Dermpath Diagnosis

The Diagnosis: Perforating Rheumatoid Nodule

Perforating rheumatoid nodule (RN) is a variant of RN that demonstrates necrobiotic material extruding through the epidermis via the process of transepidermal elimination.¹ The necrobiotic material contains fibrin and often harbors karyorrhectic debris. The pathogenesis of RN remains unclear; possible mechanisms include a small vessel vasculitis or mechanical trauma inciting a localized aggregation of inflammatory products and rheumatoid factor complexes. This induces macrophage activation, fibrin deposition, and necrosis.² The majority of patients with RNs have detectable rheumatoid factor and anticyclic citrullinated protein in the blood.³ Rheumatoid nodules are the most common cutaneous manifestations of rheumatoid arthritis (RA) and will develop in 30% to 40% of RA patients.^4,5 They typically are associated with advanced RA but may precede the onset of clinically severe RA in 5% to 10% of patients.5 Rheumatoid nodules generally range in size from 2 mm to 5 cm and are slightly more prevalent in men than in women. They present as firm painless masses typically on the extensor surfaces of the hands and olecranon process but can occur over any tendinous or ligamentlike structure.^6,7 Perforating RNs are most common on areas subjected to pressure or repeated trauma, such as the sacrum.

The diagnosis usually is clinical; however, in cases of diagnostic uncertainty, RN can be distinguished by its histologic appearance. Rheumatoid nodules demonstrate granulomatous palisading necrobiosis with a central zone of highly eosinophilic fibrinoid necrobiosis surrounded by palisading mononuclear cells and an outer zone of granulation tissue. There may be a mixed chronic inflammatory infiltrate predominantly composed of lymphocytes and histiocytes in the background.

Rheumatoid nodules typically do not require treatment; however, perforation is known to increase the risk for infection, and surgical excision generally is indicated for prophylaxis against infection, though nodules may recur in the excision area.^1,3,8 Alternatively, disease-modifying antirheumatic drugs and intralesional corticosteroids may effectively reduce the size of RNs. The differential diagnosis for perforating RNs includes epithelioid sarcoma, perforating granuloma annulare, necrobiotic xanthogranuloma, and necrobiosis lipoidica.

Epithelioid sarcoma is a malignant soft tissue tumor typically found on the upper extremities of adolescent or young adult males. They usually present as hard tender nodules that commonly ulcerate. Epithelioid sarcoma makes up less than 1% of soft tissue sarcomas.⁹ Although rare, they present a diagnostic pitfall, as the histology may mimic an inflammatory palisaded granulomatous dermatitis similar to RN and granuloma annulare, thus a high index of suspicion is required to not overlook this aggressive malignancy. Histology is typified by nodular aggregates of epithelioid cells with abundant eosinophilic cytoplasm and often with central zones of necrosis (Figure 1). Epithelioid sarcoma displays immunoreactivity to cytokeratin, CD34, and epithelial membrane antigen, but loss of integrase interactor 1 expression. Cytologic abnormalities such as pleomorphism and hyperchromatism can be helpful in distinguishing between epithelioid sarcoma and RN.

Perforating granuloma annulare is a rare subtype of granuloma annulare that presents with flesh- to red-colored papules that develop central crust or scale. Perforating granuloma annulare composes approximately 5% of granuloma annulare cases. Perforating granuloma annulare can develop on any region of the body but has an affinity for the extensor surfaces of the extremities. It most frequently occurs in young women and rarely presents as a single lesion.¹⁰ Granuloma annulare typically is not associated with joint pain, and thus it differs from most cases of RNs. Histologically, it presents with an inflammatory palisading granuloma. There may be overlying epidermal thinning or parakeratosis, which can progress to perforation and extrusion of necrobiotic material. In comparison with RN, perforating granuloma annulare displays mucin deposition in the necrobiotic zones in lieu of fibrin (Figure 2).^10,11

Necrobiotic xanthogranuloma is a rare chronic form of non-Langerhans histiocytosis that characteristically presents with yellow or violaceous indurated plaques and nodules in a periorbital distribution. It often is associated with monoclonal gammopathy of IgG-κ. Lesions will ulcerate in 40% to 50% of patients.¹² The mean age at presentation is in the sixth decade of life, and it is moderately predominant in females.13 Histopathology demonstrates palisading granulomatous formations with a lymphoplasmacytic infiltrate and zones of necrobiosis in the mid dermis extending into the panniculus. Characteristic histologic features that are variably present in necrobiotic xanthogranuloma but typically absent in RN include neutrophilic debris, cholesterol clefts, and Touton or foreign body giant cells (Figure 3).¹³

Necrobiosis lipoidica is a rare chronic granulomatous disease characterized by well-demarcated, atrophic, yellow-brown plaques on the pretibial surfaces. It typically presents in the third decade of life in women, and most cases are associated with diabetes mellitus types 1 or 2 or autoimmune conditions.14 Necrobiosis lipoidica begins as asymptomatic papules that enlarge progressively over months to years. They can become pruritic or painful and often develop ulceration. Histopathology shows horizontal zones of palisading histiocytes with intervening necrobiosis. An inflammatory infiltrate containing plasma cells also may be present (Figure 4).

The Diagnosis: Perforating Rheumatoid Nodule

Perforating rheumatoid nodule (RN) is a variant of RN that demonstrates necrobiotic material extruding through the epidermis via the process of transepidermal elimination.¹ The necrobiotic material contains fibrin and often harbors karyorrhectic debris. The pathogenesis of RN remains unclear; possible mechanisms include a small vessel vasculitis or mechanical trauma inciting a localized aggregation of inflammatory products and rheumatoid factor complexes. This induces macrophage activation, fibrin deposition, and necrosis.² The majority of patients with RNs have detectable rheumatoid factor and anticyclic citrullinated protein in the blood.³ Rheumatoid nodules are the most common cutaneous manifestations of rheumatoid arthritis (RA) and will develop in 30% to 40% of RA patients.^4,5 They typically are associated with advanced RA but may precede the onset of clinically severe RA in 5% to 10% of patients.5 Rheumatoid nodules generally range in size from 2 mm to 5 cm and are slightly more prevalent in men than in women. They present as firm painless masses typically on the extensor surfaces of the hands and olecranon process but can occur over any tendinous or ligamentlike structure.^6,7 Perforating RNs are most common on areas subjected to pressure or repeated trauma, such as the sacrum.

The diagnosis usually is clinical; however, in cases of diagnostic uncertainty, RN can be distinguished by its histologic appearance. Rheumatoid nodules demonstrate granulomatous palisading necrobiosis with a central zone of highly eosinophilic fibrinoid necrobiosis surrounded by palisading mononuclear cells and an outer zone of granulation tissue. There may be a mixed chronic inflammatory infiltrate predominantly composed of lymphocytes and histiocytes in the background.

Rheumatoid nodules typically do not require treatment; however, perforation is known to increase the risk for infection, and surgical excision generally is indicated for prophylaxis against infection, though nodules may recur in the excision area.^1,3,8 Alternatively, disease-modifying antirheumatic drugs and intralesional corticosteroids may effectively reduce the size of RNs. The differential diagnosis for perforating RNs includes epithelioid sarcoma, perforating granuloma annulare, necrobiotic xanthogranuloma, and necrobiosis lipoidica.

Epithelioid sarcoma is a malignant soft tissue tumor typically found on the upper extremities of adolescent or young adult males. They usually present as hard tender nodules that commonly ulcerate. Epithelioid sarcoma makes up less than 1% of soft tissue sarcomas.⁹ Although rare, they present a diagnostic pitfall, as the histology may mimic an inflammatory palisaded granulomatous dermatitis similar to RN and granuloma annulare, thus a high index of suspicion is required to not overlook this aggressive malignancy. Histology is typified by nodular aggregates of epithelioid cells with abundant eosinophilic cytoplasm and often with central zones of necrosis (Figure 1). Epithelioid sarcoma displays immunoreactivity to cytokeratin, CD34, and epithelial membrane antigen, but loss of integrase interactor 1 expression. Cytologic abnormalities such as pleomorphism and hyperchromatism can be helpful in distinguishing between epithelioid sarcoma and RN.

Perforating granuloma annulare is a rare subtype of granuloma annulare that presents with flesh- to red-colored papules that develop central crust or scale. Perforating granuloma annulare composes approximately 5% of granuloma annulare cases. Perforating granuloma annulare can develop on any region of the body but has an affinity for the extensor surfaces of the extremities. It most frequently occurs in young women and rarely presents as a single lesion.¹⁰ Granuloma annulare typically is not associated with joint pain, and thus it differs from most cases of RNs. Histologically, it presents with an inflammatory palisading granuloma. There may be overlying epidermal thinning or parakeratosis, which can progress to perforation and extrusion of necrobiotic material. In comparison with RN, perforating granuloma annulare displays mucin deposition in the necrobiotic zones in lieu of fibrin (Figure 2).^10,11

Necrobiotic xanthogranuloma is a rare chronic form of non-Langerhans histiocytosis that characteristically presents with yellow or violaceous indurated plaques and nodules in a periorbital distribution. It often is associated with monoclonal gammopathy of IgG-κ. Lesions will ulcerate in 40% to 50% of patients.¹² The mean age at presentation is in the sixth decade of life, and it is moderately predominant in females.13 Histopathology demonstrates palisading granulomatous formations with a lymphoplasmacytic infiltrate and zones of necrobiosis in the mid dermis extending into the panniculus. Characteristic histologic features that are variably present in necrobiotic xanthogranuloma but typically absent in RN include neutrophilic debris, cholesterol clefts, and Touton or foreign body giant cells (Figure 3).¹³

Necrobiosis lipoidica is a rare chronic granulomatous disease characterized by well-demarcated, atrophic, yellow-brown plaques on the pretibial surfaces. It typically presents in the third decade of life in women, and most cases are associated with diabetes mellitus types 1 or 2 or autoimmune conditions.14 Necrobiosis lipoidica begins as asymptomatic papules that enlarge progressively over months to years. They can become pruritic or painful and often develop ulceration. Histopathology shows horizontal zones of palisading histiocytes with intervening necrobiosis. An inflammatory infiltrate containing plasma cells also may be present (Figure 4).

The Diagnosis: Perforating Rheumatoid Nodule

Perforating rheumatoid nodule (RN) is a variant of RN that demonstrates necrobiotic material extruding through the epidermis via the process of transepidermal elimination.¹ The necrobiotic material contains fibrin and often harbors karyorrhectic debris. The pathogenesis of RN remains unclear; possible mechanisms include a small vessel vasculitis or mechanical trauma inciting a localized aggregation of inflammatory products and rheumatoid factor complexes. This induces macrophage activation, fibrin deposition, and necrosis.² The majority of patients with RNs have detectable rheumatoid factor and anticyclic citrullinated protein in the blood.³ Rheumatoid nodules are the most common cutaneous manifestations of rheumatoid arthritis (RA) and will develop in 30% to 40% of RA patients.^4,5 They typically are associated with advanced RA but may precede the onset of clinically severe RA in 5% to 10% of patients.5 Rheumatoid nodules generally range in size from 2 mm to 5 cm and are slightly more prevalent in men than in women. They present as firm painless masses typically on the extensor surfaces of the hands and olecranon process but can occur over any tendinous or ligamentlike structure.^6,7 Perforating RNs are most common on areas subjected to pressure or repeated trauma, such as the sacrum.

The diagnosis usually is clinical; however, in cases of diagnostic uncertainty, RN can be distinguished by its histologic appearance. Rheumatoid nodules demonstrate granulomatous palisading necrobiosis with a central zone of highly eosinophilic fibrinoid necrobiosis surrounded by palisading mononuclear cells and an outer zone of granulation tissue. There may be a mixed chronic inflammatory infiltrate predominantly composed of lymphocytes and histiocytes in the background.

Rheumatoid nodules typically do not require treatment; however, perforation is known to increase the risk for infection, and surgical excision generally is indicated for prophylaxis against infection, though nodules may recur in the excision area.^1,3,8 Alternatively, disease-modifying antirheumatic drugs and intralesional corticosteroids may effectively reduce the size of RNs. The differential diagnosis for perforating RNs includes epithelioid sarcoma, perforating granuloma annulare, necrobiotic xanthogranuloma, and necrobiosis lipoidica.

Epithelioid sarcoma is a malignant soft tissue tumor typically found on the upper extremities of adolescent or young adult males. They usually present as hard tender nodules that commonly ulcerate. Epithelioid sarcoma makes up less than 1% of soft tissue sarcomas.⁹ Although rare, they present a diagnostic pitfall, as the histology may mimic an inflammatory palisaded granulomatous dermatitis similar to RN and granuloma annulare, thus a high index of suspicion is required to not overlook this aggressive malignancy. Histology is typified by nodular aggregates of epithelioid cells with abundant eosinophilic cytoplasm and often with central zones of necrosis (Figure 1). Epithelioid sarcoma displays immunoreactivity to cytokeratin, CD34, and epithelial membrane antigen, but loss of integrase interactor 1 expression. Cytologic abnormalities such as pleomorphism and hyperchromatism can be helpful in distinguishing between epithelioid sarcoma and RN.

Perforating granuloma annulare is a rare subtype of granuloma annulare that presents with flesh- to red-colored papules that develop central crust or scale. Perforating granuloma annulare composes approximately 5% of granuloma annulare cases. Perforating granuloma annulare can develop on any region of the body but has an affinity for the extensor surfaces of the extremities. It most frequently occurs in young women and rarely presents as a single lesion.¹⁰ Granuloma annulare typically is not associated with joint pain, and thus it differs from most cases of RNs. Histologically, it presents with an inflammatory palisading granuloma. There may be overlying epidermal thinning or parakeratosis, which can progress to perforation and extrusion of necrobiotic material. In comparison with RN, perforating granuloma annulare displays mucin deposition in the necrobiotic zones in lieu of fibrin (Figure 2).^10,11

Necrobiotic xanthogranuloma is a rare chronic form of non-Langerhans histiocytosis that characteristically presents with yellow or violaceous indurated plaques and nodules in a periorbital distribution. It often is associated with monoclonal gammopathy of IgG-κ. Lesions will ulcerate in 40% to 50% of patients.¹² The mean age at presentation is in the sixth decade of life, and it is moderately predominant in females.13 Histopathology demonstrates palisading granulomatous formations with a lymphoplasmacytic infiltrate and zones of necrobiosis in the mid dermis extending into the panniculus. Characteristic histologic features that are variably present in necrobiotic xanthogranuloma but typically absent in RN include neutrophilic debris, cholesterol clefts, and Touton or foreign body giant cells (Figure 3).¹³

Necrobiosis lipoidica is a rare chronic granulomatous disease characterized by well-demarcated, atrophic, yellow-brown plaques on the pretibial surfaces. It typically presents in the third decade of life in women, and most cases are associated with diabetes mellitus types 1 or 2 or autoimmune conditions.14 Necrobiosis lipoidica begins as asymptomatic papules that enlarge progressively over months to years. They can become pruritic or painful and often develop ulceration. Histopathology shows horizontal zones of palisading histiocytes with intervening necrobiosis. An inflammatory infiltrate containing plasma cells also may be present (Figure 4).

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

A diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) was rendered. Subsequent needle core biopsy of a left axillary lymph node as well as bone marrow aspiration and biopsy revealed a similar diffuse blastoid infiltrate with an identical immunophenotype to that in the skin biopsy from the pretibial mass and peripheral blood.

Previously known as blastic natural killer cell leukemia/lymphoma or agranular CD4+/CD56+ hematodermic neoplasm/tumor, BPDCN is a rare, clinically aggressive hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. It often is diagnostically challenging, particularly when presenting at noncutaneous sites and in unusual (young) patient populations.¹ It was included with other myeloid neoplasms in the 2008 World Health Organization classification; however, in the 2017 classification it was categorized as a separate entity. Blastic plasmacytoid dendritic cell neoplasm typically presents in the skin of elderly patients (age range at diagnosis, 61–67 years) with or without bone marrow involvement and systemic dissemination.^1,2 The skin is the most common clinical site of disease in typical cases of BPDCN and often precedes bone marrow involvement. Thus, skin biopsy often is the key to making the diagnosis. Diagnosis of BPDCN may be delayed because of diagnostic pitfalls. Patients usually present with asymptomatic solitary or multiple lesions.^3-5 Blastic plasmacytoid dendritic cell neoplasm can present as an isolated purplish nodule or bruiselike papule or more commonly as disseminated purplish nodules, papules, and macules. Isolated nodules are found on the head and lower limbs and can be more than 10 cm in diameter. Peripheral blood and bone marrow may be minimally involved at presentation but invariably become involved with the progression of disease. Cytopenia can occur at diagnosis and in a minority of severe cases indicates bone marrow failure.^2-6

Skin involvement of BPDCN is thought to be secondary to the expression of skin migration molecules, such as cutaneous lymphocyte-associated antigen, one of the E-selectin ligands, which binds to E-selectin on high endothelial venules. In addition, the local dermal microenvironment of chemokines binding CXCR3, CXCR4, CCR6, or CCR7 present on neoplastic cells possibly leads to skin involvement. The full mechanism underlying the cutaneous tropism is still to be elucidated.^4-7 Infiltration of the oral mucosa is seen in some patients, but it may be underreported. Mucosal disease typically appears similarly to cutaneous disease.

The cutaneous differential diagnosis for BPDCN depends on the clinical presentation, extent of disease spread, and thickness of infiltration. It includes common nonneoplastic diseases such as traumatic ecchymoses; purpuric disorders; extramedullary hematopoiesis; and soft-tissue neoplasms such as angiosarcoma, Kaposi sarcoma, neuroblastoma, and vascular metastases, as well as skin involvement by other hematologic neoplasms. An adequate incisional biopsy rather than a punch or shave biopsy is recommended for diagnosis. Dermatologists should alert the pathologist that BPDCN is in the clinical differential diagnosis when possible so that judicious use of appropriate immunophenotypic markers such as CD123, CD4, CD56, and T-cell leukemia/lymphoma protein 1 will avoid misdiagnosis of this aggressive condition, in addition to excluding acute myeloid leukemia, which also may express 3 of the above markers. However, most cases of acute myeloid leukemia lack terminal deoxynucleotidyl transferase (TdT) and express monocytic and other myeloid markers. Terminal deoxynucleotidyl transferase is positive in approximately one-third of cases of BPDCN, with expression in 10% to 80% of cells.¹

It is important to include BPDCN in the differential diagnosis of immunophenotypically aberrant hematologic tumors. Diffuse large B-cell lymphoma, leg type, accounts for 4% of all primary cutaneous B-cell lymphomas.¹ Compared with BPDCN, diffuse large B-cell lymphoma usually occurs in an older age group and is of B-cell lineage. Morphologically, these neoplasms are composed of a monotonous, diffuse, nonepidermotropic infiltrate of confluent sheets of centroblasts and immunoblasts (Figure 1). They may share immunohistochemical markers of CD79a, multiple myeloma 1, Bcl-2, and Bcl-6; however, they lack plasmacytoid dendritic cell (PDC)– associated antigens such as CD4, CD56, CD123, and T-cell leukemia/lymphoma protein 1.¹

Adult T-cell leukemia/lymphoma is a neoplasm histologically composed of highly pleomorphic medium- to large-sized T cells with an irregular multilobated nuclear contour, so-called flower cells, in the peripheral blood. The nuclear chromatin is coarse and clumped with prominent nucleoli. Blastlike cells with dispersed chromatin are present in variable proportions. Most patients present with widespread lymph node and peripheral blood involvement. Skin is involved in more than half of patients with an epidermal as well as dermal pattern of infiltration (mainly perivascular)(Figure 2). Adult T-cell leukemia/lymphoma is endemic in several regions of the world, and the distribution is closely linked to the prevalence of human T-cell lymphotropic virus type 1 in the population. This neoplasm is of T-cell lineage and may share CD4 but not PDC-associated antigens with BPDCN.¹

Cutaneous involvement by T-cell lymphoblastic leukemia/lymphoma (T-LBL) is a rare occurrence with a frequency of approximately 4.3%.8 T-cell lymphoblastic leukemia/lymphoma usually presents as multiple skin lesions throughout the body. Almost all cutaneous T-LBL cases are seen in association with bone marrow and/or mediastinal, lymph node, or extranodal involvement. Cutaneous T-LBLs present as a diffuse monomorphous infiltrate located in the entire dermis and subcutis without epidermotropism, composed of medium to large blasts with finely dispersed chromatin and relatively prominent nucleoli (Figure 3). Immunophenotyping studies show an immature T-cell immunophenotype, with expression of TdT (usually uniform), CD7, and cytoplasmic CD3 and an absence of PDC-associated antigens.⁸

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a neoplasm primarily involving the skin. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection. Histologically, they show variable epidermotropism as well as dermal and subcutaneous involvement by medium to large cells with coarse clumped chromatin (Figure 4). Large blastic cells with vesicular nuclei and prominent nucleoli are infrequent. In contrast to BPCDN, the neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are positive for T-cell intracellular antigen-1 and granzyme B with loss of CD4.⁹

At the time of presentation, 27% to 87% of BPDCN patients will have bone marrow involvement, 22% to 28% will have blood involvement, and 6% to 41% will have lymph node involvement.^{1-4,6,7,10,11} The clinical course is aggressive, with a median survival of 10.0 to 19.8 months, irrespective of the initial pattern of disease.¹ Most cases have shown initial response to multiagent chemotherapy, but relapses with subsequent resistance to drugs regularly have been observed. Age has an adverse impact of prognosis. Low TdT expression has been associated with shorter survival.¹ Approximately 10% to 20% of cases of BPDCN are associated with or develop into chronic myelogenous leukemia, myelodysplastic syndrome, or acute myeloid leukemia.^1,4 Pediatric patients have a greater 5-year overall survival rate than older patients, and overall survival worsens with increasing age. The extent of cutaneous involvement and presence of systemic involvement at initial presentation do not seem to be strong predictors of survival.^{1,2,5-7,10-12} In a retrospective analysis of 90 patients, Julia et al¹² found that the type of skin disease did not predict survival. Specifically, the presence of nodular lesions and disseminated skin involvement were not adverse prognostic factors compared with macular lesions limited to 1 or 2 body areas.¹²

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

A diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) was rendered. Subsequent needle core biopsy of a left axillary lymph node as well as bone marrow aspiration and biopsy revealed a similar diffuse blastoid infiltrate with an identical immunophenotype to that in the skin biopsy from the pretibial mass and peripheral blood.

Previously known as blastic natural killer cell leukemia/lymphoma or agranular CD4+/CD56+ hematodermic neoplasm/tumor, BPDCN is a rare, clinically aggressive hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. It often is diagnostically challenging, particularly when presenting at noncutaneous sites and in unusual (young) patient populations.¹ It was included with other myeloid neoplasms in the 2008 World Health Organization classification; however, in the 2017 classification it was categorized as a separate entity. Blastic plasmacytoid dendritic cell neoplasm typically presents in the skin of elderly patients (age range at diagnosis, 61–67 years) with or without bone marrow involvement and systemic dissemination.^1,2 The skin is the most common clinical site of disease in typical cases of BPDCN and often precedes bone marrow involvement. Thus, skin biopsy often is the key to making the diagnosis. Diagnosis of BPDCN may be delayed because of diagnostic pitfalls. Patients usually present with asymptomatic solitary or multiple lesions.^3-5 Blastic plasmacytoid dendritic cell neoplasm can present as an isolated purplish nodule or bruiselike papule or more commonly as disseminated purplish nodules, papules, and macules. Isolated nodules are found on the head and lower limbs and can be more than 10 cm in diameter. Peripheral blood and bone marrow may be minimally involved at presentation but invariably become involved with the progression of disease. Cytopenia can occur at diagnosis and in a minority of severe cases indicates bone marrow failure.^2-6

Skin involvement of BPDCN is thought to be secondary to the expression of skin migration molecules, such as cutaneous lymphocyte-associated antigen, one of the E-selectin ligands, which binds to E-selectin on high endothelial venules. In addition, the local dermal microenvironment of chemokines binding CXCR3, CXCR4, CCR6, or CCR7 present on neoplastic cells possibly leads to skin involvement. The full mechanism underlying the cutaneous tropism is still to be elucidated.^4-7 Infiltration of the oral mucosa is seen in some patients, but it may be underreported. Mucosal disease typically appears similarly to cutaneous disease.

The cutaneous differential diagnosis for BPDCN depends on the clinical presentation, extent of disease spread, and thickness of infiltration. It includes common nonneoplastic diseases such as traumatic ecchymoses; purpuric disorders; extramedullary hematopoiesis; and soft-tissue neoplasms such as angiosarcoma, Kaposi sarcoma, neuroblastoma, and vascular metastases, as well as skin involvement by other hematologic neoplasms. An adequate incisional biopsy rather than a punch or shave biopsy is recommended for diagnosis. Dermatologists should alert the pathologist that BPDCN is in the clinical differential diagnosis when possible so that judicious use of appropriate immunophenotypic markers such as CD123, CD4, CD56, and T-cell leukemia/lymphoma protein 1 will avoid misdiagnosis of this aggressive condition, in addition to excluding acute myeloid leukemia, which also may express 3 of the above markers. However, most cases of acute myeloid leukemia lack terminal deoxynucleotidyl transferase (TdT) and express monocytic and other myeloid markers. Terminal deoxynucleotidyl transferase is positive in approximately one-third of cases of BPDCN, with expression in 10% to 80% of cells.¹

It is important to include BPDCN in the differential diagnosis of immunophenotypically aberrant hematologic tumors. Diffuse large B-cell lymphoma, leg type, accounts for 4% of all primary cutaneous B-cell lymphomas.¹ Compared with BPDCN, diffuse large B-cell lymphoma usually occurs in an older age group and is of B-cell lineage. Morphologically, these neoplasms are composed of a monotonous, diffuse, nonepidermotropic infiltrate of confluent sheets of centroblasts and immunoblasts (Figure 1). They may share immunohistochemical markers of CD79a, multiple myeloma 1, Bcl-2, and Bcl-6; however, they lack plasmacytoid dendritic cell (PDC)– associated antigens such as CD4, CD56, CD123, and T-cell leukemia/lymphoma protein 1.¹

Adult T-cell leukemia/lymphoma is a neoplasm histologically composed of highly pleomorphic medium- to large-sized T cells with an irregular multilobated nuclear contour, so-called flower cells, in the peripheral blood. The nuclear chromatin is coarse and clumped with prominent nucleoli. Blastlike cells with dispersed chromatin are present in variable proportions. Most patients present with widespread lymph node and peripheral blood involvement. Skin is involved in more than half of patients with an epidermal as well as dermal pattern of infiltration (mainly perivascular)(Figure 2). Adult T-cell leukemia/lymphoma is endemic in several regions of the world, and the distribution is closely linked to the prevalence of human T-cell lymphotropic virus type 1 in the population. This neoplasm is of T-cell lineage and may share CD4 but not PDC-associated antigens with BPDCN.¹

Cutaneous involvement by T-cell lymphoblastic leukemia/lymphoma (T-LBL) is a rare occurrence with a frequency of approximately 4.3%.8 T-cell lymphoblastic leukemia/lymphoma usually presents as multiple skin lesions throughout the body. Almost all cutaneous T-LBL cases are seen in association with bone marrow and/or mediastinal, lymph node, or extranodal involvement. Cutaneous T-LBLs present as a diffuse monomorphous infiltrate located in the entire dermis and subcutis without epidermotropism, composed of medium to large blasts with finely dispersed chromatin and relatively prominent nucleoli (Figure 3). Immunophenotyping studies show an immature T-cell immunophenotype, with expression of TdT (usually uniform), CD7, and cytoplasmic CD3 and an absence of PDC-associated antigens.⁸

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a neoplasm primarily involving the skin. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection. Histologically, they show variable epidermotropism as well as dermal and subcutaneous involvement by medium to large cells with coarse clumped chromatin (Figure 4). Large blastic cells with vesicular nuclei and prominent nucleoli are infrequent. In contrast to BPCDN, the neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are positive for T-cell intracellular antigen-1 and granzyme B with loss of CD4.⁹

At the time of presentation, 27% to 87% of BPDCN patients will have bone marrow involvement, 22% to 28% will have blood involvement, and 6% to 41% will have lymph node involvement.^{1-4,6,7,10,11} The clinical course is aggressive, with a median survival of 10.0 to 19.8 months, irrespective of the initial pattern of disease.¹ Most cases have shown initial response to multiagent chemotherapy, but relapses with subsequent resistance to drugs regularly have been observed. Age has an adverse impact of prognosis. Low TdT expression has been associated with shorter survival.¹ Approximately 10% to 20% of cases of BPDCN are associated with or develop into chronic myelogenous leukemia, myelodysplastic syndrome, or acute myeloid leukemia.^1,4 Pediatric patients have a greater 5-year overall survival rate than older patients, and overall survival worsens with increasing age. The extent of cutaneous involvement and presence of systemic involvement at initial presentation do not seem to be strong predictors of survival.^{1,2,5-7,10-12} In a retrospective analysis of 90 patients, Julia et al¹² found that the type of skin disease did not predict survival. Specifically, the presence of nodular lesions and disseminated skin involvement were not adverse prognostic factors compared with macular lesions limited to 1 or 2 body areas.¹²

The Diagnosis: Blastic Plasmacytoid Dendritic Cell Neoplasm

A diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) was rendered. Subsequent needle core biopsy of a left axillary lymph node as well as bone marrow aspiration and biopsy revealed a similar diffuse blastoid infiltrate with an identical immunophenotype to that in the skin biopsy from the pretibial mass and peripheral blood.

Previously known as blastic natural killer cell leukemia/lymphoma or agranular CD4+/CD56+ hematodermic neoplasm/tumor, BPDCN is a rare, clinically aggressive hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. It often is diagnostically challenging, particularly when presenting at noncutaneous sites and in unusual (young) patient populations.¹ It was included with other myeloid neoplasms in the 2008 World Health Organization classification; however, in the 2017 classification it was categorized as a separate entity. Blastic plasmacytoid dendritic cell neoplasm typically presents in the skin of elderly patients (age range at diagnosis, 61–67 years) with or without bone marrow involvement and systemic dissemination.^1,2 The skin is the most common clinical site of disease in typical cases of BPDCN and often precedes bone marrow involvement. Thus, skin biopsy often is the key to making the diagnosis. Diagnosis of BPDCN may be delayed because of diagnostic pitfalls. Patients usually present with asymptomatic solitary or multiple lesions.^3-5 Blastic plasmacytoid dendritic cell neoplasm can present as an isolated purplish nodule or bruiselike papule or more commonly as disseminated purplish nodules, papules, and macules. Isolated nodules are found on the head and lower limbs and can be more than 10 cm in diameter. Peripheral blood and bone marrow may be minimally involved at presentation but invariably become involved with the progression of disease. Cytopenia can occur at diagnosis and in a minority of severe cases indicates bone marrow failure.^2-6

Skin involvement of BPDCN is thought to be secondary to the expression of skin migration molecules, such as cutaneous lymphocyte-associated antigen, one of the E-selectin ligands, which binds to E-selectin on high endothelial venules. In addition, the local dermal microenvironment of chemokines binding CXCR3, CXCR4, CCR6, or CCR7 present on neoplastic cells possibly leads to skin involvement. The full mechanism underlying the cutaneous tropism is still to be elucidated.^4-7 Infiltration of the oral mucosa is seen in some patients, but it may be underreported. Mucosal disease typically appears similarly to cutaneous disease.

The cutaneous differential diagnosis for BPDCN depends on the clinical presentation, extent of disease spread, and thickness of infiltration. It includes common nonneoplastic diseases such as traumatic ecchymoses; purpuric disorders; extramedullary hematopoiesis; and soft-tissue neoplasms such as angiosarcoma, Kaposi sarcoma, neuroblastoma, and vascular metastases, as well as skin involvement by other hematologic neoplasms. An adequate incisional biopsy rather than a punch or shave biopsy is recommended for diagnosis. Dermatologists should alert the pathologist that BPDCN is in the clinical differential diagnosis when possible so that judicious use of appropriate immunophenotypic markers such as CD123, CD4, CD56, and T-cell leukemia/lymphoma protein 1 will avoid misdiagnosis of this aggressive condition, in addition to excluding acute myeloid leukemia, which also may express 3 of the above markers. However, most cases of acute myeloid leukemia lack terminal deoxynucleotidyl transferase (TdT) and express monocytic and other myeloid markers. Terminal deoxynucleotidyl transferase is positive in approximately one-third of cases of BPDCN, with expression in 10% to 80% of cells.¹

It is important to include BPDCN in the differential diagnosis of immunophenotypically aberrant hematologic tumors. Diffuse large B-cell lymphoma, leg type, accounts for 4% of all primary cutaneous B-cell lymphomas.¹ Compared with BPDCN, diffuse large B-cell lymphoma usually occurs in an older age group and is of B-cell lineage. Morphologically, these neoplasms are composed of a monotonous, diffuse, nonepidermotropic infiltrate of confluent sheets of centroblasts and immunoblasts (Figure 1). They may share immunohistochemical markers of CD79a, multiple myeloma 1, Bcl-2, and Bcl-6; however, they lack plasmacytoid dendritic cell (PDC)– associated antigens such as CD4, CD56, CD123, and T-cell leukemia/lymphoma protein 1.¹

Adult T-cell leukemia/lymphoma is a neoplasm histologically composed of highly pleomorphic medium- to large-sized T cells with an irregular multilobated nuclear contour, so-called flower cells, in the peripheral blood. The nuclear chromatin is coarse and clumped with prominent nucleoli. Blastlike cells with dispersed chromatin are present in variable proportions. Most patients present with widespread lymph node and peripheral blood involvement. Skin is involved in more than half of patients with an epidermal as well as dermal pattern of infiltration (mainly perivascular)(Figure 2). Adult T-cell leukemia/lymphoma is endemic in several regions of the world, and the distribution is closely linked to the prevalence of human T-cell lymphotropic virus type 1 in the population. This neoplasm is of T-cell lineage and may share CD4 but not PDC-associated antigens with BPDCN.¹

Cutaneous involvement by T-cell lymphoblastic leukemia/lymphoma (T-LBL) is a rare occurrence with a frequency of approximately 4.3%.8 T-cell lymphoblastic leukemia/lymphoma usually presents as multiple skin lesions throughout the body. Almost all cutaneous T-LBL cases are seen in association with bone marrow and/or mediastinal, lymph node, or extranodal involvement. Cutaneous T-LBLs present as a diffuse monomorphous infiltrate located in the entire dermis and subcutis without epidermotropism, composed of medium to large blasts with finely dispersed chromatin and relatively prominent nucleoli (Figure 3). Immunophenotyping studies show an immature T-cell immunophenotype, with expression of TdT (usually uniform), CD7, and cytoplasmic CD3 and an absence of PDC-associated antigens.⁸

Primary cutaneous γδ T-cell lymphoma (PCGDTL) is a neoplasm primarily involving the skin. Often rapidly fatal, PCGDTL has a broad clinical spectrum that may include indolent variants—subcutaneous, epidermotropic, and dermal. Patients typically present with nodular lesions that progress to ulceration and necrosis. Early lesions can be confused with erythema nodosum, mycosis fungoides, or infection. Histologically, they show variable epidermotropism as well as dermal and subcutaneous involvement by medium to large cells with coarse clumped chromatin (Figure 4). Large blastic cells with vesicular nuclei and prominent nucleoli are infrequent. In contrast to BPCDN, the neoplastic lymphocytes in dermal and subcutaneous PCGDTL typically are positive for T-cell intracellular antigen-1 and granzyme B with loss of CD4.⁹

At the time of presentation, 27% to 87% of BPDCN patients will have bone marrow involvement, 22% to 28% will have blood involvement, and 6% to 41% will have lymph node involvement.^{1-4,6,7,10,11} The clinical course is aggressive, with a median survival of 10.0 to 19.8 months, irrespective of the initial pattern of disease.¹ Most cases have shown initial response to multiagent chemotherapy, but relapses with subsequent resistance to drugs regularly have been observed. Age has an adverse impact of prognosis. Low TdT expression has been associated with shorter survival.¹ Approximately 10% to 20% of cases of BPDCN are associated with or develop into chronic myelogenous leukemia, myelodysplastic syndrome, or acute myeloid leukemia.^1,4 Pediatric patients have a greater 5-year overall survival rate than older patients, and overall survival worsens with increasing age. The extent of cutaneous involvement and presence of systemic involvement at initial presentation do not seem to be strong predictors of survival.^{1,2,5-7,10-12} In a retrospective analysis of 90 patients, Julia et al¹² found that the type of skin disease did not predict survival. Specifically, the presence of nodular lesions and disseminated skin involvement were not adverse prognostic factors compared with macular lesions limited to 1 or 2 body areas.¹²

The Diagnosis: Desmoplastic Spitz Nevus

Desmoplastic Spitz nevus is a rare variant of Spitz nevus that commonly presents as a red to brown papule on the head, neck, or extremities. It is pertinent to review the histologic features of this neoplasm, as it can be confused with other more sinister entities such as spitzoid melanoma. Histologically, there is a dermal infiltrate of melanocytes containing eosinophilic cytoplasm and vesicular nuclei. Junctional involvement is rare, and there should be no pagetoid spread.¹ This entity features abundant stromal fibrosis formed by dense collagen bundles, low cellular density, and polygonal-shaped melanocytes, which helps to differentiate it from melanoma.^2,3 In a retrospective study comparing the characteristics of desmoplastic Spitz nevi with desmoplastic melanoma, desmoplastic Spitz nevi histologically were more symmetric and circumscribed with greater melanocytic maturation and adnexal structure involvement.³ Although this entity demonstrates maturation from the superficial to the deep dermis, it also may feature deep dermal vascular proliferation.⁴ S-100 and SRY-related HMG box 10, SOX-10, are noted to be positive in desmoplastic Spitz nevi, which can help to differentiate it from nonmelanocytic entities (Figure 1).

Although spitzoid lesions can be ambiguous and difficult even for experts to classify, spitzoid melanoma tends to have a high Breslow thickness, high cell density, marked atypia, and an increased nucleus to cytoplasm ratio.⁵ Additionally, desmoplastic melanoma was found to more often display “melanocytic junctional nests associated with discohesive cells, variations in size and shape of the nests, lentiginous melanocytic proliferation, actinic elastosis, pagetoid spread, dermal mitosis, perineural involvement and brisk inflammatory infiltrate.”³ Given the challenge of histologically separating desmoplastic Spitz nevi from melanoma, immunostaining can be useful. For example, Hilliard et al⁶ used a p16 antibody to differentiate desmoplastic Spitz nevi from desmoplastic melanoma, finding that most desmoplastic melanomas (81.8%; n=11) were negative for p16, whereas all desmoplastic Spitz nevi were at least moderately positive. However, another study re-evaluated the utility of p16 in desmoplastic melanoma and found that 72.7% (16/22) were at least focally reactive for the immunostain.⁷ Thus, caution must be exercised when using p16.

PReferentially expressed Antigen in MElanoma (PRAME) is a newer nuclear immunohistochemical marker that tends to be positive in melanomas and negative in nevi. Desmoplastic Spitz nevi would be expected to be negative for PRAME, while desmoplastic melanoma may be positive; however, this marker seems to be less effective in desmoplastic melanoma than in most other subtypes of the malignancy. In one study, only 35% (n=20) of desmoplastic melanomas were positive for PRAME.⁸ Likewise, another study showed that some benign Spitz nevi may diffusely express PRAME.⁹ As such, PRAME should be used prudently.

For cases in which immunohistochemistry is equivocal, molecular testing may aid in differentiating Spitz nevi from melanoma. For example, comparative genomic hybridization has revealed an increased copy number of chromosome 11p in approximately 20% of Spitz nevi cases¹⁰; this finding is not seen in melanoma. Mutation analyses of HRas proto-oncogene, GTPase, HRAS; B-Raf proto-oncogene, serine/threonine kinase, BRAF; and NRAS proto-oncogene, GTPase, NRAS, also have shown some promise in distinguishing spitzoid lesions from melanoma, but these analyses may be oversimplified.¹¹ Fluorescence in situ hybridization (FISH) is another diagnostic modality that has been studied to differentiate benign nevi from melanoma. One study challenged the utility of FISH, reporting 7 of 15 desmoplastic melanomas tested positive compared to 0 of 15 sclerotic melanocytic nevi.¹² Thus, negative FISH cannot reliably rule out melanoma. Ultimately, a combination of immunostains along with FISH or another genetic study would prove to be most effective in ruling out melanoma in difficult cases. Even then, a dermatopathologist may be faced with a degree of uncertainty.

Cellular blue nevi predominantly affect adults younger than 40 years and commonly are seen on the buttocks.¹³ This benign neoplasm demonstrates areas that are distinctly sclerotic as well as those that are cellular in nature.¹⁴ This entity demonstrates a well-circumscribed dermal growth pattern with 2 main populations of cells. The sclerotic portion of the cellular blue nevus mimics that of the blue nevus in that it is noted superficially with irregular margins. The cellular aspect of the nevus features spindle cells contained within well-circumscribed nodules (Figure 2). Stromal melanophages are not uncommon, and some can be observed adjacent to nerve fibers. Although this blue nevus variant displays features of the common blue nevus, its melanocytes track along adnexal and neurovascular structures similar to the deep penetrating nevus and the desmoplastic Spitz nevus. However, these melanocytes are variable in morphology and can appear on a spectrum spanning from pale and lightly pigmented to clear.¹⁵

The breast is the most common site of origin of tumor metastasis to the skin. These cutaneous metastases can vary in both their clinical and histological presentations. For example, cutaneous metastatic breast adenocarcinoma often can present clinically as pink-violaceous papules and plaques on the breast or on other parts of the body. Histologically, it can demonstrate a varying degree of patterns such as collagen infiltration by single cells, cords, tubules, and sheets of atypical cells (Figure 3) that can be observed together in areas of mucin or can form glandular structures.16 Metastatic breast carcinoma is noted to be positive for gross cystic disease fluid protein-15, estrogen receptor, and cytokeratin 7, which can help differentiate this entity from other tumors of glandular origin.¹⁶ Although rare, primary melanoma of the breast has been reported in the literature.^17,18 These malignant melanocytic lesions easily could be differentiated from other breast tumors such as adenocarcinoma using immunohistochemical staining patterns.

Deep penetrating nevi most often are observed clinically as blue, brown, or black papules or nodules on the head or neck.¹⁹ Histologically, this lesion features a wedge-shaped infiltrate of deep dermal melanocytes with oval nuclei. It commonly extends to the reticular dermis or further into the subcutis (Figure 4).^20,21 This neoplasm frequently tracks along adnexal and neurovascular structures, resulting in a plexiform appearance.²² The adnexal involvement of deep penetrating nevi is a shared feature with desmoplastic Spitz nevi. The presence of any number of melanophages is characteristic of this lesion.²³ Lastly, there is a well-documented association between β-catenin mutations and deep penetrating nevi.²⁴ Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans cell histiocytosis that has the pathognomonic clinical finding of pink-red papules (coral beading) with a predilection for acral surfaces. Histology of affected skin reveals a dermal infiltrate of ground glass as well as eosinophilic histiocytes that most often stain positive for CD68 and human alveolar macrophage 56 but negative for S-100 and CD1a (Figure 5).²⁵ Although MRH is rare, negative staining for S-100 could serve as a useful diagnostic clue to differentiate it from other entities that are positive for S-100, such as the desmoplastic Spitz nevus. Arthritis mutilans is a potential complication of MRH, but a reported association with an underlying malignancy is seen in approximately 25% of cases.²⁶ Thus, the cutaneous, rheumatologic, and oncologic implications of this disease help to distinguish it from other differential diagnoses that may be considered.

The Diagnosis: Desmoplastic Spitz Nevus

Desmoplastic Spitz nevus is a rare variant of Spitz nevus that commonly presents as a red to brown papule on the head, neck, or extremities. It is pertinent to review the histologic features of this neoplasm, as it can be confused with other more sinister entities such as spitzoid melanoma. Histologically, there is a dermal infiltrate of melanocytes containing eosinophilic cytoplasm and vesicular nuclei. Junctional involvement is rare, and there should be no pagetoid spread.¹ This entity features abundant stromal fibrosis formed by dense collagen bundles, low cellular density, and polygonal-shaped melanocytes, which helps to differentiate it from melanoma.^2,3 In a retrospective study comparing the characteristics of desmoplastic Spitz nevi with desmoplastic melanoma, desmoplastic Spitz nevi histologically were more symmetric and circumscribed with greater melanocytic maturation and adnexal structure involvement.³ Although this entity demonstrates maturation from the superficial to the deep dermis, it also may feature deep dermal vascular proliferation.⁴ S-100 and SRY-related HMG box 10, SOX-10, are noted to be positive in desmoplastic Spitz nevi, which can help to differentiate it from nonmelanocytic entities (Figure 1).

Although spitzoid lesions can be ambiguous and difficult even for experts to classify, spitzoid melanoma tends to have a high Breslow thickness, high cell density, marked atypia, and an increased nucleus to cytoplasm ratio.⁵ Additionally, desmoplastic melanoma was found to more often display “melanocytic junctional nests associated with discohesive cells, variations in size and shape of the nests, lentiginous melanocytic proliferation, actinic elastosis, pagetoid spread, dermal mitosis, perineural involvement and brisk inflammatory infiltrate.”³ Given the challenge of histologically separating desmoplastic Spitz nevi from melanoma, immunostaining can be useful. For example, Hilliard et al⁶ used a p16 antibody to differentiate desmoplastic Spitz nevi from desmoplastic melanoma, finding that most desmoplastic melanomas (81.8%; n=11) were negative for p16, whereas all desmoplastic Spitz nevi were at least moderately positive. However, another study re-evaluated the utility of p16 in desmoplastic melanoma and found that 72.7% (16/22) were at least focally reactive for the immunostain.⁷ Thus, caution must be exercised when using p16.

PReferentially expressed Antigen in MElanoma (PRAME) is a newer nuclear immunohistochemical marker that tends to be positive in melanomas and negative in nevi. Desmoplastic Spitz nevi would be expected to be negative for PRAME, while desmoplastic melanoma may be positive; however, this marker seems to be less effective in desmoplastic melanoma than in most other subtypes of the malignancy. In one study, only 35% (n=20) of desmoplastic melanomas were positive for PRAME.⁸ Likewise, another study showed that some benign Spitz nevi may diffusely express PRAME.⁹ As such, PRAME should be used prudently.

For cases in which immunohistochemistry is equivocal, molecular testing may aid in differentiating Spitz nevi from melanoma. For example, comparative genomic hybridization has revealed an increased copy number of chromosome 11p in approximately 20% of Spitz nevi cases¹⁰; this finding is not seen in melanoma. Mutation analyses of HRas proto-oncogene, GTPase, HRAS; B-Raf proto-oncogene, serine/threonine kinase, BRAF; and NRAS proto-oncogene, GTPase, NRAS, also have shown some promise in distinguishing spitzoid lesions from melanoma, but these analyses may be oversimplified.¹¹ Fluorescence in situ hybridization (FISH) is another diagnostic modality that has been studied to differentiate benign nevi from melanoma. One study challenged the utility of FISH, reporting 7 of 15 desmoplastic melanomas tested positive compared to 0 of 15 sclerotic melanocytic nevi.¹² Thus, negative FISH cannot reliably rule out melanoma. Ultimately, a combination of immunostains along with FISH or another genetic study would prove to be most effective in ruling out melanoma in difficult cases. Even then, a dermatopathologist may be faced with a degree of uncertainty.

Cellular blue nevi predominantly affect adults younger than 40 years and commonly are seen on the buttocks.¹³ This benign neoplasm demonstrates areas that are distinctly sclerotic as well as those that are cellular in nature.¹⁴ This entity demonstrates a well-circumscribed dermal growth pattern with 2 main populations of cells. The sclerotic portion of the cellular blue nevus mimics that of the blue nevus in that it is noted superficially with irregular margins. The cellular aspect of the nevus features spindle cells contained within well-circumscribed nodules (Figure 2). Stromal melanophages are not uncommon, and some can be observed adjacent to nerve fibers. Although this blue nevus variant displays features of the common blue nevus, its melanocytes track along adnexal and neurovascular structures similar to the deep penetrating nevus and the desmoplastic Spitz nevus. However, these melanocytes are variable in morphology and can appear on a spectrum spanning from pale and lightly pigmented to clear.¹⁵

The breast is the most common site of origin of tumor metastasis to the skin. These cutaneous metastases can vary in both their clinical and histological presentations. For example, cutaneous metastatic breast adenocarcinoma often can present clinically as pink-violaceous papules and plaques on the breast or on other parts of the body. Histologically, it can demonstrate a varying degree of patterns such as collagen infiltration by single cells, cords, tubules, and sheets of atypical cells (Figure 3) that can be observed together in areas of mucin or can form glandular structures.16 Metastatic breast carcinoma is noted to be positive for gross cystic disease fluid protein-15, estrogen receptor, and cytokeratin 7, which can help differentiate this entity from other tumors of glandular origin.¹⁶ Although rare, primary melanoma of the breast has been reported in the literature.^17,18 These malignant melanocytic lesions easily could be differentiated from other breast tumors such as adenocarcinoma using immunohistochemical staining patterns.

Deep penetrating nevi most often are observed clinically as blue, brown, or black papules or nodules on the head or neck.¹⁹ Histologically, this lesion features a wedge-shaped infiltrate of deep dermal melanocytes with oval nuclei. It commonly extends to the reticular dermis or further into the subcutis (Figure 4).^20,21 This neoplasm frequently tracks along adnexal and neurovascular structures, resulting in a plexiform appearance.²² The adnexal involvement of deep penetrating nevi is a shared feature with desmoplastic Spitz nevi. The presence of any number of melanophages is characteristic of this lesion.²³ Lastly, there is a well-documented association between β-catenin mutations and deep penetrating nevi.²⁴ Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans cell histiocytosis that has the pathognomonic clinical finding of pink-red papules (coral beading) with a predilection for acral surfaces. Histology of affected skin reveals a dermal infiltrate of ground glass as well as eosinophilic histiocytes that most often stain positive for CD68 and human alveolar macrophage 56 but negative for S-100 and CD1a (Figure 5).²⁵ Although MRH is rare, negative staining for S-100 could serve as a useful diagnostic clue to differentiate it from other entities that are positive for S-100, such as the desmoplastic Spitz nevus. Arthritis mutilans is a potential complication of MRH, but a reported association with an underlying malignancy is seen in approximately 25% of cases.²⁶ Thus, the cutaneous, rheumatologic, and oncologic implications of this disease help to distinguish it from other differential diagnoses that may be considered.

The Diagnosis: Desmoplastic Spitz Nevus

Desmoplastic Spitz nevus is a rare variant of Spitz nevus that commonly presents as a red to brown papule on the head, neck, or extremities. It is pertinent to review the histologic features of this neoplasm, as it can be confused with other more sinister entities such as spitzoid melanoma. Histologically, there is a dermal infiltrate of melanocytes containing eosinophilic cytoplasm and vesicular nuclei. Junctional involvement is rare, and there should be no pagetoid spread.¹ This entity features abundant stromal fibrosis formed by dense collagen bundles, low cellular density, and polygonal-shaped melanocytes, which helps to differentiate it from melanoma.^2,3 In a retrospective study comparing the characteristics of desmoplastic Spitz nevi with desmoplastic melanoma, desmoplastic Spitz nevi histologically were more symmetric and circumscribed with greater melanocytic maturation and adnexal structure involvement.³ Although this entity demonstrates maturation from the superficial to the deep dermis, it also may feature deep dermal vascular proliferation.⁴ S-100 and SRY-related HMG box 10, SOX-10, are noted to be positive in desmoplastic Spitz nevi, which can help to differentiate it from nonmelanocytic entities (Figure 1).

Although spitzoid lesions can be ambiguous and difficult even for experts to classify, spitzoid melanoma tends to have a high Breslow thickness, high cell density, marked atypia, and an increased nucleus to cytoplasm ratio.⁵ Additionally, desmoplastic melanoma was found to more often display “melanocytic junctional nests associated with discohesive cells, variations in size and shape of the nests, lentiginous melanocytic proliferation, actinic elastosis, pagetoid spread, dermal mitosis, perineural involvement and brisk inflammatory infiltrate.”³ Given the challenge of histologically separating desmoplastic Spitz nevi from melanoma, immunostaining can be useful. For example, Hilliard et al⁶ used a p16 antibody to differentiate desmoplastic Spitz nevi from desmoplastic melanoma, finding that most desmoplastic melanomas (81.8%; n=11) were negative for p16, whereas all desmoplastic Spitz nevi were at least moderately positive. However, another study re-evaluated the utility of p16 in desmoplastic melanoma and found that 72.7% (16/22) were at least focally reactive for the immunostain.⁷ Thus, caution must be exercised when using p16.

PReferentially expressed Antigen in MElanoma (PRAME) is a newer nuclear immunohistochemical marker that tends to be positive in melanomas and negative in nevi. Desmoplastic Spitz nevi would be expected to be negative for PRAME, while desmoplastic melanoma may be positive; however, this marker seems to be less effective in desmoplastic melanoma than in most other subtypes of the malignancy. In one study, only 35% (n=20) of desmoplastic melanomas were positive for PRAME.⁸ Likewise, another study showed that some benign Spitz nevi may diffusely express PRAME.⁹ As such, PRAME should be used prudently.

For cases in which immunohistochemistry is equivocal, molecular testing may aid in differentiating Spitz nevi from melanoma. For example, comparative genomic hybridization has revealed an increased copy number of chromosome 11p in approximately 20% of Spitz nevi cases¹⁰; this finding is not seen in melanoma. Mutation analyses of HRas proto-oncogene, GTPase, HRAS; B-Raf proto-oncogene, serine/threonine kinase, BRAF; and NRAS proto-oncogene, GTPase, NRAS, also have shown some promise in distinguishing spitzoid lesions from melanoma, but these analyses may be oversimplified.¹¹ Fluorescence in situ hybridization (FISH) is another diagnostic modality that has been studied to differentiate benign nevi from melanoma. One study challenged the utility of FISH, reporting 7 of 15 desmoplastic melanomas tested positive compared to 0 of 15 sclerotic melanocytic nevi.¹² Thus, negative FISH cannot reliably rule out melanoma. Ultimately, a combination of immunostains along with FISH or another genetic study would prove to be most effective in ruling out melanoma in difficult cases. Even then, a dermatopathologist may be faced with a degree of uncertainty.

Cellular blue nevi predominantly affect adults younger than 40 years and commonly are seen on the buttocks.¹³ This benign neoplasm demonstrates areas that are distinctly sclerotic as well as those that are cellular in nature.¹⁴ This entity demonstrates a well-circumscribed dermal growth pattern with 2 main populations of cells. The sclerotic portion of the cellular blue nevus mimics that of the blue nevus in that it is noted superficially with irregular margins. The cellular aspect of the nevus features spindle cells contained within well-circumscribed nodules (Figure 2). Stromal melanophages are not uncommon, and some can be observed adjacent to nerve fibers. Although this blue nevus variant displays features of the common blue nevus, its melanocytes track along adnexal and neurovascular structures similar to the deep penetrating nevus and the desmoplastic Spitz nevus. However, these melanocytes are variable in morphology and can appear on a spectrum spanning from pale and lightly pigmented to clear.¹⁵

The breast is the most common site of origin of tumor metastasis to the skin. These cutaneous metastases can vary in both their clinical and histological presentations. For example, cutaneous metastatic breast adenocarcinoma often can present clinically as pink-violaceous papules and plaques on the breast or on other parts of the body. Histologically, it can demonstrate a varying degree of patterns such as collagen infiltration by single cells, cords, tubules, and sheets of atypical cells (Figure 3) that can be observed together in areas of mucin or can form glandular structures.16 Metastatic breast carcinoma is noted to be positive for gross cystic disease fluid protein-15, estrogen receptor, and cytokeratin 7, which can help differentiate this entity from other tumors of glandular origin.¹⁶ Although rare, primary melanoma of the breast has been reported in the literature.^17,18 These malignant melanocytic lesions easily could be differentiated from other breast tumors such as adenocarcinoma using immunohistochemical staining patterns.

Deep penetrating nevi most often are observed clinically as blue, brown, or black papules or nodules on the head or neck.¹⁹ Histologically, this lesion features a wedge-shaped infiltrate of deep dermal melanocytes with oval nuclei. It commonly extends to the reticular dermis or further into the subcutis (Figure 4).^20,21 This neoplasm frequently tracks along adnexal and neurovascular structures, resulting in a plexiform appearance.²² The adnexal involvement of deep penetrating nevi is a shared feature with desmoplastic Spitz nevi. The presence of any number of melanophages is characteristic of this lesion.²³ Lastly, there is a well-documented association between β-catenin mutations and deep penetrating nevi.²⁴ Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans cell histiocytosis that has the pathognomonic clinical finding of pink-red papules (coral beading) with a predilection for acral surfaces. Histology of affected skin reveals a dermal infiltrate of ground glass as well as eosinophilic histiocytes that most often stain positive for CD68 and human alveolar macrophage 56 but negative for S-100 and CD1a (Figure 5).²⁵ Although MRH is rare, negative staining for S-100 could serve as a useful diagnostic clue to differentiate it from other entities that are positive for S-100, such as the desmoplastic Spitz nevus. Arthritis mutilans is a potential complication of MRH, but a reported association with an underlying malignancy is seen in approximately 25% of cases.²⁶ Thus, the cutaneous, rheumatologic, and oncologic implications of this disease help to distinguish it from other differential diagnoses that may be considered.

The Diagnosis: Cutaneous Myxoma

Microscopic analysis showed features of cutaneous myxoma (quiz images). The epidermis was essentially unremarkable. Stellate to spindle cells with bland nuclear chromatin were present in the dermis with abundant pools of myxoid stroma. Colloidal iron staining highlighted the markedly increased dermal mucin.

Cutaneous myxomas (also referred to as superficial angiomyxomas) are rare, well-demarcated tumors of the dermis and subcutis.^1,2 They can present as solitary, fleshcolored nodules on the trunk, lower extremities, head, or neck, and they often measure between 1 and 5 cm.^2,3 Histologically, cutaneous myxomas are hypocellular with some stellate fibroblasts, occasional epithelial structures, and an abundant myxoid stroma, with notable thinwalled small blood vessels.^2,4 These lesions contain pools of mucin and are positive for mesenchymal mucin stains such as colloidal iron and Alcian blue.¹ Moreover, perivascular neutrophils are a distinguishing characteristic of cutaneous myxomas.⁴

Multiple cutaneous myxomas should raise concern for Carney complex,^1,5 a genodermatologic syndrome that arises due to a mutation in the protein kinase CAMP-dependent type I regulatory subunit alpha gene, PRKAR1A, on chromosome 2.^1,5 Additional cutaneous manifestations include blue nevi, lentigines, and café-aulait macules.⁵ Carney complex also is known for endocrine overactivity and cardiac myxomas, which can cause serious embolic complications.¹

Recommended management is complete excision with close follow-up, as these lesions may recur in up to one-third of cases. Although there is a potential for recurrence, metastases are uncommon.³ Even without recurrence in the presenting location, follow-up should include screening for manifestations of Carney complex.^1,3

The clinical and histological differential for cutaneous myxoma may include nerve sheath myxoma or neurofibroma. A nerve sheath myxoma is a dermal tumor that manifests as a solitary, flesh-colored nodule, measuring less than 2 cm. These lesions commonly present on the head, neck, and upper body.⁶ Cutaneous myxomas can grow larger than 2 cm, but these two lesions have a great deal of overlap in their other features.^3,6 Thus, histology can be used to distinguish them.

Nerve sheath myxomas are circumscribed nonencapsulated tumors of the dermis composed of multilobular aggregates of spindle to epithelioid cells in a mucinous matrix (Figure 1). Clefts often are present around the cell aggregates. Despite previously being termed myxoid neurothekeomas, nerve sheath myxomas are S-100 positive, whereas cellular neurothekeomas are S-100 negative and likely not of neural origin. Cutaneous myxomas, in contrast to nerve sheath myxomas, are S-100 negative. Nerve sheath myxomas are more cellular and lack the characteristic mucin pools compared with cutaneous myxomas.^1,2,6 Neurofibromas frequently are flesh colored and pedunculated, as was the lesion in our patient, yet they are vastly different microscopically. The stroma of neurofibromas can vary, but cellularity typically is greater than a cutaneous myxoma and consists of increased numbers of bland spindle cells with wavy nuclei (Schwann cells) and fibrillar cytoplasm as well as mast cells and fibroblasts (Figure 2). Neurofibromas stain positively for S-100 and SOX-10 (Sry-related HMg-box 10).^2,7 In addition to café-au-lait macules, axillary freckling, optic gliomas, and positive family history, neurofibromas are associated with neurofibromatosis type 1, which is linked to a defect in a tumor suppressor gene that codes for neurofibromin.⁷

Nodular fasciitis is a self-limited myofibroblastic neoplasm that contains fusion genes, with the most common being myosin-9–ubiquitin specific peptidase 6, MYH9-USP6, which leads to overexpression of USP6. Nodular fasciitis presents as a solitary, rapidly enlarging nodule affecting the subcutaneous tissue, muscles, or fascia.^8,9 It usually presents in the third or fourth decades of life.⁸ The arms are the most common location in adults, while the most commonly affected site in children is the head or neck. Histopathology reveals a characteristic tissue culture pattern with a proliferation of plump spindle and stellate fibroblasts as well as myofibroblasts (Figure 3). Early lesions have haphazard spindle cells with a proliferation of small blood vessels and extravasated erythrocytes. Despite increased mitotic figures, cellular atypia is rare. The fibroblasts and myofibroblasts react positively for vimentin and muscle-specific actin.⁸ This lesion is highly cellular comparatively and notably lacks the perivascular neutrophils and epithelial structures that would be expected in a cutaneous myxoma.^4,8

Spindle cell lipomas, solitary subcutaneous masses commonly presenting on the upper back in middle-aged men, also can mimic cutaneous myxomas.⁴ Histologically, these lesions may contain short bundles of spindle cells arranged in a school of fish–like pattern, mature adipocytes, or myxoid stroma and characteristic CD34 positivity (Figure 4). Spindle cell lipomas often will present with ropey collagen, which can easily distinguish them from cutaneous myxomas.⁴

The Diagnosis: Cutaneous Myxoma

Microscopic analysis showed features of cutaneous myxoma (quiz images). The epidermis was essentially unremarkable. Stellate to spindle cells with bland nuclear chromatin were present in the dermis with abundant pools of myxoid stroma. Colloidal iron staining highlighted the markedly increased dermal mucin.

Cutaneous myxomas (also referred to as superficial angiomyxomas) are rare, well-demarcated tumors of the dermis and subcutis.^1,2 They can present as solitary, fleshcolored nodules on the trunk, lower extremities, head, or neck, and they often measure between 1 and 5 cm.^2,3 Histologically, cutaneous myxomas are hypocellular with some stellate fibroblasts, occasional epithelial structures, and an abundant myxoid stroma, with notable thinwalled small blood vessels.^2,4 These lesions contain pools of mucin and are positive for mesenchymal mucin stains such as colloidal iron and Alcian blue.¹ Moreover, perivascular neutrophils are a distinguishing characteristic of cutaneous myxomas.⁴

Multiple cutaneous myxomas should raise concern for Carney complex,^1,5 a genodermatologic syndrome that arises due to a mutation in the protein kinase CAMP-dependent type I regulatory subunit alpha gene, PRKAR1A, on chromosome 2.^1,5 Additional cutaneous manifestations include blue nevi, lentigines, and café-aulait macules.⁵ Carney complex also is known for endocrine overactivity and cardiac myxomas, which can cause serious embolic complications.¹

Recommended management is complete excision with close follow-up, as these lesions may recur in up to one-third of cases. Although there is a potential for recurrence, metastases are uncommon.³ Even without recurrence in the presenting location, follow-up should include screening for manifestations of Carney complex.^1,3

The clinical and histological differential for cutaneous myxoma may include nerve sheath myxoma or neurofibroma. A nerve sheath myxoma is a dermal tumor that manifests as a solitary, flesh-colored nodule, measuring less than 2 cm. These lesions commonly present on the head, neck, and upper body.⁶ Cutaneous myxomas can grow larger than 2 cm, but these two lesions have a great deal of overlap in their other features.^3,6 Thus, histology can be used to distinguish them.

Nerve sheath myxomas are circumscribed nonencapsulated tumors of the dermis composed of multilobular aggregates of spindle to epithelioid cells in a mucinous matrix (Figure 1). Clefts often are present around the cell aggregates. Despite previously being termed myxoid neurothekeomas, nerve sheath myxomas are S-100 positive, whereas cellular neurothekeomas are S-100 negative and likely not of neural origin. Cutaneous myxomas, in contrast to nerve sheath myxomas, are S-100 negative. Nerve sheath myxomas are more cellular and lack the characteristic mucin pools compared with cutaneous myxomas.^1,2,6 Neurofibromas frequently are flesh colored and pedunculated, as was the lesion in our patient, yet they are vastly different microscopically. The stroma of neurofibromas can vary, but cellularity typically is greater than a cutaneous myxoma and consists of increased numbers of bland spindle cells with wavy nuclei (Schwann cells) and fibrillar cytoplasm as well as mast cells and fibroblasts (Figure 2). Neurofibromas stain positively for S-100 and SOX-10 (Sry-related HMg-box 10).^2,7 In addition to café-au-lait macules, axillary freckling, optic gliomas, and positive family history, neurofibromas are associated with neurofibromatosis type 1, which is linked to a defect in a tumor suppressor gene that codes for neurofibromin.⁷

Nodular fasciitis is a self-limited myofibroblastic neoplasm that contains fusion genes, with the most common being myosin-9–ubiquitin specific peptidase 6, MYH9-USP6, which leads to overexpression of USP6. Nodular fasciitis presents as a solitary, rapidly enlarging nodule affecting the subcutaneous tissue, muscles, or fascia.^8,9 It usually presents in the third or fourth decades of life.⁸ The arms are the most common location in adults, while the most commonly affected site in children is the head or neck. Histopathology reveals a characteristic tissue culture pattern with a proliferation of plump spindle and stellate fibroblasts as well as myofibroblasts (Figure 3). Early lesions have haphazard spindle cells with a proliferation of small blood vessels and extravasated erythrocytes. Despite increased mitotic figures, cellular atypia is rare. The fibroblasts and myofibroblasts react positively for vimentin and muscle-specific actin.⁸ This lesion is highly cellular comparatively and notably lacks the perivascular neutrophils and epithelial structures that would be expected in a cutaneous myxoma.^4,8

Spindle cell lipomas, solitary subcutaneous masses commonly presenting on the upper back in middle-aged men, also can mimic cutaneous myxomas.⁴ Histologically, these lesions may contain short bundles of spindle cells arranged in a school of fish–like pattern, mature adipocytes, or myxoid stroma and characteristic CD34 positivity (Figure 4). Spindle cell lipomas often will present with ropey collagen, which can easily distinguish them from cutaneous myxomas.⁴

The Diagnosis: Cutaneous Myxoma

Microscopic analysis showed features of cutaneous myxoma (quiz images). The epidermis was essentially unremarkable. Stellate to spindle cells with bland nuclear chromatin were present in the dermis with abundant pools of myxoid stroma. Colloidal iron staining highlighted the markedly increased dermal mucin.

Cutaneous myxomas (also referred to as superficial angiomyxomas) are rare, well-demarcated tumors of the dermis and subcutis.^1,2 They can present as solitary, fleshcolored nodules on the trunk, lower extremities, head, or neck, and they often measure between 1 and 5 cm.^2,3 Histologically, cutaneous myxomas are hypocellular with some stellate fibroblasts, occasional epithelial structures, and an abundant myxoid stroma, with notable thinwalled small blood vessels.^2,4 These lesions contain pools of mucin and are positive for mesenchymal mucin stains such as colloidal iron and Alcian blue.¹ Moreover, perivascular neutrophils are a distinguishing characteristic of cutaneous myxomas.⁴

Multiple cutaneous myxomas should raise concern for Carney complex,^1,5 a genodermatologic syndrome that arises due to a mutation in the protein kinase CAMP-dependent type I regulatory subunit alpha gene, PRKAR1A, on chromosome 2.^1,5 Additional cutaneous manifestations include blue nevi, lentigines, and café-aulait macules.⁵ Carney complex also is known for endocrine overactivity and cardiac myxomas, which can cause serious embolic complications.¹

Recommended management is complete excision with close follow-up, as these lesions may recur in up to one-third of cases. Although there is a potential for recurrence, metastases are uncommon.³ Even without recurrence in the presenting location, follow-up should include screening for manifestations of Carney complex.^1,3

The clinical and histological differential for cutaneous myxoma may include nerve sheath myxoma or neurofibroma. A nerve sheath myxoma is a dermal tumor that manifests as a solitary, flesh-colored nodule, measuring less than 2 cm. These lesions commonly present on the head, neck, and upper body.⁶ Cutaneous myxomas can grow larger than 2 cm, but these two lesions have a great deal of overlap in their other features.^3,6 Thus, histology can be used to distinguish them.

Nerve sheath myxomas are circumscribed nonencapsulated tumors of the dermis composed of multilobular aggregates of spindle to epithelioid cells in a mucinous matrix (Figure 1). Clefts often are present around the cell aggregates. Despite previously being termed myxoid neurothekeomas, nerve sheath myxomas are S-100 positive, whereas cellular neurothekeomas are S-100 negative and likely not of neural origin. Cutaneous myxomas, in contrast to nerve sheath myxomas, are S-100 negative. Nerve sheath myxomas are more cellular and lack the characteristic mucin pools compared with cutaneous myxomas.^1,2,6 Neurofibromas frequently are flesh colored and pedunculated, as was the lesion in our patient, yet they are vastly different microscopically. The stroma of neurofibromas can vary, but cellularity typically is greater than a cutaneous myxoma and consists of increased numbers of bland spindle cells with wavy nuclei (Schwann cells) and fibrillar cytoplasm as well as mast cells and fibroblasts (Figure 2). Neurofibromas stain positively for S-100 and SOX-10 (Sry-related HMg-box 10).^2,7 In addition to café-au-lait macules, axillary freckling, optic gliomas, and positive family history, neurofibromas are associated with neurofibromatosis type 1, which is linked to a defect in a tumor suppressor gene that codes for neurofibromin.⁷

Nodular fasciitis is a self-limited myofibroblastic neoplasm that contains fusion genes, with the most common being myosin-9–ubiquitin specific peptidase 6, MYH9-USP6, which leads to overexpression of USP6. Nodular fasciitis presents as a solitary, rapidly enlarging nodule affecting the subcutaneous tissue, muscles, or fascia.^8,9 It usually presents in the third or fourth decades of life.⁸ The arms are the most common location in adults, while the most commonly affected site in children is the head or neck. Histopathology reveals a characteristic tissue culture pattern with a proliferation of plump spindle and stellate fibroblasts as well as myofibroblasts (Figure 3). Early lesions have haphazard spindle cells with a proliferation of small blood vessels and extravasated erythrocytes. Despite increased mitotic figures, cellular atypia is rare. The fibroblasts and myofibroblasts react positively for vimentin and muscle-specific actin.⁸ This lesion is highly cellular comparatively and notably lacks the perivascular neutrophils and epithelial structures that would be expected in a cutaneous myxoma.^4,8

Spindle cell lipomas, solitary subcutaneous masses commonly presenting on the upper back in middle-aged men, also can mimic cutaneous myxomas.⁴ Histologically, these lesions may contain short bundles of spindle cells arranged in a school of fish–like pattern, mature adipocytes, or myxoid stroma and characteristic CD34 positivity (Figure 4). Spindle cell lipomas often will present with ropey collagen, which can easily distinguish them from cutaneous myxomas.⁴

The Diagnosis: Dermatomyofibroma

Dermatomyofibroma is an uncommon, benign, cutaneous mesenchymal neoplasm composed of fibroblasts and myofibroblasts.^1-3 This skin tumor was first described in 1991 by Hugel⁴ in the German literature as plaquelike fibromatosis. Pediatric dermatomyofibromas are exceedingly rare, with pediatric patients ranging in age from infants to teenagers.¹

Clinically, dermatomyofibromas appear as long-standing, isolated, ill-demarcated, flesh-colored, slightly hyperpigmented or erythematous nodules or plaques that may be raised or indurated.¹ Dermatomyofibromas may present with constant mild pain or pruritus, though in most cases the lesions are asymptomatic.^1,3 The clinical presentation of dermatomyofibroma has a few distinct differences in children compared to adults. In adulthood, dermatomyofibroma has a strong female predominance and most commonly is located on the shoulder and adjacent upper body regions, including the axilla, neck, upper arm, and upper trunk.^1-3 In childhood, the majority of dermatomyofibromas occur in young boys and usually are located on the neck with other upper body regions occurring less frequently.^1,2 A shared characteristic includes the tendency for dermatomyofibromas to have an initial period of enlargement followed by stabilization or slow growth.¹ Reported pediatric lesions have ranged in size from 4 to 60 mm with an average size of 14.9 mm (median, 12 mm).²

The diagnosis of dermatomyofibroma is based on histopathologic features in addition to clinical presentation. Histology from punch biopsy usually reveals a noninvasive dermal proliferation of bland, uniform, slender spindle cells oriented parallel to the overlying epidermis with increased and fragmented elastic fibers.^1,3 Infiltration into the mid or deep dermis is common. The adnexal structures usually are spared; the stroma contains collagen and increased small blood vessels; and there typically is no inflammatory infiltrate, except for occasional scattered mast cells.² Cytologically, the monomorphic spindleshaped tumor cells have an ill-defined, pale, eosinophilic cytoplasm and nuclei that are elongated with tapered edges.³ Dermatomyofibroma has a variable immunohistochemical profile, as it may stain focally positive for CD34 or smooth muscle actin, with occasional staining of factor XIIIa, desmin, calponin, or vimentin.^1-3 Normal to increased levels of often fragmented elastic fibers is a helpful clue in distinguishing dermatomyofibroma from dermatofibroma, hypertrophic scar, dermatofibrosarcoma protuberans, and pilar leiomyoma, in which elastic fibers typically are reduced.³ Differential diagnoses of mesenchymal tumors in children include desmoid fibromatosis, connective tissue nevus, myofibromatosis, and smooth muscle hamartoma.¹

A punch biopsy with clinical observation and followup is recommended for the management of lesions in cosmetically sensitive areas or in very young children who may not tolerate surgery. In symptomatic or cosmetically unappealing cases of dermatomyofibroma, simple surgical excision remains a viable treatment option. Recurrence is uncommon, even if only partially excised, and no instances of metastasis have been reported.^1-5

Dermatomyofibromas may be mistaken for several other entities both benign and malignant. For example, the benign dermatofibroma is the second most common fibrohistiocytic tumor of the skin and presents as a firm, nontender, minimally elevated to dome-shaped papule that usually measures less than or equal to 1 cm in diameter with or without overlying skin changes.^5,6 It primarily is seen in adults with a slight female predominance and favors the lower extremities.⁵ Patients usually are asymptomatic but often report a history of local trauma at the lesion site.⁶ Histologically, dermatofibroma is characterized by a nodular dermal proliferation of spindleshaped fibrous cells and histiocytes in a storiform pattern (Figure 1).⁶ Epidermal induction with acanthosis overlying the tumor often is found with occasional basilar hyperpigmentation.⁵ Dermatofibroma also characteristically has trapped collagen (“collagen balls”) seen at the periphery.^5,6

Piloleiomyomas are benign smooth muscle tumors arising from arrector pili muscles that may be solitary or multiple.⁵ Clinically, they typically present as firm, reddish-brown to flesh-colored papules or nodules that develop more commonly in adulthood.^5,7 Piloleiomyomas favor the extremities and trunk, particularly the shoulder, and can be associated with spontaneous or induced pain. Histologically, piloleiomyomas are well circumscribed and centered within the reticular dermis situated closely to hair follicles (Figure 2).⁵ They are composed of numerous interlacing fascicles or whorls of smooth muscle cells with abundant eosinophilic cytoplasm and blunt-ended, cigar-shaped nuclei.^5,7

Solitary cutaneous myofibroma is a benign fibrous tumor found in adolescents and adults and is the counterpart to infantile myofibromatosis.⁸ Clinically, myofibromas typically present as painless, slow-growing, firm nodules with an occasional bluish hue. Histologically, solitary cutaneous myofibromas appear in a biphasic pattern, with hemangiopericytomatous components as well as spindle cells arranged in short bundles and fascicles resembling leiomyoma (Figure 3). The spindle cells also have abundant eosinophilic cytoplasm with short plump nuclei; the random, irregularly intersecting angles can be used to help differentiate myofibromas from smooth muscle lesions.⁸ Solitary cutaneous myofibroma is in the differential diagnosis for dermatomyofibroma because of their shared myofibroblastic nature.⁹

Dermatofibrosarcoma protuberans (DFSP) is an uncommon, locally invasive sarcoma with a high recurrence rate that favors young to middle-aged adults, with rare childhood onset reported.^5,10,11 Clinically, DFSP typically presents as an asymptomatic, slow-growing, firm, flesh-colored, indurated plaque that develops into a violaceous to reddish-brown nodule.⁵ The atrophic variant of DFSP is characterized by a nonprotuberant lesion and can be especially difficult to distinguish from other entities such as dermatomyofibroma.¹¹ The majority of DFSP lesions occur on the trunk, particularly in the shoulder or pelvic region.⁵ Histologically, early plaque lesions are comprised of monomorphic spindle cells arranged in long fascicles (parallel to the skin surface), infiltrating adnexal structures, and subcutaneous adipocytes in a multilayered honeycomb pattern; the spindle cells of late nodular lesions are arranged in short fascicles in a matted or storiform pattern (Figure 4).^5,10 Early stages of DFSP as well as variations in childhood-onset DFSP can easily be misdiagnosed and incompletely excised.⁵

The Diagnosis: Dermatomyofibroma

Dermatomyofibroma is an uncommon, benign, cutaneous mesenchymal neoplasm composed of fibroblasts and myofibroblasts.^1-3 This skin tumor was first described in 1991 by Hugel⁴ in the German literature as plaquelike fibromatosis. Pediatric dermatomyofibromas are exceedingly rare, with pediatric patients ranging in age from infants to teenagers.¹

Clinically, dermatomyofibromas appear as long-standing, isolated, ill-demarcated, flesh-colored, slightly hyperpigmented or erythematous nodules or plaques that may be raised or indurated.¹ Dermatomyofibromas may present with constant mild pain or pruritus, though in most cases the lesions are asymptomatic.^1,3 The clinical presentation of dermatomyofibroma has a few distinct differences in children compared to adults. In adulthood, dermatomyofibroma has a strong female predominance and most commonly is located on the shoulder and adjacent upper body regions, including the axilla, neck, upper arm, and upper trunk.^1-3 In childhood, the majority of dermatomyofibromas occur in young boys and usually are located on the neck with other upper body regions occurring less frequently.^1,2 A shared characteristic includes the tendency for dermatomyofibromas to have an initial period of enlargement followed by stabilization or slow growth.¹ Reported pediatric lesions have ranged in size from 4 to 60 mm with an average size of 14.9 mm (median, 12 mm).²

The diagnosis of dermatomyofibroma is based on histopathologic features in addition to clinical presentation. Histology from punch biopsy usually reveals a noninvasive dermal proliferation of bland, uniform, slender spindle cells oriented parallel to the overlying epidermis with increased and fragmented elastic fibers.^1,3 Infiltration into the mid or deep dermis is common. The adnexal structures usually are spared; the stroma contains collagen and increased small blood vessels; and there typically is no inflammatory infiltrate, except for occasional scattered mast cells.² Cytologically, the monomorphic spindleshaped tumor cells have an ill-defined, pale, eosinophilic cytoplasm and nuclei that are elongated with tapered edges.³ Dermatomyofibroma has a variable immunohistochemical profile, as it may stain focally positive for CD34 or smooth muscle actin, with occasional staining of factor XIIIa, desmin, calponin, or vimentin.^1-3 Normal to increased levels of often fragmented elastic fibers is a helpful clue in distinguishing dermatomyofibroma from dermatofibroma, hypertrophic scar, dermatofibrosarcoma protuberans, and pilar leiomyoma, in which elastic fibers typically are reduced.³ Differential diagnoses of mesenchymal tumors in children include desmoid fibromatosis, connective tissue nevus, myofibromatosis, and smooth muscle hamartoma.¹

A punch biopsy with clinical observation and followup is recommended for the management of lesions in cosmetically sensitive areas or in very young children who may not tolerate surgery. In symptomatic or cosmetically unappealing cases of dermatomyofibroma, simple surgical excision remains a viable treatment option. Recurrence is uncommon, even if only partially excised, and no instances of metastasis have been reported.^1-5

Dermatomyofibromas may be mistaken for several other entities both benign and malignant. For example, the benign dermatofibroma is the second most common fibrohistiocytic tumor of the skin and presents as a firm, nontender, minimally elevated to dome-shaped papule that usually measures less than or equal to 1 cm in diameter with or without overlying skin changes.^5,6 It primarily is seen in adults with a slight female predominance and favors the lower extremities.⁵ Patients usually are asymptomatic but often report a history of local trauma at the lesion site.⁶ Histologically, dermatofibroma is characterized by a nodular dermal proliferation of spindleshaped fibrous cells and histiocytes in a storiform pattern (Figure 1).⁶ Epidermal induction with acanthosis overlying the tumor often is found with occasional basilar hyperpigmentation.⁵ Dermatofibroma also characteristically has trapped collagen (“collagen balls”) seen at the periphery.^5,6

Piloleiomyomas are benign smooth muscle tumors arising from arrector pili muscles that may be solitary or multiple.⁵ Clinically, they typically present as firm, reddish-brown to flesh-colored papules or nodules that develop more commonly in adulthood.^5,7 Piloleiomyomas favor the extremities and trunk, particularly the shoulder, and can be associated with spontaneous or induced pain. Histologically, piloleiomyomas are well circumscribed and centered within the reticular dermis situated closely to hair follicles (Figure 2).⁵ They are composed of numerous interlacing fascicles or whorls of smooth muscle cells with abundant eosinophilic cytoplasm and blunt-ended, cigar-shaped nuclei.^5,7

Solitary cutaneous myofibroma is a benign fibrous tumor found in adolescents and adults and is the counterpart to infantile myofibromatosis.⁸ Clinically, myofibromas typically present as painless, slow-growing, firm nodules with an occasional bluish hue. Histologically, solitary cutaneous myofibromas appear in a biphasic pattern, with hemangiopericytomatous components as well as spindle cells arranged in short bundles and fascicles resembling leiomyoma (Figure 3). The spindle cells also have abundant eosinophilic cytoplasm with short plump nuclei; the random, irregularly intersecting angles can be used to help differentiate myofibromas from smooth muscle lesions.⁸ Solitary cutaneous myofibroma is in the differential diagnosis for dermatomyofibroma because of their shared myofibroblastic nature.⁹

Dermatofibrosarcoma protuberans (DFSP) is an uncommon, locally invasive sarcoma with a high recurrence rate that favors young to middle-aged adults, with rare childhood onset reported.^5,10,11 Clinically, DFSP typically presents as an asymptomatic, slow-growing, firm, flesh-colored, indurated plaque that develops into a violaceous to reddish-brown nodule.⁵ The atrophic variant of DFSP is characterized by a nonprotuberant lesion and can be especially difficult to distinguish from other entities such as dermatomyofibroma.¹¹ The majority of DFSP lesions occur on the trunk, particularly in the shoulder or pelvic region.⁵ Histologically, early plaque lesions are comprised of monomorphic spindle cells arranged in long fascicles (parallel to the skin surface), infiltrating adnexal structures, and subcutaneous adipocytes in a multilayered honeycomb pattern; the spindle cells of late nodular lesions are arranged in short fascicles in a matted or storiform pattern (Figure 4).^5,10 Early stages of DFSP as well as variations in childhood-onset DFSP can easily be misdiagnosed and incompletely excised.⁵

The Diagnosis: Dermatomyofibroma

Dermatomyofibroma is an uncommon, benign, cutaneous mesenchymal neoplasm composed of fibroblasts and myofibroblasts.^1-3 This skin tumor was first described in 1991 by Hugel⁴ in the German literature as plaquelike fibromatosis. Pediatric dermatomyofibromas are exceedingly rare, with pediatric patients ranging in age from infants to teenagers.¹

Clinically, dermatomyofibromas appear as long-standing, isolated, ill-demarcated, flesh-colored, slightly hyperpigmented or erythematous nodules or plaques that may be raised or indurated.¹ Dermatomyofibromas may present with constant mild pain or pruritus, though in most cases the lesions are asymptomatic.^1,3 The clinical presentation of dermatomyofibroma has a few distinct differences in children compared to adults. In adulthood, dermatomyofibroma has a strong female predominance and most commonly is located on the shoulder and adjacent upper body regions, including the axilla, neck, upper arm, and upper trunk.^1-3 In childhood, the majority of dermatomyofibromas occur in young boys and usually are located on the neck with other upper body regions occurring less frequently.^1,2 A shared characteristic includes the tendency for dermatomyofibromas to have an initial period of enlargement followed by stabilization or slow growth.¹ Reported pediatric lesions have ranged in size from 4 to 60 mm with an average size of 14.9 mm (median, 12 mm).²

The diagnosis of dermatomyofibroma is based on histopathologic features in addition to clinical presentation. Histology from punch biopsy usually reveals a noninvasive dermal proliferation of bland, uniform, slender spindle cells oriented parallel to the overlying epidermis with increased and fragmented elastic fibers.^1,3 Infiltration into the mid or deep dermis is common. The adnexal structures usually are spared; the stroma contains collagen and increased small blood vessels; and there typically is no inflammatory infiltrate, except for occasional scattered mast cells.² Cytologically, the monomorphic spindleshaped tumor cells have an ill-defined, pale, eosinophilic cytoplasm and nuclei that are elongated with tapered edges.³ Dermatomyofibroma has a variable immunohistochemical profile, as it may stain focally positive for CD34 or smooth muscle actin, with occasional staining of factor XIIIa, desmin, calponin, or vimentin.^1-3 Normal to increased levels of often fragmented elastic fibers is a helpful clue in distinguishing dermatomyofibroma from dermatofibroma, hypertrophic scar, dermatofibrosarcoma protuberans, and pilar leiomyoma, in which elastic fibers typically are reduced.³ Differential diagnoses of mesenchymal tumors in children include desmoid fibromatosis, connective tissue nevus, myofibromatosis, and smooth muscle hamartoma.¹

A punch biopsy with clinical observation and followup is recommended for the management of lesions in cosmetically sensitive areas or in very young children who may not tolerate surgery. In symptomatic or cosmetically unappealing cases of dermatomyofibroma, simple surgical excision remains a viable treatment option. Recurrence is uncommon, even if only partially excised, and no instances of metastasis have been reported.^1-5

Dermatomyofibromas may be mistaken for several other entities both benign and malignant. For example, the benign dermatofibroma is the second most common fibrohistiocytic tumor of the skin and presents as a firm, nontender, minimally elevated to dome-shaped papule that usually measures less than or equal to 1 cm in diameter with or without overlying skin changes.^5,6 It primarily is seen in adults with a slight female predominance and favors the lower extremities.⁵ Patients usually are asymptomatic but often report a history of local trauma at the lesion site.⁶ Histologically, dermatofibroma is characterized by a nodular dermal proliferation of spindleshaped fibrous cells and histiocytes in a storiform pattern (Figure 1).⁶ Epidermal induction with acanthosis overlying the tumor often is found with occasional basilar hyperpigmentation.⁵ Dermatofibroma also characteristically has trapped collagen (“collagen balls”) seen at the periphery.^5,6

Piloleiomyomas are benign smooth muscle tumors arising from arrector pili muscles that may be solitary or multiple.⁵ Clinically, they typically present as firm, reddish-brown to flesh-colored papules or nodules that develop more commonly in adulthood.^5,7 Piloleiomyomas favor the extremities and trunk, particularly the shoulder, and can be associated with spontaneous or induced pain. Histologically, piloleiomyomas are well circumscribed and centered within the reticular dermis situated closely to hair follicles (Figure 2).⁵ They are composed of numerous interlacing fascicles or whorls of smooth muscle cells with abundant eosinophilic cytoplasm and blunt-ended, cigar-shaped nuclei.^5,7

Solitary cutaneous myofibroma is a benign fibrous tumor found in adolescents and adults and is the counterpart to infantile myofibromatosis.⁸ Clinically, myofibromas typically present as painless, slow-growing, firm nodules with an occasional bluish hue. Histologically, solitary cutaneous myofibromas appear in a biphasic pattern, with hemangiopericytomatous components as well as spindle cells arranged in short bundles and fascicles resembling leiomyoma (Figure 3). The spindle cells also have abundant eosinophilic cytoplasm with short plump nuclei; the random, irregularly intersecting angles can be used to help differentiate myofibromas from smooth muscle lesions.⁸ Solitary cutaneous myofibroma is in the differential diagnosis for dermatomyofibroma because of their shared myofibroblastic nature.⁹

Dermatofibrosarcoma protuberans (DFSP) is an uncommon, locally invasive sarcoma with a high recurrence rate that favors young to middle-aged adults, with rare childhood onset reported.^5,10,11 Clinically, DFSP typically presents as an asymptomatic, slow-growing, firm, flesh-colored, indurated plaque that develops into a violaceous to reddish-brown nodule.⁵ The atrophic variant of DFSP is characterized by a nonprotuberant lesion and can be especially difficult to distinguish from other entities such as dermatomyofibroma.¹¹ The majority of DFSP lesions occur on the trunk, particularly in the shoulder or pelvic region.⁵ Histologically, early plaque lesions are comprised of monomorphic spindle cells arranged in long fascicles (parallel to the skin surface), infiltrating adnexal structures, and subcutaneous adipocytes in a multilayered honeycomb pattern; the spindle cells of late nodular lesions are arranged in short fascicles in a matted or storiform pattern (Figure 4).^5,10 Early stages of DFSP as well as variations in childhood-onset DFSP can easily be misdiagnosed and incompletely excised.⁵

The Diagnosis: Infantile Digital Fibromatosis

Infantile digital fibromatosis (IDF) is a rare benign neoplasm of infancy prone to recurrence after resection but not to metastasis. It usually is limited to the fingers and toes.¹ One-third of cases occur at birth. Most patients develop clinical symptoms within the first year of life, but presentation can occur in adolescents and adults. The exact etiology and pathogenesis of IDF remain unclear, but trauma is thought to be a trigger.

Physical examination reveals single or multiple smooth, round, pink papules or nodules confined to the sides and backs of the fingers, sparing the thumb and first toe.^2,3 The nodules typically are firm, less than 2 cm in diameter, and often painless. Infantile digital fibromatosis exhibits an indolent progression followed by a rapid growth phase during several months, which may lead to functional impairment and joint deformities.^4,5 Histopathology displays spindle cells with eosinophilic cytoplasmic inclusions that range from round to oval with uneven distribution, lack of refraction, and a large size difference (3–15 μm).6 The inclusions are deep red with Masson trichrome staining and can express smooth muscle actin and calponin. Tumor cells usually express vimentin, smooth muscle actin, calponin, and desmin but fail to express S-100 protein. The Ki67 proliferation index is 2% to 15%.^6,7

Nonsurgical treatments for IDF include topical imiquimod, topical or intradermal injection of glucocorticoids, and intradermal injection of 5-fluorouracil. Complete resection should be reserved for cases with invasive growth that may lead to joint deformities, tendon or ligament involvement, digit or contracture deformity, and complications such as decreased joint mobility. Although there is a recurrence rate of up to 50% after excision, most lesions eventually will spontaneously regress and will leave no scar.^8-10

The clinical and histopathologic differential diagnoses of IDF include other cutaneous diseases that occur in the digits. A dermatofibroma is a round, firm, fibrohistiocytic nodule that mainly occurs on the extensor limbs. Histopathology includes both fibrous and cellular types.¹¹ Histologic analysis shows an ill-defined dermal proliferation of spindled fibroblasts with pale eosinophilic cytoplasm and bland fusiform nuclei growing in bands or fascicles that trap collagen fibers at the periphery (Figure 1). Generally, dermatofibromas have marked epidermal hyperplasia, which differs from IDF.

A digital myxoid cyst is characterized by a fleshcolored, hemispherical, and translucent cystic nodule that arises from the dorsum of the distal interphalangeal joint.¹² It commonly is associated with injury and chronic pressure. Translucent viscous liquid may flow out when the cyst is punctured, a hallmark feature of this entity. Clinical variants of myxoid cyst include myxomatous and ganglion types. Histopathology reveals excessive mucin deposited in the dermis, and the surrounding collagen is compressed to form the pseudocyst (Figure 2).

A giant cell tumor of the tendon sheath presents with asymptomatic nodules or lumps. Lesions frequently are localized to the tendon sheath, especially on the fingers and wrists, with no malignant tendency or propensity for spontaneous regression.¹³ The local recurrence rate is as high as 45%, which is related to surgical resection insufficiency.¹⁴ Histopathologic examination shows lobulated tumor tissue surrounded by dense fibrosis. The tumor cells are histiocytic with scattered giant cells (Figure 3). The characteristic osteoclastlike giant cells have eosinophilic cytoplasm and irregularly arranged nuclei in varying numbers.

Keloids are connective tissue hyperplasias caused by skin injury. Histopathologically, keloids are characterized by nodules of thick hyalinized collagen bundles and whorled fibroblasts (Figure 4). No inclusions in the fibroblasts and a history of trauma can differentiate keloids from IDF.

The Diagnosis: Infantile Digital Fibromatosis

Infantile digital fibromatosis (IDF) is a rare benign neoplasm of infancy prone to recurrence after resection but not to metastasis. It usually is limited to the fingers and toes.¹ One-third of cases occur at birth. Most patients develop clinical symptoms within the first year of life, but presentation can occur in adolescents and adults. The exact etiology and pathogenesis of IDF remain unclear, but trauma is thought to be a trigger.

Physical examination reveals single or multiple smooth, round, pink papules or nodules confined to the sides and backs of the fingers, sparing the thumb and first toe.^2,3 The nodules typically are firm, less than 2 cm in diameter, and often painless. Infantile digital fibromatosis exhibits an indolent progression followed by a rapid growth phase during several months, which may lead to functional impairment and joint deformities.^4,5 Histopathology displays spindle cells with eosinophilic cytoplasmic inclusions that range from round to oval with uneven distribution, lack of refraction, and a large size difference (3–15 μm).6 The inclusions are deep red with Masson trichrome staining and can express smooth muscle actin and calponin. Tumor cells usually express vimentin, smooth muscle actin, calponin, and desmin but fail to express S-100 protein. The Ki67 proliferation index is 2% to 15%.^6,7

Nonsurgical treatments for IDF include topical imiquimod, topical or intradermal injection of glucocorticoids, and intradermal injection of 5-fluorouracil. Complete resection should be reserved for cases with invasive growth that may lead to joint deformities, tendon or ligament involvement, digit or contracture deformity, and complications such as decreased joint mobility. Although there is a recurrence rate of up to 50% after excision, most lesions eventually will spontaneously regress and will leave no scar.^8-10

The clinical and histopathologic differential diagnoses of IDF include other cutaneous diseases that occur in the digits. A dermatofibroma is a round, firm, fibrohistiocytic nodule that mainly occurs on the extensor limbs. Histopathology includes both fibrous and cellular types.¹¹ Histologic analysis shows an ill-defined dermal proliferation of spindled fibroblasts with pale eosinophilic cytoplasm and bland fusiform nuclei growing in bands or fascicles that trap collagen fibers at the periphery (Figure 1). Generally, dermatofibromas have marked epidermal hyperplasia, which differs from IDF.

A digital myxoid cyst is characterized by a fleshcolored, hemispherical, and translucent cystic nodule that arises from the dorsum of the distal interphalangeal joint.¹² It commonly is associated with injury and chronic pressure. Translucent viscous liquid may flow out when the cyst is punctured, a hallmark feature of this entity. Clinical variants of myxoid cyst include myxomatous and ganglion types. Histopathology reveals excessive mucin deposited in the dermis, and the surrounding collagen is compressed to form the pseudocyst (Figure 2).

A giant cell tumor of the tendon sheath presents with asymptomatic nodules or lumps. Lesions frequently are localized to the tendon sheath, especially on the fingers and wrists, with no malignant tendency or propensity for spontaneous regression.¹³ The local recurrence rate is as high as 45%, which is related to surgical resection insufficiency.¹⁴ Histopathologic examination shows lobulated tumor tissue surrounded by dense fibrosis. The tumor cells are histiocytic with scattered giant cells (Figure 3). The characteristic osteoclastlike giant cells have eosinophilic cytoplasm and irregularly arranged nuclei in varying numbers.

Keloids are connective tissue hyperplasias caused by skin injury. Histopathologically, keloids are characterized by nodules of thick hyalinized collagen bundles and whorled fibroblasts (Figure 4). No inclusions in the fibroblasts and a history of trauma can differentiate keloids from IDF.

The Diagnosis: Infantile Digital Fibromatosis

Infantile digital fibromatosis (IDF) is a rare benign neoplasm of infancy prone to recurrence after resection but not to metastasis. It usually is limited to the fingers and toes.¹ One-third of cases occur at birth. Most patients develop clinical symptoms within the first year of life, but presentation can occur in adolescents and adults. The exact etiology and pathogenesis of IDF remain unclear, but trauma is thought to be a trigger.

Physical examination reveals single or multiple smooth, round, pink papules or nodules confined to the sides and backs of the fingers, sparing the thumb and first toe.^2,3 The nodules typically are firm, less than 2 cm in diameter, and often painless. Infantile digital fibromatosis exhibits an indolent progression followed by a rapid growth phase during several months, which may lead to functional impairment and joint deformities.^4,5 Histopathology displays spindle cells with eosinophilic cytoplasmic inclusions that range from round to oval with uneven distribution, lack of refraction, and a large size difference (3–15 μm).6 The inclusions are deep red with Masson trichrome staining and can express smooth muscle actin and calponin. Tumor cells usually express vimentin, smooth muscle actin, calponin, and desmin but fail to express S-100 protein. The Ki67 proliferation index is 2% to 15%.^6,7

Nonsurgical treatments for IDF include topical imiquimod, topical or intradermal injection of glucocorticoids, and intradermal injection of 5-fluorouracil. Complete resection should be reserved for cases with invasive growth that may lead to joint deformities, tendon or ligament involvement, digit or contracture deformity, and complications such as decreased joint mobility. Although there is a recurrence rate of up to 50% after excision, most lesions eventually will spontaneously regress and will leave no scar.^8-10

The clinical and histopathologic differential diagnoses of IDF include other cutaneous diseases that occur in the digits. A dermatofibroma is a round, firm, fibrohistiocytic nodule that mainly occurs on the extensor limbs. Histopathology includes both fibrous and cellular types.¹¹ Histologic analysis shows an ill-defined dermal proliferation of spindled fibroblasts with pale eosinophilic cytoplasm and bland fusiform nuclei growing in bands or fascicles that trap collagen fibers at the periphery (Figure 1). Generally, dermatofibromas have marked epidermal hyperplasia, which differs from IDF.

A digital myxoid cyst is characterized by a fleshcolored, hemispherical, and translucent cystic nodule that arises from the dorsum of the distal interphalangeal joint.¹² It commonly is associated with injury and chronic pressure. Translucent viscous liquid may flow out when the cyst is punctured, a hallmark feature of this entity. Clinical variants of myxoid cyst include myxomatous and ganglion types. Histopathology reveals excessive mucin deposited in the dermis, and the surrounding collagen is compressed to form the pseudocyst (Figure 2).

A giant cell tumor of the tendon sheath presents with asymptomatic nodules or lumps. Lesions frequently are localized to the tendon sheath, especially on the fingers and wrists, with no malignant tendency or propensity for spontaneous regression.¹³ The local recurrence rate is as high as 45%, which is related to surgical resection insufficiency.¹⁴ Histopathologic examination shows lobulated tumor tissue surrounded by dense fibrosis. The tumor cells are histiocytic with scattered giant cells (Figure 3). The characteristic osteoclastlike giant cells have eosinophilic cytoplasm and irregularly arranged nuclei in varying numbers.

Keloids are connective tissue hyperplasias caused by skin injury. Histopathologically, keloids are characterized by nodules of thick hyalinized collagen bundles and whorled fibroblasts (Figure 4). No inclusions in the fibroblasts and a history of trauma can differentiate keloids from IDF.

The Diagnosis: Schwannoma

Schwannoma, also known as neurilemmoma, is a benign encapsulated neoplasm of the peripheral nerve sheath that presents as a subcutaneous nodule.¹ It also may present in the retroperitoneum, mediastinum, and viscera (eg, gastrointestinal tract, bone, upper respiratory tract, lymph nodes). It may occur as multiple lesions when associated with certain syndromes. It usually is an asymptomatic indolent tumor with neurologic symptoms, such as pain and tenderness, in the lesions that are deeper, larger, or closer in proximity to nearby structures.^2,3

Histologically, a schwannoma is encapsulated by the perineurium of the nerve bundle from which it originates (quiz image [top]). The tumor consists of hypercellular (Antoni type A) and hypocellular (Antoni type B) areas. Antoni type A areas consist of tightly packed, spindleshaped cells with elongated wavy nuclei and indistinct cytoplasmic borders. These nuclei tend to align into parallel rows with intervening anuclear zones forming Verocay bodies (quiz image [bottom]).⁴ Verocay bodies are not seen in all schwannomas, and similar formations may be seen in other tumors as well. Solitary circumscribed neuromas also have Verocay bodies, whereas dermatofibromas and leiomyomas have Verocay-like bodies. Antoni type B areas have scattered spindled or ovoid cells in an edematous or myxoid matrix interspersed with inflammatory cells such as lymphocytes and histiocytes. Vessels with thick hyalinized walls are a helpful feature in diagnosis.² Schwann cells of a schwannoma stain diffusely positive with S-100 protein. The capsule stains positively with epithelial membrane antigen due to the presence of perineurial cells.²

The morphologic variants of this entity include conventional (common, solitary), cellular, plexiform, ancient, melanotic, epithelioid, pseudoglandular, neuroblastomalike, and microcystic/reticular schwannomas. There are additional variants that are associated with genetic syndromes, such as multiple cutaneous plexiform schwannomas linked with neurofibromatosis type 2, psammomatous melanotic schwannoma presenting in Carney complex, schwannomatosis, and segmental schwannomatosis (a distinct form of neurofibromatosis characterized by multiple schwannomas localized to one limb). Either presentation may have alteration or deletion of the neurofibromatosis type 2 gene, NF2, on chromosome 22.^2,5

Nodular fasciitis is a benign tumor of fibroblasts and myofibroblasts that usually arises in the subcutaneous tissues. It most commonly occurs in the upper extremities, trunk, head, and neck. It presents as a single, often painful, rapidly growing, subcutaneous nodule. Histologically, lesions mostly are well circumscribed yet unencapsulated, in contrast to schwannomas. They may be hypocellular or hypercellular and are composed of uniform spindle cells with a feathery or fascicular (tissue culture–like) appearance in a loose, myxoid to collagenous stroma. There may be foci of hemorrhage and conspicuous mitoses but not atypical figures (Figure 1). Immunohistochemically, the cells stain positively for smooth muscle actin and negatively for S-100 protein, which sets it apart from a schwannoma. Most cases contain fusion genes, with myosin heavy chain 9 ubiquitin-specific peptidase 6, MYH9-USP6, being the most common fusion product.⁶

Solitary circumscribed neuroma (palisaded encapsulated neuroma) is a benign, usually solitary dermal lesion. It most commonly occurs in middle-aged to elderly adults as a small (<1 cm), firm, flesh-colored to pink papule on the face (ie, cheeks, nose, nasolabial folds) and less commonly in the oral and acral regions and on the eyelids and penis. The lesion usually is unilobular; however, other growth patterns such as plexiform, multilobular, and fungating variants have been identified. Histologically, it is a well-circumscribed nodule with a thin capsule of perineurium that is composed of interlacing bundles of Schwann cells with a characteristic clefting artifact (Figure 2). Cells have wavy dark nuclei with scant cytoplasm that occasionally form palisades or Verocay bodies causing these lesions to be confused with schwannomas. Immunohistochemically, the Schwann cells stain positively with S-100 protein, and the perineurium stains positively with epithelial membrane antigen, Claudin-1, and Glut-1. Neurofilament protein stains axons throughout neuromas, whereas in schwannoma, the expression often is limited to entrapped axons at the periphery of the tumor.⁷

Angioleiomyoma is an uncommon, benign, smooth muscle neoplasm of the skin and subcutaneous tissue that originates from vascular smooth muscle. It most commonly presents in adult females aged 30 to 60 years, with a predilection for the lower limbs. These tumors typically are solitary, slow growing, and less than 2 cm in diameter and may be painful upon compression. Similar to schwannoma, angioleiomyoma is an encapsulated lesion composed of interlacing, uniform, smooth muscle bundles distributed around vessels (Figure 3). Smooth muscle cells have oval- or cigar-shaped nuclei with a small perinuclear vacuole of glycogen. Immunohistochemically, there is strong diffuse staining for smooth muscle actin and h-caldesmon. Recurrence after excision is rare.^2,8

Neurofibroma is a common, mostly sporadic, benign tumor of nerve sheath origin. The solitary type may be localized (well circumscribed, unencapsulated) or diffuse. The presence of multiple, deep, and plexiform lesions is associated with neurofibromatosis type 1 (von Recklinghausen disease) that is caused by germline mutations in the NF1 gene. Histologically, the tumor is composed of Schwann cells, fibroblasts, perineurial cells, and nerve axons within an extracellular myxoid to collagenous matrix (Figure 4). The diffuse type is an ill-defined proliferation that entraps adnexal structures. The plexiform type is defined by multinodular serpentine fascicles. Immunohistochemically, the Schwann cells stain positive for S-100 protein and SOX10 (SRY-Box Transcription Factor 10). Epithelial membrane antigen stains admixed perineurial cells. Neurofilament protein highlights intratumoral axons, which generally are not found throughout schwannomas. Transformation to a malignant peripheral nerve sheath tumor occurs in up to 10% of patients with neurofibromatosis type 1, usually in plexiform neurofibromas, and is characterized by increased cellularity, atypia, mitotic activity, and necrosis.⁹

The Diagnosis: Schwannoma

Schwannoma, also known as neurilemmoma, is a benign encapsulated neoplasm of the peripheral nerve sheath that presents as a subcutaneous nodule.¹ It also may present in the retroperitoneum, mediastinum, and viscera (eg, gastrointestinal tract, bone, upper respiratory tract, lymph nodes). It may occur as multiple lesions when associated with certain syndromes. It usually is an asymptomatic indolent tumor with neurologic symptoms, such as pain and tenderness, in the lesions that are deeper, larger, or closer in proximity to nearby structures.^2,3

Histologically, a schwannoma is encapsulated by the perineurium of the nerve bundle from which it originates (quiz image [top]). The tumor consists of hypercellular (Antoni type A) and hypocellular (Antoni type B) areas. Antoni type A areas consist of tightly packed, spindleshaped cells with elongated wavy nuclei and indistinct cytoplasmic borders. These nuclei tend to align into parallel rows with intervening anuclear zones forming Verocay bodies (quiz image [bottom]).⁴ Verocay bodies are not seen in all schwannomas, and similar formations may be seen in other tumors as well. Solitary circumscribed neuromas also have Verocay bodies, whereas dermatofibromas and leiomyomas have Verocay-like bodies. Antoni type B areas have scattered spindled or ovoid cells in an edematous or myxoid matrix interspersed with inflammatory cells such as lymphocytes and histiocytes. Vessels with thick hyalinized walls are a helpful feature in diagnosis.² Schwann cells of a schwannoma stain diffusely positive with S-100 protein. The capsule stains positively with epithelial membrane antigen due to the presence of perineurial cells.²

The morphologic variants of this entity include conventional (common, solitary), cellular, plexiform, ancient, melanotic, epithelioid, pseudoglandular, neuroblastomalike, and microcystic/reticular schwannomas. There are additional variants that are associated with genetic syndromes, such as multiple cutaneous plexiform schwannomas linked with neurofibromatosis type 2, psammomatous melanotic schwannoma presenting in Carney complex, schwannomatosis, and segmental schwannomatosis (a distinct form of neurofibromatosis characterized by multiple schwannomas localized to one limb). Either presentation may have alteration or deletion of the neurofibromatosis type 2 gene, NF2, on chromosome 22.^2,5

Nodular fasciitis is a benign tumor of fibroblasts and myofibroblasts that usually arises in the subcutaneous tissues. It most commonly occurs in the upper extremities, trunk, head, and neck. It presents as a single, often painful, rapidly growing, subcutaneous nodule. Histologically, lesions mostly are well circumscribed yet unencapsulated, in contrast to schwannomas. They may be hypocellular or hypercellular and are composed of uniform spindle cells with a feathery or fascicular (tissue culture–like) appearance in a loose, myxoid to collagenous stroma. There may be foci of hemorrhage and conspicuous mitoses but not atypical figures (Figure 1). Immunohistochemically, the cells stain positively for smooth muscle actin and negatively for S-100 protein, which sets it apart from a schwannoma. Most cases contain fusion genes, with myosin heavy chain 9 ubiquitin-specific peptidase 6, MYH9-USP6, being the most common fusion product.⁶

Solitary circumscribed neuroma (palisaded encapsulated neuroma) is a benign, usually solitary dermal lesion. It most commonly occurs in middle-aged to elderly adults as a small (<1 cm), firm, flesh-colored to pink papule on the face (ie, cheeks, nose, nasolabial folds) and less commonly in the oral and acral regions and on the eyelids and penis. The lesion usually is unilobular; however, other growth patterns such as plexiform, multilobular, and fungating variants have been identified. Histologically, it is a well-circumscribed nodule with a thin capsule of perineurium that is composed of interlacing bundles of Schwann cells with a characteristic clefting artifact (Figure 2). Cells have wavy dark nuclei with scant cytoplasm that occasionally form palisades or Verocay bodies causing these lesions to be confused with schwannomas. Immunohistochemically, the Schwann cells stain positively with S-100 protein, and the perineurium stains positively with epithelial membrane antigen, Claudin-1, and Glut-1. Neurofilament protein stains axons throughout neuromas, whereas in schwannoma, the expression often is limited to entrapped axons at the periphery of the tumor.⁷

Angioleiomyoma is an uncommon, benign, smooth muscle neoplasm of the skin and subcutaneous tissue that originates from vascular smooth muscle. It most commonly presents in adult females aged 30 to 60 years, with a predilection for the lower limbs. These tumors typically are solitary, slow growing, and less than 2 cm in diameter and may be painful upon compression. Similar to schwannoma, angioleiomyoma is an encapsulated lesion composed of interlacing, uniform, smooth muscle bundles distributed around vessels (Figure 3). Smooth muscle cells have oval- or cigar-shaped nuclei with a small perinuclear vacuole of glycogen. Immunohistochemically, there is strong diffuse staining for smooth muscle actin and h-caldesmon. Recurrence after excision is rare.^2,8

Neurofibroma is a common, mostly sporadic, benign tumor of nerve sheath origin. The solitary type may be localized (well circumscribed, unencapsulated) or diffuse. The presence of multiple, deep, and plexiform lesions is associated with neurofibromatosis type 1 (von Recklinghausen disease) that is caused by germline mutations in the NF1 gene. Histologically, the tumor is composed of Schwann cells, fibroblasts, perineurial cells, and nerve axons within an extracellular myxoid to collagenous matrix (Figure 4). The diffuse type is an ill-defined proliferation that entraps adnexal structures. The plexiform type is defined by multinodular serpentine fascicles. Immunohistochemically, the Schwann cells stain positive for S-100 protein and SOX10 (SRY-Box Transcription Factor 10). Epithelial membrane antigen stains admixed perineurial cells. Neurofilament protein highlights intratumoral axons, which generally are not found throughout schwannomas. Transformation to a malignant peripheral nerve sheath tumor occurs in up to 10% of patients with neurofibromatosis type 1, usually in plexiform neurofibromas, and is characterized by increased cellularity, atypia, mitotic activity, and necrosis.⁹

The Diagnosis: Schwannoma

Schwannoma, also known as neurilemmoma, is a benign encapsulated neoplasm of the peripheral nerve sheath that presents as a subcutaneous nodule.¹ It also may present in the retroperitoneum, mediastinum, and viscera (eg, gastrointestinal tract, bone, upper respiratory tract, lymph nodes). It may occur as multiple lesions when associated with certain syndromes. It usually is an asymptomatic indolent tumor with neurologic symptoms, such as pain and tenderness, in the lesions that are deeper, larger, or closer in proximity to nearby structures.^2,3

Histologically, a schwannoma is encapsulated by the perineurium of the nerve bundle from which it originates (quiz image [top]). The tumor consists of hypercellular (Antoni type A) and hypocellular (Antoni type B) areas. Antoni type A areas consist of tightly packed, spindleshaped cells with elongated wavy nuclei and indistinct cytoplasmic borders. These nuclei tend to align into parallel rows with intervening anuclear zones forming Verocay bodies (quiz image [bottom]).⁴ Verocay bodies are not seen in all schwannomas, and similar formations may be seen in other tumors as well. Solitary circumscribed neuromas also have Verocay bodies, whereas dermatofibromas and leiomyomas have Verocay-like bodies. Antoni type B areas have scattered spindled or ovoid cells in an edematous or myxoid matrix interspersed with inflammatory cells such as lymphocytes and histiocytes. Vessels with thick hyalinized walls are a helpful feature in diagnosis.² Schwann cells of a schwannoma stain diffusely positive with S-100 protein. The capsule stains positively with epithelial membrane antigen due to the presence of perineurial cells.²

The morphologic variants of this entity include conventional (common, solitary), cellular, plexiform, ancient, melanotic, epithelioid, pseudoglandular, neuroblastomalike, and microcystic/reticular schwannomas. There are additional variants that are associated with genetic syndromes, such as multiple cutaneous plexiform schwannomas linked with neurofibromatosis type 2, psammomatous melanotic schwannoma presenting in Carney complex, schwannomatosis, and segmental schwannomatosis (a distinct form of neurofibromatosis characterized by multiple schwannomas localized to one limb). Either presentation may have alteration or deletion of the neurofibromatosis type 2 gene, NF2, on chromosome 22.^2,5

Nodular fasciitis is a benign tumor of fibroblasts and myofibroblasts that usually arises in the subcutaneous tissues. It most commonly occurs in the upper extremities, trunk, head, and neck. It presents as a single, often painful, rapidly growing, subcutaneous nodule. Histologically, lesions mostly are well circumscribed yet unencapsulated, in contrast to schwannomas. They may be hypocellular or hypercellular and are composed of uniform spindle cells with a feathery or fascicular (tissue culture–like) appearance in a loose, myxoid to collagenous stroma. There may be foci of hemorrhage and conspicuous mitoses but not atypical figures (Figure 1). Immunohistochemically, the cells stain positively for smooth muscle actin and negatively for S-100 protein, which sets it apart from a schwannoma. Most cases contain fusion genes, with myosin heavy chain 9 ubiquitin-specific peptidase 6, MYH9-USP6, being the most common fusion product.⁶

Solitary circumscribed neuroma (palisaded encapsulated neuroma) is a benign, usually solitary dermal lesion. It most commonly occurs in middle-aged to elderly adults as a small (<1 cm), firm, flesh-colored to pink papule on the face (ie, cheeks, nose, nasolabial folds) and less commonly in the oral and acral regions and on the eyelids and penis. The lesion usually is unilobular; however, other growth patterns such as plexiform, multilobular, and fungating variants have been identified. Histologically, it is a well-circumscribed nodule with a thin capsule of perineurium that is composed of interlacing bundles of Schwann cells with a characteristic clefting artifact (Figure 2). Cells have wavy dark nuclei with scant cytoplasm that occasionally form palisades or Verocay bodies causing these lesions to be confused with schwannomas. Immunohistochemically, the Schwann cells stain positively with S-100 protein, and the perineurium stains positively with epithelial membrane antigen, Claudin-1, and Glut-1. Neurofilament protein stains axons throughout neuromas, whereas in schwannoma, the expression often is limited to entrapped axons at the periphery of the tumor.⁷

Angioleiomyoma is an uncommon, benign, smooth muscle neoplasm of the skin and subcutaneous tissue that originates from vascular smooth muscle. It most commonly presents in adult females aged 30 to 60 years, with a predilection for the lower limbs. These tumors typically are solitary, slow growing, and less than 2 cm in diameter and may be painful upon compression. Similar to schwannoma, angioleiomyoma is an encapsulated lesion composed of interlacing, uniform, smooth muscle bundles distributed around vessels (Figure 3). Smooth muscle cells have oval- or cigar-shaped nuclei with a small perinuclear vacuole of glycogen. Immunohistochemically, there is strong diffuse staining for smooth muscle actin and h-caldesmon. Recurrence after excision is rare.^2,8

Neurofibroma is a common, mostly sporadic, benign tumor of nerve sheath origin. The solitary type may be localized (well circumscribed, unencapsulated) or diffuse. The presence of multiple, deep, and plexiform lesions is associated with neurofibromatosis type 1 (von Recklinghausen disease) that is caused by germline mutations in the NF1 gene. Histologically, the tumor is composed of Schwann cells, fibroblasts, perineurial cells, and nerve axons within an extracellular myxoid to collagenous matrix (Figure 4). The diffuse type is an ill-defined proliferation that entraps adnexal structures. The plexiform type is defined by multinodular serpentine fascicles. Immunohistochemically, the Schwann cells stain positive for S-100 protein and SOX10 (SRY-Box Transcription Factor 10). Epithelial membrane antigen stains admixed perineurial cells. Neurofilament protein highlights intratumoral axons, which generally are not found throughout schwannomas. Transformation to a malignant peripheral nerve sheath tumor occurs in up to 10% of patients with neurofibromatosis type 1, usually in plexiform neurofibromas, and is characterized by increased cellularity, atypia, mitotic activity, and necrosis.⁹

The Diagnosis: Primary Cutaneous Carcinosarcoma

The immunohistochemical findings supported an epithelial component consistent with moderately differentiated squamous cell carcinoma (SCC) and a mesenchymal component with features consistent with a sarcoma. Consequently, the lesion was diagnosed as a primary cutaneous carcinosarcoma (PCCS).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm consisting of malignant epithelial (carcinoma) and mesenchymal (sarcoma) components.¹ Primary cutaneous carcinosarcomas are uncommon, poorly understood, primary cutaneous tumors.^2,3 Characteristic of this tumor, cytokeratins highlight the epithelial component while vimentin highlights the mesenchymal component.⁴ Histologically, the sarcomatous components of PCCS often are highly variable, with an absence of transitional areas within the epithelial component, which frequently resembles basal cell carcinoma and/ or SCC.^5-7 Primary cutaneous carcinosarcoma favors areas of chronic UV radiation exposure, particularly on the head and neck. Most tumors present with a slowly growing, polypoid, flesh-colored to erythematous nodule due to the infiltrative mesenchymal component.⁷ Primary cutaneous carcinosarcoma primarily is diagnosed in elderly patients, with the majority of cases diagnosed in the eighth or ninth decades of life (range, 32–98 years).^1,8 Men appear to be twice as likely to be diagnosed with a PCCS compared to women.¹ Primary cutaneous carcinosarcomas are recognized as aggressive tumors with a high propensity to metastasize and recur locally, necessitating early diagnosis and treatment.⁴ Accurate diagnosis of PCCSs can be challenging due to the biphasic nature of the neoplasm as well as poor differentiation or unequal proportions of the epithelial and mesenchymal components.⁵ Additionally, overlapping diagnostic criteria coupled with vague demarcation between soft-tissue sarcomas and distinct carcinomas also may contribute to a delay in diagnosis.⁹ Treatment is achieved surgically by complete wide resection, with no evidence to support the use of adjuvant or neoadjuvant external beam radiation therapy. Due to the small number of reported cases, no treatment recommendations currently exist.¹

Surgical management with wide local excision has been disappointing, with recurrence rates reported as high as 33%.⁶ Primary cutaneous carcinosarcoma has an estimated overall recurrence rate of 19% and a 5-year disease-free rate of 50%.¹⁰ Risk factors associated with poorer prognosis include tumors with adnexal subtype, age less than 65 years, rapid tumor growth, a tumor greater than 20 mm at presentation, and a long-standing tumor lasting up to 30 years.^2,4 Although wide local excision and Mohs micrographic surgery (MMS) both have been utilized successfully, MMS has been shown to result in a cure rate of greater than 98%.⁶

Atypical fibroxanthoma (AFX) is a cutaneous tumor of fibrohistiocytic mesenchymal origin that typically manifests on sun-damaged skin in elderly individuals. Clinically, it presents as a rapidly growing neoplasm that often ulcerates and bleeds. These heterogenous neoplasms have several distinct characteristics, including dense cellularity with disorganized, large, pleomorphic, and atypical-appearing spindle-shaped cells arising in the upper layers of the dermis, often disseminating into the reticular dermis and occasionally into the subcutaneous fat (Figure 1). The neoplastic cells often exhibit hyperchromic and irregular nuclei, multinucleated giant cells, and atypical mitotic figures. In most cases, negative immunohistochemical staining with SOX-10, S-100, cytokeratins, desmin, and caldesmon will allow pathologists to differentiate between AFX and other common tumors on the differential diagnosis, such as SCC, melanoma, and leiomyosarcoma. CD10 and procollagen type 1 are positive antigenic markers in AFX, but they are not specific. The standard treatment of AFX includes wide local excision or MMS for superior margin control.¹¹

Spindle cell SCC presents as a raised or exophytic nodule, often with spontaneous bleeding and central ulceration. It usually presents on sun-damaged skin or in individuals with a history of ionizing radiation. Histologically, it is characterized by atypical spindleshaped keratinocytes in the dermis existing as single cells or cohesive nests along with keratin pearls (Figure 2). The atypical spindle cells may comprise the entire tumor or only a small portion. The use of immunohistochemical markers often is required to establish a definitive diagnosis. Spindle cell SCC stains positively, albeit frequently focally, for p63, p40, and high-molecular-weight cytokeratins such as cytokeratin 5/6, while S-100 protein, SOX-10, MART-1/Melan-A, and muscle-specific actin stains typically are negative. Wide local excision or MMS is recommended for treatment of these lesions.¹²

Primary cutaneous myoepithelial carcinomas are uncommon neoplasms of myoepithelial differentiation. Clinically, they often arise as soft nodular lesions on the head, neck, and lower extremities with a bimodal age distribution (50 years). Histologically cutaneous myoepithelial tumors are well-differentiated, dermal-based nodules without connection to the overlying epidermis (Figure 3). The myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show variability in cell growth patterns. One of the most common growth patterns is oval to round cells forming cords and chains in a chondromyxoid stroma. Most cases display an immunophenotyped co-expression of an epithelial cytokeratin and S-100 protein. Myoepithelial markers also may be present, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin. Surgical removal with wide local excision or MMS is essential.¹³

Leiomyosarcoma (LMS) is a tumor that originates from smooth muscle and rarely develops in the dermis.¹⁴ Pleomorphic LMS is a morphologic variant of LMS that has a low propensity to metastasize but commonly exhibits local recurrence.¹⁵ Leiomyosarcoma can present in any age group but most commonly manifests in individuals aged 50 to 70 years. Clinically, LMS presents as a firm solitary nodule with a smooth pink surface or a more exophytic tumor with a reddish or brown color on the extensor surface of the lower limbs; it is less common on the scalp and face.¹⁴ Histologically, most cases of pleomorphic LMS show small foci of fascicles consisting of smooth muscle tumor cells in addition to cellular pleomorphism (Figure 4).¹⁵ Many of these cells demonstrate a clear perinuclear vacuole that generally is appreciated in neoplastic smooth muscle cells.¹⁴ Pleomorphic LMS typically stains positively for at least one smooth muscle marker including desmin, h-caldesmon, muscle-specific actin, α-smooth muscle actin, or smooth muscle myosin in the leiomyosarcomatous fascicular areas.¹⁶ Complete surgical excision is the treatment of choice, and the best results are obtained with MMS.¹⁴

The Diagnosis: Primary Cutaneous Carcinosarcoma

The immunohistochemical findings supported an epithelial component consistent with moderately differentiated squamous cell carcinoma (SCC) and a mesenchymal component with features consistent with a sarcoma. Consequently, the lesion was diagnosed as a primary cutaneous carcinosarcoma (PCCS).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm consisting of malignant epithelial (carcinoma) and mesenchymal (sarcoma) components.¹ Primary cutaneous carcinosarcomas are uncommon, poorly understood, primary cutaneous tumors.^2,3 Characteristic of this tumor, cytokeratins highlight the epithelial component while vimentin highlights the mesenchymal component.⁴ Histologically, the sarcomatous components of PCCS often are highly variable, with an absence of transitional areas within the epithelial component, which frequently resembles basal cell carcinoma and/ or SCC.^5-7 Primary cutaneous carcinosarcoma favors areas of chronic UV radiation exposure, particularly on the head and neck. Most tumors present with a slowly growing, polypoid, flesh-colored to erythematous nodule due to the infiltrative mesenchymal component.⁷ Primary cutaneous carcinosarcoma primarily is diagnosed in elderly patients, with the majority of cases diagnosed in the eighth or ninth decades of life (range, 32–98 years).^1,8 Men appear to be twice as likely to be diagnosed with a PCCS compared to women.¹ Primary cutaneous carcinosarcomas are recognized as aggressive tumors with a high propensity to metastasize and recur locally, necessitating early diagnosis and treatment.⁴ Accurate diagnosis of PCCSs can be challenging due to the biphasic nature of the neoplasm as well as poor differentiation or unequal proportions of the epithelial and mesenchymal components.⁵ Additionally, overlapping diagnostic criteria coupled with vague demarcation between soft-tissue sarcomas and distinct carcinomas also may contribute to a delay in diagnosis.⁹ Treatment is achieved surgically by complete wide resection, with no evidence to support the use of adjuvant or neoadjuvant external beam radiation therapy. Due to the small number of reported cases, no treatment recommendations currently exist.¹

Surgical management with wide local excision has been disappointing, with recurrence rates reported as high as 33%.⁶ Primary cutaneous carcinosarcoma has an estimated overall recurrence rate of 19% and a 5-year disease-free rate of 50%.¹⁰ Risk factors associated with poorer prognosis include tumors with adnexal subtype, age less than 65 years, rapid tumor growth, a tumor greater than 20 mm at presentation, and a long-standing tumor lasting up to 30 years.^2,4 Although wide local excision and Mohs micrographic surgery (MMS) both have been utilized successfully, MMS has been shown to result in a cure rate of greater than 98%.⁶

Atypical fibroxanthoma (AFX) is a cutaneous tumor of fibrohistiocytic mesenchymal origin that typically manifests on sun-damaged skin in elderly individuals. Clinically, it presents as a rapidly growing neoplasm that often ulcerates and bleeds. These heterogenous neoplasms have several distinct characteristics, including dense cellularity with disorganized, large, pleomorphic, and atypical-appearing spindle-shaped cells arising in the upper layers of the dermis, often disseminating into the reticular dermis and occasionally into the subcutaneous fat (Figure 1). The neoplastic cells often exhibit hyperchromic and irregular nuclei, multinucleated giant cells, and atypical mitotic figures. In most cases, negative immunohistochemical staining with SOX-10, S-100, cytokeratins, desmin, and caldesmon will allow pathologists to differentiate between AFX and other common tumors on the differential diagnosis, such as SCC, melanoma, and leiomyosarcoma. CD10 and procollagen type 1 are positive antigenic markers in AFX, but they are not specific. The standard treatment of AFX includes wide local excision or MMS for superior margin control.¹¹

Spindle cell SCC presents as a raised or exophytic nodule, often with spontaneous bleeding and central ulceration. It usually presents on sun-damaged skin or in individuals with a history of ionizing radiation. Histologically, it is characterized by atypical spindleshaped keratinocytes in the dermis existing as single cells or cohesive nests along with keratin pearls (Figure 2). The atypical spindle cells may comprise the entire tumor or only a small portion. The use of immunohistochemical markers often is required to establish a definitive diagnosis. Spindle cell SCC stains positively, albeit frequently focally, for p63, p40, and high-molecular-weight cytokeratins such as cytokeratin 5/6, while S-100 protein, SOX-10, MART-1/Melan-A, and muscle-specific actin stains typically are negative. Wide local excision or MMS is recommended for treatment of these lesions.¹²

Primary cutaneous myoepithelial carcinomas are uncommon neoplasms of myoepithelial differentiation. Clinically, they often arise as soft nodular lesions on the head, neck, and lower extremities with a bimodal age distribution (50 years). Histologically cutaneous myoepithelial tumors are well-differentiated, dermal-based nodules without connection to the overlying epidermis (Figure 3). The myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show variability in cell growth patterns. One of the most common growth patterns is oval to round cells forming cords and chains in a chondromyxoid stroma. Most cases display an immunophenotyped co-expression of an epithelial cytokeratin and S-100 protein. Myoepithelial markers also may be present, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin. Surgical removal with wide local excision or MMS is essential.¹³

Leiomyosarcoma (LMS) is a tumor that originates from smooth muscle and rarely develops in the dermis.¹⁴ Pleomorphic LMS is a morphologic variant of LMS that has a low propensity to metastasize but commonly exhibits local recurrence.¹⁵ Leiomyosarcoma can present in any age group but most commonly manifests in individuals aged 50 to 70 years. Clinically, LMS presents as a firm solitary nodule with a smooth pink surface or a more exophytic tumor with a reddish or brown color on the extensor surface of the lower limbs; it is less common on the scalp and face.¹⁴ Histologically, most cases of pleomorphic LMS show small foci of fascicles consisting of smooth muscle tumor cells in addition to cellular pleomorphism (Figure 4).¹⁵ Many of these cells demonstrate a clear perinuclear vacuole that generally is appreciated in neoplastic smooth muscle cells.¹⁴ Pleomorphic LMS typically stains positively for at least one smooth muscle marker including desmin, h-caldesmon, muscle-specific actin, α-smooth muscle actin, or smooth muscle myosin in the leiomyosarcomatous fascicular areas.¹⁶ Complete surgical excision is the treatment of choice, and the best results are obtained with MMS.¹⁴

The Diagnosis: Primary Cutaneous Carcinosarcoma

The immunohistochemical findings supported an epithelial component consistent with moderately differentiated squamous cell carcinoma (SCC) and a mesenchymal component with features consistent with a sarcoma. Consequently, the lesion was diagnosed as a primary cutaneous carcinosarcoma (PCCS).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm consisting of malignant epithelial (carcinoma) and mesenchymal (sarcoma) components.¹ Primary cutaneous carcinosarcomas are uncommon, poorly understood, primary cutaneous tumors.^2,3 Characteristic of this tumor, cytokeratins highlight the epithelial component while vimentin highlights the mesenchymal component.⁴ Histologically, the sarcomatous components of PCCS often are highly variable, with an absence of transitional areas within the epithelial component, which frequently resembles basal cell carcinoma and/ or SCC.^5-7 Primary cutaneous carcinosarcoma favors areas of chronic UV radiation exposure, particularly on the head and neck. Most tumors present with a slowly growing, polypoid, flesh-colored to erythematous nodule due to the infiltrative mesenchymal component.⁷ Primary cutaneous carcinosarcoma primarily is diagnosed in elderly patients, with the majority of cases diagnosed in the eighth or ninth decades of life (range, 32–98 years).^1,8 Men appear to be twice as likely to be diagnosed with a PCCS compared to women.¹ Primary cutaneous carcinosarcomas are recognized as aggressive tumors with a high propensity to metastasize and recur locally, necessitating early diagnosis and treatment.⁴ Accurate diagnosis of PCCSs can be challenging due to the biphasic nature of the neoplasm as well as poor differentiation or unequal proportions of the epithelial and mesenchymal components.⁵ Additionally, overlapping diagnostic criteria coupled with vague demarcation between soft-tissue sarcomas and distinct carcinomas also may contribute to a delay in diagnosis.⁹ Treatment is achieved surgically by complete wide resection, with no evidence to support the use of adjuvant or neoadjuvant external beam radiation therapy. Due to the small number of reported cases, no treatment recommendations currently exist.¹

Surgical management with wide local excision has been disappointing, with recurrence rates reported as high as 33%.⁶ Primary cutaneous carcinosarcoma has an estimated overall recurrence rate of 19% and a 5-year disease-free rate of 50%.¹⁰ Risk factors associated with poorer prognosis include tumors with adnexal subtype, age less than 65 years, rapid tumor growth, a tumor greater than 20 mm at presentation, and a long-standing tumor lasting up to 30 years.^2,4 Although wide local excision and Mohs micrographic surgery (MMS) both have been utilized successfully, MMS has been shown to result in a cure rate of greater than 98%.⁶

Atypical fibroxanthoma (AFX) is a cutaneous tumor of fibrohistiocytic mesenchymal origin that typically manifests on sun-damaged skin in elderly individuals. Clinically, it presents as a rapidly growing neoplasm that often ulcerates and bleeds. These heterogenous neoplasms have several distinct characteristics, including dense cellularity with disorganized, large, pleomorphic, and atypical-appearing spindle-shaped cells arising in the upper layers of the dermis, often disseminating into the reticular dermis and occasionally into the subcutaneous fat (Figure 1). The neoplastic cells often exhibit hyperchromic and irregular nuclei, multinucleated giant cells, and atypical mitotic figures. In most cases, negative immunohistochemical staining with SOX-10, S-100, cytokeratins, desmin, and caldesmon will allow pathologists to differentiate between AFX and other common tumors on the differential diagnosis, such as SCC, melanoma, and leiomyosarcoma. CD10 and procollagen type 1 are positive antigenic markers in AFX, but they are not specific. The standard treatment of AFX includes wide local excision or MMS for superior margin control.¹¹

Spindle cell SCC presents as a raised or exophytic nodule, often with spontaneous bleeding and central ulceration. It usually presents on sun-damaged skin or in individuals with a history of ionizing radiation. Histologically, it is characterized by atypical spindleshaped keratinocytes in the dermis existing as single cells or cohesive nests along with keratin pearls (Figure 2). The atypical spindle cells may comprise the entire tumor or only a small portion. The use of immunohistochemical markers often is required to establish a definitive diagnosis. Spindle cell SCC stains positively, albeit frequently focally, for p63, p40, and high-molecular-weight cytokeratins such as cytokeratin 5/6, while S-100 protein, SOX-10, MART-1/Melan-A, and muscle-specific actin stains typically are negative. Wide local excision or MMS is recommended for treatment of these lesions.¹²

Primary cutaneous myoepithelial carcinomas are uncommon neoplasms of myoepithelial differentiation. Clinically, they often arise as soft nodular lesions on the head, neck, and lower extremities with a bimodal age distribution (50 years). Histologically cutaneous myoepithelial tumors are well-differentiated, dermal-based nodules without connection to the overlying epidermis (Figure 3). The myoepithelial cells can exhibit spindled, epithelioid, plasmacytoid, or clear cell morphologic features and show variability in cell growth patterns. One of the most common growth patterns is oval to round cells forming cords and chains in a chondromyxoid stroma. Most cases display an immunophenotyped co-expression of an epithelial cytokeratin and S-100 protein. Myoepithelial markers also may be present, including keratins, smooth muscle actin, calponin, glial fibrillary acidic protein, p63, and desmin. Surgical removal with wide local excision or MMS is essential.¹³

Leiomyosarcoma (LMS) is a tumor that originates from smooth muscle and rarely develops in the dermis.¹⁴ Pleomorphic LMS is a morphologic variant of LMS that has a low propensity to metastasize but commonly exhibits local recurrence.¹⁵ Leiomyosarcoma can present in any age group but most commonly manifests in individuals aged 50 to 70 years. Clinically, LMS presents as a firm solitary nodule with a smooth pink surface or a more exophytic tumor with a reddish or brown color on the extensor surface of the lower limbs; it is less common on the scalp and face.¹⁴ Histologically, most cases of pleomorphic LMS show small foci of fascicles consisting of smooth muscle tumor cells in addition to cellular pleomorphism (Figure 4).¹⁵ Many of these cells demonstrate a clear perinuclear vacuole that generally is appreciated in neoplastic smooth muscle cells.¹⁴ Pleomorphic LMS typically stains positively for at least one smooth muscle marker including desmin, h-caldesmon, muscle-specific actin, α-smooth muscle actin, or smooth muscle myosin in the leiomyosarcomatous fascicular areas.¹⁶ Complete surgical excision is the treatment of choice, and the best results are obtained with MMS.¹⁴

The Diagnosis: Levamisole-Induced Vasculopathy

Biopsy of one of the bullous retiform purpura on the leg (Figure 1) revealed a combined leukocytoclastic vasculitis and thrombotic vasculopathy (quiz images). Periodic acid-Schiff and Gram stains, with adequate controls, were negative for pathogenic fungal and bacterial organisms. Although this reaction pattern has an extensive differential, in this clinical setting with associated cocaine-positive urine toxicologic analysis, perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), and leukopenia, the histopathologic findings were consistent with levamisole-induced vasculopathy (LIV).^1,2 Although not specific, leukocytoclastic vasculitis and thrombotic vasculopathy have been reported as the classic histopathologic findings of LIV. In addition, interstitial and perivascular neovascularization have been reported as a potential histopathologic finding associated with this entity but was not seen in our case.³  

Levamisole is an anthelminthic agent used to adulterate cocaine, a practice first noted in 2003 with increasing incidence.¹ Both levamisole and cocaine stimulate the sympathetic nervous system by increasing dopamine in the euphoric areas of the brain.^1,3 By combining the 2 substances, preparation costs are reduced and stimulant effects are enhanced. It is estimated that 69% to 80% of cocaine in the United States is contaminated with levamisole.^2,4,5 The constellation of findings seen in patients abusing levamisole-contaminated cocaine include agranulocytosis; p-ANCA; and a tender, vasculitic, retiform purpura presentation. The most common sites for the purpura include the cheeks and ears. The purpura can progress to bullous lesions, as seen in our patient, followed by necrosis.^4,6 Recurrent use of levamisole-contaminated cocaine is associated with recurrent agranulocytosis and classic skin findings, which is suggestive of a causal relationship.⁶  

Serologic testing for levamisole exposure presents a challenge. The half-life of levamisole is relatively short (estimated at 5.6 hours) and is found in urine samples approximately 3% of the time.^1,3,6 The volatile diagnostic characteristics of levamisole make concrete laboratory confirmation difficult. Although a skin biopsy can be helpful to rule out other causes of vasculitislike presentations, it is not specific for LIV. Therefore, clinical suspicion for LIV should remain high in patients who present with the cutaneous findings described as well as agranulocytosis, positive p-ANCA, and a history of cocaine use with a skin biopsy showing leukocytoclastic vasculitis and thrombotic vasculopathy.  

The differential diagnosis for LIV with retiform bullous lesions includes several other vasculitides and vesiculobullous diseases. Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystem vasculitis that is characterized by eosinophilia, asthma, and rhinosinusitis. Eosinophilic granulomatosis with polyangiitis primarily affects small and medium arteries in the skin and respiratory tract and occurs in 3 stages: prodromal, eosinophilic, and vasculitic. These stages are characterized by mild asthma or rhinitis, eosinophilia with multiorgan infiltration, and vasculitis with extravascular granulomatosis, respectively. Diagnosis often is clinical based on these findings and laboratory evaluation. Eosinophilic granulomatosis with polyangiitis presents with positive p-ANCA in 40% to 60% of patients.⁷ The vasculitis stage of EGPA presents with cutaneous findings in 60% of cases, including palpable purpura, infiltrated papules and plaques, urticaria, necrotizing lesions, and rarely vesicles and bullae.⁸ Classic histopathologic features include leukocytoclastic or eosinophilic vasculitis, an eosinophilic infiltrate, granuloma formation, and eosinophilic granule deposition onto collagen fibrils (otherwise known as flame figures)(Figure 2). Biopsy of these lesions with the aforementioned findings, in constellation with the described systemic signs and symptoms, can aid in diagnosis of EGPA.  

Polyarteritis nodosa (PAN) is a vasculitis that can be either multisystem or limited to one organ. Classic PAN affects the small- to medium-sized vessels. When there is multisystem involvement, it most often affects the skin, gastrointestinal tract, and kidneys. It presents with subcutaneous or dermal nodules, necrotic lesions, livedo reticularis, hypertension, abdominal pain, and an acute abdomen.⁹ When PAN is in its limited form, it most commonly occurs in the skin. The cutaneous manifestations of skin-limited PAN are identical to classic PAN, most commonly occurring on the legs and arms and less often on the trunk, head, and neck.¹⁰ To aid in diagnosis, biopsies of cutaneous lesions are beneficial. Dermatopathologic examination of PAN reveals fibrinoid necrosis of small and medium vessels with a perivascular mononuclear inflammatory infiltrate (Figure 3). Cutaneous PAN rarely progresses to multisystem classic PAN and carries a more favorable prognosis.  

Microvascular occlusion syndromes can result in clinical presentations that resemble LIV. Idiopathic thrombocytopenic purpura is a hematologic autoimmune condition resulting in destruction of platelets and subsequent thrombocytopenia. Idiopathic thrombocytopenic purpura can be either primary or secondary to infections, drugs, malignancy, or other autoimmune conditions. Clinically, it presents as mucosal or cutaneous bleeding, epistaxis, hematochezia, or hematuria and can result in substantial hemorrhage. On the skin, it can appear as petechiae and ecchymoses in dependent areas and rarely hemorrhagic bullae of the skin and mucous membranes in cases of severe thrombocytopenia.^11,12 Biopsies of these lesions will show notable extravasation of red blood cells with incipient hemorrhagic bullae formation (Figure 4). Recognition of hemorrhagic bullae as a presentation of idiopathic thrombocytopenic purpura is critical to identifying severe underlying disease.  

Beyond other vasculitides and microvascular occlusion syndromes, vessel-invasive microorganisms can result in similar histopathologic and clinical presentations to LIV. Ecthyma gangrenosum (EG) is a septic vasculitis, often caused by Pseudomonas aeruginosa, usually affecting immunocompromised patients. Ecthyma gangrenosum presents with vesiculobullous lesions with erythematous violaceous borders that develop into hemorrhagic bullae with necrotic centers.¹³ Biopsy of EG will show vascular occlusion and basophilic granular material within or around vessels, suggestive of bacterial sepsis (Figure 5). The detection of an infectious agent on histopathology allows one to easily distinguish between EG and LIV.  

The Diagnosis: Levamisole-Induced Vasculopathy

Biopsy of one of the bullous retiform purpura on the leg (Figure 1) revealed a combined leukocytoclastic vasculitis and thrombotic vasculopathy (quiz images). Periodic acid-Schiff and Gram stains, with adequate controls, were negative for pathogenic fungal and bacterial organisms. Although this reaction pattern has an extensive differential, in this clinical setting with associated cocaine-positive urine toxicologic analysis, perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), and leukopenia, the histopathologic findings were consistent with levamisole-induced vasculopathy (LIV).^1,2 Although not specific, leukocytoclastic vasculitis and thrombotic vasculopathy have been reported as the classic histopathologic findings of LIV. In addition, interstitial and perivascular neovascularization have been reported as a potential histopathologic finding associated with this entity but was not seen in our case.³  

Levamisole is an anthelminthic agent used to adulterate cocaine, a practice first noted in 2003 with increasing incidence.¹ Both levamisole and cocaine stimulate the sympathetic nervous system by increasing dopamine in the euphoric areas of the brain.^1,3 By combining the 2 substances, preparation costs are reduced and stimulant effects are enhanced. It is estimated that 69% to 80% of cocaine in the United States is contaminated with levamisole.^2,4,5 The constellation of findings seen in patients abusing levamisole-contaminated cocaine include agranulocytosis; p-ANCA; and a tender, vasculitic, retiform purpura presentation. The most common sites for the purpura include the cheeks and ears. The purpura can progress to bullous lesions, as seen in our patient, followed by necrosis.^4,6 Recurrent use of levamisole-contaminated cocaine is associated with recurrent agranulocytosis and classic skin findings, which is suggestive of a causal relationship.⁶  

Serologic testing for levamisole exposure presents a challenge. The half-life of levamisole is relatively short (estimated at 5.6 hours) and is found in urine samples approximately 3% of the time.^1,3,6 The volatile diagnostic characteristics of levamisole make concrete laboratory confirmation difficult. Although a skin biopsy can be helpful to rule out other causes of vasculitislike presentations, it is not specific for LIV. Therefore, clinical suspicion for LIV should remain high in patients who present with the cutaneous findings described as well as agranulocytosis, positive p-ANCA, and a history of cocaine use with a skin biopsy showing leukocytoclastic vasculitis and thrombotic vasculopathy.  

The differential diagnosis for LIV with retiform bullous lesions includes several other vasculitides and vesiculobullous diseases. Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystem vasculitis that is characterized by eosinophilia, asthma, and rhinosinusitis. Eosinophilic granulomatosis with polyangiitis primarily affects small and medium arteries in the skin and respiratory tract and occurs in 3 stages: prodromal, eosinophilic, and vasculitic. These stages are characterized by mild asthma or rhinitis, eosinophilia with multiorgan infiltration, and vasculitis with extravascular granulomatosis, respectively. Diagnosis often is clinical based on these findings and laboratory evaluation. Eosinophilic granulomatosis with polyangiitis presents with positive p-ANCA in 40% to 60% of patients.⁷ The vasculitis stage of EGPA presents with cutaneous findings in 60% of cases, including palpable purpura, infiltrated papules and plaques, urticaria, necrotizing lesions, and rarely vesicles and bullae.⁸ Classic histopathologic features include leukocytoclastic or eosinophilic vasculitis, an eosinophilic infiltrate, granuloma formation, and eosinophilic granule deposition onto collagen fibrils (otherwise known as flame figures)(Figure 2). Biopsy of these lesions with the aforementioned findings, in constellation with the described systemic signs and symptoms, can aid in diagnosis of EGPA.  

Polyarteritis nodosa (PAN) is a vasculitis that can be either multisystem or limited to one organ. Classic PAN affects the small- to medium-sized vessels. When there is multisystem involvement, it most often affects the skin, gastrointestinal tract, and kidneys. It presents with subcutaneous or dermal nodules, necrotic lesions, livedo reticularis, hypertension, abdominal pain, and an acute abdomen.⁹ When PAN is in its limited form, it most commonly occurs in the skin. The cutaneous manifestations of skin-limited PAN are identical to classic PAN, most commonly occurring on the legs and arms and less often on the trunk, head, and neck.¹⁰ To aid in diagnosis, biopsies of cutaneous lesions are beneficial. Dermatopathologic examination of PAN reveals fibrinoid necrosis of small and medium vessels with a perivascular mononuclear inflammatory infiltrate (Figure 3). Cutaneous PAN rarely progresses to multisystem classic PAN and carries a more favorable prognosis.  

Microvascular occlusion syndromes can result in clinical presentations that resemble LIV. Idiopathic thrombocytopenic purpura is a hematologic autoimmune condition resulting in destruction of platelets and subsequent thrombocytopenia. Idiopathic thrombocytopenic purpura can be either primary or secondary to infections, drugs, malignancy, or other autoimmune conditions. Clinically, it presents as mucosal or cutaneous bleeding, epistaxis, hematochezia, or hematuria and can result in substantial hemorrhage. On the skin, it can appear as petechiae and ecchymoses in dependent areas and rarely hemorrhagic bullae of the skin and mucous membranes in cases of severe thrombocytopenia.^11,12 Biopsies of these lesions will show notable extravasation of red blood cells with incipient hemorrhagic bullae formation (Figure 4). Recognition of hemorrhagic bullae as a presentation of idiopathic thrombocytopenic purpura is critical to identifying severe underlying disease.  

Beyond other vasculitides and microvascular occlusion syndromes, vessel-invasive microorganisms can result in similar histopathologic and clinical presentations to LIV. Ecthyma gangrenosum (EG) is a septic vasculitis, often caused by Pseudomonas aeruginosa, usually affecting immunocompromised patients. Ecthyma gangrenosum presents with vesiculobullous lesions with erythematous violaceous borders that develop into hemorrhagic bullae with necrotic centers.¹³ Biopsy of EG will show vascular occlusion and basophilic granular material within or around vessels, suggestive of bacterial sepsis (Figure 5). The detection of an infectious agent on histopathology allows one to easily distinguish between EG and LIV.  

The Diagnosis: Levamisole-Induced Vasculopathy

Biopsy of one of the bullous retiform purpura on the leg (Figure 1) revealed a combined leukocytoclastic vasculitis and thrombotic vasculopathy (quiz images). Periodic acid-Schiff and Gram stains, with adequate controls, were negative for pathogenic fungal and bacterial organisms. Although this reaction pattern has an extensive differential, in this clinical setting with associated cocaine-positive urine toxicologic analysis, perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), and leukopenia, the histopathologic findings were consistent with levamisole-induced vasculopathy (LIV).^1,2 Although not specific, leukocytoclastic vasculitis and thrombotic vasculopathy have been reported as the classic histopathologic findings of LIV. In addition, interstitial and perivascular neovascularization have been reported as a potential histopathologic finding associated with this entity but was not seen in our case.³  

Levamisole is an anthelminthic agent used to adulterate cocaine, a practice first noted in 2003 with increasing incidence.¹ Both levamisole and cocaine stimulate the sympathetic nervous system by increasing dopamine in the euphoric areas of the brain.^1,3 By combining the 2 substances, preparation costs are reduced and stimulant effects are enhanced. It is estimated that 69% to 80% of cocaine in the United States is contaminated with levamisole.^2,4,5 The constellation of findings seen in patients abusing levamisole-contaminated cocaine include agranulocytosis; p-ANCA; and a tender, vasculitic, retiform purpura presentation. The most common sites for the purpura include the cheeks and ears. The purpura can progress to bullous lesions, as seen in our patient, followed by necrosis.^4,6 Recurrent use of levamisole-contaminated cocaine is associated with recurrent agranulocytosis and classic skin findings, which is suggestive of a causal relationship.⁶  

Serologic testing for levamisole exposure presents a challenge. The half-life of levamisole is relatively short (estimated at 5.6 hours) and is found in urine samples approximately 3% of the time.^1,3,6 The volatile diagnostic characteristics of levamisole make concrete laboratory confirmation difficult. Although a skin biopsy can be helpful to rule out other causes of vasculitislike presentations, it is not specific for LIV. Therefore, clinical suspicion for LIV should remain high in patients who present with the cutaneous findings described as well as agranulocytosis, positive p-ANCA, and a history of cocaine use with a skin biopsy showing leukocytoclastic vasculitis and thrombotic vasculopathy.  

The differential diagnosis for LIV with retiform bullous lesions includes several other vasculitides and vesiculobullous diseases. Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystem vasculitis that is characterized by eosinophilia, asthma, and rhinosinusitis. Eosinophilic granulomatosis with polyangiitis primarily affects small and medium arteries in the skin and respiratory tract and occurs in 3 stages: prodromal, eosinophilic, and vasculitic. These stages are characterized by mild asthma or rhinitis, eosinophilia with multiorgan infiltration, and vasculitis with extravascular granulomatosis, respectively. Diagnosis often is clinical based on these findings and laboratory evaluation. Eosinophilic granulomatosis with polyangiitis presents with positive p-ANCA in 40% to 60% of patients.⁷ The vasculitis stage of EGPA presents with cutaneous findings in 60% of cases, including palpable purpura, infiltrated papules and plaques, urticaria, necrotizing lesions, and rarely vesicles and bullae.⁸ Classic histopathologic features include leukocytoclastic or eosinophilic vasculitis, an eosinophilic infiltrate, granuloma formation, and eosinophilic granule deposition onto collagen fibrils (otherwise known as flame figures)(Figure 2). Biopsy of these lesions with the aforementioned findings, in constellation with the described systemic signs and symptoms, can aid in diagnosis of EGPA.  

Polyarteritis nodosa (PAN) is a vasculitis that can be either multisystem or limited to one organ. Classic PAN affects the small- to medium-sized vessels. When there is multisystem involvement, it most often affects the skin, gastrointestinal tract, and kidneys. It presents with subcutaneous or dermal nodules, necrotic lesions, livedo reticularis, hypertension, abdominal pain, and an acute abdomen.⁹ When PAN is in its limited form, it most commonly occurs in the skin. The cutaneous manifestations of skin-limited PAN are identical to classic PAN, most commonly occurring on the legs and arms and less often on the trunk, head, and neck.¹⁰ To aid in diagnosis, biopsies of cutaneous lesions are beneficial. Dermatopathologic examination of PAN reveals fibrinoid necrosis of small and medium vessels with a perivascular mononuclear inflammatory infiltrate (Figure 3). Cutaneous PAN rarely progresses to multisystem classic PAN and carries a more favorable prognosis.  

Microvascular occlusion syndromes can result in clinical presentations that resemble LIV. Idiopathic thrombocytopenic purpura is a hematologic autoimmune condition resulting in destruction of platelets and subsequent thrombocytopenia. Idiopathic thrombocytopenic purpura can be either primary or secondary to infections, drugs, malignancy, or other autoimmune conditions. Clinically, it presents as mucosal or cutaneous bleeding, epistaxis, hematochezia, or hematuria and can result in substantial hemorrhage. On the skin, it can appear as petechiae and ecchymoses in dependent areas and rarely hemorrhagic bullae of the skin and mucous membranes in cases of severe thrombocytopenia.^11,12 Biopsies of these lesions will show notable extravasation of red blood cells with incipient hemorrhagic bullae formation (Figure 4). Recognition of hemorrhagic bullae as a presentation of idiopathic thrombocytopenic purpura is critical to identifying severe underlying disease.  

Beyond other vasculitides and microvascular occlusion syndromes, vessel-invasive microorganisms can result in similar histopathologic and clinical presentations to LIV. Ecthyma gangrenosum (EG) is a septic vasculitis, often caused by Pseudomonas aeruginosa, usually affecting immunocompromised patients. Ecthyma gangrenosum presents with vesiculobullous lesions with erythematous violaceous borders that develop into hemorrhagic bullae with necrotic centers.¹³ Biopsy of EG will show vascular occlusion and basophilic granular material within or around vessels, suggestive of bacterial sepsis (Figure 5). The detection of an infectious agent on histopathology allows one to easily distinguish between EG and LIV.  

The Diagnosis: Cystic Panfolliculoma 

Panfolliculoma is a rare tumor of follicular origin.¹ Clinical examination can reveal a papule, nodule, or tumor that typically is mistaken for an epidermal inclusion cyst, trichoepithelioma, or basal cell carcinoma (BCC).² As with other benign follicular neoplasms, it often exhibits a protracted growth pattern.^3,4 Most cases reported in the literature have been shown to occur in the head or neck region. One hypothesis is that separation into the various components of the hair follicle occurs at a higher frequency in areas with a higher hair density such as the face and scalp.⁴ The lesion typically presents in patients aged 20 to 70 years, as in our patient, with cases equally distributed among males and females.^4,5 Neill et al1 reported a rare case of cystic panfolliculoma occurring on the right forearm of a 64-year-old woman. 

As its name suggests, panfolliculoma is exceptional in that it displays features of all segments of the hair follicle, including the infundibulum, isthmus, stem, and bulb.⁶ Although not necessary for diagnosis, immunohistochemical staining can be utilized to identify each hair follicle component on histopathologic examination. Panfolliculoma stains positive for 34βE12 and cytokeratin 5/6, highlighting infundibular and isthmus keratinocytes and the outer root sheath, respectively. Additionally, Ber-EP4 labels germinative cells, while CD34 highlights contiguous fibrotic stroma and trichilemmal areas.^3,4 

In our patient, histopathology revealed a cystic structure that was lined by an infundibular epithelium with a prominent granular layer. Solid collections of basaloid germinative cells that demonstrated peripheral palisading were observed (quiz image [top]). Cells with trichohyalin granules, indicative of inner root sheath differentiation, were encased by matrical cells (quiz image [bottom]).  

Historically, panfolliculomas characteristically have been known to reside in the dermis, with only focal connection to the epidermis, if at all present. Nevertheless, Harris et al⁷ detailed 2 cases that displayed predominant epidermal involvement, defined by the term epidermal panfolliculoma. In a study performed by Shan and Guo,² an additional 9 cases (19 panfolliculomas) were found to have similar findings, for which the term superficial panfolliculoma was suggested. In cases that display a primary epidermal component, common mimickers include tumor of the follicular infundibulum and the reactive process of follicular induction.⁷ 

Cystic panfolliculoma is a rare subtype further characterized as a lesion with distinctive features of a panfolliculoma that arises from a cyst wall composed of the follicular infundibulum.^2,6 The origin of cystic panfolliculoma has not been fully elucidated. It has been hypothesized that the formation of such lesions may arise due to epithelial-mesenchymal interactions. One explanation is that basal cells with stem cell capability may progress into hair follicle structures after communication with underlying dermal cells during invagination of the epidermis, while the epithelial cells not in close proximity to dermal cells maintain stem cell capability.⁸ 

The histologic differential diagnosis of cystic panfolliculoma includes dilated pore of Winer, epidermal inclusion cyst, pilar cyst, trichofolliculoma, folliculosebaceous cystic hamartoma, cystic trichoblastoma, and BCC.⁵ Panfolliculoma can mimic both trichoblastoma and trichoepithelioma on a low-power field; however, the latter follicular tumors lack differentiation to the infundibulum, isthmus, outer root sheath, or hair shaft, as in a panfolliculoma.⁴ Trichoblastoma is composed of germinative hair follicle cells, with differentiation limited to the hair germ and papilla (Figure 1).⁹ Panfolliculoma additionally differs from trichoblastoma by having a more prevalent epithelial factor compared to a more pronounced stromal factor in trichoblastoma.¹ The cystic subtype of trichoblastoma differs from cystic panfolliculoma in that the cyst wall develops from the infundibulum only and has germinative cells protruding outwards from the cyst wall.  

Although BCCs may arise in cystic structures, panfolliculomas can be discerned from this entity by their sharp demarcation, lack of peritumoral clefting, and presence of cytokeratin 20-positive Merkel cells.⁵ Unlike panfolliculoma, the tumor islands in BCC commonly display peripheral palisading of nuclei with a surrounding fibromyxoid stroma (Figure 2). Additionally, BCCs can exhibit crowding of nuclei, atypia, and mitoses.⁶ 

Folliculosebaceous cystic hamartomas and cystic panfolliculomas both contain a cystic structure with differentiation of the cyst wall to the hair follicle. However, folliculosebaceous cystic hamartomas are dilated infundibulocystic configurations that contain sebaceous glands emanating from the cyst wall (Figure 3). Kimura et al¹⁰ described defining features of the mesenchymal component of this follicular tumor, including an increase in fibroplasia, vascularity, and adipose tissue. In addition, the epithelial aspect exhibits clefting among the stroma and uninvolved dermis.⁶

Dilated pore of Winer consists of a cystic opening with connection to the epidermis. The cyst wall resembles the follicular infundibulum, and the cavity is filled with lamellar orthokeratosis (Figure 4).^5,11 Epidermal inclusion cysts also contain a cyst wall that resembles the infundibular epithelium, without differentiation to all segments of the hair follicle. They are lined by a stratified squamous epithelium, retain a granular layer, and contain lamellar keratin within the cyst cavity.^5,12 

In summary, panfolliculoma is a rare benign neoplasm that demonstrates differentiation to each component of the hair follicle structure. Our case demonstrates a unique subtype showcasing cystic changes that infrequently has been described in the literature. 

The Diagnosis: Cystic Panfolliculoma 

Panfolliculoma is a rare tumor of follicular origin.¹ Clinical examination can reveal a papule, nodule, or tumor that typically is mistaken for an epidermal inclusion cyst, trichoepithelioma, or basal cell carcinoma (BCC).² As with other benign follicular neoplasms, it often exhibits a protracted growth pattern.^3,4 Most cases reported in the literature have been shown to occur in the head or neck region. One hypothesis is that separation into the various components of the hair follicle occurs at a higher frequency in areas with a higher hair density such as the face and scalp.⁴ The lesion typically presents in patients aged 20 to 70 years, as in our patient, with cases equally distributed among males and females.^4,5 Neill et al1 reported a rare case of cystic panfolliculoma occurring on the right forearm of a 64-year-old woman. 

As its name suggests, panfolliculoma is exceptional in that it displays features of all segments of the hair follicle, including the infundibulum, isthmus, stem, and bulb.⁶ Although not necessary for diagnosis, immunohistochemical staining can be utilized to identify each hair follicle component on histopathologic examination. Panfolliculoma stains positive for 34βE12 and cytokeratin 5/6, highlighting infundibular and isthmus keratinocytes and the outer root sheath, respectively. Additionally, Ber-EP4 labels germinative cells, while CD34 highlights contiguous fibrotic stroma and trichilemmal areas.^3,4 

In our patient, histopathology revealed a cystic structure that was lined by an infundibular epithelium with a prominent granular layer. Solid collections of basaloid germinative cells that demonstrated peripheral palisading were observed (quiz image [top]). Cells with trichohyalin granules, indicative of inner root sheath differentiation, were encased by matrical cells (quiz image [bottom]).  

Historically, panfolliculomas characteristically have been known to reside in the dermis, with only focal connection to the epidermis, if at all present. Nevertheless, Harris et al⁷ detailed 2 cases that displayed predominant epidermal involvement, defined by the term epidermal panfolliculoma. In a study performed by Shan and Guo,² an additional 9 cases (19 panfolliculomas) were found to have similar findings, for which the term superficial panfolliculoma was suggested. In cases that display a primary epidermal component, common mimickers include tumor of the follicular infundibulum and the reactive process of follicular induction.⁷ 

Cystic panfolliculoma is a rare subtype further characterized as a lesion with distinctive features of a panfolliculoma that arises from a cyst wall composed of the follicular infundibulum.^2,6 The origin of cystic panfolliculoma has not been fully elucidated. It has been hypothesized that the formation of such lesions may arise due to epithelial-mesenchymal interactions. One explanation is that basal cells with stem cell capability may progress into hair follicle structures after communication with underlying dermal cells during invagination of the epidermis, while the epithelial cells not in close proximity to dermal cells maintain stem cell capability.⁸ 

The histologic differential diagnosis of cystic panfolliculoma includes dilated pore of Winer, epidermal inclusion cyst, pilar cyst, trichofolliculoma, folliculosebaceous cystic hamartoma, cystic trichoblastoma, and BCC.⁵ Panfolliculoma can mimic both trichoblastoma and trichoepithelioma on a low-power field; however, the latter follicular tumors lack differentiation to the infundibulum, isthmus, outer root sheath, or hair shaft, as in a panfolliculoma.⁴ Trichoblastoma is composed of germinative hair follicle cells, with differentiation limited to the hair germ and papilla (Figure 1).⁹ Panfolliculoma additionally differs from trichoblastoma by having a more prevalent epithelial factor compared to a more pronounced stromal factor in trichoblastoma.¹ The cystic subtype of trichoblastoma differs from cystic panfolliculoma in that the cyst wall develops from the infundibulum only and has germinative cells protruding outwards from the cyst wall.  

Although BCCs may arise in cystic structures, panfolliculomas can be discerned from this entity by their sharp demarcation, lack of peritumoral clefting, and presence of cytokeratin 20-positive Merkel cells.⁵ Unlike panfolliculoma, the tumor islands in BCC commonly display peripheral palisading of nuclei with a surrounding fibromyxoid stroma (Figure 2). Additionally, BCCs can exhibit crowding of nuclei, atypia, and mitoses.⁶ 

Folliculosebaceous cystic hamartomas and cystic panfolliculomas both contain a cystic structure with differentiation of the cyst wall to the hair follicle. However, folliculosebaceous cystic hamartomas are dilated infundibulocystic configurations that contain sebaceous glands emanating from the cyst wall (Figure 3). Kimura et al¹⁰ described defining features of the mesenchymal component of this follicular tumor, including an increase in fibroplasia, vascularity, and adipose tissue. In addition, the epithelial aspect exhibits clefting among the stroma and uninvolved dermis.⁶

Dilated pore of Winer consists of a cystic opening with connection to the epidermis. The cyst wall resembles the follicular infundibulum, and the cavity is filled with lamellar orthokeratosis (Figure 4).^5,11 Epidermal inclusion cysts also contain a cyst wall that resembles the infundibular epithelium, without differentiation to all segments of the hair follicle. They are lined by a stratified squamous epithelium, retain a granular layer, and contain lamellar keratin within the cyst cavity.^5,12 

In summary, panfolliculoma is a rare benign neoplasm that demonstrates differentiation to each component of the hair follicle structure. Our case demonstrates a unique subtype showcasing cystic changes that infrequently has been described in the literature. 

The Diagnosis: Cystic Panfolliculoma 

Panfolliculoma is a rare tumor of follicular origin.¹ Clinical examination can reveal a papule, nodule, or tumor that typically is mistaken for an epidermal inclusion cyst, trichoepithelioma, or basal cell carcinoma (BCC).² As with other benign follicular neoplasms, it often exhibits a protracted growth pattern.^3,4 Most cases reported in the literature have been shown to occur in the head or neck region. One hypothesis is that separation into the various components of the hair follicle occurs at a higher frequency in areas with a higher hair density such as the face and scalp.⁴ The lesion typically presents in patients aged 20 to 70 years, as in our patient, with cases equally distributed among males and females.^4,5 Neill et al1 reported a rare case of cystic panfolliculoma occurring on the right forearm of a 64-year-old woman. 

As its name suggests, panfolliculoma is exceptional in that it displays features of all segments of the hair follicle, including the infundibulum, isthmus, stem, and bulb.⁶ Although not necessary for diagnosis, immunohistochemical staining can be utilized to identify each hair follicle component on histopathologic examination. Panfolliculoma stains positive for 34βE12 and cytokeratin 5/6, highlighting infundibular and isthmus keratinocytes and the outer root sheath, respectively. Additionally, Ber-EP4 labels germinative cells, while CD34 highlights contiguous fibrotic stroma and trichilemmal areas.^3,4 

In our patient, histopathology revealed a cystic structure that was lined by an infundibular epithelium with a prominent granular layer. Solid collections of basaloid germinative cells that demonstrated peripheral palisading were observed (quiz image [top]). Cells with trichohyalin granules, indicative of inner root sheath differentiation, were encased by matrical cells (quiz image [bottom]).  

Historically, panfolliculomas characteristically have been known to reside in the dermis, with only focal connection to the epidermis, if at all present. Nevertheless, Harris et al⁷ detailed 2 cases that displayed predominant epidermal involvement, defined by the term epidermal panfolliculoma. In a study performed by Shan and Guo,² an additional 9 cases (19 panfolliculomas) were found to have similar findings, for which the term superficial panfolliculoma was suggested. In cases that display a primary epidermal component, common mimickers include tumor of the follicular infundibulum and the reactive process of follicular induction.⁷ 

Cystic panfolliculoma is a rare subtype further characterized as a lesion with distinctive features of a panfolliculoma that arises from a cyst wall composed of the follicular infundibulum.^2,6 The origin of cystic panfolliculoma has not been fully elucidated. It has been hypothesized that the formation of such lesions may arise due to epithelial-mesenchymal interactions. One explanation is that basal cells with stem cell capability may progress into hair follicle structures after communication with underlying dermal cells during invagination of the epidermis, while the epithelial cells not in close proximity to dermal cells maintain stem cell capability.⁸ 

The histologic differential diagnosis of cystic panfolliculoma includes dilated pore of Winer, epidermal inclusion cyst, pilar cyst, trichofolliculoma, folliculosebaceous cystic hamartoma, cystic trichoblastoma, and BCC.⁵ Panfolliculoma can mimic both trichoblastoma and trichoepithelioma on a low-power field; however, the latter follicular tumors lack differentiation to the infundibulum, isthmus, outer root sheath, or hair shaft, as in a panfolliculoma.⁴ Trichoblastoma is composed of germinative hair follicle cells, with differentiation limited to the hair germ and papilla (Figure 1).⁹ Panfolliculoma additionally differs from trichoblastoma by having a more prevalent epithelial factor compared to a more pronounced stromal factor in trichoblastoma.¹ The cystic subtype of trichoblastoma differs from cystic panfolliculoma in that the cyst wall develops from the infundibulum only and has germinative cells protruding outwards from the cyst wall.  

Although BCCs may arise in cystic structures, panfolliculomas can be discerned from this entity by their sharp demarcation, lack of peritumoral clefting, and presence of cytokeratin 20-positive Merkel cells.⁵ Unlike panfolliculoma, the tumor islands in BCC commonly display peripheral palisading of nuclei with a surrounding fibromyxoid stroma (Figure 2). Additionally, BCCs can exhibit crowding of nuclei, atypia, and mitoses.⁶ 

Folliculosebaceous cystic hamartomas and cystic panfolliculomas both contain a cystic structure with differentiation of the cyst wall to the hair follicle. However, folliculosebaceous cystic hamartomas are dilated infundibulocystic configurations that contain sebaceous glands emanating from the cyst wall (Figure 3). Kimura et al¹⁰ described defining features of the mesenchymal component of this follicular tumor, including an increase in fibroplasia, vascularity, and adipose tissue. In addition, the epithelial aspect exhibits clefting among the stroma and uninvolved dermis.⁶

Dilated pore of Winer consists of a cystic opening with connection to the epidermis. The cyst wall resembles the follicular infundibulum, and the cavity is filled with lamellar orthokeratosis (Figure 4).^5,11 Epidermal inclusion cysts also contain a cyst wall that resembles the infundibular epithelium, without differentiation to all segments of the hair follicle. They are lined by a stratified squamous epithelium, retain a granular layer, and contain lamellar keratin within the cyst cavity.^5,12 

In summary, panfolliculoma is a rare benign neoplasm that demonstrates differentiation to each component of the hair follicle structure. Our case demonstrates a unique subtype showcasing cystic changes that infrequently has been described in the literature.