like appearance (Figure 4). It also is common to see erythrocyte extravasation adjacent to myxoid stroma.¹¹ Positive stains include vimentin, smooth muscle actin, and CD68, though immunohistochemistry often is not necessary for diagnosis.¹² There often is abundant mitotic activity in nodular fasciitis, especially in early lesions, and the differential diagnosis includes sarcoma. Although nodular fasciitis is mitotically active, it does not show atypical mitotic figures. Nodular fasciitis commonly harbors a gene translocation of the MYH9 gene’s promoter region to the USP6 gene’s coding region.¹³

The Diagnosis: Lichen Planus Pemphigoides

Lichen planus pemphigoides (LPP) is a rare acquired autoimmune blistering disorder with an estimated worldwide prevalence of approximately 1 in 1,000,000 individuals.¹ It often manifests with overlapping features of both LP and bullous pemphigoid (BP). The condition usually presents in the fifth decade of life and has a slight female predominance.² Although primarily idiopathic, it has been associated with certain medications and treatments, such as angiotensin-converting enzyme inhibitors, programmed cell death protein 1 inhibitors, programmed cell death ligand 1 inhibitors, labetalol, narrowband UVB, and psoralen plus UVA.^3,4

Patients initially present with lesions of classic lichen planus (LP) with pink-purple, flat-topped, pruritic, polygonal papules and plaques.⁵ After weeks to months, tense vesicles and bullae usually develop on the sites of LP as well as on uninvolved skin. One study found a mean lag time of about 8.3 months for blistering to present after LP,⁵ but concurrent presentations of both have been reported.¹ In addition, oral mucosal involvement has been seen in 36% of cases. The most commonly affected sites are the extremities; however, involvement can be widespread.²

The pathogenesis of LPP currently is unknown. It has been proposed that in LP, injury of basal keratinocytes exposes hidden basement membrane and hemidesmosome antigens including BP180, a 180 kDa transmembrane protein of the basement membrane zone (BMZ),⁶ which triggers an immune response where T cells recognize the extracellular portion of BP180 and antibodies are formed against the likely autoantigen.1 One study has suggested that the autoantigen in LPP is the MCW-4 epitope within the C-terminal end of the NC16A domain of BP180.⁷

Histopathology of LPP reveals characteristics of both LP as well as BP. Typical features of LP on hematoxylin and eosin (H&E) staining include lichenoid lymphocytic interface dermatitis, sawtooth rete ridges, wedge-shaped hypergranulosis, and colloid bodies, as demonstrated from the biopsy of our patient’s gluteal cleft lesion (quiz image 1), while the predominant feature of BP on H&E staining includes a subepidermal bulla with eosinophils.² Typically, direct immunofluorescence (DIF) shows linear deposits of IgG and/or C3 along the BMZ. Indirect immunofluorescence (IIF) often reveals IgG against the roof of the BMZ in a human split-skin substrate.¹ Antibodies against BP180 or uncommonly BP230 often are detected on enzyme-linked immunosorbent assay (ELISA). For our patient, IIF and ELISA tests were positive. Given the clinical presentation with recurrent oral and gluteal cleft erosions, histologic findings, and the results of our patient’s immunological testing, the diagnosis of LPP was made.

Topical steroids often are used to treat localized disease of LPP.8 Oral prednisone also may be given for widespread or unresponsive disease.⁹ Other treatments include azathioprine, mycophenolate mofetil, hydroxychloroquine, dapsone, tetracycline in combination with nicotinamide, acitretin, ustekinumab, baricitinib, and rituximab with intravenous immunoglobulin.^3,8,10-12 Any potential medication culprits should be discontinued.⁹ Patients with oral involvement may require a soft diet to avoid further mucosal insult.¹⁰ Additionally, providers should consider dentistry, ophthalmology, and/or otolaryngology referrals depending on disease severity.

Bullous pemphigoid, the most common autoimmune blistering disease, has an estimated incidence of 10 to 43 per million individuals per year.² Classically, it presents with tense bullae on the skin of the lower abdomen, thighs, groin, forearms, and axillae. Circulating antibodies against 2 BMZ proteins—BP180 and BP230—are important factors in BP pathogenesis.² Diagnosis of BP is based on clinical features, histologic findings, and immunological studies including DIF, IIF, and ELISA. An eosinophil-rich subepidermal split typically is seen on H&E staining (Figure 1).

Direct immunofluorescence displays linear IgG and/ or C3 staining at the BMZ. Indirect immunofluorescence on a human salt-split skin substrate commonly shows linear BMZ deposition on the roof of the blister.² Indirect immunofluorescence for IgG deposition on monkey esophagus substrate shows linear BMZ deposition. Antibodies against the NC16A domain of BP180 (NC16A-BP180) are dominant, but BP230 antibodies against BP230 also are detected with ELISA.² Further studies have indicated that the NC16A epitopes of BP180 that are targeted in BP are MCW-0-3,² different from the autoantigen MCW-4 that is targeted in LPP.⁷

Paraneoplastic pemphigus (PNP) is another diagnosis to consider. Patients with PNP initially present with oral findings—most commonly chronic, erosive, and painful mucositis—followed by cutaneous involvement, which varies from the development of bullae to the formation of plaques similar to those of LP.¹³ The latter, in combination with oral erosions, may appear clinically similar to LPP. The results of DIF in conjugation with IIF and ELISA may help to further differentiate these disorders. Direct immunofluorescence in PNP typically reveals positive intercellular and/or BMZ IgG and C3, while DIF in LPP reveals depositions along the BMZ alone. Indirect immunofluorescence performed on rat bladder epithelium is particularly useful, as binding of IgG to rat bladder epithelium is characteristic of PNP and not seen in other disorders.¹⁴ Lastly, patients with PNP may develop IgG antibodies to various antigens such as desmoplakin I, desmoplakin II, envoplakin, periplakin, BP230, desmoglein 1, and desmoglein 3, which would not be expected in LPP patients.¹⁵ Hematoxylin and eosin staining differs from LPP, primarily with the location of the blister being intraepidermal. Acantholysis with hemorrhagic bullae can be seen (Figure 2).

Classic LP is an inflammatory disorder that mainly affects adults, with an estimated incidence of less than 1%.¹⁶ The classic form presents with purple, flat-topped, pruritic, polygonal papules and plaques of varying size that often are characterized by Wickham striae. Lichen planus possesses a broad spectrum of subtypes involving different locations, though skin lesions usually are localized to the extremities. Despite an unknown etiology, activated T cells and T helper type 1 cytokines are considered key in keratinocyte injury. Compact orthokeratosis, wedge-shaped hypergranulosis, focal dyskeratosis, and colloid bodies typically are found on H&E staining, along with a dense bandlike lymphohistiocytic infiltrate at the dermoepidermal junction (DEJ)(Figure 3). Direct immunofluorescence typically shows a shaggy band of fibrinogen along the DEJ in addition to colloid bodies that stain with various autoantibodies including IgM, IgG, IgA, and C3.¹⁶

Bullous LP is a rare variant of LP that commonly develops on the oral mucosa and the legs, with blisters confined on pre-existing LP lesions.⁹ The pathogenesis is related to an epidermal inflammatory infiltrate that leads to basal layer destruction followed by dermal-epidermal separations that cause blistering.¹⁷ Bullous LP does not have positive DIF, IIF, or ELISA because the pathophysiology does not involve autoantibody production. Histopathology typically displays an extensive inflammatory infiltrate and degeneration of the basal keratinocytes, resulting in large dermal-epidermal separations called Max-Joseph spaces (Figure 4).¹⁷ Colloid bodies are prominent in bullous LP but rarely are seen in LPP; eosinophils also are much more prominent in LPP compared to bullous LP.¹⁸ Unlike in LPP, DIF usually is negative in bullous LP, though lichenoid lesions may exhibit globular deposition of IgM, IgG, and IgA in the colloid bodies of the lower epidermis and/or papillary dermis. Similar to LP, DIF of the biopsy specimen shows linear or shaggy deposits of fibrinogen at the DEJ.¹⁷

The Diagnosis: Lichen Planus Pemphigoides

Lichen planus pemphigoides (LPP) is a rare acquired autoimmune blistering disorder with an estimated worldwide prevalence of approximately 1 in 1,000,000 individuals.¹ It often manifests with overlapping features of both LP and bullous pemphigoid (BP). The condition usually presents in the fifth decade of life and has a slight female predominance.² Although primarily idiopathic, it has been associated with certain medications and treatments, such as angiotensin-converting enzyme inhibitors, programmed cell death protein 1 inhibitors, programmed cell death ligand 1 inhibitors, labetalol, narrowband UVB, and psoralen plus UVA.^3,4

Patients initially present with lesions of classic lichen planus (LP) with pink-purple, flat-topped, pruritic, polygonal papules and plaques.⁵ After weeks to months, tense vesicles and bullae usually develop on the sites of LP as well as on uninvolved skin. One study found a mean lag time of about 8.3 months for blistering to present after LP,⁵ but concurrent presentations of both have been reported.¹ In addition, oral mucosal involvement has been seen in 36% of cases. The most commonly affected sites are the extremities; however, involvement can be widespread.²

The pathogenesis of LPP currently is unknown. It has been proposed that in LP, injury of basal keratinocytes exposes hidden basement membrane and hemidesmosome antigens including BP180, a 180 kDa transmembrane protein of the basement membrane zone (BMZ),⁶ which triggers an immune response where T cells recognize the extracellular portion of BP180 and antibodies are formed against the likely autoantigen.1 One study has suggested that the autoantigen in LPP is the MCW-4 epitope within the C-terminal end of the NC16A domain of BP180.⁷

Histopathology of LPP reveals characteristics of both LP as well as BP. Typical features of LP on hematoxylin and eosin (H&E) staining include lichenoid lymphocytic interface dermatitis, sawtooth rete ridges, wedge-shaped hypergranulosis, and colloid bodies, as demonstrated from the biopsy of our patient’s gluteal cleft lesion (quiz image 1), while the predominant feature of BP on H&E staining includes a subepidermal bulla with eosinophils.² Typically, direct immunofluorescence (DIF) shows linear deposits of IgG and/or C3 along the BMZ. Indirect immunofluorescence (IIF) often reveals IgG against the roof of the BMZ in a human split-skin substrate.¹ Antibodies against BP180 or uncommonly BP230 often are detected on enzyme-linked immunosorbent assay (ELISA). For our patient, IIF and ELISA tests were positive. Given the clinical presentation with recurrent oral and gluteal cleft erosions, histologic findings, and the results of our patient’s immunological testing, the diagnosis of LPP was made.

Topical steroids often are used to treat localized disease of LPP.8 Oral prednisone also may be given for widespread or unresponsive disease.⁹ Other treatments include azathioprine, mycophenolate mofetil, hydroxychloroquine, dapsone, tetracycline in combination with nicotinamide, acitretin, ustekinumab, baricitinib, and rituximab with intravenous immunoglobulin.^3,8,10-12 Any potential medication culprits should be discontinued.⁹ Patients with oral involvement may require a soft diet to avoid further mucosal insult.¹⁰ Additionally, providers should consider dentistry, ophthalmology, and/or otolaryngology referrals depending on disease severity.

Bullous pemphigoid, the most common autoimmune blistering disease, has an estimated incidence of 10 to 43 per million individuals per year.² Classically, it presents with tense bullae on the skin of the lower abdomen, thighs, groin, forearms, and axillae. Circulating antibodies against 2 BMZ proteins—BP180 and BP230—are important factors in BP pathogenesis.² Diagnosis of BP is based on clinical features, histologic findings, and immunological studies including DIF, IIF, and ELISA. An eosinophil-rich subepidermal split typically is seen on H&E staining (Figure 1).

Direct immunofluorescence displays linear IgG and/ or C3 staining at the BMZ. Indirect immunofluorescence on a human salt-split skin substrate commonly shows linear BMZ deposition on the roof of the blister.² Indirect immunofluorescence for IgG deposition on monkey esophagus substrate shows linear BMZ deposition. Antibodies against the NC16A domain of BP180 (NC16A-BP180) are dominant, but BP230 antibodies against BP230 also are detected with ELISA.² Further studies have indicated that the NC16A epitopes of BP180 that are targeted in BP are MCW-0-3,² different from the autoantigen MCW-4 that is targeted in LPP.⁷

Paraneoplastic pemphigus (PNP) is another diagnosis to consider. Patients with PNP initially present with oral findings—most commonly chronic, erosive, and painful mucositis—followed by cutaneous involvement, which varies from the development of bullae to the formation of plaques similar to those of LP.¹³ The latter, in combination with oral erosions, may appear clinically similar to LPP. The results of DIF in conjugation with IIF and ELISA may help to further differentiate these disorders. Direct immunofluorescence in PNP typically reveals positive intercellular and/or BMZ IgG and C3, while DIF in LPP reveals depositions along the BMZ alone. Indirect immunofluorescence performed on rat bladder epithelium is particularly useful, as binding of IgG to rat bladder epithelium is characteristic of PNP and not seen in other disorders.¹⁴ Lastly, patients with PNP may develop IgG antibodies to various antigens such as desmoplakin I, desmoplakin II, envoplakin, periplakin, BP230, desmoglein 1, and desmoglein 3, which would not be expected in LPP patients.¹⁵ Hematoxylin and eosin staining differs from LPP, primarily with the location of the blister being intraepidermal. Acantholysis with hemorrhagic bullae can be seen (Figure 2).

Classic LP is an inflammatory disorder that mainly affects adults, with an estimated incidence of less than 1%.¹⁶ The classic form presents with purple, flat-topped, pruritic, polygonal papules and plaques of varying size that often are characterized by Wickham striae. Lichen planus possesses a broad spectrum of subtypes involving different locations, though skin lesions usually are localized to the extremities. Despite an unknown etiology, activated T cells and T helper type 1 cytokines are considered key in keratinocyte injury. Compact orthokeratosis, wedge-shaped hypergranulosis, focal dyskeratosis, and colloid bodies typically are found on H&E staining, along with a dense bandlike lymphohistiocytic infiltrate at the dermoepidermal junction (DEJ)(Figure 3). Direct immunofluorescence typically shows a shaggy band of fibrinogen along the DEJ in addition to colloid bodies that stain with various autoantibodies including IgM, IgG, IgA, and C3.¹⁶

Bullous LP is a rare variant of LP that commonly develops on the oral mucosa and the legs, with blisters confined on pre-existing LP lesions.⁹ The pathogenesis is related to an epidermal inflammatory infiltrate that leads to basal layer destruction followed by dermal-epidermal separations that cause blistering.¹⁷ Bullous LP does not have positive DIF, IIF, or ELISA because the pathophysiology does not involve autoantibody production. Histopathology typically displays an extensive inflammatory infiltrate and degeneration of the basal keratinocytes, resulting in large dermal-epidermal separations called Max-Joseph spaces (Figure 4).¹⁷ Colloid bodies are prominent in bullous LP but rarely are seen in LPP; eosinophils also are much more prominent in LPP compared to bullous LP.¹⁸ Unlike in LPP, DIF usually is negative in bullous LP, though lichenoid lesions may exhibit globular deposition of IgM, IgG, and IgA in the colloid bodies of the lower epidermis and/or papillary dermis. Similar to LP, DIF of the biopsy specimen shows linear or shaggy deposits of fibrinogen at the DEJ.¹⁷

The Diagnosis: Lichen Planus Pemphigoides

Lichen planus pemphigoides (LPP) is a rare acquired autoimmune blistering disorder with an estimated worldwide prevalence of approximately 1 in 1,000,000 individuals.¹ It often manifests with overlapping features of both LP and bullous pemphigoid (BP). The condition usually presents in the fifth decade of life and has a slight female predominance.² Although primarily idiopathic, it has been associated with certain medications and treatments, such as angiotensin-converting enzyme inhibitors, programmed cell death protein 1 inhibitors, programmed cell death ligand 1 inhibitors, labetalol, narrowband UVB, and psoralen plus UVA.^3,4

Patients initially present with lesions of classic lichen planus (LP) with pink-purple, flat-topped, pruritic, polygonal papules and plaques.⁵ After weeks to months, tense vesicles and bullae usually develop on the sites of LP as well as on uninvolved skin. One study found a mean lag time of about 8.3 months for blistering to present after LP,⁵ but concurrent presentations of both have been reported.¹ In addition, oral mucosal involvement has been seen in 36% of cases. The most commonly affected sites are the extremities; however, involvement can be widespread.²

The pathogenesis of LPP currently is unknown. It has been proposed that in LP, injury of basal keratinocytes exposes hidden basement membrane and hemidesmosome antigens including BP180, a 180 kDa transmembrane protein of the basement membrane zone (BMZ),⁶ which triggers an immune response where T cells recognize the extracellular portion of BP180 and antibodies are formed against the likely autoantigen.1 One study has suggested that the autoantigen in LPP is the MCW-4 epitope within the C-terminal end of the NC16A domain of BP180.⁷

Histopathology of LPP reveals characteristics of both LP as well as BP. Typical features of LP on hematoxylin and eosin (H&E) staining include lichenoid lymphocytic interface dermatitis, sawtooth rete ridges, wedge-shaped hypergranulosis, and colloid bodies, as demonstrated from the biopsy of our patient’s gluteal cleft lesion (quiz image 1), while the predominant feature of BP on H&E staining includes a subepidermal bulla with eosinophils.² Typically, direct immunofluorescence (DIF) shows linear deposits of IgG and/or C3 along the BMZ. Indirect immunofluorescence (IIF) often reveals IgG against the roof of the BMZ in a human split-skin substrate.¹ Antibodies against BP180 or uncommonly BP230 often are detected on enzyme-linked immunosorbent assay (ELISA). For our patient, IIF and ELISA tests were positive. Given the clinical presentation with recurrent oral and gluteal cleft erosions, histologic findings, and the results of our patient’s immunological testing, the diagnosis of LPP was made.

Topical steroids often are used to treat localized disease of LPP.8 Oral prednisone also may be given for widespread or unresponsive disease.⁹ Other treatments include azathioprine, mycophenolate mofetil, hydroxychloroquine, dapsone, tetracycline in combination with nicotinamide, acitretin, ustekinumab, baricitinib, and rituximab with intravenous immunoglobulin.^3,8,10-12 Any potential medication culprits should be discontinued.⁹ Patients with oral involvement may require a soft diet to avoid further mucosal insult.¹⁰ Additionally, providers should consider dentistry, ophthalmology, and/or otolaryngology referrals depending on disease severity.

Bullous pemphigoid, the most common autoimmune blistering disease, has an estimated incidence of 10 to 43 per million individuals per year.² Classically, it presents with tense bullae on the skin of the lower abdomen, thighs, groin, forearms, and axillae. Circulating antibodies against 2 BMZ proteins—BP180 and BP230—are important factors in BP pathogenesis.² Diagnosis of BP is based on clinical features, histologic findings, and immunological studies including DIF, IIF, and ELISA. An eosinophil-rich subepidermal split typically is seen on H&E staining (Figure 1).

Direct immunofluorescence displays linear IgG and/ or C3 staining at the BMZ. Indirect immunofluorescence on a human salt-split skin substrate commonly shows linear BMZ deposition on the roof of the blister.² Indirect immunofluorescence for IgG deposition on monkey esophagus substrate shows linear BMZ deposition. Antibodies against the NC16A domain of BP180 (NC16A-BP180) are dominant, but BP230 antibodies against BP230 also are detected with ELISA.² Further studies have indicated that the NC16A epitopes of BP180 that are targeted in BP are MCW-0-3,² different from the autoantigen MCW-4 that is targeted in LPP.⁷

Paraneoplastic pemphigus (PNP) is another diagnosis to consider. Patients with PNP initially present with oral findings—most commonly chronic, erosive, and painful mucositis—followed by cutaneous involvement, which varies from the development of bullae to the formation of plaques similar to those of LP.¹³ The latter, in combination with oral erosions, may appear clinically similar to LPP. The results of DIF in conjugation with IIF and ELISA may help to further differentiate these disorders. Direct immunofluorescence in PNP typically reveals positive intercellular and/or BMZ IgG and C3, while DIF in LPP reveals depositions along the BMZ alone. Indirect immunofluorescence performed on rat bladder epithelium is particularly useful, as binding of IgG to rat bladder epithelium is characteristic of PNP and not seen in other disorders.¹⁴ Lastly, patients with PNP may develop IgG antibodies to various antigens such as desmoplakin I, desmoplakin II, envoplakin, periplakin, BP230, desmoglein 1, and desmoglein 3, which would not be expected in LPP patients.¹⁵ Hematoxylin and eosin staining differs from LPP, primarily with the location of the blister being intraepidermal. Acantholysis with hemorrhagic bullae can be seen (Figure 2).

Classic LP is an inflammatory disorder that mainly affects adults, with an estimated incidence of less than 1%.¹⁶ The classic form presents with purple, flat-topped, pruritic, polygonal papules and plaques of varying size that often are characterized by Wickham striae. Lichen planus possesses a broad spectrum of subtypes involving different locations, though skin lesions usually are localized to the extremities. Despite an unknown etiology, activated T cells and T helper type 1 cytokines are considered key in keratinocyte injury. Compact orthokeratosis, wedge-shaped hypergranulosis, focal dyskeratosis, and colloid bodies typically are found on H&E staining, along with a dense bandlike lymphohistiocytic infiltrate at the dermoepidermal junction (DEJ)(Figure 3). Direct immunofluorescence typically shows a shaggy band of fibrinogen along the DEJ in addition to colloid bodies that stain with various autoantibodies including IgM, IgG, IgA, and C3.¹⁶

Bullous LP is a rare variant of LP that commonly develops on the oral mucosa and the legs, with blisters confined on pre-existing LP lesions.⁹ The pathogenesis is related to an epidermal inflammatory infiltrate that leads to basal layer destruction followed by dermal-epidermal separations that cause blistering.¹⁷ Bullous LP does not have positive DIF, IIF, or ELISA because the pathophysiology does not involve autoantibody production. Histopathology typically displays an extensive inflammatory infiltrate and degeneration of the basal keratinocytes, resulting in large dermal-epidermal separations called Max-Joseph spaces (Figure 4).¹⁷ Colloid bodies are prominent in bullous LP but rarely are seen in LPP; eosinophils also are much more prominent in LPP compared to bullous LP.¹⁸ Unlike in LPP, DIF usually is negative in bullous LP, though lichenoid lesions may exhibit globular deposition of IgM, IgG, and IgA in the colloid bodies of the lower epidermis and/or papillary dermis. Similar to LP, DIF of the biopsy specimen shows linear or shaggy deposits of fibrinogen at the DEJ.¹⁷

The Diagnosis: Superficial Angiomyxoma

Superficial angiomyxoma is a rare, benign, cutaneous tumor of a myxoid matrix and blood vessels that was first described in association with Carney complex.¹ Tumors may be solitary or multiple. A recent review of cases in the literature revealed a roughly equal distribution of superficial angiomyxomas in males and females occurring most frequently on the head and neck, extremities, and trunk or back. The peak incidence is between the fourth and fifth decades of life.² Superficial angiomyxomas can occur sporadically or in association with Carney complex, an autosomal-dominant condition with germline inactivating mutations in protein kinase A, PRKAR1A. Interestingly, sporadic cases of superficial angiomyxoma also have shown loss of PRKAR1A expression on immunohistochemistry (IHC).³

Common histologic mimics of superficial angiomyxoma include aggressive angiomyxoma and angiomyofibroblastoma.⁴ It is thought that these 3 distinct tumor entities may arise from a common pluripotent cell of origin located near connective tissue vasculature, which may contribute to the similarities observed between them.⁵ For example, aggressive angiomyxomas and angiomyofibroblastomas also demonstrate a similar myxoid background and vascular proliferation that can closely mimic superficial angiomyxomas clinically. However, the vessels of superficial angiomyxomas tend to be long and thin walled, while aggressive angiomyxomas are characterized by large and thick-walled vessels and angiomyofibroblastomas by abundant smaller vessels. Additionally, unlike superficial angiomyxomas, both aggressive angiomyxomas and angiomyofibroblastomas typically occur in the genital tract of young to middle-aged women.⁶

Histopathologic examination is imperative for differentiating between superficial angiomyxoma and more aggressive histologic mimics. Superficial angiomyxomas typically consist of a rich myxoid stroma, thin-walled or arborizing blood vessels, and spindled to stellate fibroblastlike cells (quiz image 2).³ Although not prominent in our case, superficial angiomyxomas also frequently present with stromal neutrophils and epithelial components, including keratinous cysts, basaloid buds, and strands of squamous epithelium.⁷ Minimal cellular atypia, mitotic activity, and nuclear pleomorphism often are seen, with IHC negative for desmin, estrogen receptor, and progesterone receptor; positive for CD34 and smooth muscle actin; and variable for S-100 and muscle-specific actin. Although IHC has limited utility in the diagnosis of superficial angiomyxomas, it may be useful to rule out other differential diagnoses.^2,3 Superficial angiomyxomas usually show fibroblastic stromal cells, proteoglycan matrix, and collagen fibers on electron microscopy.⁸ Importantly, histopathologic examination of aggressive angiomyxoma will comparatively present with more invasive, infiltrative, and less well-circumscribed tumors.⁹ Other differential diagnoses on histology may include neurofibroma, focal cutaneous mucinosis, spindle cell lipoma, and myxofibrosarcoma. Additional considerations include fibroepithelial polyp, nevus lipomatosis, angiomyxolipoma, and anetoderma.

An important differential diagnosis in the evaluation of superficial angiomyxoma is neurofibroma, a benign peripheral nerve sheath tumor that presents as a smooth, flesh-colored, and painless papule or nodule commonly associated with the buttonhole sign. Histopathology of neurofibroma features elongated spindle cells with comma-shaped or buckled wavy nuclei and variably sized collagen bundles described as “shredded carrots” (Figure 1).¹⁰ Occasional mast cells also can be seen. Immunohistochemistry targeting elements of peripheral nerve sheaths may assist in the diagnosis of neurofibromas, including positive S-100 and SOX10 in Schwann cells, epithelial membrane antigen in perineural cells, and fingerprint positivity for CD34 in fibroblasts.¹⁰

Cutaneous mucinoses encompass a diverse group of connective tissue disorders characterized by accumulation of mucin in the skin. Solitary focal cutaneous mucinoses (FCMs) are individual isolated lesions of mucin deposits that are unassociated with systemic conditions.¹¹ Conversely, multiple FCMs presenting with multiple cutaneous lesions also have been described in association with systemic diseases such as scleroderma, systemic lupus erythematosus, and thyroid disease.¹² Solitary FCM typically presents as an asymptomatic, flesh-colored papule or nodule on the extremities. It often arises in mid to late adulthood with a slightly increased frequency among males.¹² Histopathology of solitary FCM commonly demonstrates a dome-shaped pool of basophilic mucin in the upper dermis sparing involvement of the underlying subcutaneous tissue (Figure 2).¹³ Notably, FCM often lacks the vascularity as well as stromal neutrophils and epithelial elements that are seen in superficial angiomyxomas. Although hematoxylin and eosin stains can be sufficient for diagnosis of solitary FCM, additional stains for mucin such as Alcian blue, colloidal iron, or toluidine blue also may be considered to support the diagnosis.¹²

Spindle cell lipomas (SCLs) are rare, benign, subcutaneous, adipocytic tumors that arise on the upper back, posterior neck, or shoulders of middle-aged or elderly adult males.¹⁴ The clinical presentation often is an asymptomatic, well-circumscribed, mobile subcutaneous mass that is firmer than a common lipoma. Histologically, SCLs are characterized by mature adipocytes, spindle cells, and wire or ropelike collagen fibers in a myxoid background (Figure 3). The spindle cells usually are bland with a notable bipolar shape and blunted ends. Infiltrative growth patterns or mitotic figures are uncommon. Diagnosis can be supported by IHC, as SCLs stain diffusely positive for CD34 with loss of the retinoblastoma protein.⁷

Another important differential diagnosis to consider is myxofibrosarcoma, a rare and malignant myxoid cutaneous tumor. Clinically, it presents asymptomatically as an indolent, slow-growing nodule on the limbs and limb girdles.⁷ Histopathologic features demonstrate a multilobular tumor composed of a mixture of hypocellular and hypercellular regions with incomplete fibrous septae (Figure 4). The presence of curvilinear vasculature is characteristic. Multinucleated giant cells and cellular atypia with nuclear pleomorphism also can be seen. Although IHC findings generally are not specific, they can be used to rule out other potential diagnoses. Myxofibrosarcomas stain positive for vimentin and occasionally smooth muscle actin, muscle-specific actin, and CD34.⁷

Superficial angiomyxomas are benign; however, excision is recommended to distinguish between mimics. Local recurrence after excision is common in 30% to 40% of patients.¹⁵ Mohs micrographic surgery has been considered, especially if the following are present: tumor characteristics (eg, poorly circumscribed), location (eg, head and neck or other cosmetically or functionally sensitive areas), and likelihood of recurrence (high for superficial angiomyxomas). 16 This case otherwise highlights a rare example of superficial angiomyxomas involving the buttocks.

The Diagnosis: Superficial Angiomyxoma

Superficial angiomyxoma is a rare, benign, cutaneous tumor of a myxoid matrix and blood vessels that was first described in association with Carney complex.¹ Tumors may be solitary or multiple. A recent review of cases in the literature revealed a roughly equal distribution of superficial angiomyxomas in males and females occurring most frequently on the head and neck, extremities, and trunk or back. The peak incidence is between the fourth and fifth decades of life.² Superficial angiomyxomas can occur sporadically or in association with Carney complex, an autosomal-dominant condition with germline inactivating mutations in protein kinase A, PRKAR1A. Interestingly, sporadic cases of superficial angiomyxoma also have shown loss of PRKAR1A expression on immunohistochemistry (IHC).³

Common histologic mimics of superficial angiomyxoma include aggressive angiomyxoma and angiomyofibroblastoma.⁴ It is thought that these 3 distinct tumor entities may arise from a common pluripotent cell of origin located near connective tissue vasculature, which may contribute to the similarities observed between them.⁵ For example, aggressive angiomyxomas and angiomyofibroblastomas also demonstrate a similar myxoid background and vascular proliferation that can closely mimic superficial angiomyxomas clinically. However, the vessels of superficial angiomyxomas tend to be long and thin walled, while aggressive angiomyxomas are characterized by large and thick-walled vessels and angiomyofibroblastomas by abundant smaller vessels. Additionally, unlike superficial angiomyxomas, both aggressive angiomyxomas and angiomyofibroblastomas typically occur in the genital tract of young to middle-aged women.⁶

Histopathologic examination is imperative for differentiating between superficial angiomyxoma and more aggressive histologic mimics. Superficial angiomyxomas typically consist of a rich myxoid stroma, thin-walled or arborizing blood vessels, and spindled to stellate fibroblastlike cells (quiz image 2).³ Although not prominent in our case, superficial angiomyxomas also frequently present with stromal neutrophils and epithelial components, including keratinous cysts, basaloid buds, and strands of squamous epithelium.⁷ Minimal cellular atypia, mitotic activity, and nuclear pleomorphism often are seen, with IHC negative for desmin, estrogen receptor, and progesterone receptor; positive for CD34 and smooth muscle actin; and variable for S-100 and muscle-specific actin. Although IHC has limited utility in the diagnosis of superficial angiomyxomas, it may be useful to rule out other differential diagnoses.^2,3 Superficial angiomyxomas usually show fibroblastic stromal cells, proteoglycan matrix, and collagen fibers on electron microscopy.⁸ Importantly, histopathologic examination of aggressive angiomyxoma will comparatively present with more invasive, infiltrative, and less well-circumscribed tumors.⁹ Other differential diagnoses on histology may include neurofibroma, focal cutaneous mucinosis, spindle cell lipoma, and myxofibrosarcoma. Additional considerations include fibroepithelial polyp, nevus lipomatosis, angiomyxolipoma, and anetoderma.

An important differential diagnosis in the evaluation of superficial angiomyxoma is neurofibroma, a benign peripheral nerve sheath tumor that presents as a smooth, flesh-colored, and painless papule or nodule commonly associated with the buttonhole sign. Histopathology of neurofibroma features elongated spindle cells with comma-shaped or buckled wavy nuclei and variably sized collagen bundles described as “shredded carrots” (Figure 1).¹⁰ Occasional mast cells also can be seen. Immunohistochemistry targeting elements of peripheral nerve sheaths may assist in the diagnosis of neurofibromas, including positive S-100 and SOX10 in Schwann cells, epithelial membrane antigen in perineural cells, and fingerprint positivity for CD34 in fibroblasts.¹⁰

Cutaneous mucinoses encompass a diverse group of connective tissue disorders characterized by accumulation of mucin in the skin. Solitary focal cutaneous mucinoses (FCMs) are individual isolated lesions of mucin deposits that are unassociated with systemic conditions.¹¹ Conversely, multiple FCMs presenting with multiple cutaneous lesions also have been described in association with systemic diseases such as scleroderma, systemic lupus erythematosus, and thyroid disease.¹² Solitary FCM typically presents as an asymptomatic, flesh-colored papule or nodule on the extremities. It often arises in mid to late adulthood with a slightly increased frequency among males.¹² Histopathology of solitary FCM commonly demonstrates a dome-shaped pool of basophilic mucin in the upper dermis sparing involvement of the underlying subcutaneous tissue (Figure 2).¹³ Notably, FCM often lacks the vascularity as well as stromal neutrophils and epithelial elements that are seen in superficial angiomyxomas. Although hematoxylin and eosin stains can be sufficient for diagnosis of solitary FCM, additional stains for mucin such as Alcian blue, colloidal iron, or toluidine blue also may be considered to support the diagnosis.¹²

Spindle cell lipomas (SCLs) are rare, benign, subcutaneous, adipocytic tumors that arise on the upper back, posterior neck, or shoulders of middle-aged or elderly adult males.¹⁴ The clinical presentation often is an asymptomatic, well-circumscribed, mobile subcutaneous mass that is firmer than a common lipoma. Histologically, SCLs are characterized by mature adipocytes, spindle cells, and wire or ropelike collagen fibers in a myxoid background (Figure 3). The spindle cells usually are bland with a notable bipolar shape and blunted ends. Infiltrative growth patterns or mitotic figures are uncommon. Diagnosis can be supported by IHC, as SCLs stain diffusely positive for CD34 with loss of the retinoblastoma protein.⁷

Another important differential diagnosis to consider is myxofibrosarcoma, a rare and malignant myxoid cutaneous tumor. Clinically, it presents asymptomatically as an indolent, slow-growing nodule on the limbs and limb girdles.⁷ Histopathologic features demonstrate a multilobular tumor composed of a mixture of hypocellular and hypercellular regions with incomplete fibrous septae (Figure 4). The presence of curvilinear vasculature is characteristic. Multinucleated giant cells and cellular atypia with nuclear pleomorphism also can be seen. Although IHC findings generally are not specific, they can be used to rule out other potential diagnoses. Myxofibrosarcomas stain positive for vimentin and occasionally smooth muscle actin, muscle-specific actin, and CD34.⁷

Superficial angiomyxomas are benign; however, excision is recommended to distinguish between mimics. Local recurrence after excision is common in 30% to 40% of patients.¹⁵ Mohs micrographic surgery has been considered, especially if the following are present: tumor characteristics (eg, poorly circumscribed), location (eg, head and neck or other cosmetically or functionally sensitive areas), and likelihood of recurrence (high for superficial angiomyxomas). 16 This case otherwise highlights a rare example of superficial angiomyxomas involving the buttocks.

The Diagnosis: Superficial Angiomyxoma

Superficial angiomyxoma is a rare, benign, cutaneous tumor of a myxoid matrix and blood vessels that was first described in association with Carney complex.¹ Tumors may be solitary or multiple. A recent review of cases in the literature revealed a roughly equal distribution of superficial angiomyxomas in males and females occurring most frequently on the head and neck, extremities, and trunk or back. The peak incidence is between the fourth and fifth decades of life.² Superficial angiomyxomas can occur sporadically or in association with Carney complex, an autosomal-dominant condition with germline inactivating mutations in protein kinase A, PRKAR1A. Interestingly, sporadic cases of superficial angiomyxoma also have shown loss of PRKAR1A expression on immunohistochemistry (IHC).³

Common histologic mimics of superficial angiomyxoma include aggressive angiomyxoma and angiomyofibroblastoma.⁴ It is thought that these 3 distinct tumor entities may arise from a common pluripotent cell of origin located near connective tissue vasculature, which may contribute to the similarities observed between them.⁵ For example, aggressive angiomyxomas and angiomyofibroblastomas also demonstrate a similar myxoid background and vascular proliferation that can closely mimic superficial angiomyxomas clinically. However, the vessels of superficial angiomyxomas tend to be long and thin walled, while aggressive angiomyxomas are characterized by large and thick-walled vessels and angiomyofibroblastomas by abundant smaller vessels. Additionally, unlike superficial angiomyxomas, both aggressive angiomyxomas and angiomyofibroblastomas typically occur in the genital tract of young to middle-aged women.⁶

Histopathologic examination is imperative for differentiating between superficial angiomyxoma and more aggressive histologic mimics. Superficial angiomyxomas typically consist of a rich myxoid stroma, thin-walled or arborizing blood vessels, and spindled to stellate fibroblastlike cells (quiz image 2).³ Although not prominent in our case, superficial angiomyxomas also frequently present with stromal neutrophils and epithelial components, including keratinous cysts, basaloid buds, and strands of squamous epithelium.⁷ Minimal cellular atypia, mitotic activity, and nuclear pleomorphism often are seen, with IHC negative for desmin, estrogen receptor, and progesterone receptor; positive for CD34 and smooth muscle actin; and variable for S-100 and muscle-specific actin. Although IHC has limited utility in the diagnosis of superficial angiomyxomas, it may be useful to rule out other differential diagnoses.^2,3 Superficial angiomyxomas usually show fibroblastic stromal cells, proteoglycan matrix, and collagen fibers on electron microscopy.⁸ Importantly, histopathologic examination of aggressive angiomyxoma will comparatively present with more invasive, infiltrative, and less well-circumscribed tumors.⁹ Other differential diagnoses on histology may include neurofibroma, focal cutaneous mucinosis, spindle cell lipoma, and myxofibrosarcoma. Additional considerations include fibroepithelial polyp, nevus lipomatosis, angiomyxolipoma, and anetoderma.

An important differential diagnosis in the evaluation of superficial angiomyxoma is neurofibroma, a benign peripheral nerve sheath tumor that presents as a smooth, flesh-colored, and painless papule or nodule commonly associated with the buttonhole sign. Histopathology of neurofibroma features elongated spindle cells with comma-shaped or buckled wavy nuclei and variably sized collagen bundles described as “shredded carrots” (Figure 1).¹⁰ Occasional mast cells also can be seen. Immunohistochemistry targeting elements of peripheral nerve sheaths may assist in the diagnosis of neurofibromas, including positive S-100 and SOX10 in Schwann cells, epithelial membrane antigen in perineural cells, and fingerprint positivity for CD34 in fibroblasts.¹⁰

Cutaneous mucinoses encompass a diverse group of connective tissue disorders characterized by accumulation of mucin in the skin. Solitary focal cutaneous mucinoses (FCMs) are individual isolated lesions of mucin deposits that are unassociated with systemic conditions.¹¹ Conversely, multiple FCMs presenting with multiple cutaneous lesions also have been described in association with systemic diseases such as scleroderma, systemic lupus erythematosus, and thyroid disease.¹² Solitary FCM typically presents as an asymptomatic, flesh-colored papule or nodule on the extremities. It often arises in mid to late adulthood with a slightly increased frequency among males.¹² Histopathology of solitary FCM commonly demonstrates a dome-shaped pool of basophilic mucin in the upper dermis sparing involvement of the underlying subcutaneous tissue (Figure 2).¹³ Notably, FCM often lacks the vascularity as well as stromal neutrophils and epithelial elements that are seen in superficial angiomyxomas. Although hematoxylin and eosin stains can be sufficient for diagnosis of solitary FCM, additional stains for mucin such as Alcian blue, colloidal iron, or toluidine blue also may be considered to support the diagnosis.¹²

Spindle cell lipomas (SCLs) are rare, benign, subcutaneous, adipocytic tumors that arise on the upper back, posterior neck, or shoulders of middle-aged or elderly adult males.¹⁴ The clinical presentation often is an asymptomatic, well-circumscribed, mobile subcutaneous mass that is firmer than a common lipoma. Histologically, SCLs are characterized by mature adipocytes, spindle cells, and wire or ropelike collagen fibers in a myxoid background (Figure 3). The spindle cells usually are bland with a notable bipolar shape and blunted ends. Infiltrative growth patterns or mitotic figures are uncommon. Diagnosis can be supported by IHC, as SCLs stain diffusely positive for CD34 with loss of the retinoblastoma protein.⁷

Another important differential diagnosis to consider is myxofibrosarcoma, a rare and malignant myxoid cutaneous tumor. Clinically, it presents asymptomatically as an indolent, slow-growing nodule on the limbs and limb girdles.⁷ Histopathologic features demonstrate a multilobular tumor composed of a mixture of hypocellular and hypercellular regions with incomplete fibrous septae (Figure 4). The presence of curvilinear vasculature is characteristic. Multinucleated giant cells and cellular atypia with nuclear pleomorphism also can be seen. Although IHC findings generally are not specific, they can be used to rule out other potential diagnoses. Myxofibrosarcomas stain positive for vimentin and occasionally smooth muscle actin, muscle-specific actin, and CD34.⁷

Superficial angiomyxomas are benign; however, excision is recommended to distinguish between mimics. Local recurrence after excision is common in 30% to 40% of patients.¹⁵ Mohs micrographic surgery has been considered, especially if the following are present: tumor characteristics (eg, poorly circumscribed), location (eg, head and neck or other cosmetically or functionally sensitive areas), and likelihood of recurrence (high for superficial angiomyxomas). 16 This case otherwise highlights a rare example of superficial angiomyxomas involving the buttocks.

The Diagnosis: Endocrine Mucin-Producing Sweat Gland Carcinoma

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare cutaneous adnexal tumor that characteristically presents as slowgrowing, flesh-colored papules, nodules, or cystic lesions around the periorbital skin in elderly female patients.¹ Histopathology of EMPSGCs reveals well-circumscribed multinodular dermal lesions that can be either cystic or solid and often are arranged in papillary and cribriform patterns (quiz image). Nests of uniform tumor cells are composed of small- to medium-sized epithelial cells with monomorphic nuclei showing fine to stippled chromatin.² Histologically, EMPSGC resembles a solid papillary carcinoma of the breast, which is attributed to their common embryologic origin.³ Intracytoplasmic and extracellular mucin often are seen on hematoxylin and eosin staining.² Variable immunohistochemical stain expression has been reported, including positive staining with synaptophysin and chromogranin. Other markers include cytokeratin CAM 5.2, epithelial membrane antigen, estrogen or progesterone receptors, and cytokeratin 7.⁴ Endocrine mucin-producing sweat gland carcinoma is thought to be a precursor to invasive neuroendocrine-type primary cutaneous mucinous carcinoma. Primary cutaneous mucinous carcinoma has been associated with EMPSGC in approximately 35.7% of cases. Histologically, primary cutaneous mucinous carcinoma that has transformed from EMPSGC would show an infiltration of tumor nests with desmoplastic stroma or mucin pools with clusters of tumor cells.²

Primary cutaneous adenoid cystic carcinoma is a rare malignant tumor that often presents on the head and neck. It usually appears as a single, slowly growing subcutaneous nodule or multinodular plaque.^5,6 Histologic features include basaloid cells in alternating tubular and cribriform patterns. The cribriform areas are composed of pseudoglandular adenoid spaces that contain mucin, basement membrane zone material, and cellular debris from necrotic neoplastic cells (Figure 1).⁷ Primary cutaneous adenoid cystic carcinoma predominantly is dermal with extension to the subcutaneous tissue. True ductal structures that demonstrate decapitation secretion also may be present.⁷

Basal cell carcinoma (adenoid type) presents as a pigmented or nonpigmented nodule or ulcer on sunexposed areas of the head and neck. Histopathology reveals basaloid cells surrounding islands of connective tissue resulting in a lacelike pattern (Figure 2). The lumina may contain a colloidal substance or amorphous granular material.⁸ The characteristic features of basal cell carcinomas, such as nests of basaloid cells with peripheral palisading cells, retraction of adjacent stroma, increased apoptosis and mitotic figures, and connection to the epidermis, can be helpful to distinguish basal cell carcinoma histologically from EMPSGC.²

Apocrine hidrocystomas clinically present as round, flesh-colored, shiny or translucent, dome-shaped papules or nodules near the eyelid margin or lateral canthus.⁹ Histologically, they are composed of proliferating apocrine secretory coils with an epithelial side of cuboidal or columnar cells and a luminal side exhibiting decapitation secretion (Figure 3).² An epidermal connection is absent.⁹ Apocrine hidrocystomas may exhibit complex architecture and papillary ductal hyperplasia that are difficult to distinguish from EMPSGC, especially if EMPSGC presents with cystic morphology. Apocrine cytomorphology and the lack of neuroendocrine marker expression and mucin production distinguish apocrine hidrocystomas. Furthermore, hidrocystomas infrequently demonstrate the nodular, solid, cribriform areas appreciated in EMPSGC.²

Microcystic adnexal carcinoma is a rare, slowly growing, locally aggressive sweat gland tumor that commonly presents as a flesh-colored to yellow papule, nodule, or plaque on the central face.¹⁰ Histopathologic examination reveals both eccrine and follicular differentiation. Keratin cysts, bland keratinocyte cords, and epithelium with ductal differentiation is observed in the superficial layers (Figure 4). Deep invasion into the subcutis and perineural invasion frequently is observed.

The Diagnosis: Endocrine Mucin-Producing Sweat Gland Carcinoma

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare cutaneous adnexal tumor that characteristically presents as slowgrowing, flesh-colored papules, nodules, or cystic lesions around the periorbital skin in elderly female patients.¹ Histopathology of EMPSGCs reveals well-circumscribed multinodular dermal lesions that can be either cystic or solid and often are arranged in papillary and cribriform patterns (quiz image). Nests of uniform tumor cells are composed of small- to medium-sized epithelial cells with monomorphic nuclei showing fine to stippled chromatin.² Histologically, EMPSGC resembles a solid papillary carcinoma of the breast, which is attributed to their common embryologic origin.³ Intracytoplasmic and extracellular mucin often are seen on hematoxylin and eosin staining.² Variable immunohistochemical stain expression has been reported, including positive staining with synaptophysin and chromogranin. Other markers include cytokeratin CAM 5.2, epithelial membrane antigen, estrogen or progesterone receptors, and cytokeratin 7.⁴ Endocrine mucin-producing sweat gland carcinoma is thought to be a precursor to invasive neuroendocrine-type primary cutaneous mucinous carcinoma. Primary cutaneous mucinous carcinoma has been associated with EMPSGC in approximately 35.7% of cases. Histologically, primary cutaneous mucinous carcinoma that has transformed from EMPSGC would show an infiltration of tumor nests with desmoplastic stroma or mucin pools with clusters of tumor cells.²

Primary cutaneous adenoid cystic carcinoma is a rare malignant tumor that often presents on the head and neck. It usually appears as a single, slowly growing subcutaneous nodule or multinodular plaque.^5,6 Histologic features include basaloid cells in alternating tubular and cribriform patterns. The cribriform areas are composed of pseudoglandular adenoid spaces that contain mucin, basement membrane zone material, and cellular debris from necrotic neoplastic cells (Figure 1).⁷ Primary cutaneous adenoid cystic carcinoma predominantly is dermal with extension to the subcutaneous tissue. True ductal structures that demonstrate decapitation secretion also may be present.⁷

Basal cell carcinoma (adenoid type) presents as a pigmented or nonpigmented nodule or ulcer on sunexposed areas of the head and neck. Histopathology reveals basaloid cells surrounding islands of connective tissue resulting in a lacelike pattern (Figure 2). The lumina may contain a colloidal substance or amorphous granular material.⁸ The characteristic features of basal cell carcinomas, such as nests of basaloid cells with peripheral palisading cells, retraction of adjacent stroma, increased apoptosis and mitotic figures, and connection to the epidermis, can be helpful to distinguish basal cell carcinoma histologically from EMPSGC.²

Apocrine hidrocystomas clinically present as round, flesh-colored, shiny or translucent, dome-shaped papules or nodules near the eyelid margin or lateral canthus.⁹ Histologically, they are composed of proliferating apocrine secretory coils with an epithelial side of cuboidal or columnar cells and a luminal side exhibiting decapitation secretion (Figure 3).² An epidermal connection is absent.⁹ Apocrine hidrocystomas may exhibit complex architecture and papillary ductal hyperplasia that are difficult to distinguish from EMPSGC, especially if EMPSGC presents with cystic morphology. Apocrine cytomorphology and the lack of neuroendocrine marker expression and mucin production distinguish apocrine hidrocystomas. Furthermore, hidrocystomas infrequently demonstrate the nodular, solid, cribriform areas appreciated in EMPSGC.²

Microcystic adnexal carcinoma is a rare, slowly growing, locally aggressive sweat gland tumor that commonly presents as a flesh-colored to yellow papule, nodule, or plaque on the central face.¹⁰ Histopathologic examination reveals both eccrine and follicular differentiation. Keratin cysts, bland keratinocyte cords, and epithelium with ductal differentiation is observed in the superficial layers (Figure 4). Deep invasion into the subcutis and perineural invasion frequently is observed.

The Diagnosis: Endocrine Mucin-Producing Sweat Gland Carcinoma

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare cutaneous adnexal tumor that characteristically presents as slowgrowing, flesh-colored papules, nodules, or cystic lesions around the periorbital skin in elderly female patients.¹ Histopathology of EMPSGCs reveals well-circumscribed multinodular dermal lesions that can be either cystic or solid and often are arranged in papillary and cribriform patterns (quiz image). Nests of uniform tumor cells are composed of small- to medium-sized epithelial cells with monomorphic nuclei showing fine to stippled chromatin.² Histologically, EMPSGC resembles a solid papillary carcinoma of the breast, which is attributed to their common embryologic origin.³ Intracytoplasmic and extracellular mucin often are seen on hematoxylin and eosin staining.² Variable immunohistochemical stain expression has been reported, including positive staining with synaptophysin and chromogranin. Other markers include cytokeratin CAM 5.2, epithelial membrane antigen, estrogen or progesterone receptors, and cytokeratin 7.⁴ Endocrine mucin-producing sweat gland carcinoma is thought to be a precursor to invasive neuroendocrine-type primary cutaneous mucinous carcinoma. Primary cutaneous mucinous carcinoma has been associated with EMPSGC in approximately 35.7% of cases. Histologically, primary cutaneous mucinous carcinoma that has transformed from EMPSGC would show an infiltration of tumor nests with desmoplastic stroma or mucin pools with clusters of tumor cells.²

Primary cutaneous adenoid cystic carcinoma is a rare malignant tumor that often presents on the head and neck. It usually appears as a single, slowly growing subcutaneous nodule or multinodular plaque.^5,6 Histologic features include basaloid cells in alternating tubular and cribriform patterns. The cribriform areas are composed of pseudoglandular adenoid spaces that contain mucin, basement membrane zone material, and cellular debris from necrotic neoplastic cells (Figure 1).⁷ Primary cutaneous adenoid cystic carcinoma predominantly is dermal with extension to the subcutaneous tissue. True ductal structures that demonstrate decapitation secretion also may be present.⁷

Basal cell carcinoma (adenoid type) presents as a pigmented or nonpigmented nodule or ulcer on sunexposed areas of the head and neck. Histopathology reveals basaloid cells surrounding islands of connective tissue resulting in a lacelike pattern (Figure 2). The lumina may contain a colloidal substance or amorphous granular material.⁸ The characteristic features of basal cell carcinomas, such as nests of basaloid cells with peripheral palisading cells, retraction of adjacent stroma, increased apoptosis and mitotic figures, and connection to the epidermis, can be helpful to distinguish basal cell carcinoma histologically from EMPSGC.²

Apocrine hidrocystomas clinically present as round, flesh-colored, shiny or translucent, dome-shaped papules or nodules near the eyelid margin or lateral canthus.⁹ Histologically, they are composed of proliferating apocrine secretory coils with an epithelial side of cuboidal or columnar cells and a luminal side exhibiting decapitation secretion (Figure 3).² An epidermal connection is absent.⁹ Apocrine hidrocystomas may exhibit complex architecture and papillary ductal hyperplasia that are difficult to distinguish from EMPSGC, especially if EMPSGC presents with cystic morphology. Apocrine cytomorphology and the lack of neuroendocrine marker expression and mucin production distinguish apocrine hidrocystomas. Furthermore, hidrocystomas infrequently demonstrate the nodular, solid, cribriform areas appreciated in EMPSGC.²

Microcystic adnexal carcinoma is a rare, slowly growing, locally aggressive sweat gland tumor that commonly presents as a flesh-colored to yellow papule, nodule, or plaque on the central face.¹⁰ Histopathologic examination reveals both eccrine and follicular differentiation. Keratin cysts, bland keratinocyte cords, and epithelium with ductal differentiation is observed in the superficial layers (Figure 4). Deep invasion into the subcutis and perineural invasion frequently is observed.

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

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

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

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

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

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

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

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

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

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

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

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

The Diagnosis: Pseudoangiomatous Squamous Cell Carcinoma

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

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

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

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

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

The Diagnosis: Hybrid Schwannoma-Perineurioma

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

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

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

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

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

The Diagnosis: Hybrid Schwannoma-Perineurioma

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

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

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

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

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

The Diagnosis: Hybrid Schwannoma-Perineurioma

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

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

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

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

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

The Diagnosis: Tuberous Xanthoma

The skin biopsy revealed a nodular collection of foam cells (quiz image [bottom]). Tuberous xanthoma was the most likely diagnosis based on the patient’s history as well as the clinical and histologic findings. Tuberous xanthomas are flat or elevated nodules in the dermis and subcutaneous tissue, commonly occurring on the skin over the joints.¹ Smaller nodules and papules often are referred to as tuberoeruptive xanthomas and exist on a continuum with the larger tuberous xanthomas. All xanthomas appear histologically similar, with collections of foam cells present within the dermis.² Foam cells form when serum lipoproteins diffuse through capillary walls, deposit in the skin or tendons, and are scavenged by monocytes.3 Tuberous xanthomas, along with tendinous, eruptive, and planar xanthomas, are the most likely to be associated with hyperlipidemia.⁴ They may indicate an underlying disorder of lipid metabolism, such as familial hypercholesterolemia.^1,3 This is the most common cause of inheritable cardiovascular disease, with a prevalence of approximately 1:250.² Premature cardiovascular disease risk increases 2 to 4 times in patients with familial hypercholesterolemia and tendinous xanthomas,¹ illustrating that recognition of cutaneous lesions can lead to earlier diagnosis and prevention of patient morbidity and mortality.

Juvenile xanthogranuloma typically presents as smooth yellow papules or nodules on the head and neck, with a characteristic “setting-sun” appearance (ie, yellow center with an erythematous halo) on dermoscopy.⁵ Histologically, juvenile xanthogranulomas are composed of foam cells and a mixed lymphohistiocytic infiltrate with eosinophils within the dermis. Giant cells with a ring of nuclei surrounded by cytoplasm containing lipid vacuoles (called Touton giant cells) are characteristic (Figure 1). In contrast to tuberous xanthomas, juvenile xanthogranulomas often present within the first year of life.⁶

Keloid scars are more prevalent in patients with skin of color. They are characterized by eosinophilic keloidal collagen with a whorled proliferation of fibroblasts on histology (Figure 2).⁷ They occur spontaneously or at sites of injury and present as bluish-red or flesh-colored firm papules or nodules.⁸ In our patient, keloid scars were an unlikely diagnosis due to the lack of trauma and the absence of keloidal collagen on histology.

Necrobiosis lipoidica diabeticorum typically presents as an erythematous, yellow-brown, circular plaque on the anterior lower leg in patients with diabetes mellitus; it rarely occurs in children.⁹ Microscopy shows palisaded granulomas surrounding necrobiotic collagen arranged horizontally in a layer cake–like fashion (Figure 3).^9,10 The etiology of necrobiosis lipoidica diabeticorum currently is unknown, though immune complex deposition may contribute to its pathology. It has been associated with type 1 diabetes mellitus, though severity of the lesions is not associated with extent of glycemic control.¹⁰

Rosai-Dorfman disease is an uncommon disorder characterized by a proliferation of histiocytes that most often presents as bilateral cervical lymphadenopathy in children and young adults but rarely can present with cutaneous lesions when extranodal involvement is present.^11,12 The cutaneous form most commonly presents as red papules or nodules. On histology, the lesions exhibit a nodular dermal proliferation of histiocytes and smaller lymphocytoid cells with a marbled or starry sky–like appearance on low power (Figure 4). On higher magnification, the characteristic finding of emperipolesis can be seen.11 On immunohistochemistry, the histiocytes stain positively for CD68 and S-100. Although the pathogenesis currently is unknown, evidence of clonality indicates the disease may be related to a neoplastic process.¹²

The Diagnosis: Tuberous Xanthoma

The skin biopsy revealed a nodular collection of foam cells (quiz image [bottom]). Tuberous xanthoma was the most likely diagnosis based on the patient’s history as well as the clinical and histologic findings. Tuberous xanthomas are flat or elevated nodules in the dermis and subcutaneous tissue, commonly occurring on the skin over the joints.¹ Smaller nodules and papules often are referred to as tuberoeruptive xanthomas and exist on a continuum with the larger tuberous xanthomas. All xanthomas appear histologically similar, with collections of foam cells present within the dermis.² Foam cells form when serum lipoproteins diffuse through capillary walls, deposit in the skin or tendons, and are scavenged by monocytes.3 Tuberous xanthomas, along with tendinous, eruptive, and planar xanthomas, are the most likely to be associated with hyperlipidemia.⁴ They may indicate an underlying disorder of lipid metabolism, such as familial hypercholesterolemia.^1,3 This is the most common cause of inheritable cardiovascular disease, with a prevalence of approximately 1:250.² Premature cardiovascular disease risk increases 2 to 4 times in patients with familial hypercholesterolemia and tendinous xanthomas,¹ illustrating that recognition of cutaneous lesions can lead to earlier diagnosis and prevention of patient morbidity and mortality.

Juvenile xanthogranuloma typically presents as smooth yellow papules or nodules on the head and neck, with a characteristic “setting-sun” appearance (ie, yellow center with an erythematous halo) on dermoscopy.⁵ Histologically, juvenile xanthogranulomas are composed of foam cells and a mixed lymphohistiocytic infiltrate with eosinophils within the dermis. Giant cells with a ring of nuclei surrounded by cytoplasm containing lipid vacuoles (called Touton giant cells) are characteristic (Figure 1). In contrast to tuberous xanthomas, juvenile xanthogranulomas often present within the first year of life.⁶

Keloid scars are more prevalent in patients with skin of color. They are characterized by eosinophilic keloidal collagen with a whorled proliferation of fibroblasts on histology (Figure 2).⁷ They occur spontaneously or at sites of injury and present as bluish-red or flesh-colored firm papules or nodules.⁸ In our patient, keloid scars were an unlikely diagnosis due to the lack of trauma and the absence of keloidal collagen on histology.

Necrobiosis lipoidica diabeticorum typically presents as an erythematous, yellow-brown, circular plaque on the anterior lower leg in patients with diabetes mellitus; it rarely occurs in children.⁹ Microscopy shows palisaded granulomas surrounding necrobiotic collagen arranged horizontally in a layer cake–like fashion (Figure 3).^9,10 The etiology of necrobiosis lipoidica diabeticorum currently is unknown, though immune complex deposition may contribute to its pathology. It has been associated with type 1 diabetes mellitus, though severity of the lesions is not associated with extent of glycemic control.¹⁰

Rosai-Dorfman disease is an uncommon disorder characterized by a proliferation of histiocytes that most often presents as bilateral cervical lymphadenopathy in children and young adults but rarely can present with cutaneous lesions when extranodal involvement is present.^11,12 The cutaneous form most commonly presents as red papules or nodules. On histology, the lesions exhibit a nodular dermal proliferation of histiocytes and smaller lymphocytoid cells with a marbled or starry sky–like appearance on low power (Figure 4). On higher magnification, the characteristic finding of emperipolesis can be seen.11 On immunohistochemistry, the histiocytes stain positively for CD68 and S-100. Although the pathogenesis currently is unknown, evidence of clonality indicates the disease may be related to a neoplastic process.¹²

The Diagnosis: Tuberous Xanthoma

The skin biopsy revealed a nodular collection of foam cells (quiz image [bottom]). Tuberous xanthoma was the most likely diagnosis based on the patient’s history as well as the clinical and histologic findings. Tuberous xanthomas are flat or elevated nodules in the dermis and subcutaneous tissue, commonly occurring on the skin over the joints.¹ Smaller nodules and papules often are referred to as tuberoeruptive xanthomas and exist on a continuum with the larger tuberous xanthomas. All xanthomas appear histologically similar, with collections of foam cells present within the dermis.² Foam cells form when serum lipoproteins diffuse through capillary walls, deposit in the skin or tendons, and are scavenged by monocytes.3 Tuberous xanthomas, along with tendinous, eruptive, and planar xanthomas, are the most likely to be associated with hyperlipidemia.⁴ They may indicate an underlying disorder of lipid metabolism, such as familial hypercholesterolemia.^1,3 This is the most common cause of inheritable cardiovascular disease, with a prevalence of approximately 1:250.² Premature cardiovascular disease risk increases 2 to 4 times in patients with familial hypercholesterolemia and tendinous xanthomas,¹ illustrating that recognition of cutaneous lesions can lead to earlier diagnosis and prevention of patient morbidity and mortality.

Juvenile xanthogranuloma typically presents as smooth yellow papules or nodules on the head and neck, with a characteristic “setting-sun” appearance (ie, yellow center with an erythematous halo) on dermoscopy.⁵ Histologically, juvenile xanthogranulomas are composed of foam cells and a mixed lymphohistiocytic infiltrate with eosinophils within the dermis. Giant cells with a ring of nuclei surrounded by cytoplasm containing lipid vacuoles (called Touton giant cells) are characteristic (Figure 1). In contrast to tuberous xanthomas, juvenile xanthogranulomas often present within the first year of life.⁶

Keloid scars are more prevalent in patients with skin of color. They are characterized by eosinophilic keloidal collagen with a whorled proliferation of fibroblasts on histology (Figure 2).⁷ They occur spontaneously or at sites of injury and present as bluish-red or flesh-colored firm papules or nodules.⁸ In our patient, keloid scars were an unlikely diagnosis due to the lack of trauma and the absence of keloidal collagen on histology.

Necrobiosis lipoidica diabeticorum typically presents as an erythematous, yellow-brown, circular plaque on the anterior lower leg in patients with diabetes mellitus; it rarely occurs in children.⁹ Microscopy shows palisaded granulomas surrounding necrobiotic collagen arranged horizontally in a layer cake–like fashion (Figure 3).^9,10 The etiology of necrobiosis lipoidica diabeticorum currently is unknown, though immune complex deposition may contribute to its pathology. It has been associated with type 1 diabetes mellitus, though severity of the lesions is not associated with extent of glycemic control.¹⁰

Rosai-Dorfman disease is an uncommon disorder characterized by a proliferation of histiocytes that most often presents as bilateral cervical lymphadenopathy in children and young adults but rarely can present with cutaneous lesions when extranodal involvement is present.^11,12 The cutaneous form most commonly presents as red papules or nodules. On histology, the lesions exhibit a nodular dermal proliferation of histiocytes and smaller lymphocytoid cells with a marbled or starry sky–like appearance on low power (Figure 4). On higher magnification, the characteristic finding of emperipolesis can be seen.11 On immunohistochemistry, the histiocytes stain positively for CD68 and S-100. Although the pathogenesis currently is unknown, evidence of clonality indicates the disease may be related to a neoplastic process.¹²

The Diagnosis: Metastatic Carcinoid Tumor

Carcinoid tumors are derived from neuroendocrine cell compartments and generally arise in the gastrointestinal tract, with a quarter of carcinoids arising in the small bowel.¹ Carcinoid tumors have an incidence of approximately 2 to 5 per 100,000 patients.² Metastasis of carcinoids is approximately 31.2% to 46.7%.¹ Metastasis to the skin is uncommon; we present a rare case of a carcinoid tumor of the terminal ileum with metastasis to the scalp.

Unlike our patient, most patients with carcinoid tumors have an indolent clinical course. The most common cutaneous symptom is flushing, which occurs in 75% of patients.³ Secreted vasoactive peptides such as serotonin may cause other symptoms such as tachycardia, diarrhea, and bronchospasm; together, these symptoms comprise carcinoid syndrome. Carcinoid syndrome requires metastasis of the tumor to the liver or a site outside of the gastrointestinal tract because the liver will metabolize the secreted serotonin. However, even in patients with liver metastasis, carcinoid syndrome only occurs in approximately 10% of patients.⁴ Common skin findings of carcinoid syndrome include pellagralike dermatitis, flushing, and sclerodermalike changes.⁵ Our patient experienced several episodes of presyncope with symptoms of dyspnea, lightheadedness, and flushing but did not have bronchospasm or recurrent diarrhea. Intramuscular octreotide improved some symptoms.

The scalp accounts for approximately 15% of cutaneous metastases, the most common being from the lung, renal, and breast cancers.⁶ Cutaneous metastases of carcinoid tumors are rare. A PubMed search of articles indexed for MEDLINE using the terms metastatic AND [carcinoid OR neuroendocrine] tumors AND [skin OR cutaneous] revealed 47 cases.^7-11 Similar to other skin metastases, cutaneous metastases of carcinoid tumors commonly present as firm erythematous nodules of varying sizes that may be asymptomatic, tender, or pruritic (Figure 1). Cases of carcinoid tumors with cutaneous metastasis as the initial and only presenting sign are exceedingly rare.¹²

Histology of carcinoid tumors reveals a dermal neoplasm composed of loosely cohesive, mildly atypical, polygonal cells with salt-and-pepper chromatin and eosinophilic cytoplasm, which are similar findings to the primary tumor. The cells may grow in the typical trabecular or organoid neuroendocrine pattern or exhibit a pseudoglandular growth pattern with prominent vessels (quiz image, top).¹² Positive chromogranin and synaptophysin immunostaining are the most common and reliable markers used for the diagnosis of carcinoid tumors.

An important histopathologic differential diagnosis is the aggressive Merkel cell carcinoma, which also demonstrates homogenous salt-and-pepper chromatin but exhibits a higher mitotic rate and positive cytokeratin 20 staining (Figure 2).¹³ Basal cell carcinoma (BCC) also may display similar features, including a blue tumor at scanning magnification and nodular or infiltrative growth patterns. The cell morphology of BCC is characterized by islands of basaloid cells with minimal cytoplasm and frequent apoptosis, connecting to the epidermis with peripheral palisading, retraction artifact, and a myxoid stroma; BCC lacks the salt-and-pepper chromatin commonly seen in carcinoid tumors (Figure 3). Basal cell carcinoma is characterized by positive BerEP4 (epithelial cell adhesion molecule immunostain), cytokeratin 5/6, and cytokeratin 14 uptake. Cytokeratin 20, often used to diagnose Merkel cell carcinoma, is negative in BCC. Chromogranin and synaptophysin occasionally may be positive in BCC.¹⁴

The superficial Ewing sarcoma family of tumors also may be included in the differential diagnosis of small round cell tumors of the skin, but they are very rare. These tumors possess strong positive membranous staining of cytokeratin 99 and also can stain positively for synaptophysin and chromogranin.¹⁵ Epithelial membrane antigen, which is negative in Ewing sarcomas, is positive in carcinoid tumors.¹⁶ Neuroendocrine tumors of all sites share similar basic morphologic patterns, and multiple primary tumors should be considered, including small cell lung carcinoma (Figure 4).^17,18 Red granulations and true glandular lumina typically are not seen in the lungs but are common in gastrointestinal carcinoids.¹⁸ Regarding immunohistochemistry, TTF-1 is negative and CDX2 is positive in gastroenteropancreatic carcinoids, suggesting that these 2 markers can help distinguish carcinoids of unknown primary origin.¹⁹

Metastases in carcinoid tumors are common, with one study noting that the highest frequency of small intestinal metastases was from the ileal subset.²⁰ At the time of diagnosis, 58% to 64% of patients with small intestine carcinoid tumors already had nonlocalized disease, with frequent sites being the lymph nodes (89.8%), liver (44.1%), lungs (13.6%), and peritoneum (13.6%). Regional and distant metastases are associated with substantially worse prognoses, with survival rates of 71.7% and 38.5%, respectively.¹ Treatment of symptomatic unresectable disease focuses on symptomatic management with somatostatin analogs that also control tumor growth.²¹

We present a rare case of scalp metastasis of a carcinoid tumor of the terminal ileum. Distant metastasis is associated with poorer prognosis and should be considered in patients with a known history of a carcinoid tumor.

Acknowledgment—We would like to acknowledge the Research Histology and Tissue Imaging Core at University of Illinois Chicago Research Resources Center for the immunohistochemistry studies.

The Diagnosis: Metastatic Carcinoid Tumor

Carcinoid tumors are derived from neuroendocrine cell compartments and generally arise in the gastrointestinal tract, with a quarter of carcinoids arising in the small bowel.¹ Carcinoid tumors have an incidence of approximately 2 to 5 per 100,000 patients.² Metastasis of carcinoids is approximately 31.2% to 46.7%.¹ Metastasis to the skin is uncommon; we present a rare case of a carcinoid tumor of the terminal ileum with metastasis to the scalp.

Unlike our patient, most patients with carcinoid tumors have an indolent clinical course. The most common cutaneous symptom is flushing, which occurs in 75% of patients.³ Secreted vasoactive peptides such as serotonin may cause other symptoms such as tachycardia, diarrhea, and bronchospasm; together, these symptoms comprise carcinoid syndrome. Carcinoid syndrome requires metastasis of the tumor to the liver or a site outside of the gastrointestinal tract because the liver will metabolize the secreted serotonin. However, even in patients with liver metastasis, carcinoid syndrome only occurs in approximately 10% of patients.⁴ Common skin findings of carcinoid syndrome include pellagralike dermatitis, flushing, and sclerodermalike changes.⁵ Our patient experienced several episodes of presyncope with symptoms of dyspnea, lightheadedness, and flushing but did not have bronchospasm or recurrent diarrhea. Intramuscular octreotide improved some symptoms.

The scalp accounts for approximately 15% of cutaneous metastases, the most common being from the lung, renal, and breast cancers.⁶ Cutaneous metastases of carcinoid tumors are rare. A PubMed search of articles indexed for MEDLINE using the terms metastatic AND [carcinoid OR neuroendocrine] tumors AND [skin OR cutaneous] revealed 47 cases.^7-11 Similar to other skin metastases, cutaneous metastases of carcinoid tumors commonly present as firm erythematous nodules of varying sizes that may be asymptomatic, tender, or pruritic (Figure 1). Cases of carcinoid tumors with cutaneous metastasis as the initial and only presenting sign are exceedingly rare.¹²

Histology of carcinoid tumors reveals a dermal neoplasm composed of loosely cohesive, mildly atypical, polygonal cells with salt-and-pepper chromatin and eosinophilic cytoplasm, which are similar findings to the primary tumor. The cells may grow in the typical trabecular or organoid neuroendocrine pattern or exhibit a pseudoglandular growth pattern with prominent vessels (quiz image, top).¹² Positive chromogranin and synaptophysin immunostaining are the most common and reliable markers used for the diagnosis of carcinoid tumors.

An important histopathologic differential diagnosis is the aggressive Merkel cell carcinoma, which also demonstrates homogenous salt-and-pepper chromatin but exhibits a higher mitotic rate and positive cytokeratin 20 staining (Figure 2).¹³ Basal cell carcinoma (BCC) also may display similar features, including a blue tumor at scanning magnification and nodular or infiltrative growth patterns. The cell morphology of BCC is characterized by islands of basaloid cells with minimal cytoplasm and frequent apoptosis, connecting to the epidermis with peripheral palisading, retraction artifact, and a myxoid stroma; BCC lacks the salt-and-pepper chromatin commonly seen in carcinoid tumors (Figure 3). Basal cell carcinoma is characterized by positive BerEP4 (epithelial cell adhesion molecule immunostain), cytokeratin 5/6, and cytokeratin 14 uptake. Cytokeratin 20, often used to diagnose Merkel cell carcinoma, is negative in BCC. Chromogranin and synaptophysin occasionally may be positive in BCC.¹⁴

The superficial Ewing sarcoma family of tumors also may be included in the differential diagnosis of small round cell tumors of the skin, but they are very rare. These tumors possess strong positive membranous staining of cytokeratin 99 and also can stain positively for synaptophysin and chromogranin.¹⁵ Epithelial membrane antigen, which is negative in Ewing sarcomas, is positive in carcinoid tumors.¹⁶ Neuroendocrine tumors of all sites share similar basic morphologic patterns, and multiple primary tumors should be considered, including small cell lung carcinoma (Figure 4).^17,18 Red granulations and true glandular lumina typically are not seen in the lungs but are common in gastrointestinal carcinoids.¹⁸ Regarding immunohistochemistry, TTF-1 is negative and CDX2 is positive in gastroenteropancreatic carcinoids, suggesting that these 2 markers can help distinguish carcinoids of unknown primary origin.¹⁹

Metastases in carcinoid tumors are common, with one study noting that the highest frequency of small intestinal metastases was from the ileal subset.²⁰ At the time of diagnosis, 58% to 64% of patients with small intestine carcinoid tumors already had nonlocalized disease, with frequent sites being the lymph nodes (89.8%), liver (44.1%), lungs (13.6%), and peritoneum (13.6%). Regional and distant metastases are associated with substantially worse prognoses, with survival rates of 71.7% and 38.5%, respectively.¹ Treatment of symptomatic unresectable disease focuses on symptomatic management with somatostatin analogs that also control tumor growth.²¹

We present a rare case of scalp metastasis of a carcinoid tumor of the terminal ileum. Distant metastasis is associated with poorer prognosis and should be considered in patients with a known history of a carcinoid tumor.

Acknowledgment—We would like to acknowledge the Research Histology and Tissue Imaging Core at University of Illinois Chicago Research Resources Center for the immunohistochemistry studies.

The Diagnosis: Metastatic Carcinoid Tumor

Carcinoid tumors are derived from neuroendocrine cell compartments and generally arise in the gastrointestinal tract, with a quarter of carcinoids arising in the small bowel.¹ Carcinoid tumors have an incidence of approximately 2 to 5 per 100,000 patients.² Metastasis of carcinoids is approximately 31.2% to 46.7%.¹ Metastasis to the skin is uncommon; we present a rare case of a carcinoid tumor of the terminal ileum with metastasis to the scalp.

Unlike our patient, most patients with carcinoid tumors have an indolent clinical course. The most common cutaneous symptom is flushing, which occurs in 75% of patients.³ Secreted vasoactive peptides such as serotonin may cause other symptoms such as tachycardia, diarrhea, and bronchospasm; together, these symptoms comprise carcinoid syndrome. Carcinoid syndrome requires metastasis of the tumor to the liver or a site outside of the gastrointestinal tract because the liver will metabolize the secreted serotonin. However, even in patients with liver metastasis, carcinoid syndrome only occurs in approximately 10% of patients.⁴ Common skin findings of carcinoid syndrome include pellagralike dermatitis, flushing, and sclerodermalike changes.⁵ Our patient experienced several episodes of presyncope with symptoms of dyspnea, lightheadedness, and flushing but did not have bronchospasm or recurrent diarrhea. Intramuscular octreotide improved some symptoms.

The scalp accounts for approximately 15% of cutaneous metastases, the most common being from the lung, renal, and breast cancers.⁶ Cutaneous metastases of carcinoid tumors are rare. A PubMed search of articles indexed for MEDLINE using the terms metastatic AND [carcinoid OR neuroendocrine] tumors AND [skin OR cutaneous] revealed 47 cases.^7-11 Similar to other skin metastases, cutaneous metastases of carcinoid tumors commonly present as firm erythematous nodules of varying sizes that may be asymptomatic, tender, or pruritic (Figure 1). Cases of carcinoid tumors with cutaneous metastasis as the initial and only presenting sign are exceedingly rare.¹²

Histology of carcinoid tumors reveals a dermal neoplasm composed of loosely cohesive, mildly atypical, polygonal cells with salt-and-pepper chromatin and eosinophilic cytoplasm, which are similar findings to the primary tumor. The cells may grow in the typical trabecular or organoid neuroendocrine pattern or exhibit a pseudoglandular growth pattern with prominent vessels (quiz image, top).¹² Positive chromogranin and synaptophysin immunostaining are the most common and reliable markers used for the diagnosis of carcinoid tumors.

An important histopathologic differential diagnosis is the aggressive Merkel cell carcinoma, which also demonstrates homogenous salt-and-pepper chromatin but exhibits a higher mitotic rate and positive cytokeratin 20 staining (Figure 2).¹³ Basal cell carcinoma (BCC) also may display similar features, including a blue tumor at scanning magnification and nodular or infiltrative growth patterns. The cell morphology of BCC is characterized by islands of basaloid cells with minimal cytoplasm and frequent apoptosis, connecting to the epidermis with peripheral palisading, retraction artifact, and a myxoid stroma; BCC lacks the salt-and-pepper chromatin commonly seen in carcinoid tumors (Figure 3). Basal cell carcinoma is characterized by positive BerEP4 (epithelial cell adhesion molecule immunostain), cytokeratin 5/6, and cytokeratin 14 uptake. Cytokeratin 20, often used to diagnose Merkel cell carcinoma, is negative in BCC. Chromogranin and synaptophysin occasionally may be positive in BCC.¹⁴

The superficial Ewing sarcoma family of tumors also may be included in the differential diagnosis of small round cell tumors of the skin, but they are very rare. These tumors possess strong positive membranous staining of cytokeratin 99 and also can stain positively for synaptophysin and chromogranin.¹⁵ Epithelial membrane antigen, which is negative in Ewing sarcomas, is positive in carcinoid tumors.¹⁶ Neuroendocrine tumors of all sites share similar basic morphologic patterns, and multiple primary tumors should be considered, including small cell lung carcinoma (Figure 4).^17,18 Red granulations and true glandular lumina typically are not seen in the lungs but are common in gastrointestinal carcinoids.¹⁸ Regarding immunohistochemistry, TTF-1 is negative and CDX2 is positive in gastroenteropancreatic carcinoids, suggesting that these 2 markers can help distinguish carcinoids of unknown primary origin.¹⁹

Metastases in carcinoid tumors are common, with one study noting that the highest frequency of small intestinal metastases was from the ileal subset.²⁰ At the time of diagnosis, 58% to 64% of patients with small intestine carcinoid tumors already had nonlocalized disease, with frequent sites being the lymph nodes (89.8%), liver (44.1%), lungs (13.6%), and peritoneum (13.6%). Regional and distant metastases are associated with substantially worse prognoses, with survival rates of 71.7% and 38.5%, respectively.¹ Treatment of symptomatic unresectable disease focuses on symptomatic management with somatostatin analogs that also control tumor growth.²¹

We present a rare case of scalp metastasis of a carcinoid tumor of the terminal ileum. Distant metastasis is associated with poorer prognosis and should be considered in patients with a known history of a carcinoid tumor.

Acknowledgment—We would like to acknowledge the Research Histology and Tissue Imaging Core at University of Illinois Chicago Research Resources Center for the immunohistochemistry studies.

The Diagnosis: Cutaneous Lymphoid Hyperplasia

Cutaneous lymphoid hyperplasia (CLH)(also known as pseudolymphoma or lymphocytoma cutis) is a benign inflammatory condition that typically presents as a flesh-colored to erythematous or violaceous papule or nodule on the head or neck. Cutaneous lymphoid hyperplasia may arise in response to an antigenic stimulus, such as an insect bite, infectious agent (eg, Borrelia species), medication, or foreign body (eg, tattoos and piercings).^1,2 Given the benign nature and potential for spontaneous resolution, treatment is conservative; however, high-potency topical steroids, cryosurgery, surgical excision, or local radiotherapy may lead to improvement.³ Our patient was started on clobetasol ointment 0.05% and topical tacrolimus 0.1%. After 3 months of use, she reported lesion improvement, but a new lesion appeared on the nose superior to the original. She was offered a steroid injection and liquid nitrogen freezing but was lost to follow-up.

The histopathologic features of CLH are variable and can resemble a cutaneous B- or T-cell lymphoma (quiz images). If there is B-cell predominance, histopathology typically shows a dense dermal infiltrate of lymphocytes admixed with sparse histiocytes, eosinophils, and plasma cells. Multiple germinal-center phenotype lymphoid follicles also may be seen.⁴ Histopathology of T-cell–predominant CLH commonly shows CD4⁺ T helper lymphocytes admixed with CD8⁺ T cells within the dermis with possible papillary dermal edema and red cell extravasation.⁵ Immunohistochemical stains for CD3, CD4, CD8, and CD20 usually are positive. Most lymphocytes are CD3⁺ T cells. Admixed clusters of CD20⁺ B cells may be present.

Angiolymphoid hyperplasia with eosinophilia is a vascular tumor of the skin composed of endothelial cells and inflammatory cells.^6,7 The condition presents as single or multiple flesh-colored to purple papules most commonly on the face, scalp, and ears.⁸ Histologically, lesions appear as well-circumscribed collections of blood vessels composed of plump endothelial cells and an inflammatory infiltrate with lymphocytes and eosinophils (Figure 1A). Endothelial cells also may have an epithelioid appearance.⁷ Apparent fenestrations—holes within endothelial cells—may be present (Figure 1B). Surgical excision is the preferred treatment of angiolymphoid hyperplasia with eosinophilia. Success with laser and cryosurgery also has been reported.

Granuloma faciale typically presents as a solitary redbrown papule or plaque on the face. Linear arborizing vessels and dilated follicular openings with brown globules frequently are seen on dermoscopy.⁹ Although it may resemble CLH clinically, the histopathology of granuloma faciale is characterized by a perivascular and interstitial dermal infiltrate of numerous eosinophils admixed with lymphocytes, plasma cells, and neutrophils underneath a grenz zone (Figure 2).¹⁰ Leukocytoclastic vasculitis may be seen in early lesions, and lesions can show variable angiocentric fibrosis.¹¹ Treatment options include intralesional triamcinolone, topical steroids or calcineurin inhibitors, topical psoralen plus UVA, surgical excision, and laser therapy, but outcomes are variable.¹²

Leukemia cutis is a malignant hematopoietic skin infiltration that presents as multiple pink to red-brown, firm, hemorrhagic papules most frequently involving the head, neck, and trunk.¹³ Rarely, lesions of leukemia cutis may present as ulcers or bullae. Most lesions occur at presentation of systemic leukemia or in the setting of established leukemia. The cutaneous involvement portends a poor prognosis, strongly correlating with additional extramedullary leukemic involvement.¹⁴ Histologic features vary based on the specific type of leukemia (eg, acute myelogenous leukemia). Generally, neoplastic infiltration of the dermis and subcutaneous tissue in a nodular, diffuse, perivascular, or interstitial pattern is seen (Figure 3).¹⁵ Leukemia cutis typically resolves after successful treatment of the underlying leukemia.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. In its early stages, MF presents as erythematous, brown, scaly patches and plaques. With progression to the tumor stage of disease, clonal expansion of CD4⁺ T cells leads to the development of purple papules and nodules.¹⁶ Microscopic findings of MF are dependent on the stage of disease. Early patch lesions show superficial or lichenoid lymphocytic infiltration of the epidermal basal layer.¹⁷ In the plaque stage, dermal infiltrates and epidermotropism become more pronounced, with increased atypical lymphocytes with cerebriform nuclei and interspersed inflammatory cells (Figure 4). In the tumor stage, lymphocytic infiltrates may involve the entirety of the dermis or extend into the subcutaneous tissue, and malignant cells become larger in size.¹⁷ Mycosis fungoides lesions typically stain positive for helper T-cell markers with a minority staining positive for CD8.

The Diagnosis: Cutaneous Lymphoid Hyperplasia

Cutaneous lymphoid hyperplasia (CLH)(also known as pseudolymphoma or lymphocytoma cutis) is a benign inflammatory condition that typically presents as a flesh-colored to erythematous or violaceous papule or nodule on the head or neck. Cutaneous lymphoid hyperplasia may arise in response to an antigenic stimulus, such as an insect bite, infectious agent (eg, Borrelia species), medication, or foreign body (eg, tattoos and piercings).^1,2 Given the benign nature and potential for spontaneous resolution, treatment is conservative; however, high-potency topical steroids, cryosurgery, surgical excision, or local radiotherapy may lead to improvement.³ Our patient was started on clobetasol ointment 0.05% and topical tacrolimus 0.1%. After 3 months of use, she reported lesion improvement, but a new lesion appeared on the nose superior to the original. She was offered a steroid injection and liquid nitrogen freezing but was lost to follow-up.

The histopathologic features of CLH are variable and can resemble a cutaneous B- or T-cell lymphoma (quiz images). If there is B-cell predominance, histopathology typically shows a dense dermal infiltrate of lymphocytes admixed with sparse histiocytes, eosinophils, and plasma cells. Multiple germinal-center phenotype lymphoid follicles also may be seen.⁴ Histopathology of T-cell–predominant CLH commonly shows CD4⁺ T helper lymphocytes admixed with CD8⁺ T cells within the dermis with possible papillary dermal edema and red cell extravasation.⁵ Immunohistochemical stains for CD3, CD4, CD8, and CD20 usually are positive. Most lymphocytes are CD3⁺ T cells. Admixed clusters of CD20⁺ B cells may be present.

Angiolymphoid hyperplasia with eosinophilia is a vascular tumor of the skin composed of endothelial cells and inflammatory cells.^6,7 The condition presents as single or multiple flesh-colored to purple papules most commonly on the face, scalp, and ears.⁸ Histologically, lesions appear as well-circumscribed collections of blood vessels composed of plump endothelial cells and an inflammatory infiltrate with lymphocytes and eosinophils (Figure 1A). Endothelial cells also may have an epithelioid appearance.⁷ Apparent fenestrations—holes within endothelial cells—may be present (Figure 1B). Surgical excision is the preferred treatment of angiolymphoid hyperplasia with eosinophilia. Success with laser and cryosurgery also has been reported.

Granuloma faciale typically presents as a solitary redbrown papule or plaque on the face. Linear arborizing vessels and dilated follicular openings with brown globules frequently are seen on dermoscopy.⁹ Although it may resemble CLH clinically, the histopathology of granuloma faciale is characterized by a perivascular and interstitial dermal infiltrate of numerous eosinophils admixed with lymphocytes, plasma cells, and neutrophils underneath a grenz zone (Figure 2).¹⁰ Leukocytoclastic vasculitis may be seen in early lesions, and lesions can show variable angiocentric fibrosis.¹¹ Treatment options include intralesional triamcinolone, topical steroids or calcineurin inhibitors, topical psoralen plus UVA, surgical excision, and laser therapy, but outcomes are variable.¹²

Leukemia cutis is a malignant hematopoietic skin infiltration that presents as multiple pink to red-brown, firm, hemorrhagic papules most frequently involving the head, neck, and trunk.¹³ Rarely, lesions of leukemia cutis may present as ulcers or bullae. Most lesions occur at presentation of systemic leukemia or in the setting of established leukemia. The cutaneous involvement portends a poor prognosis, strongly correlating with additional extramedullary leukemic involvement.¹⁴ Histologic features vary based on the specific type of leukemia (eg, acute myelogenous leukemia). Generally, neoplastic infiltration of the dermis and subcutaneous tissue in a nodular, diffuse, perivascular, or interstitial pattern is seen (Figure 3).¹⁵ Leukemia cutis typically resolves after successful treatment of the underlying leukemia.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. In its early stages, MF presents as erythematous, brown, scaly patches and plaques. With progression to the tumor stage of disease, clonal expansion of CD4⁺ T cells leads to the development of purple papules and nodules.¹⁶ Microscopic findings of MF are dependent on the stage of disease. Early patch lesions show superficial or lichenoid lymphocytic infiltration of the epidermal basal layer.¹⁷ In the plaque stage, dermal infiltrates and epidermotropism become more pronounced, with increased atypical lymphocytes with cerebriform nuclei and interspersed inflammatory cells (Figure 4). In the tumor stage, lymphocytic infiltrates may involve the entirety of the dermis or extend into the subcutaneous tissue, and malignant cells become larger in size.¹⁷ Mycosis fungoides lesions typically stain positive for helper T-cell markers with a minority staining positive for CD8.

The Diagnosis: Cutaneous Lymphoid Hyperplasia

Cutaneous lymphoid hyperplasia (CLH)(also known as pseudolymphoma or lymphocytoma cutis) is a benign inflammatory condition that typically presents as a flesh-colored to erythematous or violaceous papule or nodule on the head or neck. Cutaneous lymphoid hyperplasia may arise in response to an antigenic stimulus, such as an insect bite, infectious agent (eg, Borrelia species), medication, or foreign body (eg, tattoos and piercings).^1,2 Given the benign nature and potential for spontaneous resolution, treatment is conservative; however, high-potency topical steroids, cryosurgery, surgical excision, or local radiotherapy may lead to improvement.³ Our patient was started on clobetasol ointment 0.05% and topical tacrolimus 0.1%. After 3 months of use, she reported lesion improvement, but a new lesion appeared on the nose superior to the original. She was offered a steroid injection and liquid nitrogen freezing but was lost to follow-up.

The histopathologic features of CLH are variable and can resemble a cutaneous B- or T-cell lymphoma (quiz images). If there is B-cell predominance, histopathology typically shows a dense dermal infiltrate of lymphocytes admixed with sparse histiocytes, eosinophils, and plasma cells. Multiple germinal-center phenotype lymphoid follicles also may be seen.⁴ Histopathology of T-cell–predominant CLH commonly shows CD4⁺ T helper lymphocytes admixed with CD8⁺ T cells within the dermis with possible papillary dermal edema and red cell extravasation.⁵ Immunohistochemical stains for CD3, CD4, CD8, and CD20 usually are positive. Most lymphocytes are CD3⁺ T cells. Admixed clusters of CD20⁺ B cells may be present.

Angiolymphoid hyperplasia with eosinophilia is a vascular tumor of the skin composed of endothelial cells and inflammatory cells.^6,7 The condition presents as single or multiple flesh-colored to purple papules most commonly on the face, scalp, and ears.⁸ Histologically, lesions appear as well-circumscribed collections of blood vessels composed of plump endothelial cells and an inflammatory infiltrate with lymphocytes and eosinophils (Figure 1A). Endothelial cells also may have an epithelioid appearance.⁷ Apparent fenestrations—holes within endothelial cells—may be present (Figure 1B). Surgical excision is the preferred treatment of angiolymphoid hyperplasia with eosinophilia. Success with laser and cryosurgery also has been reported.

Granuloma faciale typically presents as a solitary redbrown papule or plaque on the face. Linear arborizing vessels and dilated follicular openings with brown globules frequently are seen on dermoscopy.⁹ Although it may resemble CLH clinically, the histopathology of granuloma faciale is characterized by a perivascular and interstitial dermal infiltrate of numerous eosinophils admixed with lymphocytes, plasma cells, and neutrophils underneath a grenz zone (Figure 2).¹⁰ Leukocytoclastic vasculitis may be seen in early lesions, and lesions can show variable angiocentric fibrosis.¹¹ Treatment options include intralesional triamcinolone, topical steroids or calcineurin inhibitors, topical psoralen plus UVA, surgical excision, and laser therapy, but outcomes are variable.¹²

Leukemia cutis is a malignant hematopoietic skin infiltration that presents as multiple pink to red-brown, firm, hemorrhagic papules most frequently involving the head, neck, and trunk.¹³ Rarely, lesions of leukemia cutis may present as ulcers or bullae. Most lesions occur at presentation of systemic leukemia or in the setting of established leukemia. The cutaneous involvement portends a poor prognosis, strongly correlating with additional extramedullary leukemic involvement.¹⁴ Histologic features vary based on the specific type of leukemia (eg, acute myelogenous leukemia). Generally, neoplastic infiltration of the dermis and subcutaneous tissue in a nodular, diffuse, perivascular, or interstitial pattern is seen (Figure 3).¹⁵ Leukemia cutis typically resolves after successful treatment of the underlying leukemia.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. In its early stages, MF presents as erythematous, brown, scaly patches and plaques. With progression to the tumor stage of disease, clonal expansion of CD4⁺ T cells leads to the development of purple papules and nodules.¹⁶ Microscopic findings of MF are dependent on the stage of disease. Early patch lesions show superficial or lichenoid lymphocytic infiltration of the epidermal basal layer.¹⁷ In the plaque stage, dermal infiltrates and epidermotropism become more pronounced, with increased atypical lymphocytes with cerebriform nuclei and interspersed inflammatory cells (Figure 4). In the tumor stage, lymphocytic infiltrates may involve the entirety of the dermis or extend into the subcutaneous tissue, and malignant cells become larger in size.¹⁷ Mycosis fungoides lesions typically stain positive for helper T-cell markers with a minority staining positive for CD8.

The Diagnosis: Leiomyosarcoma

Cutaneous leiomyosarcomas are relatively rare neoplasms that favor the head, neck, and extremities of older adults.¹ Dermal leiomyosarcomas originate from arrector pili and are locally aggressive, whereas subcutaneous leiomyosarcomas arise from vascular smooth muscle and metastasize in 30% to 60% of cases.² Clinically, leiomyosarcomas present as solitary, firm, well-circumscribed nodules with possible ulceration and crusting.³ Histopathology of leiomyosarcoma shows fascicles of atypical spindle cells with blunt-ended nuclei and perinuclear glycogen vacuoles, variable atypia, and mitotic figures (quiz images). Definitive diagnosis is based on positive immunohistochemical staining for desmin and smooth muscle actin.⁴ Treatment entails complete removal via wide local excision or Mohs micrographic surgery.⁵

Atypical fibroxanthoma (AFX) is a malignant fibrohistiocytic neoplasm that arises in the dermis and preferentially affects the head and neck in older individuals.³ Atypical fibroxanthoma presents as a nonspecific, pinkred, sometimes ulcerated papule on sun-damaged skin that may clinically resemble a squamous cell carcinoma (SCC) or basal cell carcinoma.6 Histopathology shows pleomorphic spindle cells with hyperchromatic nuclei and abundant cytoplasm mixed with multinucleated giant cells and scattered mitotic figures (Figure 1). Immunohistochemistry is essential for distinguishing AFX from other spindle cell neoplasms. Atypical fibroxanthoma stains positively for vimentin, procollagen-1, CD10, and CD68 but is negative for S-100, human melanoma black 45, Melan-A, desmin, cytokeratin, p40, and p63.⁶ Treatment includes wide local excision or Mohs micrographic surgery.

Melanoma is an aggressive cancer with the propensity to metastasize. Both desmoplastic and spindle cell variants demonstrate atypical spindled melanocytes on histology, and desmoplasia is seen in the desmoplastic variant (Figure 2). In some cases, evaluation of the epidermis for melanoma in situ may aid in diagnosis.⁷ Clinical and prognostic features differ between the 2 variants. Desmoplastic melanomas usually present on the head and neck as scarlike nodules with a low rate of nodal involvement, while spindle cell melanomas can occur anywhere on the body, often are amelanotic, and are associated with widespread metastatic disease at the time of presentation.⁸ SOX10 (SRY-box transcription factor 10) and S-100 may be the only markers that are positive in desmoplastic melanoma.^9,10 Treatment depends on the thickness of the lesion.¹¹

Spindle cell SCC is a histologic variant of SCC characterized by spindled epithelial cells. Spindle cell SCC typically presents as an ulcerated or exophytic mass in sun-exposed areas or areas exposed to ionizing radiation, or in immunocompromised individuals. Histopathology shows spindled pleomorphic keratinocytes with elongated nuclei infiltrating the dermis and minimal keratinization (Figure 3).¹² Immunohistochemistry is necessary to distinguish spindle cell SCC from other spindle cell tumors such as spindle cell melanoma, AFX, and leiomyosarcoma. Spindle cell SCC is positive for high-molecular-weight cytokeratin, p40, and p63. Mohs micrographic surgery provides the highest cure rate, and radiation therapy may be considered when clear surgical margins cannot be obtained.⁶

Undifferentiated pleomorphic sarcoma (UPS) (formerly known as malignant fibrous histiocytoma) describes tumors that resemble AFX but are more invasive. They commonly involve the soft tissue with a higher risk for both recurrence and metastasis than AFX.¹³ Histopathology shows marked cytologic pleomorphism, bizarre cellular forms, atypical mitoses, and ulceration (Figure 4).¹⁴ Diagnosis of UPS is by exclusion and is dependent on immunohistochemical studies. In contrast to AFX, UPS is more likely to be positive for LN-2 (CD74).⁶ Undifferentiated pleomorphic sarcoma has been treated with surgical excision in combination with chemical and radiation therapy, but due to limited data, optimal management is less clear compared to AFX.¹⁵ There is a substantial risk for local recurrence and metastasis, and the lungs are the most common sites of distant metastasis.¹³ In a study of 23 individuals with high-grade UPS, 5-year metastasis-free survival and local recurrence-free survival were 26% and 16%, respectively.¹⁰

The Diagnosis: Leiomyosarcoma

Cutaneous leiomyosarcomas are relatively rare neoplasms that favor the head, neck, and extremities of older adults.¹ Dermal leiomyosarcomas originate from arrector pili and are locally aggressive, whereas subcutaneous leiomyosarcomas arise from vascular smooth muscle and metastasize in 30% to 60% of cases.² Clinically, leiomyosarcomas present as solitary, firm, well-circumscribed nodules with possible ulceration and crusting.³ Histopathology of leiomyosarcoma shows fascicles of atypical spindle cells with blunt-ended nuclei and perinuclear glycogen vacuoles, variable atypia, and mitotic figures (quiz images). Definitive diagnosis is based on positive immunohistochemical staining for desmin and smooth muscle actin.⁴ Treatment entails complete removal via wide local excision or Mohs micrographic surgery.⁵

Atypical fibroxanthoma (AFX) is a malignant fibrohistiocytic neoplasm that arises in the dermis and preferentially affects the head and neck in older individuals.³ Atypical fibroxanthoma presents as a nonspecific, pinkred, sometimes ulcerated papule on sun-damaged skin that may clinically resemble a squamous cell carcinoma (SCC) or basal cell carcinoma.6 Histopathology shows pleomorphic spindle cells with hyperchromatic nuclei and abundant cytoplasm mixed with multinucleated giant cells and scattered mitotic figures (Figure 1). Immunohistochemistry is essential for distinguishing AFX from other spindle cell neoplasms. Atypical fibroxanthoma stains positively for vimentin, procollagen-1, CD10, and CD68 but is negative for S-100, human melanoma black 45, Melan-A, desmin, cytokeratin, p40, and p63.⁶ Treatment includes wide local excision or Mohs micrographic surgery.

Melanoma is an aggressive cancer with the propensity to metastasize. Both desmoplastic and spindle cell variants demonstrate atypical spindled melanocytes on histology, and desmoplasia is seen in the desmoplastic variant (Figure 2). In some cases, evaluation of the epidermis for melanoma in situ may aid in diagnosis.⁷ Clinical and prognostic features differ between the 2 variants. Desmoplastic melanomas usually present on the head and neck as scarlike nodules with a low rate of nodal involvement, while spindle cell melanomas can occur anywhere on the body, often are amelanotic, and are associated with widespread metastatic disease at the time of presentation.⁸ SOX10 (SRY-box transcription factor 10) and S-100 may be the only markers that are positive in desmoplastic melanoma.^9,10 Treatment depends on the thickness of the lesion.¹¹

Spindle cell SCC is a histologic variant of SCC characterized by spindled epithelial cells. Spindle cell SCC typically presents as an ulcerated or exophytic mass in sun-exposed areas or areas exposed to ionizing radiation, or in immunocompromised individuals. Histopathology shows spindled pleomorphic keratinocytes with elongated nuclei infiltrating the dermis and minimal keratinization (Figure 3).¹² Immunohistochemistry is necessary to distinguish spindle cell SCC from other spindle cell tumors such as spindle cell melanoma, AFX, and leiomyosarcoma. Spindle cell SCC is positive for high-molecular-weight cytokeratin, p40, and p63. Mohs micrographic surgery provides the highest cure rate, and radiation therapy may be considered when clear surgical margins cannot be obtained.⁶

Undifferentiated pleomorphic sarcoma (UPS) (formerly known as malignant fibrous histiocytoma) describes tumors that resemble AFX but are more invasive. They commonly involve the soft tissue with a higher risk for both recurrence and metastasis than AFX.¹³ Histopathology shows marked cytologic pleomorphism, bizarre cellular forms, atypical mitoses, and ulceration (Figure 4).¹⁴ Diagnosis of UPS is by exclusion and is dependent on immunohistochemical studies. In contrast to AFX, UPS is more likely to be positive for LN-2 (CD74).⁶ Undifferentiated pleomorphic sarcoma has been treated with surgical excision in combination with chemical and radiation therapy, but due to limited data, optimal management is less clear compared to AFX.¹⁵ There is a substantial risk for local recurrence and metastasis, and the lungs are the most common sites of distant metastasis.¹³ In a study of 23 individuals with high-grade UPS, 5-year metastasis-free survival and local recurrence-free survival were 26% and 16%, respectively.¹⁰

The Diagnosis: Leiomyosarcoma

Cutaneous leiomyosarcomas are relatively rare neoplasms that favor the head, neck, and extremities of older adults.¹ Dermal leiomyosarcomas originate from arrector pili and are locally aggressive, whereas subcutaneous leiomyosarcomas arise from vascular smooth muscle and metastasize in 30% to 60% of cases.² Clinically, leiomyosarcomas present as solitary, firm, well-circumscribed nodules with possible ulceration and crusting.³ Histopathology of leiomyosarcoma shows fascicles of atypical spindle cells with blunt-ended nuclei and perinuclear glycogen vacuoles, variable atypia, and mitotic figures (quiz images). Definitive diagnosis is based on positive immunohistochemical staining for desmin and smooth muscle actin.⁴ Treatment entails complete removal via wide local excision or Mohs micrographic surgery.⁵

Atypical fibroxanthoma (AFX) is a malignant fibrohistiocytic neoplasm that arises in the dermis and preferentially affects the head and neck in older individuals.³ Atypical fibroxanthoma presents as a nonspecific, pinkred, sometimes ulcerated papule on sun-damaged skin that may clinically resemble a squamous cell carcinoma (SCC) or basal cell carcinoma.6 Histopathology shows pleomorphic spindle cells with hyperchromatic nuclei and abundant cytoplasm mixed with multinucleated giant cells and scattered mitotic figures (Figure 1). Immunohistochemistry is essential for distinguishing AFX from other spindle cell neoplasms. Atypical fibroxanthoma stains positively for vimentin, procollagen-1, CD10, and CD68 but is negative for S-100, human melanoma black 45, Melan-A, desmin, cytokeratin, p40, and p63.⁶ Treatment includes wide local excision or Mohs micrographic surgery.

Melanoma is an aggressive cancer with the propensity to metastasize. Both desmoplastic and spindle cell variants demonstrate atypical spindled melanocytes on histology, and desmoplasia is seen in the desmoplastic variant (Figure 2). In some cases, evaluation of the epidermis for melanoma in situ may aid in diagnosis.⁷ Clinical and prognostic features differ between the 2 variants. Desmoplastic melanomas usually present on the head and neck as scarlike nodules with a low rate of nodal involvement, while spindle cell melanomas can occur anywhere on the body, often are amelanotic, and are associated with widespread metastatic disease at the time of presentation.⁸ SOX10 (SRY-box transcription factor 10) and S-100 may be the only markers that are positive in desmoplastic melanoma.^9,10 Treatment depends on the thickness of the lesion.¹¹

Spindle cell SCC is a histologic variant of SCC characterized by spindled epithelial cells. Spindle cell SCC typically presents as an ulcerated or exophytic mass in sun-exposed areas or areas exposed to ionizing radiation, or in immunocompromised individuals. Histopathology shows spindled pleomorphic keratinocytes with elongated nuclei infiltrating the dermis and minimal keratinization (Figure 3).¹² Immunohistochemistry is necessary to distinguish spindle cell SCC from other spindle cell tumors such as spindle cell melanoma, AFX, and leiomyosarcoma. Spindle cell SCC is positive for high-molecular-weight cytokeratin, p40, and p63. Mohs micrographic surgery provides the highest cure rate, and radiation therapy may be considered when clear surgical margins cannot be obtained.⁶

Undifferentiated pleomorphic sarcoma (UPS) (formerly known as malignant fibrous histiocytoma) describes tumors that resemble AFX but are more invasive. They commonly involve the soft tissue with a higher risk for both recurrence and metastasis than AFX.¹³ Histopathology shows marked cytologic pleomorphism, bizarre cellular forms, atypical mitoses, and ulceration (Figure 4).¹⁴ Diagnosis of UPS is by exclusion and is dependent on immunohistochemical studies. In contrast to AFX, UPS is more likely to be positive for LN-2 (CD74).⁶ Undifferentiated pleomorphic sarcoma has been treated with surgical excision in combination with chemical and radiation therapy, but due to limited data, optimal management is less clear compared to AFX.¹⁵ There is a substantial risk for local recurrence and metastasis, and the lungs are the most common sites of distant metastasis.¹³ In a study of 23 individuals with high-grade UPS, 5-year metastasis-free survival and local recurrence-free survival were 26% and 16%, respectively.¹⁰