Dermatopathology

The Diagnosis: Ruptured Molluscum

Molluscum contagiosum (MC) is caused by a DNA virus (MC virus) belonging to the poxvirus family. Molluscum contagiosum is common and predominantly seen in children and young adults. In sexually active adults, the lesions commonly occur in the genital region, abdomen, and inner thighs. In immunocompromised individuals, including those with AIDS, the lesions are more extensive and may cause disfigurement.¹ Molluscum contagiosum involving epidermoid cysts has been reported.²

Histopathologically, MC can be classified as noninflammatory or inflammatory. In noninflamed lesions, multiple large, intracytoplasmic, eosinophilic inclusions (Henderson-Paterson bodies) appear within the lobulated endophytic and hyperplastic epidermis. Ultrastructurally, these bodies show membrane-bound collections of MC virus.¹ Replicating Henderson-Paterson bodies can result in rupture and inflammation. This case demonstrates a palisading granuloma containing keratin with few Henderson-Paterson bodies (quiz image) due to prior rupture of a molluscum or molluscoid cyst.

Rheumatoid nodules, the most characteristic histopathologic lesions of rheumatoid arthritis, are most commonly found in the subcutis at points of pressure and may occur in connective tissue of numerous organs. Rheumatoid nodules are firm, nontender, and mobile within the subcutaneous tissue but may be fixed to underlying structures including the periosteum, tendons, or bursae.^3,4 Occasionally, superficial nodules may perforate the epidermis.⁵ The inner central necrobiotic zone appears as intensely eosinophilic, amorphous fibrin and other cellular debris. This central area is surrounded by histiocytes in a palisaded configuration (Figure 1). Multinucleated foreign body giant cells also may be present. Occasionally, mast cells, eosinophils, and neutrophils are present.^6,7

Lupus miliaris disseminatus faciei presents with multiple discrete, smooth, yellow-brown to red, dome-shaped papules. The lesions typically are located on the central and lateral sides of the face and infrequently involve the neck. Other sites including the axillae, arms, hands, legs, and groin occasionally can be involved. Diascopy may reveal an apple jelly color.^8,9 The histopathologic hallmark of lupus miliaris disseminatus faciei is an epithelioid cell granuloma with central necrosis (Figure 2).

Epithelioid sarcoma (ES) is a soft tissue tumor with a known propensity for local recurrence, regional lymph node involvement, sporotrichoid spread, and distant metastases.¹⁰ The name was coined by Enzinger¹¹ in 1970 during a review of 62 cases of a “peculiar form of sarcoma that has repeatedly been confused with a chronic inflammatory process, a necrotizing granuloma, and a squamous cell carcinoma.” Epithelioid sarcoma tends to grow slowly in a nodular or multinodular manner along fascial structures and tendons, often with central necrosis and ulceration of the overlying skin. Histopathologically, classic ES shows nodular masses of uniform plump epithelioid cells with abundant eosinophilic cytoplasm and prominent central necrosis. A biphasic pattern is typical with spindle cells merging with epithelioid cells. Cellular atypia is relatively mild and mitoses are rare (Figure 3). Recurrent or metastatic lesions can show a greater degree of pleomorphism.¹² Given the low-grade atypia in early lesions, this sarcoma is easily misdiagnosed as granulomatous dermatitis. Immunohistochemically, the majority of ES cases are positive for cytokeratins and epithelial membrane antigen; SMARCB1/INI-1 expression is characteristically lost.¹³

Granulomatosis with polyangiitis (formerly Wegener granulomatosis) is an autoimmune vasculitis highly associated with antineutrophil cytoplasmic antibodies. Clinical manifestations include systemic necrotizing vasculitis; necrotizing glomerulonephritis; and granulomatous inflammation, which predominantly involves the upper respiratory tract, skin, and mucosa.^14,15 Skin involvement may be the initial manifestation of the disease and consists of palpable purpura, papules, ulcerations, vesicles, subcutaneous nodules, necrotizing ulcerations, papulonecrotic lesions, and petechiae. None of the findings are pathognomonic. The cutaneous histopathologic spectrum includes leukocytoclastic vasculitis, extravascular palisading granulomas, and granulomatous vasculitis.¹⁶ In the acute lesions of granulomatosis with polyangiitis, the predominant pattern of inflammation is not granulomatous but purulent with the appearance of an abscess. As it evolves, it develops a central zone of necrosis with extensive karyorrhectic debris and palisades of macrophages with scattered multinucleated giant cells (Figure 4).¹⁷

The Diagnosis: Ruptured Molluscum

Molluscum contagiosum (MC) is caused by a DNA virus (MC virus) belonging to the poxvirus family. Molluscum contagiosum is common and predominantly seen in children and young adults. In sexually active adults, the lesions commonly occur in the genital region, abdomen, and inner thighs. In immunocompromised individuals, including those with AIDS, the lesions are more extensive and may cause disfigurement.¹ Molluscum contagiosum involving epidermoid cysts has been reported.²

Histopathologically, MC can be classified as noninflammatory or inflammatory. In noninflamed lesions, multiple large, intracytoplasmic, eosinophilic inclusions (Henderson-Paterson bodies) appear within the lobulated endophytic and hyperplastic epidermis. Ultrastructurally, these bodies show membrane-bound collections of MC virus.¹ Replicating Henderson-Paterson bodies can result in rupture and inflammation. This case demonstrates a palisading granuloma containing keratin with few Henderson-Paterson bodies (quiz image) due to prior rupture of a molluscum or molluscoid cyst.

Rheumatoid nodules, the most characteristic histopathologic lesions of rheumatoid arthritis, are most commonly found in the subcutis at points of pressure and may occur in connective tissue of numerous organs. Rheumatoid nodules are firm, nontender, and mobile within the subcutaneous tissue but may be fixed to underlying structures including the periosteum, tendons, or bursae.^3,4 Occasionally, superficial nodules may perforate the epidermis.⁵ The inner central necrobiotic zone appears as intensely eosinophilic, amorphous fibrin and other cellular debris. This central area is surrounded by histiocytes in a palisaded configuration (Figure 1). Multinucleated foreign body giant cells also may be present. Occasionally, mast cells, eosinophils, and neutrophils are present.^6,7

Lupus miliaris disseminatus faciei presents with multiple discrete, smooth, yellow-brown to red, dome-shaped papules. The lesions typically are located on the central and lateral sides of the face and infrequently involve the neck. Other sites including the axillae, arms, hands, legs, and groin occasionally can be involved. Diascopy may reveal an apple jelly color.^8,9 The histopathologic hallmark of lupus miliaris disseminatus faciei is an epithelioid cell granuloma with central necrosis (Figure 2).

Epithelioid sarcoma (ES) is a soft tissue tumor with a known propensity for local recurrence, regional lymph node involvement, sporotrichoid spread, and distant metastases.¹⁰ The name was coined by Enzinger¹¹ in 1970 during a review of 62 cases of a “peculiar form of sarcoma that has repeatedly been confused with a chronic inflammatory process, a necrotizing granuloma, and a squamous cell carcinoma.” Epithelioid sarcoma tends to grow slowly in a nodular or multinodular manner along fascial structures and tendons, often with central necrosis and ulceration of the overlying skin. Histopathologically, classic ES shows nodular masses of uniform plump epithelioid cells with abundant eosinophilic cytoplasm and prominent central necrosis. A biphasic pattern is typical with spindle cells merging with epithelioid cells. Cellular atypia is relatively mild and mitoses are rare (Figure 3). Recurrent or metastatic lesions can show a greater degree of pleomorphism.¹² Given the low-grade atypia in early lesions, this sarcoma is easily misdiagnosed as granulomatous dermatitis. Immunohistochemically, the majority of ES cases are positive for cytokeratins and epithelial membrane antigen; SMARCB1/INI-1 expression is characteristically lost.¹³

Granulomatosis with polyangiitis (formerly Wegener granulomatosis) is an autoimmune vasculitis highly associated with antineutrophil cytoplasmic antibodies. Clinical manifestations include systemic necrotizing vasculitis; necrotizing glomerulonephritis; and granulomatous inflammation, which predominantly involves the upper respiratory tract, skin, and mucosa.^14,15 Skin involvement may be the initial manifestation of the disease and consists of palpable purpura, papules, ulcerations, vesicles, subcutaneous nodules, necrotizing ulcerations, papulonecrotic lesions, and petechiae. None of the findings are pathognomonic. The cutaneous histopathologic spectrum includes leukocytoclastic vasculitis, extravascular palisading granulomas, and granulomatous vasculitis.¹⁶ In the acute lesions of granulomatosis with polyangiitis, the predominant pattern of inflammation is not granulomatous but purulent with the appearance of an abscess. As it evolves, it develops a central zone of necrosis with extensive karyorrhectic debris and palisades of macrophages with scattered multinucleated giant cells (Figure 4).¹⁷

The Diagnosis: Ruptured Molluscum

Molluscum contagiosum (MC) is caused by a DNA virus (MC virus) belonging to the poxvirus family. Molluscum contagiosum is common and predominantly seen in children and young adults. In sexually active adults, the lesions commonly occur in the genital region, abdomen, and inner thighs. In immunocompromised individuals, including those with AIDS, the lesions are more extensive and may cause disfigurement.¹ Molluscum contagiosum involving epidermoid cysts has been reported.²

Histopathologically, MC can be classified as noninflammatory or inflammatory. In noninflamed lesions, multiple large, intracytoplasmic, eosinophilic inclusions (Henderson-Paterson bodies) appear within the lobulated endophytic and hyperplastic epidermis. Ultrastructurally, these bodies show membrane-bound collections of MC virus.¹ Replicating Henderson-Paterson bodies can result in rupture and inflammation. This case demonstrates a palisading granuloma containing keratin with few Henderson-Paterson bodies (quiz image) due to prior rupture of a molluscum or molluscoid cyst.

Rheumatoid nodules, the most characteristic histopathologic lesions of rheumatoid arthritis, are most commonly found in the subcutis at points of pressure and may occur in connective tissue of numerous organs. Rheumatoid nodules are firm, nontender, and mobile within the subcutaneous tissue but may be fixed to underlying structures including the periosteum, tendons, or bursae.^3,4 Occasionally, superficial nodules may perforate the epidermis.⁵ The inner central necrobiotic zone appears as intensely eosinophilic, amorphous fibrin and other cellular debris. This central area is surrounded by histiocytes in a palisaded configuration (Figure 1). Multinucleated foreign body giant cells also may be present. Occasionally, mast cells, eosinophils, and neutrophils are present.^6,7

Lupus miliaris disseminatus faciei presents with multiple discrete, smooth, yellow-brown to red, dome-shaped papules. The lesions typically are located on the central and lateral sides of the face and infrequently involve the neck. Other sites including the axillae, arms, hands, legs, and groin occasionally can be involved. Diascopy may reveal an apple jelly color.^8,9 The histopathologic hallmark of lupus miliaris disseminatus faciei is an epithelioid cell granuloma with central necrosis (Figure 2).

Epithelioid sarcoma (ES) is a soft tissue tumor with a known propensity for local recurrence, regional lymph node involvement, sporotrichoid spread, and distant metastases.¹⁰ The name was coined by Enzinger¹¹ in 1970 during a review of 62 cases of a “peculiar form of sarcoma that has repeatedly been confused with a chronic inflammatory process, a necrotizing granuloma, and a squamous cell carcinoma.” Epithelioid sarcoma tends to grow slowly in a nodular or multinodular manner along fascial structures and tendons, often with central necrosis and ulceration of the overlying skin. Histopathologically, classic ES shows nodular masses of uniform plump epithelioid cells with abundant eosinophilic cytoplasm and prominent central necrosis. A biphasic pattern is typical with spindle cells merging with epithelioid cells. Cellular atypia is relatively mild and mitoses are rare (Figure 3). Recurrent or metastatic lesions can show a greater degree of pleomorphism.¹² Given the low-grade atypia in early lesions, this sarcoma is easily misdiagnosed as granulomatous dermatitis. Immunohistochemically, the majority of ES cases are positive for cytokeratins and epithelial membrane antigen; SMARCB1/INI-1 expression is characteristically lost.¹³

Granulomatosis with polyangiitis (formerly Wegener granulomatosis) is an autoimmune vasculitis highly associated with antineutrophil cytoplasmic antibodies. Clinical manifestations include systemic necrotizing vasculitis; necrotizing glomerulonephritis; and granulomatous inflammation, which predominantly involves the upper respiratory tract, skin, and mucosa.^14,15 Skin involvement may be the initial manifestation of the disease and consists of palpable purpura, papules, ulcerations, vesicles, subcutaneous nodules, necrotizing ulcerations, papulonecrotic lesions, and petechiae. None of the findings are pathognomonic. The cutaneous histopathologic spectrum includes leukocytoclastic vasculitis, extravascular palisading granulomas, and granulomatous vasculitis.¹⁶ In the acute lesions of granulomatosis with polyangiitis, the predominant pattern of inflammation is not granulomatous but purulent with the appearance of an abscess. As it evolves, it develops a central zone of necrosis with extensive karyorrhectic debris and palisades of macrophages with scattered multinucleated giant cells (Figure 4).¹⁷

Cutaneous B-cell lymphomas represent a group of lymphomas derived from B lymphocytes in various stages of differentiation. The skin can be the site of primary or secondary involvement of any of the B-cell lymphomas. Primary cutaneous B-cell lymphomas present in the skin without evidence of extracutaneous disease at the time of diagnosis.¹ The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues recognizes 5 distinct primary cutaneous B-cell lymphoma subtypes: primary cutaneous follicle center lymphoma; primary cutaneous marginal zone lymphoma; primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type; DLBCL, not otherwise specified; and intravascular DLBCL.^1-3 The DLBCL, not otherwise specified, category includes less common provisional entities with insufficient evidence to be recognized as distinct diseases. Epstein-Barr virus (EBV)–positive DLBCL is a rare subtype in this group.⁴

This article reviews the different clinicopathologic subtypes of primary cutaneous B-cell lymphoma. It also serves to help dermatologists recognize primary cutaneous EBV-positive DLBCL as a rare and aggressive form of this disease.

Case Report

An 84-year-old white man presented with a pruritic eruption on the arms, legs, back, neck, and face of 5 months’ duration. His medical history was notable for prostate cancer that was successfully treated with radiation therapy 6 years prior. The patient denied any constitutional symptoms such as fever, chills, night sweats, or weight loss, and review of systems was negative. The patient was taking prednisone, which alleviated the pruritus, but the lesions persisted.

Physical examination revealed multiple pink to erythematous papules and subcutaneous nodules involving the face, neck, back, arms, and legs (Figure 1). No scale, crust, or ulceration was present. Palpation of the cervical, supraclavicular, axillary, and inguinal lymph nodes was negative for lymphadenopathy.

Punch biopsies of representative lesions on the upper back and right arm revealed diffuse and nodular infiltrates of large atypical lymphoid cells with scattered centroblasts and immunoblasts (Figures 2 and 3). Immunohistochemical staining demonstrated CD79, MUM-1, and EBV-encoded RNA positivity among the neoplastic cells. The Ki-67 proliferative index was greater than 90%. The neoplastic cells were negative for CD5, CD10, CD20, CD21, CD30, CD56, CD123, CD138, PAX5, C-MYC, BCL-2, BCL-6, cyclin D1, TCL-1A, and terminal deoxynucleotidyl transferase. Polymerase chain reaction showed a clonal B-cell population.

A peripheral blood smear did not show evidence of a B-cell lymphoproliferative process. A bone marrow biopsy was performed and did not show evidence of B-cell lymphoid neoplasia but did show reactive lymphoid aggregates composed of CD4⁺ and CD10⁺ T cells. Peripheral blood T-cell rearrangement and JAK2 were negative.

Based on clinical and histologic findings, the patient was diagnosed with primary cutaneous EBV-positive DLBCL. The patient was started on CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy for treatment of this aggressive cutaneous lymphoma, which initially resulted in clinical improvement of the lesions and complete involution of the subcutaneous nodules. After the sixth cycle of CHOP, he developed faintly erythematous indurated papules on the upper arms, chest, and back. Biopsy confirmed recurrence of the EBV-positive cutaneous lymphoma, and he started salvage chemotherapy with gemcitabine, oxaliplatin, and rituximab every 2 weeks; however, 4 months later (9 months after the initial presentation) he died from complications of the disease.

Comment

Etiology
Epstein-Barr virus–positive DLBCL, also called EBV-positive DLBCL of the elderly, was initially described in 2003 by Oyama et al⁵ and was included as a provisional entity in the 2008 World Health Organization classification system as a rare subtype of the DLBCL, not otherwise specified, category.² It is defined as an EBV-positive monoclonal large B-cell proliferation that occurs in immunocompetent patients older than 50 years.⁶ Epstein-Barr virus is a human herpesvirus that demonstrates tropism for lymphocytes and survives in human hosts by establishing latency in B cells. Under normal immune conditions, the proliferation of EBV-infected B cells is prevented by cytotoxic T cells.⁷ It is important to recognize that patients with EBV-positive DLBCL do not have a known immunodeficiency state; therefore, it has been postulated that EBV-positive DLBCL might be caused by age-related senescence of the immune system.^4,8

Epidemiology and Clinical Features
Epstein-Barr virus–positive DLBCL is more common in Asian countries than in Western countries, and there is a slight male predominance.⁶ A majority of patients present with extranodal disease at the time of diagnosis, and the skin is the most common extranodal site of involvement.^6,9 Rare cases of primary cutaneous involvement also have been described.^7,9,10 Cutaneous manifestations include erythematous papules and subcutaneous nodules. Other sites of extranodal involvement include the lungs, oral cavity, pharynx, gastrointestinal tract, and bone marrow.^8,9 However, EBV-positive DLBCL is an aggressive lymphoma and prognosis is poor irrespective of the primary site of involvement.

Histopathology
Two morphologic subtypes can be seen on histology. The polymorphic pattern is characterized by a broad range of B-cell maturation with admixed reactive cells (eg, lymphocytes, histiocytes, plasma cells). The monomorphic or large-cell pattern is characterized by monotonous sheets of large transformed B cells.^4,11 Many cases show both histologic patterns, and these morphologic variants do not impart any clinical or prognostic significance. Regardless of the histologic subtype, the neoplastic cells express pan B-cell antigens (eg, CD19, CD20, CD79a, PAX5), as well as MUM-1, BCL-2, and EBV-encoded RNA.⁴ Cases with plasmablastic features, as in our patient, may show weak or absent CD20 staining.¹² Detection of EBV by in situ hybridization is required for the diagnosis.

Diagnosis
Workup for a suspected cutaneous lymphoma should include a complete history and physical examination; laboratory studies; and relevant imaging evaluation such as computed tomography of the chest, abdomen, and pelvis with or without whole-body positron emission tomography. A bone marrow biopsy and aspirate also should be performed in all cutaneous lymphomas with intermediate to aggressive clinical behavior. Accurate staging evaluation is integral to confirm the absence of extracutaneous involvement and to provide prognostic and anatomic information for the appropriate selection of treatment.¹³

Prognosis and Management
Primary cutaneous lymphomas tend to have different clinical behaviors and prognoses compared to histologically similar systemic lymphomas; therefore, different therapeutic strategies are warranted.¹⁴ Epstein-Barr virus–positive DLBCL has an aggressive clinical course with a median survival of 2 years.⁸ Patients with EBV-positive DLBCL have a poorer overall survival and treatment response when compared to patients with EBV-negative DLBCLs.⁴ Primary cutaneous B-cell lymphomas with indolent behavior, such as primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma, can be treated with surgical excision, radiation therapy, or observation.¹⁵ No standard treatment exists for EBV-positive DLBCL, but R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), which is the standard treatment of primary cutaneous DLBCL, leg type, may provide a survival benefit.^13,15 Further studies are required to determine optimal treatment strategies.

Conclusion

Although rare, EBV-positive DLBCL is an important entity to consider when evaluating a patient with a suspected primary cutaneous lymphoma. Workup to rule out an underlying systemic lymphoma with relevant laboratory evaluation, imaging studies, and bone marrow biopsy is critical. Prognosis is poor and treatment is difficult, as standard treatment protocols have yet to be determined.

Cutaneous B-cell lymphomas represent a group of lymphomas derived from B lymphocytes in various stages of differentiation. The skin can be the site of primary or secondary involvement of any of the B-cell lymphomas. Primary cutaneous B-cell lymphomas present in the skin without evidence of extracutaneous disease at the time of diagnosis.¹ The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues recognizes 5 distinct primary cutaneous B-cell lymphoma subtypes: primary cutaneous follicle center lymphoma; primary cutaneous marginal zone lymphoma; primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type; DLBCL, not otherwise specified; and intravascular DLBCL.^1-3 The DLBCL, not otherwise specified, category includes less common provisional entities with insufficient evidence to be recognized as distinct diseases. Epstein-Barr virus (EBV)–positive DLBCL is a rare subtype in this group.⁴

This article reviews the different clinicopathologic subtypes of primary cutaneous B-cell lymphoma. It also serves to help dermatologists recognize primary cutaneous EBV-positive DLBCL as a rare and aggressive form of this disease.

Case Report

An 84-year-old white man presented with a pruritic eruption on the arms, legs, back, neck, and face of 5 months’ duration. His medical history was notable for prostate cancer that was successfully treated with radiation therapy 6 years prior. The patient denied any constitutional symptoms such as fever, chills, night sweats, or weight loss, and review of systems was negative. The patient was taking prednisone, which alleviated the pruritus, but the lesions persisted.

Physical examination revealed multiple pink to erythematous papules and subcutaneous nodules involving the face, neck, back, arms, and legs (Figure 1). No scale, crust, or ulceration was present. Palpation of the cervical, supraclavicular, axillary, and inguinal lymph nodes was negative for lymphadenopathy.

Punch biopsies of representative lesions on the upper back and right arm revealed diffuse and nodular infiltrates of large atypical lymphoid cells with scattered centroblasts and immunoblasts (Figures 2 and 3). Immunohistochemical staining demonstrated CD79, MUM-1, and EBV-encoded RNA positivity among the neoplastic cells. The Ki-67 proliferative index was greater than 90%. The neoplastic cells were negative for CD5, CD10, CD20, CD21, CD30, CD56, CD123, CD138, PAX5, C-MYC, BCL-2, BCL-6, cyclin D1, TCL-1A, and terminal deoxynucleotidyl transferase. Polymerase chain reaction showed a clonal B-cell population.

A peripheral blood smear did not show evidence of a B-cell lymphoproliferative process. A bone marrow biopsy was performed and did not show evidence of B-cell lymphoid neoplasia but did show reactive lymphoid aggregates composed of CD4⁺ and CD10⁺ T cells. Peripheral blood T-cell rearrangement and JAK2 were negative.

Based on clinical and histologic findings, the patient was diagnosed with primary cutaneous EBV-positive DLBCL. The patient was started on CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy for treatment of this aggressive cutaneous lymphoma, which initially resulted in clinical improvement of the lesions and complete involution of the subcutaneous nodules. After the sixth cycle of CHOP, he developed faintly erythematous indurated papules on the upper arms, chest, and back. Biopsy confirmed recurrence of the EBV-positive cutaneous lymphoma, and he started salvage chemotherapy with gemcitabine, oxaliplatin, and rituximab every 2 weeks; however, 4 months later (9 months after the initial presentation) he died from complications of the disease.

Comment

Etiology
Epstein-Barr virus–positive DLBCL, also called EBV-positive DLBCL of the elderly, was initially described in 2003 by Oyama et al⁵ and was included as a provisional entity in the 2008 World Health Organization classification system as a rare subtype of the DLBCL, not otherwise specified, category.² It is defined as an EBV-positive monoclonal large B-cell proliferation that occurs in immunocompetent patients older than 50 years.⁶ Epstein-Barr virus is a human herpesvirus that demonstrates tropism for lymphocytes and survives in human hosts by establishing latency in B cells. Under normal immune conditions, the proliferation of EBV-infected B cells is prevented by cytotoxic T cells.⁷ It is important to recognize that patients with EBV-positive DLBCL do not have a known immunodeficiency state; therefore, it has been postulated that EBV-positive DLBCL might be caused by age-related senescence of the immune system.^4,8

Epidemiology and Clinical Features
Epstein-Barr virus–positive DLBCL is more common in Asian countries than in Western countries, and there is a slight male predominance.⁶ A majority of patients present with extranodal disease at the time of diagnosis, and the skin is the most common extranodal site of involvement.^6,9 Rare cases of primary cutaneous involvement also have been described.^7,9,10 Cutaneous manifestations include erythematous papules and subcutaneous nodules. Other sites of extranodal involvement include the lungs, oral cavity, pharynx, gastrointestinal tract, and bone marrow.^8,9 However, EBV-positive DLBCL is an aggressive lymphoma and prognosis is poor irrespective of the primary site of involvement.

Histopathology
Two morphologic subtypes can be seen on histology. The polymorphic pattern is characterized by a broad range of B-cell maturation with admixed reactive cells (eg, lymphocytes, histiocytes, plasma cells). The monomorphic or large-cell pattern is characterized by monotonous sheets of large transformed B cells.^4,11 Many cases show both histologic patterns, and these morphologic variants do not impart any clinical or prognostic significance. Regardless of the histologic subtype, the neoplastic cells express pan B-cell antigens (eg, CD19, CD20, CD79a, PAX5), as well as MUM-1, BCL-2, and EBV-encoded RNA.⁴ Cases with plasmablastic features, as in our patient, may show weak or absent CD20 staining.¹² Detection of EBV by in situ hybridization is required for the diagnosis.

Diagnosis
Workup for a suspected cutaneous lymphoma should include a complete history and physical examination; laboratory studies; and relevant imaging evaluation such as computed tomography of the chest, abdomen, and pelvis with or without whole-body positron emission tomography. A bone marrow biopsy and aspirate also should be performed in all cutaneous lymphomas with intermediate to aggressive clinical behavior. Accurate staging evaluation is integral to confirm the absence of extracutaneous involvement and to provide prognostic and anatomic information for the appropriate selection of treatment.¹³

Prognosis and Management
Primary cutaneous lymphomas tend to have different clinical behaviors and prognoses compared to histologically similar systemic lymphomas; therefore, different therapeutic strategies are warranted.¹⁴ Epstein-Barr virus–positive DLBCL has an aggressive clinical course with a median survival of 2 years.⁸ Patients with EBV-positive DLBCL have a poorer overall survival and treatment response when compared to patients with EBV-negative DLBCLs.⁴ Primary cutaneous B-cell lymphomas with indolent behavior, such as primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma, can be treated with surgical excision, radiation therapy, or observation.¹⁵ No standard treatment exists for EBV-positive DLBCL, but R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), which is the standard treatment of primary cutaneous DLBCL, leg type, may provide a survival benefit.^13,15 Further studies are required to determine optimal treatment strategies.

Conclusion

Although rare, EBV-positive DLBCL is an important entity to consider when evaluating a patient with a suspected primary cutaneous lymphoma. Workup to rule out an underlying systemic lymphoma with relevant laboratory evaluation, imaging studies, and bone marrow biopsy is critical. Prognosis is poor and treatment is difficult, as standard treatment protocols have yet to be determined.

Cutaneous B-cell lymphomas represent a group of lymphomas derived from B lymphocytes in various stages of differentiation. The skin can be the site of primary or secondary involvement of any of the B-cell lymphomas. Primary cutaneous B-cell lymphomas present in the skin without evidence of extracutaneous disease at the time of diagnosis.¹ The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues recognizes 5 distinct primary cutaneous B-cell lymphoma subtypes: primary cutaneous follicle center lymphoma; primary cutaneous marginal zone lymphoma; primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type; DLBCL, not otherwise specified; and intravascular DLBCL.^1-3 The DLBCL, not otherwise specified, category includes less common provisional entities with insufficient evidence to be recognized as distinct diseases. Epstein-Barr virus (EBV)–positive DLBCL is a rare subtype in this group.⁴

This article reviews the different clinicopathologic subtypes of primary cutaneous B-cell lymphoma. It also serves to help dermatologists recognize primary cutaneous EBV-positive DLBCL as a rare and aggressive form of this disease.

Case Report

An 84-year-old white man presented with a pruritic eruption on the arms, legs, back, neck, and face of 5 months’ duration. His medical history was notable for prostate cancer that was successfully treated with radiation therapy 6 years prior. The patient denied any constitutional symptoms such as fever, chills, night sweats, or weight loss, and review of systems was negative. The patient was taking prednisone, which alleviated the pruritus, but the lesions persisted.

Physical examination revealed multiple pink to erythematous papules and subcutaneous nodules involving the face, neck, back, arms, and legs (Figure 1). No scale, crust, or ulceration was present. Palpation of the cervical, supraclavicular, axillary, and inguinal lymph nodes was negative for lymphadenopathy.

Punch biopsies of representative lesions on the upper back and right arm revealed diffuse and nodular infiltrates of large atypical lymphoid cells with scattered centroblasts and immunoblasts (Figures 2 and 3). Immunohistochemical staining demonstrated CD79, MUM-1, and EBV-encoded RNA positivity among the neoplastic cells. The Ki-67 proliferative index was greater than 90%. The neoplastic cells were negative for CD5, CD10, CD20, CD21, CD30, CD56, CD123, CD138, PAX5, C-MYC, BCL-2, BCL-6, cyclin D1, TCL-1A, and terminal deoxynucleotidyl transferase. Polymerase chain reaction showed a clonal B-cell population.

A peripheral blood smear did not show evidence of a B-cell lymphoproliferative process. A bone marrow biopsy was performed and did not show evidence of B-cell lymphoid neoplasia but did show reactive lymphoid aggregates composed of CD4⁺ and CD10⁺ T cells. Peripheral blood T-cell rearrangement and JAK2 were negative.

Based on clinical and histologic findings, the patient was diagnosed with primary cutaneous EBV-positive DLBCL. The patient was started on CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy for treatment of this aggressive cutaneous lymphoma, which initially resulted in clinical improvement of the lesions and complete involution of the subcutaneous nodules. After the sixth cycle of CHOP, he developed faintly erythematous indurated papules on the upper arms, chest, and back. Biopsy confirmed recurrence of the EBV-positive cutaneous lymphoma, and he started salvage chemotherapy with gemcitabine, oxaliplatin, and rituximab every 2 weeks; however, 4 months later (9 months after the initial presentation) he died from complications of the disease.

Comment

Etiology
Epstein-Barr virus–positive DLBCL, also called EBV-positive DLBCL of the elderly, was initially described in 2003 by Oyama et al⁵ and was included as a provisional entity in the 2008 World Health Organization classification system as a rare subtype of the DLBCL, not otherwise specified, category.² It is defined as an EBV-positive monoclonal large B-cell proliferation that occurs in immunocompetent patients older than 50 years.⁶ Epstein-Barr virus is a human herpesvirus that demonstrates tropism for lymphocytes and survives in human hosts by establishing latency in B cells. Under normal immune conditions, the proliferation of EBV-infected B cells is prevented by cytotoxic T cells.⁷ It is important to recognize that patients with EBV-positive DLBCL do not have a known immunodeficiency state; therefore, it has been postulated that EBV-positive DLBCL might be caused by age-related senescence of the immune system.^4,8

Epidemiology and Clinical Features
Epstein-Barr virus–positive DLBCL is more common in Asian countries than in Western countries, and there is a slight male predominance.⁶ A majority of patients present with extranodal disease at the time of diagnosis, and the skin is the most common extranodal site of involvement.^6,9 Rare cases of primary cutaneous involvement also have been described.^7,9,10 Cutaneous manifestations include erythematous papules and subcutaneous nodules. Other sites of extranodal involvement include the lungs, oral cavity, pharynx, gastrointestinal tract, and bone marrow.^8,9 However, EBV-positive DLBCL is an aggressive lymphoma and prognosis is poor irrespective of the primary site of involvement.

Histopathology
Two morphologic subtypes can be seen on histology. The polymorphic pattern is characterized by a broad range of B-cell maturation with admixed reactive cells (eg, lymphocytes, histiocytes, plasma cells). The monomorphic or large-cell pattern is characterized by monotonous sheets of large transformed B cells.^4,11 Many cases show both histologic patterns, and these morphologic variants do not impart any clinical or prognostic significance. Regardless of the histologic subtype, the neoplastic cells express pan B-cell antigens (eg, CD19, CD20, CD79a, PAX5), as well as MUM-1, BCL-2, and EBV-encoded RNA.⁴ Cases with plasmablastic features, as in our patient, may show weak or absent CD20 staining.¹² Detection of EBV by in situ hybridization is required for the diagnosis.

Diagnosis
Workup for a suspected cutaneous lymphoma should include a complete history and physical examination; laboratory studies; and relevant imaging evaluation such as computed tomography of the chest, abdomen, and pelvis with or without whole-body positron emission tomography. A bone marrow biopsy and aspirate also should be performed in all cutaneous lymphomas with intermediate to aggressive clinical behavior. Accurate staging evaluation is integral to confirm the absence of extracutaneous involvement and to provide prognostic and anatomic information for the appropriate selection of treatment.¹³

Prognosis and Management
Primary cutaneous lymphomas tend to have different clinical behaviors and prognoses compared to histologically similar systemic lymphomas; therefore, different therapeutic strategies are warranted.¹⁴ Epstein-Barr virus–positive DLBCL has an aggressive clinical course with a median survival of 2 years.⁸ Patients with EBV-positive DLBCL have a poorer overall survival and treatment response when compared to patients with EBV-negative DLBCLs.⁴ Primary cutaneous B-cell lymphomas with indolent behavior, such as primary cutaneous marginal zone lymphoma and primary cutaneous follicle center lymphoma, can be treated with surgical excision, radiation therapy, or observation.¹⁵ No standard treatment exists for EBV-positive DLBCL, but R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), which is the standard treatment of primary cutaneous DLBCL, leg type, may provide a survival benefit.^13,15 Further studies are required to determine optimal treatment strategies.

Conclusion

Although rare, EBV-positive DLBCL is an important entity to consider when evaluating a patient with a suspected primary cutaneous lymphoma. Workup to rule out an underlying systemic lymphoma with relevant laboratory evaluation, imaging studies, and bone marrow biopsy is critical. Prognosis is poor and treatment is difficult, as standard treatment protocols have yet to be determined.

The Diagnosis: Acute Generalized Exanthematous Pustulosis

Histopathology demonstrated spongiosis with subcorneal pustules and an overlying basket-weave pattern stratum corneum. There was mild papillary dermal edema with scattered dermal neutrophils and rare eosinophils (Figure). The patient's clinical presentation and histopathology were consistent with acute generalized exanthematous pustulosis (AGEP). The inciting agent in this case was the contrast medium iopamidol. The patient was treated with a short course of prednisone, triamcinolone cream, diphenhydramine, and acetaminophen. Within 1 week the pustules and erythema had resolved.

Acute generalized exanthematous pustulosis is an uncommon T cell-mediated cutaneous reaction characterized by widespread progressive erythema with numerous nonfollicular pinpoint pustules. The patient usually is well appearing; however, he/she often will have concurrent fever and facial edema. Mucous membranes rarely are involved. Laboratory results typically are notable only for leukocytosis with neutrophilia.

The pustular eruption typically occurs within 1 to 2 days after exposure to an inciting agent¹; however, this latent period can range from 1 hour to nearly 4 weeks in some studies.² Systemic medications are the cause in approximately 90% of cases, with antibiotics being the most common category. Frequently implicated medications include β-lactams, macrolides, quinolones, sulfonamides, proton pump inhibitors, hydroxychloroquine, terbinafine, nonsteroidal anti-inflammatory drugs, diltiazem, ketoconazole, and fluconazole. Acute generalized exanthematous pustulosis also has been rarely reported following contact with mercury, viral and bacterial infections, and spider bites.³

Iodinated contrast agents have long been known to cause immediate and delayed adverse cutaneous reactions. However, one consensus study indicated that these reactions occur in only 0.05% to 0.10% of patients.⁴ Although rare, iodinated contrast media (eg, iopamidol, iohexol, ioversol, iodixanol, iomeprol, iobitridol, iopromide) have been reported as a cause of AGEP. A PubMed search of articles indexed for MEDLINE using the terms acute generalized exanthematous pustulosis, contrast, iodine, and iodinated revealed 10 adult cases reported in 6 articles in the English-language literature.^1,5-9 The most recent articles focus on methods to identify the causative agent. If the etiology of the reaction is unclear, patch or intradermal testing can help to confirm the causative agent. These tests also can help determine similar agents to which the patient may cross-react.^4,5

It can be difficult to differentiate AGEP from other cutaneous drug reactions and other nonfollicular pustular conditions. Drug-induced hypersensitivity syndrome typically presents with facial edema and a morbilliform rash. Although it can present with pustules, the latent period is longer (2-6 weeks), and there frequently are signs of multiorgan involvement including hepatic dysfunction, eosinophilia, atypical lymphocytosis, and lymphadenopathy. Patients with generalized pustular psoriasis often have a history of plaque psoriasis; the pustules are more concentrated in flexural sites; the eruption is gradual in onset; and histologically there tends to be features of psoriasis including parakeratosis, Munro microabscesses, and dilated blood vessels.¹⁰ Subcorneal pustular dermatosis also is more concentrated in flexural sites and frequently has an annular or serpiginous configuration. The onset also is gradual, and it follows a more chronic course than AGEP. Exfoliative erythroderma presents with widespread erythema and superficial desquamating scale. It often occurs in association with systemic symptoms and can be the result of a drug reaction or underlying inflammatory dermatosis such as psoriasis, mycosis fungoides, or pityriasis rubra pilaris.

Acute generalized exanthematous pustulosis usually resolves spontaneously within 2 weeks and is associated with a superficial desquamation as it clears. Appropriate treatment includes discontinuing the offending agent; monitoring for systemic involvement; and treating the patient's symptoms with antihistamines, analgesics, topical steroids, and emollients. In more severe or persistent cases, treatment with systemic steroids and tumor necrosis factor α inhibitors has been attempted, though their efficacy remains unclear. We report a case of iopamidol-induced AGEP that highlights the importance of eliciting a history of contrast exposure from a patient with suspected AGEP.

The Diagnosis: Acute Generalized Exanthematous Pustulosis

Histopathology demonstrated spongiosis with subcorneal pustules and an overlying basket-weave pattern stratum corneum. There was mild papillary dermal edema with scattered dermal neutrophils and rare eosinophils (Figure). The patient's clinical presentation and histopathology were consistent with acute generalized exanthematous pustulosis (AGEP). The inciting agent in this case was the contrast medium iopamidol. The patient was treated with a short course of prednisone, triamcinolone cream, diphenhydramine, and acetaminophen. Within 1 week the pustules and erythema had resolved.

Acute generalized exanthematous pustulosis is an uncommon T cell-mediated cutaneous reaction characterized by widespread progressive erythema with numerous nonfollicular pinpoint pustules. The patient usually is well appearing; however, he/she often will have concurrent fever and facial edema. Mucous membranes rarely are involved. Laboratory results typically are notable only for leukocytosis with neutrophilia.

The pustular eruption typically occurs within 1 to 2 days after exposure to an inciting agent¹; however, this latent period can range from 1 hour to nearly 4 weeks in some studies.² Systemic medications are the cause in approximately 90% of cases, with antibiotics being the most common category. Frequently implicated medications include β-lactams, macrolides, quinolones, sulfonamides, proton pump inhibitors, hydroxychloroquine, terbinafine, nonsteroidal anti-inflammatory drugs, diltiazem, ketoconazole, and fluconazole. Acute generalized exanthematous pustulosis also has been rarely reported following contact with mercury, viral and bacterial infections, and spider bites.³

Iodinated contrast agents have long been known to cause immediate and delayed adverse cutaneous reactions. However, one consensus study indicated that these reactions occur in only 0.05% to 0.10% of patients.⁴ Although rare, iodinated contrast media (eg, iopamidol, iohexol, ioversol, iodixanol, iomeprol, iobitridol, iopromide) have been reported as a cause of AGEP. A PubMed search of articles indexed for MEDLINE using the terms acute generalized exanthematous pustulosis, contrast, iodine, and iodinated revealed 10 adult cases reported in 6 articles in the English-language literature.^1,5-9 The most recent articles focus on methods to identify the causative agent. If the etiology of the reaction is unclear, patch or intradermal testing can help to confirm the causative agent. These tests also can help determine similar agents to which the patient may cross-react.^4,5

It can be difficult to differentiate AGEP from other cutaneous drug reactions and other nonfollicular pustular conditions. Drug-induced hypersensitivity syndrome typically presents with facial edema and a morbilliform rash. Although it can present with pustules, the latent period is longer (2-6 weeks), and there frequently are signs of multiorgan involvement including hepatic dysfunction, eosinophilia, atypical lymphocytosis, and lymphadenopathy. Patients with generalized pustular psoriasis often have a history of plaque psoriasis; the pustules are more concentrated in flexural sites; the eruption is gradual in onset; and histologically there tends to be features of psoriasis including parakeratosis, Munro microabscesses, and dilated blood vessels.¹⁰ Subcorneal pustular dermatosis also is more concentrated in flexural sites and frequently has an annular or serpiginous configuration. The onset also is gradual, and it follows a more chronic course than AGEP. Exfoliative erythroderma presents with widespread erythema and superficial desquamating scale. It often occurs in association with systemic symptoms and can be the result of a drug reaction or underlying inflammatory dermatosis such as psoriasis, mycosis fungoides, or pityriasis rubra pilaris.

Acute generalized exanthematous pustulosis usually resolves spontaneously within 2 weeks and is associated with a superficial desquamation as it clears. Appropriate treatment includes discontinuing the offending agent; monitoring for systemic involvement; and treating the patient's symptoms with antihistamines, analgesics, topical steroids, and emollients. In more severe or persistent cases, treatment with systemic steroids and tumor necrosis factor α inhibitors has been attempted, though their efficacy remains unclear. We report a case of iopamidol-induced AGEP that highlights the importance of eliciting a history of contrast exposure from a patient with suspected AGEP.

The Diagnosis: Acute Generalized Exanthematous Pustulosis

Histopathology demonstrated spongiosis with subcorneal pustules and an overlying basket-weave pattern stratum corneum. There was mild papillary dermal edema with scattered dermal neutrophils and rare eosinophils (Figure). The patient's clinical presentation and histopathology were consistent with acute generalized exanthematous pustulosis (AGEP). The inciting agent in this case was the contrast medium iopamidol. The patient was treated with a short course of prednisone, triamcinolone cream, diphenhydramine, and acetaminophen. Within 1 week the pustules and erythema had resolved.

Acute generalized exanthematous pustulosis is an uncommon T cell-mediated cutaneous reaction characterized by widespread progressive erythema with numerous nonfollicular pinpoint pustules. The patient usually is well appearing; however, he/she often will have concurrent fever and facial edema. Mucous membranes rarely are involved. Laboratory results typically are notable only for leukocytosis with neutrophilia.

The pustular eruption typically occurs within 1 to 2 days after exposure to an inciting agent¹; however, this latent period can range from 1 hour to nearly 4 weeks in some studies.² Systemic medications are the cause in approximately 90% of cases, with antibiotics being the most common category. Frequently implicated medications include β-lactams, macrolides, quinolones, sulfonamides, proton pump inhibitors, hydroxychloroquine, terbinafine, nonsteroidal anti-inflammatory drugs, diltiazem, ketoconazole, and fluconazole. Acute generalized exanthematous pustulosis also has been rarely reported following contact with mercury, viral and bacterial infections, and spider bites.³

Iodinated contrast agents have long been known to cause immediate and delayed adverse cutaneous reactions. However, one consensus study indicated that these reactions occur in only 0.05% to 0.10% of patients.⁴ Although rare, iodinated contrast media (eg, iopamidol, iohexol, ioversol, iodixanol, iomeprol, iobitridol, iopromide) have been reported as a cause of AGEP. A PubMed search of articles indexed for MEDLINE using the terms acute generalized exanthematous pustulosis, contrast, iodine, and iodinated revealed 10 adult cases reported in 6 articles in the English-language literature.^1,5-9 The most recent articles focus on methods to identify the causative agent. If the etiology of the reaction is unclear, patch or intradermal testing can help to confirm the causative agent. These tests also can help determine similar agents to which the patient may cross-react.^4,5

It can be difficult to differentiate AGEP from other cutaneous drug reactions and other nonfollicular pustular conditions. Drug-induced hypersensitivity syndrome typically presents with facial edema and a morbilliform rash. Although it can present with pustules, the latent period is longer (2-6 weeks), and there frequently are signs of multiorgan involvement including hepatic dysfunction, eosinophilia, atypical lymphocytosis, and lymphadenopathy. Patients with generalized pustular psoriasis often have a history of plaque psoriasis; the pustules are more concentrated in flexural sites; the eruption is gradual in onset; and histologically there tends to be features of psoriasis including parakeratosis, Munro microabscesses, and dilated blood vessels.¹⁰ Subcorneal pustular dermatosis also is more concentrated in flexural sites and frequently has an annular or serpiginous configuration. The onset also is gradual, and it follows a more chronic course than AGEP. Exfoliative erythroderma presents with widespread erythema and superficial desquamating scale. It often occurs in association with systemic symptoms and can be the result of a drug reaction or underlying inflammatory dermatosis such as psoriasis, mycosis fungoides, or pityriasis rubra pilaris.

Acute generalized exanthematous pustulosis usually resolves spontaneously within 2 weeks and is associated with a superficial desquamation as it clears. Appropriate treatment includes discontinuing the offending agent; monitoring for systemic involvement; and treating the patient's symptoms with antihistamines, analgesics, topical steroids, and emollients. In more severe or persistent cases, treatment with systemic steroids and tumor necrosis factor α inhibitors has been attempted, though their efficacy remains unclear. We report a case of iopamidol-induced AGEP that highlights the importance of eliciting a history of contrast exposure from a patient with suspected AGEP.

Fibrofolliculomas and trichodiscomas typically present on the head or neck as smooth, flesh-colored, dome-shaped papules. These two entities are considered to constitute two separate time points on a spectrum of histopathologic changes in mantleoma differentiation.¹ Histologically, both are benign hamartomas of the pilosebaceous subunit and collectively are known as mantleomas. We present an unusual case of a concomitant fibrofolliculoma and trichodiscoma on the abdomen.

Case Report

An asymptomatic 54-year-old man presented for a routine full-body skin examination. A solitary, 2×1-cm, subcutaneous, doughy, mobile nodule was found on the left side of the abdomen with an overlying 2-mm yellow fleshy papule. The patient declined excision of the lesion, and it was recommended that he return for follow-up 3 months later.

The patient did not present for follow-up until 4.5 years later, at which point the lesion had grown to 3.0×2.5 cm in size. An excision was performed, at which time the lesion was noted to be cystic, extruding an oily, yellow-white liquid. Bacterial culture was negative. Histopathologic sections showed a dome-shaped papule with connection to the overlying epidermis. Epithelial extensions from the infundibular epithelium formed a fenestrated pattern surrounding a fibrous and mucinous stroma (Figure, A and B). The differential diagnosis at this time included an epidermal inclusion cyst, fibroma, intradermal nevus, verruca, hemangioma, angiofibroma, and lipoma.^2-4

The same lesion cut in a different plane of sectioning showed an expansile dermal nodule comprising clusters of sebaceous lobules surrounding a fibrous and mucinous stroma. Within the second lesion, fibrous and stromal components predominated over epithelial components (Figure, C). A diagnosis of fibrofolliculoma showing features of a trichodiscoma arising in the unusual location of the abdomen was made.

Comment

Solitary fibrofolliculomas and trichodiscomas are flesh-colored, dome-shaped papules that generally present on the face, specifically on the chin, nose, cheeks, ears, and eyebrows without considerable symptoms.^2,4,5 Clinically, fibrofolliculomas are indistinguishable from trichodiscomas but demonstrate different features on biopsy.^1,5

Fibrofolliculomas and trichodiscomas are well known for their association with Birt-Hogg-Dubé (BHD) syndrome when they present concomitantly and typically arise earlier in the third decade of life than solitary fibrofolliculomas; however, there have been reports of solitary fibrofolliculomas in patients aged 1 to 36 years.^4,6 The triad of BHD syndrome consists of multiple fibrofolliculomas, trichodiscomas, and acrochordons, and it is acquired in an autosomal-dominant manner, unlike solitary fibrofolliculomas, which typically are not inherited. Birt-Hogg-Dubé syndrome is caused by a mutation in the FLCN gene that codes for the tumor-suppressor protein folliculin, which when mutated can cause unregulated proliferation of cells.⁷ Solitary fibrofolliculomas and the multiple fibrofolliculomas seen in BHD syndrome are histologically similar.

Fibrofolliculoma can be clinically indistinguishable from fibroepithelioma of Pinkus, perifollicular fibroma, trichilemmoma, trichodiscoma, trichoepithelioma, and trichofolliculoma. All typically present clinically as flesh-colored papules,¹ although histologic distinction can be made (Table).^5,8-13

Fibrofolliculoma is a benign hamartoma that arises from the pilosebaceous follicle and consists of an expansion of the fibrous root sheath, which typically surrounds the hair follicle along with proliferating bands or ribbons of perifollicular connective tissue. As such, the hair follicle may be dilated and filled with keratin in the expanded infundibulum.⁸ Follicles also may be surrounded by a myxoid stroma.² In contrast, trichodiscoma is characterized by connective tissue with mature sebaceous lobules in the periphery. It has a myxoid stroma, as opposed to the more fibrous stroma seen in fibrofolliculomas.

Ackerman et al¹ considered both fibrofolliculomas and trichodiscomas to be hamartomas of the epithelial hair follicle. The exact etiology of each of these hamartomas is unknown, but the undifferentiated epithelial strands protruding from the hair follicle in a fibrofolliculoma lie in close proximity to sebaceous glands. Furthermore, the authors postulated that fibrofolliculomas and trichodiscomas constitute a spectrum that encompasses the differentiation process of a mantleoma, with fibrofolliculoma representing the beginning of mantleoma differentiation and trichodiscoma representing the end. This end stage of follicular differentiation is one in which there is a predominant stroma and the previously undifferentiated epithelium has formed into sebaceous ducts and lobules in the stroma.¹

Most cases of fibrofolliculoma and/or trichodiscoma arise in areas of dense sebaceous follicle concentration (eg, face), further supporting the hypothesis that sebaceous gland proliferation contributes to fibrofolliculoma.¹⁴ The case described here, with the fibrofolliculoma arising on the abdomen in conjunction with a trichodiscoma, is therefore worth noting because its location differs from what has been observed in previously reported cases.⁴

There are both surgical and medical options for treatment of fibrofolliculoma. Although surgical excision is an option for a single lesion, patients with multiple fibrofolliculomas or BHD may prefer removal with the combined CO₂ laser and erbium-doped YAG laser.¹⁵

Conclusion

We present a rare case of concomitant fibrofolliculoma and trichodiscoma arising on the unusual location of the abdomen. This report highlights the histopathologic features of multiple adnexal tumors and emphasizes the importance of biopsy for differentiating fibrofolliculoma and trichodiscoma.

Fibrofolliculomas and trichodiscomas typically present on the head or neck as smooth, flesh-colored, dome-shaped papules. These two entities are considered to constitute two separate time points on a spectrum of histopathologic changes in mantleoma differentiation.¹ Histologically, both are benign hamartomas of the pilosebaceous subunit and collectively are known as mantleomas. We present an unusual case of a concomitant fibrofolliculoma and trichodiscoma on the abdomen.

Case Report

An asymptomatic 54-year-old man presented for a routine full-body skin examination. A solitary, 2×1-cm, subcutaneous, doughy, mobile nodule was found on the left side of the abdomen with an overlying 2-mm yellow fleshy papule. The patient declined excision of the lesion, and it was recommended that he return for follow-up 3 months later.

The patient did not present for follow-up until 4.5 years later, at which point the lesion had grown to 3.0×2.5 cm in size. An excision was performed, at which time the lesion was noted to be cystic, extruding an oily, yellow-white liquid. Bacterial culture was negative. Histopathologic sections showed a dome-shaped papule with connection to the overlying epidermis. Epithelial extensions from the infundibular epithelium formed a fenestrated pattern surrounding a fibrous and mucinous stroma (Figure, A and B). The differential diagnosis at this time included an epidermal inclusion cyst, fibroma, intradermal nevus, verruca, hemangioma, angiofibroma, and lipoma.^2-4

The same lesion cut in a different plane of sectioning showed an expansile dermal nodule comprising clusters of sebaceous lobules surrounding a fibrous and mucinous stroma. Within the second lesion, fibrous and stromal components predominated over epithelial components (Figure, C). A diagnosis of fibrofolliculoma showing features of a trichodiscoma arising in the unusual location of the abdomen was made.

Comment

Solitary fibrofolliculomas and trichodiscomas are flesh-colored, dome-shaped papules that generally present on the face, specifically on the chin, nose, cheeks, ears, and eyebrows without considerable symptoms.^2,4,5 Clinically, fibrofolliculomas are indistinguishable from trichodiscomas but demonstrate different features on biopsy.^1,5

Fibrofolliculomas and trichodiscomas are well known for their association with Birt-Hogg-Dubé (BHD) syndrome when they present concomitantly and typically arise earlier in the third decade of life than solitary fibrofolliculomas; however, there have been reports of solitary fibrofolliculomas in patients aged 1 to 36 years.^4,6 The triad of BHD syndrome consists of multiple fibrofolliculomas, trichodiscomas, and acrochordons, and it is acquired in an autosomal-dominant manner, unlike solitary fibrofolliculomas, which typically are not inherited. Birt-Hogg-Dubé syndrome is caused by a mutation in the FLCN gene that codes for the tumor-suppressor protein folliculin, which when mutated can cause unregulated proliferation of cells.⁷ Solitary fibrofolliculomas and the multiple fibrofolliculomas seen in BHD syndrome are histologically similar.

Fibrofolliculoma can be clinically indistinguishable from fibroepithelioma of Pinkus, perifollicular fibroma, trichilemmoma, trichodiscoma, trichoepithelioma, and trichofolliculoma. All typically present clinically as flesh-colored papules,¹ although histologic distinction can be made (Table).^5,8-13

Fibrofolliculoma is a benign hamartoma that arises from the pilosebaceous follicle and consists of an expansion of the fibrous root sheath, which typically surrounds the hair follicle along with proliferating bands or ribbons of perifollicular connective tissue. As such, the hair follicle may be dilated and filled with keratin in the expanded infundibulum.⁸ Follicles also may be surrounded by a myxoid stroma.² In contrast, trichodiscoma is characterized by connective tissue with mature sebaceous lobules in the periphery. It has a myxoid stroma, as opposed to the more fibrous stroma seen in fibrofolliculomas.

Ackerman et al¹ considered both fibrofolliculomas and trichodiscomas to be hamartomas of the epithelial hair follicle. The exact etiology of each of these hamartomas is unknown, but the undifferentiated epithelial strands protruding from the hair follicle in a fibrofolliculoma lie in close proximity to sebaceous glands. Furthermore, the authors postulated that fibrofolliculomas and trichodiscomas constitute a spectrum that encompasses the differentiation process of a mantleoma, with fibrofolliculoma representing the beginning of mantleoma differentiation and trichodiscoma representing the end. This end stage of follicular differentiation is one in which there is a predominant stroma and the previously undifferentiated epithelium has formed into sebaceous ducts and lobules in the stroma.¹

Most cases of fibrofolliculoma and/or trichodiscoma arise in areas of dense sebaceous follicle concentration (eg, face), further supporting the hypothesis that sebaceous gland proliferation contributes to fibrofolliculoma.¹⁴ The case described here, with the fibrofolliculoma arising on the abdomen in conjunction with a trichodiscoma, is therefore worth noting because its location differs from what has been observed in previously reported cases.⁴

There are both surgical and medical options for treatment of fibrofolliculoma. Although surgical excision is an option for a single lesion, patients with multiple fibrofolliculomas or BHD may prefer removal with the combined CO₂ laser and erbium-doped YAG laser.¹⁵

Conclusion

We present a rare case of concomitant fibrofolliculoma and trichodiscoma arising on the unusual location of the abdomen. This report highlights the histopathologic features of multiple adnexal tumors and emphasizes the importance of biopsy for differentiating fibrofolliculoma and trichodiscoma.

Fibrofolliculomas and trichodiscomas typically present on the head or neck as smooth, flesh-colored, dome-shaped papules. These two entities are considered to constitute two separate time points on a spectrum of histopathologic changes in mantleoma differentiation.¹ Histologically, both are benign hamartomas of the pilosebaceous subunit and collectively are known as mantleomas. We present an unusual case of a concomitant fibrofolliculoma and trichodiscoma on the abdomen.

Case Report

An asymptomatic 54-year-old man presented for a routine full-body skin examination. A solitary, 2×1-cm, subcutaneous, doughy, mobile nodule was found on the left side of the abdomen with an overlying 2-mm yellow fleshy papule. The patient declined excision of the lesion, and it was recommended that he return for follow-up 3 months later.

The patient did not present for follow-up until 4.5 years later, at which point the lesion had grown to 3.0×2.5 cm in size. An excision was performed, at which time the lesion was noted to be cystic, extruding an oily, yellow-white liquid. Bacterial culture was negative. Histopathologic sections showed a dome-shaped papule with connection to the overlying epidermis. Epithelial extensions from the infundibular epithelium formed a fenestrated pattern surrounding a fibrous and mucinous stroma (Figure, A and B). The differential diagnosis at this time included an epidermal inclusion cyst, fibroma, intradermal nevus, verruca, hemangioma, angiofibroma, and lipoma.^2-4

The same lesion cut in a different plane of sectioning showed an expansile dermal nodule comprising clusters of sebaceous lobules surrounding a fibrous and mucinous stroma. Within the second lesion, fibrous and stromal components predominated over epithelial components (Figure, C). A diagnosis of fibrofolliculoma showing features of a trichodiscoma arising in the unusual location of the abdomen was made.

Comment

Solitary fibrofolliculomas and trichodiscomas are flesh-colored, dome-shaped papules that generally present on the face, specifically on the chin, nose, cheeks, ears, and eyebrows without considerable symptoms.^2,4,5 Clinically, fibrofolliculomas are indistinguishable from trichodiscomas but demonstrate different features on biopsy.^1,5

Fibrofolliculomas and trichodiscomas are well known for their association with Birt-Hogg-Dubé (BHD) syndrome when they present concomitantly and typically arise earlier in the third decade of life than solitary fibrofolliculomas; however, there have been reports of solitary fibrofolliculomas in patients aged 1 to 36 years.^4,6 The triad of BHD syndrome consists of multiple fibrofolliculomas, trichodiscomas, and acrochordons, and it is acquired in an autosomal-dominant manner, unlike solitary fibrofolliculomas, which typically are not inherited. Birt-Hogg-Dubé syndrome is caused by a mutation in the FLCN gene that codes for the tumor-suppressor protein folliculin, which when mutated can cause unregulated proliferation of cells.⁷ Solitary fibrofolliculomas and the multiple fibrofolliculomas seen in BHD syndrome are histologically similar.

Fibrofolliculoma can be clinically indistinguishable from fibroepithelioma of Pinkus, perifollicular fibroma, trichilemmoma, trichodiscoma, trichoepithelioma, and trichofolliculoma. All typically present clinically as flesh-colored papules,¹ although histologic distinction can be made (Table).^5,8-13

Fibrofolliculoma is a benign hamartoma that arises from the pilosebaceous follicle and consists of an expansion of the fibrous root sheath, which typically surrounds the hair follicle along with proliferating bands or ribbons of perifollicular connective tissue. As such, the hair follicle may be dilated and filled with keratin in the expanded infundibulum.⁸ Follicles also may be surrounded by a myxoid stroma.² In contrast, trichodiscoma is characterized by connective tissue with mature sebaceous lobules in the periphery. It has a myxoid stroma, as opposed to the more fibrous stroma seen in fibrofolliculomas.

Ackerman et al¹ considered both fibrofolliculomas and trichodiscomas to be hamartomas of the epithelial hair follicle. The exact etiology of each of these hamartomas is unknown, but the undifferentiated epithelial strands protruding from the hair follicle in a fibrofolliculoma lie in close proximity to sebaceous glands. Furthermore, the authors postulated that fibrofolliculomas and trichodiscomas constitute a spectrum that encompasses the differentiation process of a mantleoma, with fibrofolliculoma representing the beginning of mantleoma differentiation and trichodiscoma representing the end. This end stage of follicular differentiation is one in which there is a predominant stroma and the previously undifferentiated epithelium has formed into sebaceous ducts and lobules in the stroma.¹

Most cases of fibrofolliculoma and/or trichodiscoma arise in areas of dense sebaceous follicle concentration (eg, face), further supporting the hypothesis that sebaceous gland proliferation contributes to fibrofolliculoma.¹⁴ The case described here, with the fibrofolliculoma arising on the abdomen in conjunction with a trichodiscoma, is therefore worth noting because its location differs from what has been observed in previously reported cases.⁴

There are both surgical and medical options for treatment of fibrofolliculoma. Although surgical excision is an option for a single lesion, patients with multiple fibrofolliculomas or BHD may prefer removal with the combined CO₂ laser and erbium-doped YAG laser.¹⁵

Conclusion

We present a rare case of concomitant fibrofolliculoma and trichodiscoma arising on the unusual location of the abdomen. This report highlights the histopathologic features of multiple adnexal tumors and emphasizes the importance of biopsy for differentiating fibrofolliculoma and trichodiscoma.

The Diagnosis: Cutaneous Macroglobulinosis

Waldenström macroglobulinemia is a lymphoplasmacytic lymphoma that produces a circulating monoclonal IgM. Incidence in the United States is 1500 patients annually, most commonly men in their 70s.¹ The disease process is largely indolent, with early symptoms consisting of generalized weakness, weight loss, and fatigue. Signs of lymphadenopathy, hepatosplenomegaly, and cytopenia may emerge as the disease progresses. Diagnostic criteria include bone marrow biopsy with plasmacytoid/plasmacellular infiltrate; IgM monoclonal gammopathy; and end-organ damage, which may include cutaneous manifestations.²

Cutaneous findings in Waldenström macroglobulinemia are nonspecific and secondary to the disease's hematologic manifestations, presenting as livedo reticularis, purpura, and mucosal bleeding.³ True cutaneous involvement of the disease is rare and was first described in 1978 by Tichenor.⁴ Specific cutaneous lesions have 2 separate clinical presentations: (1) a primary cutaneous infiltrate of lymphoplasmacytic cells, and (2) deposition of IgM in the dermis.⁵ Although the primary infiltrate of neoplastic cells appears as erythematous firm papules or plaques on the face and trunk, similar to other manifestations of leukemia cutis, deposition of IgM presents as translucent papules and plaques and is located more distally, particularly on the extensor extremities.6 These depositional plaques are not pruritic but may be tender if located over sites of pressure, as seen with the plantar presentation in our patient.

Histologically, cutaneous macroglobulinosis demonstrates IgM deposition in perieccrine, perivascular, or intravascular tissue that is periodic acid-Schiff (PAS) positive.⁷ Staining with Congo red and Alcian blue is negative. In our case, biopsy showed a nodular deposition of hypocellular globular material that stained brightly with PAS and PAS diastase. With Masson trichome stain, intensity of staining diminished, suggesting that the deposition was not composed of collagen; rather, this deposition appeared to consist of IgM storage papules on immunohistochemistry (Figure 1). Further workup revealed borderline pancytopenia and elevated globulins with a monoclonal peak on serum protein electrophoresis, confirming the diagnosis of cutaneous macroglobulinosis secondary to Waldenström macroglobulinemia.

A PubMed search of articles indexed for MEDLINE using the terms cutaneous, macroglobulinosis, macroglobulinemia, Waldenström's macroglobulinemia, Waldenström's macroglobulinaemia, and macroglobulinemia cutis revealed a total of 19 cases of cutaneous macroglobulinosis (including this case). The average age of presentation in these cases is 60 years (range, 29-83 years) with a predisposition for men (68% [13/19]). The development of cutaneous macroglobulinosis primarily has been noted following diagnosis of Waldenström macroglobulinemia (53% [10/19]), with some cases prior to diagnosis (37% [7/19]) or at the time of diagnosis (11% [2/19]). The presence of cutaneous lesions does not correlate with prognosis of the underlying malignancy.^5,8,9

Systemic treatment of the underlying macroglobulinemia has been suggested for symptomatic cases of cutaneous macroglobulinosis.³ Prior therapy has consisted primarily of chlorambucil; however, treatment with rituximab, occasionally in conjunction with the proteasome inhibitor bortezomib, recently has been reported.¹⁰ Because of the symptomatic nature of our patient's lesions, she was referred to the oncology department and started on rituximab therapy. The lesions improved with therapy and have remained stable following treatment.

The differential diagnosis for tender pink papules and plaques on the arms and legs includes tophaceous gout, plantar fibromatosis, erythropoietic protoporphyria, and acral fibrokeratoma.

Gouty tophi commonly accumulate as painful, edematous, yellow to whitish nodules and tumors with erythema, often overlying joints or extensor surfaces. Histopathologic examination after formalin fixation shows needle-shaped clefts within feathery amorphous pink areas surrounded by granuloma (Figure 2).¹¹ Yellow, needle-shaped, negatively birefringent crystals can be viewed under polarized microscopy in alcohol-fixed samples.

Plantar fibromatosis (Ledderhose disease) is a benign proliferation of the plantar aponeurosis linked to alcohol use; liver disease; and notably epilepsy,¹² a component of our patient's medical history. Large nodules appear grossly on the plantar feet and may progress to contractures in more advanced lesions. Biopsy reveals bland hyperproliferation of fibroblasts in a background of fascial fibrous tissue (Figure 3).¹² Clinically, this diagnosis is part of the differential diagnosis of plantar nodules but appears histologically different than cutaneous macroglobulinosis because there are no hyaline deposits in plantar fibromatosis.

Erythropoietic protoporphyria is a rare disorder that primarily arises due to a congenital deficiency in the ferrochelatase enzyme involved in heme biosynthesis. Erythropoietic protoporphyria is the most common porphyria among children and typically presents in infancy or early childhood as a painful photosensitivity with ensuing cutaneous manifestations and possible hepatobiliary disease. Edema and severe burning pain can be noted within minutes of sun exposure in a dose-response relationship.13 Histologic findings of erythropoietic protoporphyria differ based on acute or chronic skin changes. Acute lesions exhibit a predominantly neutrophilic interstitial dermal infiltrate with vacuoles and intercellular edema. Chronic changes include the accumulation of a PAS-positive, amorphous, hyalinelike substance, similar to the microscopic findings of cutaneous macroglobulinosis (Figure 4).¹³

An acral fibrokeratoma is a benign fibroepithelial tumor that clinically appears as a flesh-colored or slightly erythematous exophytic nodule that most commonly is found on the fingers or toes. Thought to arise from trauma to the affected area, it is histologically characterized by interwoven collagenous bundles with overlying epidermal hyperkeratosis, acanthosis, and deep thickened rete ridges¹⁴ (Figure 5). Although multiple acral fibrokeratomas have been reported (similar to presentations of prurigo nodularis),15 they more commonly appear as solitary lesions as opposed to the numerous translucent papules seen in our patient.

The Diagnosis: Cutaneous Macroglobulinosis

Waldenström macroglobulinemia is a lymphoplasmacytic lymphoma that produces a circulating monoclonal IgM. Incidence in the United States is 1500 patients annually, most commonly men in their 70s.¹ The disease process is largely indolent, with early symptoms consisting of generalized weakness, weight loss, and fatigue. Signs of lymphadenopathy, hepatosplenomegaly, and cytopenia may emerge as the disease progresses. Diagnostic criteria include bone marrow biopsy with plasmacytoid/plasmacellular infiltrate; IgM monoclonal gammopathy; and end-organ damage, which may include cutaneous manifestations.²

Cutaneous findings in Waldenström macroglobulinemia are nonspecific and secondary to the disease's hematologic manifestations, presenting as livedo reticularis, purpura, and mucosal bleeding.³ True cutaneous involvement of the disease is rare and was first described in 1978 by Tichenor.⁴ Specific cutaneous lesions have 2 separate clinical presentations: (1) a primary cutaneous infiltrate of lymphoplasmacytic cells, and (2) deposition of IgM in the dermis.⁵ Although the primary infiltrate of neoplastic cells appears as erythematous firm papules or plaques on the face and trunk, similar to other manifestations of leukemia cutis, deposition of IgM presents as translucent papules and plaques and is located more distally, particularly on the extensor extremities.6 These depositional plaques are not pruritic but may be tender if located over sites of pressure, as seen with the plantar presentation in our patient.

Histologically, cutaneous macroglobulinosis demonstrates IgM deposition in perieccrine, perivascular, or intravascular tissue that is periodic acid-Schiff (PAS) positive.⁷ Staining with Congo red and Alcian blue is negative. In our case, biopsy showed a nodular deposition of hypocellular globular material that stained brightly with PAS and PAS diastase. With Masson trichome stain, intensity of staining diminished, suggesting that the deposition was not composed of collagen; rather, this deposition appeared to consist of IgM storage papules on immunohistochemistry (Figure 1). Further workup revealed borderline pancytopenia and elevated globulins with a monoclonal peak on serum protein electrophoresis, confirming the diagnosis of cutaneous macroglobulinosis secondary to Waldenström macroglobulinemia.

A PubMed search of articles indexed for MEDLINE using the terms cutaneous, macroglobulinosis, macroglobulinemia, Waldenström's macroglobulinemia, Waldenström's macroglobulinaemia, and macroglobulinemia cutis revealed a total of 19 cases of cutaneous macroglobulinosis (including this case). The average age of presentation in these cases is 60 years (range, 29-83 years) with a predisposition for men (68% [13/19]). The development of cutaneous macroglobulinosis primarily has been noted following diagnosis of Waldenström macroglobulinemia (53% [10/19]), with some cases prior to diagnosis (37% [7/19]) or at the time of diagnosis (11% [2/19]). The presence of cutaneous lesions does not correlate with prognosis of the underlying malignancy.^5,8,9

Systemic treatment of the underlying macroglobulinemia has been suggested for symptomatic cases of cutaneous macroglobulinosis.³ Prior therapy has consisted primarily of chlorambucil; however, treatment with rituximab, occasionally in conjunction with the proteasome inhibitor bortezomib, recently has been reported.¹⁰ Because of the symptomatic nature of our patient's lesions, she was referred to the oncology department and started on rituximab therapy. The lesions improved with therapy and have remained stable following treatment.

The differential diagnosis for tender pink papules and plaques on the arms and legs includes tophaceous gout, plantar fibromatosis, erythropoietic protoporphyria, and acral fibrokeratoma.

Gouty tophi commonly accumulate as painful, edematous, yellow to whitish nodules and tumors with erythema, often overlying joints or extensor surfaces. Histopathologic examination after formalin fixation shows needle-shaped clefts within feathery amorphous pink areas surrounded by granuloma (Figure 2).¹¹ Yellow, needle-shaped, negatively birefringent crystals can be viewed under polarized microscopy in alcohol-fixed samples.

Plantar fibromatosis (Ledderhose disease) is a benign proliferation of the plantar aponeurosis linked to alcohol use; liver disease; and notably epilepsy,¹² a component of our patient's medical history. Large nodules appear grossly on the plantar feet and may progress to contractures in more advanced lesions. Biopsy reveals bland hyperproliferation of fibroblasts in a background of fascial fibrous tissue (Figure 3).¹² Clinically, this diagnosis is part of the differential diagnosis of plantar nodules but appears histologically different than cutaneous macroglobulinosis because there are no hyaline deposits in plantar fibromatosis.

Erythropoietic protoporphyria is a rare disorder that primarily arises due to a congenital deficiency in the ferrochelatase enzyme involved in heme biosynthesis. Erythropoietic protoporphyria is the most common porphyria among children and typically presents in infancy or early childhood as a painful photosensitivity with ensuing cutaneous manifestations and possible hepatobiliary disease. Edema and severe burning pain can be noted within minutes of sun exposure in a dose-response relationship.13 Histologic findings of erythropoietic protoporphyria differ based on acute or chronic skin changes. Acute lesions exhibit a predominantly neutrophilic interstitial dermal infiltrate with vacuoles and intercellular edema. Chronic changes include the accumulation of a PAS-positive, amorphous, hyalinelike substance, similar to the microscopic findings of cutaneous macroglobulinosis (Figure 4).¹³

An acral fibrokeratoma is a benign fibroepithelial tumor that clinically appears as a flesh-colored or slightly erythematous exophytic nodule that most commonly is found on the fingers or toes. Thought to arise from trauma to the affected area, it is histologically characterized by interwoven collagenous bundles with overlying epidermal hyperkeratosis, acanthosis, and deep thickened rete ridges¹⁴ (Figure 5). Although multiple acral fibrokeratomas have been reported (similar to presentations of prurigo nodularis),15 they more commonly appear as solitary lesions as opposed to the numerous translucent papules seen in our patient.

The Diagnosis: Cutaneous Macroglobulinosis

Waldenström macroglobulinemia is a lymphoplasmacytic lymphoma that produces a circulating monoclonal IgM. Incidence in the United States is 1500 patients annually, most commonly men in their 70s.¹ The disease process is largely indolent, with early symptoms consisting of generalized weakness, weight loss, and fatigue. Signs of lymphadenopathy, hepatosplenomegaly, and cytopenia may emerge as the disease progresses. Diagnostic criteria include bone marrow biopsy with plasmacytoid/plasmacellular infiltrate; IgM monoclonal gammopathy; and end-organ damage, which may include cutaneous manifestations.²

Cutaneous findings in Waldenström macroglobulinemia are nonspecific and secondary to the disease's hematologic manifestations, presenting as livedo reticularis, purpura, and mucosal bleeding.³ True cutaneous involvement of the disease is rare and was first described in 1978 by Tichenor.⁴ Specific cutaneous lesions have 2 separate clinical presentations: (1) a primary cutaneous infiltrate of lymphoplasmacytic cells, and (2) deposition of IgM in the dermis.⁵ Although the primary infiltrate of neoplastic cells appears as erythematous firm papules or plaques on the face and trunk, similar to other manifestations of leukemia cutis, deposition of IgM presents as translucent papules and plaques and is located more distally, particularly on the extensor extremities.6 These depositional plaques are not pruritic but may be tender if located over sites of pressure, as seen with the plantar presentation in our patient.

Histologically, cutaneous macroglobulinosis demonstrates IgM deposition in perieccrine, perivascular, or intravascular tissue that is periodic acid-Schiff (PAS) positive.⁷ Staining with Congo red and Alcian blue is negative. In our case, biopsy showed a nodular deposition of hypocellular globular material that stained brightly with PAS and PAS diastase. With Masson trichome stain, intensity of staining diminished, suggesting that the deposition was not composed of collagen; rather, this deposition appeared to consist of IgM storage papules on immunohistochemistry (Figure 1). Further workup revealed borderline pancytopenia and elevated globulins with a monoclonal peak on serum protein electrophoresis, confirming the diagnosis of cutaneous macroglobulinosis secondary to Waldenström macroglobulinemia.

A PubMed search of articles indexed for MEDLINE using the terms cutaneous, macroglobulinosis, macroglobulinemia, Waldenström's macroglobulinemia, Waldenström's macroglobulinaemia, and macroglobulinemia cutis revealed a total of 19 cases of cutaneous macroglobulinosis (including this case). The average age of presentation in these cases is 60 years (range, 29-83 years) with a predisposition for men (68% [13/19]). The development of cutaneous macroglobulinosis primarily has been noted following diagnosis of Waldenström macroglobulinemia (53% [10/19]), with some cases prior to diagnosis (37% [7/19]) or at the time of diagnosis (11% [2/19]). The presence of cutaneous lesions does not correlate with prognosis of the underlying malignancy.^5,8,9

Systemic treatment of the underlying macroglobulinemia has been suggested for symptomatic cases of cutaneous macroglobulinosis.³ Prior therapy has consisted primarily of chlorambucil; however, treatment with rituximab, occasionally in conjunction with the proteasome inhibitor bortezomib, recently has been reported.¹⁰ Because of the symptomatic nature of our patient's lesions, she was referred to the oncology department and started on rituximab therapy. The lesions improved with therapy and have remained stable following treatment.

The differential diagnosis for tender pink papules and plaques on the arms and legs includes tophaceous gout, plantar fibromatosis, erythropoietic protoporphyria, and acral fibrokeratoma.

Gouty tophi commonly accumulate as painful, edematous, yellow to whitish nodules and tumors with erythema, often overlying joints or extensor surfaces. Histopathologic examination after formalin fixation shows needle-shaped clefts within feathery amorphous pink areas surrounded by granuloma (Figure 2).¹¹ Yellow, needle-shaped, negatively birefringent crystals can be viewed under polarized microscopy in alcohol-fixed samples.

Plantar fibromatosis (Ledderhose disease) is a benign proliferation of the plantar aponeurosis linked to alcohol use; liver disease; and notably epilepsy,¹² a component of our patient's medical history. Large nodules appear grossly on the plantar feet and may progress to contractures in more advanced lesions. Biopsy reveals bland hyperproliferation of fibroblasts in a background of fascial fibrous tissue (Figure 3).¹² Clinically, this diagnosis is part of the differential diagnosis of plantar nodules but appears histologically different than cutaneous macroglobulinosis because there are no hyaline deposits in plantar fibromatosis.

Erythropoietic protoporphyria is a rare disorder that primarily arises due to a congenital deficiency in the ferrochelatase enzyme involved in heme biosynthesis. Erythropoietic protoporphyria is the most common porphyria among children and typically presents in infancy or early childhood as a painful photosensitivity with ensuing cutaneous manifestations and possible hepatobiliary disease. Edema and severe burning pain can be noted within minutes of sun exposure in a dose-response relationship.13 Histologic findings of erythropoietic protoporphyria differ based on acute or chronic skin changes. Acute lesions exhibit a predominantly neutrophilic interstitial dermal infiltrate with vacuoles and intercellular edema. Chronic changes include the accumulation of a PAS-positive, amorphous, hyalinelike substance, similar to the microscopic findings of cutaneous macroglobulinosis (Figure 4).¹³

An acral fibrokeratoma is a benign fibroepithelial tumor that clinically appears as a flesh-colored or slightly erythematous exophytic nodule that most commonly is found on the fingers or toes. Thought to arise from trauma to the affected area, it is histologically characterized by interwoven collagenous bundles with overlying epidermal hyperkeratosis, acanthosis, and deep thickened rete ridges¹⁴ (Figure 5). Although multiple acral fibrokeratomas have been reported (similar to presentations of prurigo nodularis),15 they more commonly appear as solitary lesions as opposed to the numerous translucent papules seen in our patient.

Cross-contamination of pathology specimens is a rare but nonnegligible source of potential morbidity in clinical practice. Contaminant tissue fragments, colloquially referred to as floaters, typically are readily identifiable based on obvious cytomorphologic differences, especially if the tissues arise from different organs; however, one cannot rely on such distinctions in a pathology laboratory dedicated to a single organ system (eg, dermatopathology). The inability to identify quickly and confidently the presence of a contaminant puts the patient at risk for misdiagnosis, which can lead to unnecessary morbidity or even mortality in the case of cancer misdiagnosis. Studies that have been conducted to estimate the incidence of this type of error have suggested an overall incidence rate between approximately 1% and 3%.^1,2 Awareness of this phenomenon and careful scrutiny when the histopathologic evidence diverges considerably from the clinical impression is critical for minimizing the negative outcomes that could result from the presence of contaminant tissue. We present a case in which cross-contamination of a pathology specimen led to an initial erroneous diagnosis of an aggressive cutaneous melanoma in a patient with a benign adnexal neoplasm.

Case Report

A 72-year-old man was referred to the Pigmented Lesion and Melanoma Program at Stanford University Medical Center and Cancer Institute (Palo Alto, California) for evaluation and treatment of a presumed stage IIB melanoma on the right preauricular cheek based on a shave biopsy that had been performed (<1 month prior) by his local dermatology provider and subsequently read by an affiliated out-of-state dermatopathology laboratory. Per the clinical history that was gathered at the current presentation, neither the patient nor his wife had noticed the lesion prior to his dermatology provider pointing it out on the day of the biopsy. Additionally, he denied associated pain, bleeding, or ulceration. According to outside medical records, the referring dermatology provider described the lesion as a 4-mm pink pearly papule with telangiectasia favoring a diagnosis of basal cell carcinoma, and a diagnostic shave biopsy was performed. On presentation to our clinic, physical examination of the right preauricular cheek revealed a 4×3-mm depressed erythematous scar with no evidence of residual pigmentation or nodularity (Figure 1). There was no clinically appreciable regional lymphadenopathy.

The original dermatopathology report indicated an invasive melanoma with the following pathologic characteristics: superficial spreading type, Breslow depth of at least 2.16 mm, ulceration, and a mitotic index of 8 mitotic figures/mm² with transection of the invasive component at the peripheral and deep margins. There was no evidence of regression, perineural invasion, lymphovascular invasion, or microsatellites. Interestingly, the report indicated that there also was a basaloid proliferation with features of cylindroma in the same pathology slide adjacent to the aggressive invasive melanoma that was described. Given the complexity of cases referred to our academic center, the standard of care includes internal dermatopathology review of all outside pathology specimens. This review proved critical to this patient’s care in light of the considerable divergence of the initial pathologic diagnosis and the reported clinical features of the lesion.

Internal review of the single pathology slide received from the referring provider showed a total of 4 sections, 3 of which are shown here (Figure 2A). Three sections, including the one not shown, were all consistent with a diagnosis of cylindroma and showed no evidence of a melanocytic proliferation (Figure 2B). However, the fourth section demonstrated marked morphologic dissimilarity compared to the other 3 sections. This outlier section showed a thick cutaneous melanoma with a Breslow depth of at least 2.1 mm, ulceration, a mitotic rate of 12 mitotic figures/mm², and broad transection of the invasive component at the peripheral and deep margins (Figures 2C and 2D). Correlation with the gross description of tissue processing on the original pathology report indicating that the specimen had been trisected raised suspicion that the fourth and very dissimilar section could be a contaminant from another source that was incorporated into our patient’s histologic sections during processing. Taken together, these discrepancies made the diagnosis of cylindroma alone far more likely than cutaneous melanoma, but we needed conclusive evidence given the dramatic difference in prognosis and management between a cylindroma and an aggressive cutaneous melanoma.

For further diagnostic clarification, we performed polymorphic short tandem repeat (STR) analysis, a well-described forensic pathology technique, to determine if the melanoma and cylindroma specimens derived from different patients, as we hypothesized. This analysis revealed differences in all but one DNA locus tested between the cylindroma specimen and the melanoma specimen, confirming our hypothesis (Figure 3). Subsequent discussion of the case with staff from the dermatopathology laboratory that processed this specimen provided further support for our suspicion that the invasive melanoma specimen was part of a case processed prior to our patient’s benign lesion. Therefore, the wide local excision for treatment of the suspected melanoma fortunately was canceled, and the patient did not require further treatment of the benign cylindroma. The patient expressed relief and gratitude for this critical clarification and change in management.

Comment

Shah et al³ reported a similar case in which a benign granuloma of the lung masqueraded as a squamous cell carcinoma due to histopathologic contamination. Although few similar cases have been described in the literature, the risk posed by such contamination is remarkable, regardless of whether it occurs during specimen grossing, embedding, sectioning, or staining.^1,4,5 This risk is amplified in facilities that process specimens originating predominantly from a single organ system or tissue type, as is often the case in dedicated dermatopathology laboratories. In this scenario, it is unlikely that one could use the presence of tissues from 2 different organ systems on a single slide as a way of easily recognizing the presence of a contaminant and rectifying the error. Additionally, the presence of malignant cells in the contaminant further complicates the problem and requires an investigation that can conclusively distinguish the contaminant from the patient’s actual tissue.

In our case, our dermatology and dermatopathology teams partnered with our molecular pathology team to find a solution. Polymorphic STR analysis via polymerase chain reaction amplification is a sensitive method employed commonly in forensic DNA laboratories for determining whether a sample submitted as evidence belongs to a given suspect.⁶ Although much more commonly used in forensics, STR analysis does have known roles in clinical medicine, such as chimerism testing after bone marrow or allogeneic stem cell transplantation.⁷ Given the relatively short period of time it takes along with the convenience of commercially available kits, a high discriminative ability, and well-validated interpretation procedures, STR analysis is an excellent method for determining if a given tissue sample came from a given patient, which is what was needed in our case.

The combined clinical, histopathologic, and molecular data in our case allowed for confident clarification of our patient’s diagnosis, sparing him the morbidity of wide local excision on the face, sentinel lymph node biopsy, and emotional distress associated with a diagnosis of aggressive cutaneous melanoma. Our case highlights the critical importance of internal review of pathology specimens in ensuring proper diagnosis and management and reminds us that, though rare, accidental contamination during processing of pathology specimens is a potential adverse event that must be considered, especially when a pathologic finding diverges considerably from what is anticipated based on the patient’s history and physical examination.

Acknowledgment
The authors express gratitude to the patient described herein who graciously provided permission for us to publish his case and clinical photography.

Cross-contamination of pathology specimens is a rare but nonnegligible source of potential morbidity in clinical practice. Contaminant tissue fragments, colloquially referred to as floaters, typically are readily identifiable based on obvious cytomorphologic differences, especially if the tissues arise from different organs; however, one cannot rely on such distinctions in a pathology laboratory dedicated to a single organ system (eg, dermatopathology). The inability to identify quickly and confidently the presence of a contaminant puts the patient at risk for misdiagnosis, which can lead to unnecessary morbidity or even mortality in the case of cancer misdiagnosis. Studies that have been conducted to estimate the incidence of this type of error have suggested an overall incidence rate between approximately 1% and 3%.^1,2 Awareness of this phenomenon and careful scrutiny when the histopathologic evidence diverges considerably from the clinical impression is critical for minimizing the negative outcomes that could result from the presence of contaminant tissue. We present a case in which cross-contamination of a pathology specimen led to an initial erroneous diagnosis of an aggressive cutaneous melanoma in a patient with a benign adnexal neoplasm.

Case Report

A 72-year-old man was referred to the Pigmented Lesion and Melanoma Program at Stanford University Medical Center and Cancer Institute (Palo Alto, California) for evaluation and treatment of a presumed stage IIB melanoma on the right preauricular cheek based on a shave biopsy that had been performed (<1 month prior) by his local dermatology provider and subsequently read by an affiliated out-of-state dermatopathology laboratory. Per the clinical history that was gathered at the current presentation, neither the patient nor his wife had noticed the lesion prior to his dermatology provider pointing it out on the day of the biopsy. Additionally, he denied associated pain, bleeding, or ulceration. According to outside medical records, the referring dermatology provider described the lesion as a 4-mm pink pearly papule with telangiectasia favoring a diagnosis of basal cell carcinoma, and a diagnostic shave biopsy was performed. On presentation to our clinic, physical examination of the right preauricular cheek revealed a 4×3-mm depressed erythematous scar with no evidence of residual pigmentation or nodularity (Figure 1). There was no clinically appreciable regional lymphadenopathy.

The original dermatopathology report indicated an invasive melanoma with the following pathologic characteristics: superficial spreading type, Breslow depth of at least 2.16 mm, ulceration, and a mitotic index of 8 mitotic figures/mm² with transection of the invasive component at the peripheral and deep margins. There was no evidence of regression, perineural invasion, lymphovascular invasion, or microsatellites. Interestingly, the report indicated that there also was a basaloid proliferation with features of cylindroma in the same pathology slide adjacent to the aggressive invasive melanoma that was described. Given the complexity of cases referred to our academic center, the standard of care includes internal dermatopathology review of all outside pathology specimens. This review proved critical to this patient’s care in light of the considerable divergence of the initial pathologic diagnosis and the reported clinical features of the lesion.

Internal review of the single pathology slide received from the referring provider showed a total of 4 sections, 3 of which are shown here (Figure 2A). Three sections, including the one not shown, were all consistent with a diagnosis of cylindroma and showed no evidence of a melanocytic proliferation (Figure 2B). However, the fourth section demonstrated marked morphologic dissimilarity compared to the other 3 sections. This outlier section showed a thick cutaneous melanoma with a Breslow depth of at least 2.1 mm, ulceration, a mitotic rate of 12 mitotic figures/mm², and broad transection of the invasive component at the peripheral and deep margins (Figures 2C and 2D). Correlation with the gross description of tissue processing on the original pathology report indicating that the specimen had been trisected raised suspicion that the fourth and very dissimilar section could be a contaminant from another source that was incorporated into our patient’s histologic sections during processing. Taken together, these discrepancies made the diagnosis of cylindroma alone far more likely than cutaneous melanoma, but we needed conclusive evidence given the dramatic difference in prognosis and management between a cylindroma and an aggressive cutaneous melanoma.

For further diagnostic clarification, we performed polymorphic short tandem repeat (STR) analysis, a well-described forensic pathology technique, to determine if the melanoma and cylindroma specimens derived from different patients, as we hypothesized. This analysis revealed differences in all but one DNA locus tested between the cylindroma specimen and the melanoma specimen, confirming our hypothesis (Figure 3). Subsequent discussion of the case with staff from the dermatopathology laboratory that processed this specimen provided further support for our suspicion that the invasive melanoma specimen was part of a case processed prior to our patient’s benign lesion. Therefore, the wide local excision for treatment of the suspected melanoma fortunately was canceled, and the patient did not require further treatment of the benign cylindroma. The patient expressed relief and gratitude for this critical clarification and change in management.

Comment

Shah et al³ reported a similar case in which a benign granuloma of the lung masqueraded as a squamous cell carcinoma due to histopathologic contamination. Although few similar cases have been described in the literature, the risk posed by such contamination is remarkable, regardless of whether it occurs during specimen grossing, embedding, sectioning, or staining.^1,4,5 This risk is amplified in facilities that process specimens originating predominantly from a single organ system or tissue type, as is often the case in dedicated dermatopathology laboratories. In this scenario, it is unlikely that one could use the presence of tissues from 2 different organ systems on a single slide as a way of easily recognizing the presence of a contaminant and rectifying the error. Additionally, the presence of malignant cells in the contaminant further complicates the problem and requires an investigation that can conclusively distinguish the contaminant from the patient’s actual tissue.

In our case, our dermatology and dermatopathology teams partnered with our molecular pathology team to find a solution. Polymorphic STR analysis via polymerase chain reaction amplification is a sensitive method employed commonly in forensic DNA laboratories for determining whether a sample submitted as evidence belongs to a given suspect.⁶ Although much more commonly used in forensics, STR analysis does have known roles in clinical medicine, such as chimerism testing after bone marrow or allogeneic stem cell transplantation.⁷ Given the relatively short period of time it takes along with the convenience of commercially available kits, a high discriminative ability, and well-validated interpretation procedures, STR analysis is an excellent method for determining if a given tissue sample came from a given patient, which is what was needed in our case.

The combined clinical, histopathologic, and molecular data in our case allowed for confident clarification of our patient’s diagnosis, sparing him the morbidity of wide local excision on the face, sentinel lymph node biopsy, and emotional distress associated with a diagnosis of aggressive cutaneous melanoma. Our case highlights the critical importance of internal review of pathology specimens in ensuring proper diagnosis and management and reminds us that, though rare, accidental contamination during processing of pathology specimens is a potential adverse event that must be considered, especially when a pathologic finding diverges considerably from what is anticipated based on the patient’s history and physical examination.

Acknowledgment
The authors express gratitude to the patient described herein who graciously provided permission for us to publish his case and clinical photography.

Cross-contamination of pathology specimens is a rare but nonnegligible source of potential morbidity in clinical practice. Contaminant tissue fragments, colloquially referred to as floaters, typically are readily identifiable based on obvious cytomorphologic differences, especially if the tissues arise from different organs; however, one cannot rely on such distinctions in a pathology laboratory dedicated to a single organ system (eg, dermatopathology). The inability to identify quickly and confidently the presence of a contaminant puts the patient at risk for misdiagnosis, which can lead to unnecessary morbidity or even mortality in the case of cancer misdiagnosis. Studies that have been conducted to estimate the incidence of this type of error have suggested an overall incidence rate between approximately 1% and 3%.^1,2 Awareness of this phenomenon and careful scrutiny when the histopathologic evidence diverges considerably from the clinical impression is critical for minimizing the negative outcomes that could result from the presence of contaminant tissue. We present a case in which cross-contamination of a pathology specimen led to an initial erroneous diagnosis of an aggressive cutaneous melanoma in a patient with a benign adnexal neoplasm.

Case Report

A 72-year-old man was referred to the Pigmented Lesion and Melanoma Program at Stanford University Medical Center and Cancer Institute (Palo Alto, California) for evaluation and treatment of a presumed stage IIB melanoma on the right preauricular cheek based on a shave biopsy that had been performed (<1 month prior) by his local dermatology provider and subsequently read by an affiliated out-of-state dermatopathology laboratory. Per the clinical history that was gathered at the current presentation, neither the patient nor his wife had noticed the lesion prior to his dermatology provider pointing it out on the day of the biopsy. Additionally, he denied associated pain, bleeding, or ulceration. According to outside medical records, the referring dermatology provider described the lesion as a 4-mm pink pearly papule with telangiectasia favoring a diagnosis of basal cell carcinoma, and a diagnostic shave biopsy was performed. On presentation to our clinic, physical examination of the right preauricular cheek revealed a 4×3-mm depressed erythematous scar with no evidence of residual pigmentation or nodularity (Figure 1). There was no clinically appreciable regional lymphadenopathy.

The original dermatopathology report indicated an invasive melanoma with the following pathologic characteristics: superficial spreading type, Breslow depth of at least 2.16 mm, ulceration, and a mitotic index of 8 mitotic figures/mm² with transection of the invasive component at the peripheral and deep margins. There was no evidence of regression, perineural invasion, lymphovascular invasion, or microsatellites. Interestingly, the report indicated that there also was a basaloid proliferation with features of cylindroma in the same pathology slide adjacent to the aggressive invasive melanoma that was described. Given the complexity of cases referred to our academic center, the standard of care includes internal dermatopathology review of all outside pathology specimens. This review proved critical to this patient’s care in light of the considerable divergence of the initial pathologic diagnosis and the reported clinical features of the lesion.

Internal review of the single pathology slide received from the referring provider showed a total of 4 sections, 3 of which are shown here (Figure 2A). Three sections, including the one not shown, were all consistent with a diagnosis of cylindroma and showed no evidence of a melanocytic proliferation (Figure 2B). However, the fourth section demonstrated marked morphologic dissimilarity compared to the other 3 sections. This outlier section showed a thick cutaneous melanoma with a Breslow depth of at least 2.1 mm, ulceration, a mitotic rate of 12 mitotic figures/mm², and broad transection of the invasive component at the peripheral and deep margins (Figures 2C and 2D). Correlation with the gross description of tissue processing on the original pathology report indicating that the specimen had been trisected raised suspicion that the fourth and very dissimilar section could be a contaminant from another source that was incorporated into our patient’s histologic sections during processing. Taken together, these discrepancies made the diagnosis of cylindroma alone far more likely than cutaneous melanoma, but we needed conclusive evidence given the dramatic difference in prognosis and management between a cylindroma and an aggressive cutaneous melanoma.

For further diagnostic clarification, we performed polymorphic short tandem repeat (STR) analysis, a well-described forensic pathology technique, to determine if the melanoma and cylindroma specimens derived from different patients, as we hypothesized. This analysis revealed differences in all but one DNA locus tested between the cylindroma specimen and the melanoma specimen, confirming our hypothesis (Figure 3). Subsequent discussion of the case with staff from the dermatopathology laboratory that processed this specimen provided further support for our suspicion that the invasive melanoma specimen was part of a case processed prior to our patient’s benign lesion. Therefore, the wide local excision for treatment of the suspected melanoma fortunately was canceled, and the patient did not require further treatment of the benign cylindroma. The patient expressed relief and gratitude for this critical clarification and change in management.

Comment

Shah et al³ reported a similar case in which a benign granuloma of the lung masqueraded as a squamous cell carcinoma due to histopathologic contamination. Although few similar cases have been described in the literature, the risk posed by such contamination is remarkable, regardless of whether it occurs during specimen grossing, embedding, sectioning, or staining.^1,4,5 This risk is amplified in facilities that process specimens originating predominantly from a single organ system or tissue type, as is often the case in dedicated dermatopathology laboratories. In this scenario, it is unlikely that one could use the presence of tissues from 2 different organ systems on a single slide as a way of easily recognizing the presence of a contaminant and rectifying the error. Additionally, the presence of malignant cells in the contaminant further complicates the problem and requires an investigation that can conclusively distinguish the contaminant from the patient’s actual tissue.

In our case, our dermatology and dermatopathology teams partnered with our molecular pathology team to find a solution. Polymorphic STR analysis via polymerase chain reaction amplification is a sensitive method employed commonly in forensic DNA laboratories for determining whether a sample submitted as evidence belongs to a given suspect.⁶ Although much more commonly used in forensics, STR analysis does have known roles in clinical medicine, such as chimerism testing after bone marrow or allogeneic stem cell transplantation.⁷ Given the relatively short period of time it takes along with the convenience of commercially available kits, a high discriminative ability, and well-validated interpretation procedures, STR analysis is an excellent method for determining if a given tissue sample came from a given patient, which is what was needed in our case.

The combined clinical, histopathologic, and molecular data in our case allowed for confident clarification of our patient’s diagnosis, sparing him the morbidity of wide local excision on the face, sentinel lymph node biopsy, and emotional distress associated with a diagnosis of aggressive cutaneous melanoma. Our case highlights the critical importance of internal review of pathology specimens in ensuring proper diagnosis and management and reminds us that, though rare, accidental contamination during processing of pathology specimens is a potential adverse event that must be considered, especially when a pathologic finding diverges considerably from what is anticipated based on the patient’s history and physical examination.

Acknowledgment
The authors express gratitude to the patient described herein who graciously provided permission for us to publish his case and clinical photography.

The Diagnosis: Pemphigus Vegetans

A punch biopsy was taken from the verrucous plaque, and microscopic examination demonstrated prominent epidermal hyperplasia with intraepidermal eosinophilic microabscesses and a superficial dermatitis with abundant eosinophils (Figure 1A). Suprabasal acantholytic cleft formation was noted in a focal area (Figure 1B). Another punch biopsy was performed from the perilesional skin for direct immunofluorescence examination, which revealed intercellular deposits of IgG and C3 throughout the lower half of the epidermis (Figure 1C). Indirect immunofluorescence performed on monkey esophagus substrate showed circulating intercellular IgG antibodies in all the titers of up to 1/160 and an elevated level of IgG antidesmoglein 3 (anti-Dsg3) antibody (enzyme-linked immunosorbent assay index value, >200 RU/mL [reference range, <20 RU/mL]).

Because there was a solitary lesion, the decision was made to perform local treatment. One intralesional triamcinolone acetonide injection (20 mg/mL) resulted in remarkable flattening of the lesion (Figure 2). Subsequently, treatment was continued with clobetasol propionate ointment 3 times weekly for 1 month. During a follow-up period of 2 years, no signs of local relapse or new lesions elsewhere were noted, and the patient continued to be on long-term longitudinal evaluation.

Pemphigus vegetans (PV) is an uncommon variant of pemphigus, typically manifesting with vegetating erosions and plaques localized to the intertriginous areas of the body. Local factors such as semiocclusion, maceration, and/or bacterial or fungal colonization have been hypothesized to account for the distinctive localization and vegetation of the lesions.^1,2 Traditionally, 2 clinical subtypes of PV have been described: (1) Hallopeau type presenting with pustules that later evolve into vegetating plaques, and (2) Neumann type that initially manifests as vesicles and bullae with a more disseminated distribution, transforming into hypertrophic masses with erosions.^1-5 However, this distinction may not always be clear, and patients with features of both forms have been reported.^2,5

At present, our case would best be regarded as a localized form of PV presenting with a solitary lesion. It may progress to more disseminated disease or remain localized during its course; the literature contains reports exemplifying both possibilities. In a large retrospective study from Tunisia encompassing almost 3 decades, the majority of the patients initially presented with unifocal involvement; however, the disease eventually became multifocal in almost all patients during the study period, emphasizing the need for long-term follow-up.² There also are reports of PV confined to a single anatomic site, such as the scalp, sole, or vulva, that remained localized for years.^2,4,6,7 Involvement of the oral mucosa is an important finding of PV and the presenting concern in approximately three-quarters of patients.² Interestingly, the oral mucosa was not involved in our patient despite the high titer of anti-Dsg3 antibody, which suggests the need for the presence of other factors for clinical expression of the disease.

Although PV is considered a vegetating clinicomorphologic variant of pemphigus vulgaris, PV is histopathologically distinguished from pemphigus vulgaris by the presence of epidermal hyperplasia and intraepidermal eosinophilic microabscesses. Importantly, the epidermis displays signs of exuberant proliferation such as pseudoepitheliomatous hyperplasia and/or papillomatosis of a varying degree.^1,2,5 Of note, suprabasal acantholysis is usually overshadowed by the changes in PV and presents only focally, as in our patient. The most common autoantibody profile is IgG targeting Dsg3; however, a spectrum of other autoantibodies has been identified, such as IgG antidesmocollin 3, IgA anti-Dsg3, and IgG anti-Dsg1.^8,9

The most important differential diagnosis of PV is pyodermatitis-pyostomatitis vegetans. These 2 entities share many clinical and histopathological features; however, direct immunofluorescence is helpfulfor differentiation because it generally is negative in pyodermatitis-pyostomatitis vegetans.^2,10 Furthermore, there is a well-established association between pyodermatitis-pyostomatitis vegetans and inflammatory bowel disorders, whereas PV has anecdotally been linked to malignancy, human immunodeficiency virus infection, and heroin abuse.^1,2,10 Our patient was seronegative for human immunodeficiency virus and denied weight loss or loss of appetite. For those cases of PV involving a single anatomic site, the differential diagnosis is broader and encompasses dermatoses such as verrucae, syphilitic chancre, condylomata lata, granuloma inguinale, herpes simplex virus infection, and Kaposi sarcoma.

Treatment of PV is similar to pemphigus vulgaris and consists of a combination of systemic corticosteroids and steroid-sparing agents.^1,5 On the other hand, more limited presentations of PV may be suitable for intralesional treatment with triamcinolone acetonide, thus avoiding potential adverse effects of systemic therapy.^1,2 In our case with localized involvement, a favorable response was obtained with intralesional triamcinolone acetonide, and we plan to utilize systemic corticosteroids if the disease becomes generalized during follow-up.

The Diagnosis: Pemphigus Vegetans

A punch biopsy was taken from the verrucous plaque, and microscopic examination demonstrated prominent epidermal hyperplasia with intraepidermal eosinophilic microabscesses and a superficial dermatitis with abundant eosinophils (Figure 1A). Suprabasal acantholytic cleft formation was noted in a focal area (Figure 1B). Another punch biopsy was performed from the perilesional skin for direct immunofluorescence examination, which revealed intercellular deposits of IgG and C3 throughout the lower half of the epidermis (Figure 1C). Indirect immunofluorescence performed on monkey esophagus substrate showed circulating intercellular IgG antibodies in all the titers of up to 1/160 and an elevated level of IgG antidesmoglein 3 (anti-Dsg3) antibody (enzyme-linked immunosorbent assay index value, >200 RU/mL [reference range, <20 RU/mL]).

Because there was a solitary lesion, the decision was made to perform local treatment. One intralesional triamcinolone acetonide injection (20 mg/mL) resulted in remarkable flattening of the lesion (Figure 2). Subsequently, treatment was continued with clobetasol propionate ointment 3 times weekly for 1 month. During a follow-up period of 2 years, no signs of local relapse or new lesions elsewhere were noted, and the patient continued to be on long-term longitudinal evaluation.

Pemphigus vegetans (PV) is an uncommon variant of pemphigus, typically manifesting with vegetating erosions and plaques localized to the intertriginous areas of the body. Local factors such as semiocclusion, maceration, and/or bacterial or fungal colonization have been hypothesized to account for the distinctive localization and vegetation of the lesions.^1,2 Traditionally, 2 clinical subtypes of PV have been described: (1) Hallopeau type presenting with pustules that later evolve into vegetating plaques, and (2) Neumann type that initially manifests as vesicles and bullae with a more disseminated distribution, transforming into hypertrophic masses with erosions.^1-5 However, this distinction may not always be clear, and patients with features of both forms have been reported.^2,5

At present, our case would best be regarded as a localized form of PV presenting with a solitary lesion. It may progress to more disseminated disease or remain localized during its course; the literature contains reports exemplifying both possibilities. In a large retrospective study from Tunisia encompassing almost 3 decades, the majority of the patients initially presented with unifocal involvement; however, the disease eventually became multifocal in almost all patients during the study period, emphasizing the need for long-term follow-up.² There also are reports of PV confined to a single anatomic site, such as the scalp, sole, or vulva, that remained localized for years.^2,4,6,7 Involvement of the oral mucosa is an important finding of PV and the presenting concern in approximately three-quarters of patients.² Interestingly, the oral mucosa was not involved in our patient despite the high titer of anti-Dsg3 antibody, which suggests the need for the presence of other factors for clinical expression of the disease.

Although PV is considered a vegetating clinicomorphologic variant of pemphigus vulgaris, PV is histopathologically distinguished from pemphigus vulgaris by the presence of epidermal hyperplasia and intraepidermal eosinophilic microabscesses. Importantly, the epidermis displays signs of exuberant proliferation such as pseudoepitheliomatous hyperplasia and/or papillomatosis of a varying degree.^1,2,5 Of note, suprabasal acantholysis is usually overshadowed by the changes in PV and presents only focally, as in our patient. The most common autoantibody profile is IgG targeting Dsg3; however, a spectrum of other autoantibodies has been identified, such as IgG antidesmocollin 3, IgA anti-Dsg3, and IgG anti-Dsg1.^8,9

The most important differential diagnosis of PV is pyodermatitis-pyostomatitis vegetans. These 2 entities share many clinical and histopathological features; however, direct immunofluorescence is helpfulfor differentiation because it generally is negative in pyodermatitis-pyostomatitis vegetans.^2,10 Furthermore, there is a well-established association between pyodermatitis-pyostomatitis vegetans and inflammatory bowel disorders, whereas PV has anecdotally been linked to malignancy, human immunodeficiency virus infection, and heroin abuse.^1,2,10 Our patient was seronegative for human immunodeficiency virus and denied weight loss or loss of appetite. For those cases of PV involving a single anatomic site, the differential diagnosis is broader and encompasses dermatoses such as verrucae, syphilitic chancre, condylomata lata, granuloma inguinale, herpes simplex virus infection, and Kaposi sarcoma.

Treatment of PV is similar to pemphigus vulgaris and consists of a combination of systemic corticosteroids and steroid-sparing agents.^1,5 On the other hand, more limited presentations of PV may be suitable for intralesional treatment with triamcinolone acetonide, thus avoiding potential adverse effects of systemic therapy.^1,2 In our case with localized involvement, a favorable response was obtained with intralesional triamcinolone acetonide, and we plan to utilize systemic corticosteroids if the disease becomes generalized during follow-up.

The Diagnosis: Pemphigus Vegetans

A punch biopsy was taken from the verrucous plaque, and microscopic examination demonstrated prominent epidermal hyperplasia with intraepidermal eosinophilic microabscesses and a superficial dermatitis with abundant eosinophils (Figure 1A). Suprabasal acantholytic cleft formation was noted in a focal area (Figure 1B). Another punch biopsy was performed from the perilesional skin for direct immunofluorescence examination, which revealed intercellular deposits of IgG and C3 throughout the lower half of the epidermis (Figure 1C). Indirect immunofluorescence performed on monkey esophagus substrate showed circulating intercellular IgG antibodies in all the titers of up to 1/160 and an elevated level of IgG antidesmoglein 3 (anti-Dsg3) antibody (enzyme-linked immunosorbent assay index value, >200 RU/mL [reference range, <20 RU/mL]).

Because there was a solitary lesion, the decision was made to perform local treatment. One intralesional triamcinolone acetonide injection (20 mg/mL) resulted in remarkable flattening of the lesion (Figure 2). Subsequently, treatment was continued with clobetasol propionate ointment 3 times weekly for 1 month. During a follow-up period of 2 years, no signs of local relapse or new lesions elsewhere were noted, and the patient continued to be on long-term longitudinal evaluation.

Pemphigus vegetans (PV) is an uncommon variant of pemphigus, typically manifesting with vegetating erosions and plaques localized to the intertriginous areas of the body. Local factors such as semiocclusion, maceration, and/or bacterial or fungal colonization have been hypothesized to account for the distinctive localization and vegetation of the lesions.^1,2 Traditionally, 2 clinical subtypes of PV have been described: (1) Hallopeau type presenting with pustules that later evolve into vegetating plaques, and (2) Neumann type that initially manifests as vesicles and bullae with a more disseminated distribution, transforming into hypertrophic masses with erosions.^1-5 However, this distinction may not always be clear, and patients with features of both forms have been reported.^2,5

At present, our case would best be regarded as a localized form of PV presenting with a solitary lesion. It may progress to more disseminated disease or remain localized during its course; the literature contains reports exemplifying both possibilities. In a large retrospective study from Tunisia encompassing almost 3 decades, the majority of the patients initially presented with unifocal involvement; however, the disease eventually became multifocal in almost all patients during the study period, emphasizing the need for long-term follow-up.² There also are reports of PV confined to a single anatomic site, such as the scalp, sole, or vulva, that remained localized for years.^2,4,6,7 Involvement of the oral mucosa is an important finding of PV and the presenting concern in approximately three-quarters of patients.² Interestingly, the oral mucosa was not involved in our patient despite the high titer of anti-Dsg3 antibody, which suggests the need for the presence of other factors for clinical expression of the disease.

Although PV is considered a vegetating clinicomorphologic variant of pemphigus vulgaris, PV is histopathologically distinguished from pemphigus vulgaris by the presence of epidermal hyperplasia and intraepidermal eosinophilic microabscesses. Importantly, the epidermis displays signs of exuberant proliferation such as pseudoepitheliomatous hyperplasia and/or papillomatosis of a varying degree.^1,2,5 Of note, suprabasal acantholysis is usually overshadowed by the changes in PV and presents only focally, as in our patient. The most common autoantibody profile is IgG targeting Dsg3; however, a spectrum of other autoantibodies has been identified, such as IgG antidesmocollin 3, IgA anti-Dsg3, and IgG anti-Dsg1.^8,9

The most important differential diagnosis of PV is pyodermatitis-pyostomatitis vegetans. These 2 entities share many clinical and histopathological features; however, direct immunofluorescence is helpfulfor differentiation because it generally is negative in pyodermatitis-pyostomatitis vegetans.^2,10 Furthermore, there is a well-established association between pyodermatitis-pyostomatitis vegetans and inflammatory bowel disorders, whereas PV has anecdotally been linked to malignancy, human immunodeficiency virus infection, and heroin abuse.^1,2,10 Our patient was seronegative for human immunodeficiency virus and denied weight loss or loss of appetite. For those cases of PV involving a single anatomic site, the differential diagnosis is broader and encompasses dermatoses such as verrucae, syphilitic chancre, condylomata lata, granuloma inguinale, herpes simplex virus infection, and Kaposi sarcoma.

Treatment of PV is similar to pemphigus vulgaris and consists of a combination of systemic corticosteroids and steroid-sparing agents.^1,5 On the other hand, more limited presentations of PV may be suitable for intralesional treatment with triamcinolone acetonide, thus avoiding potential adverse effects of systemic therapy.^1,2 In our case with localized involvement, a favorable response was obtained with intralesional triamcinolone acetonide, and we plan to utilize systemic corticosteroids if the disease becomes generalized during follow-up.

Case Report

A 57-year-old black woman with a history of dialysis-dependent end-stage renal disease, diabetes mellitus (DM), hypertension, diastolic congestive heart failure, and chronic bronchitis was admitted to Howard University Hospital (Washington, DC) for acute chest pain and shortness of breath. During her hospital stay the dermatology team was consulted for evaluation of two 1.6-cm teardrop-shaped, yellow-white-chalky plaques noted in the center of an atrophic, hyperpigmented, shiny, contracted split-thickness skin graft (STSG) on the right posterior forearm (Figure 1). Twenty years prior, the patient received STSGs on the right and left forearm secondary to caustic burns. Two months before the current admission she noticed 2 adjacent teardrop-shaped white plaques within the center of the STSG on the right forearm. At a 3-month follow-up, she had developed more lesions within both graft sites of the bilateral forearm. There was no notable pruritus associated with the lesions.

A 4-mm punch biopsy showed an orthokeratotic plug with basophilic inflammatory debris adjacent to acanthotic epidermis, necrotic basophilic debris at the superficial dermis with epidermal canals extending from the base of the lesion superiorly, and transepidermal elimination of elastic fibers (Figure 2A). A Verhoeff-van Gieson stain revealed the necrotic basophilic debris located in the superficial dermis admixed with a cluster of black wavy elastic fibers establishing the identity of the perforating substance (Figure 2B). Masson trichrome stain revealed loss of collagen structure within the aggregate of elastic fibers adjacent to the epidermis and no collagen within epidermal canals (Figure 2C). These histopathologic findings together with the clinical presentation were consistent with a diagnosis of acquired perforating dermatosis (APD).

Comment

Presentation
Acquired perforating dermatosis is a dermatologic condition characterized by multiple pruritic, dome-shaped papules and plaques with central keratotic plugs giving a craterlike appearance.^1-4 A green-brown or black crust with an erythematous border typically surrounds the primary lesions.⁴ Acquired perforating dermatosis favors a distribution over the trunk, gluteal region, and the extensor surfaces of the upper and lower extremities. Palmoplantar, intertriginous, and mucous membrane regions typically are spared.⁴ Occasionally, APD may present as generalized nodules and papules. Our case consisting of lesions that were localized to STSGs on the forearms supports the typical distribution; however, the presentation of APD occurring within a skin graft is unique.

From an epidemiologic standpoint, APD is more likely to affect men than women (1.5:1 ratio). Additionally, APD’s affected age range is 29 to 96 years (mean, 56.8 years),⁵ which is consistent with our patient’s age. Acquired perforating dermatosis has no racial predilection, though there is a predominance among black patients with concomitant chronic renal failure, as seen in our patient.³

Pathogenesis
The etiology of APD remains unknown.⁶ Some believe that the uremic or calcium deposits on the skin of patients with chronic kidney disease may trigger chronic pruritus, leading to epithelial hyperplasia and the development of perforating lesions.^1,3 A prominent theory in the literature is that superficial trauma, such as scratching, induces necrosis of tissue, facilitating transepidermal elimination of connective tissue components.⁷ The Köbner phenomenon, which can easily be induced by scratching the skin, supports this idea.⁸ Fujimoto et al⁹ suggested that scratching exposes keratinocytes to advanced glycation end product–modified extracellular matrix proteins, particularly types I and III collagen. This exposure leads to the terminal differentiation of keratinocytes with the advanced glycation end receptor (CD36) followed by the upward movement of keratinocytes with glycated collagen. Others postulate fibronectin, involved in epidermal cell signaling, locomotion, and differentiation, is an antigenic trigger because patients with DM and uremia have increased levels of fibronectin in the serum and at sites of perforating skin lesions.¹⁰

Diseases Associated With APD
Acquired perforating dermatosis is an umbrella term for perforating disease found in adults. It is associated with systemic diseases, such as DM and pruritus of renal failure.¹¹ Our patient had both dialysis-dependent end-stage renal disease and DM. Acquired perforating dermatosis is observed in 4.5% to 11% of patients on hemodialysis^12,13; however, APD may occur prior to or in the absence of dialysis.³ Other examples of systemic conditions associated with APD include obstructive uropathy, chronic nephritis, anuria, and hypertensive nephrosclerosis. Koebnerization also may trigger lesions to manifest in a linear pattern after localized trauma to the skin.⁷ Acquired perforating dermatosis is associated with other types of trauma, such as healing herpes zoster, or following exposure to drugs, such as tumor necrosis factor α inhibitors, bevacizumab, telaprevir, sorafenib, sirolimus, and indinavir.^14-16 Rarely, there have been associations with a history of insect bites, scabies, lymphoma, and hepatobiliary disease.^1-3

Histopathology
Acquired perforating dermatosis is classified as a perforating disease, along with reactive perforating collagenosis, elastosis perforans serpiginosa (EPS), perforating folliculitis, and perforating calcific elastosis. Perforating diseases are histologically characterized by the transepidermal penetration and elimination of altered connective tissue and inflammatory cells.⁵ Each disease differs based on their clinical and histological characteristics.

Histologic sections of APD show a plug of crusting or hyperkeratosis with variable parakeratosis, acanthosis, and occasional dyskeratotic keratinocytes. In the dermis, aggregates of neutrophils, lymphocytes, macrophages, or multinucleated giant cells may be found.¹⁷ The histologic findings vary depending on the stage of evolution of the individual lesion. Early lesions show a concave depression with acanthosis, vacuolation of basal keratinocytes, and dermal inflammation.⁴ Additionally, transepidermal channels filled with keratin, pyknotic nuclear debris, inflammatory cells, elastin, or collagen can be noted.³ Over time, the elastic fibers, as detected by the Verhoeff-van Gieson stain, dissipate and the collagen acquires a basophilic staining. Adjacent to the channels, the basement membrane remains intact in early lesions but later shows discontinuities and electron-dense fibrinlike material.³ Occasionally, amorphous degenerated material within the perforations is the major histologic finding.¹¹ Usually, the material cannot be clearly identified as collagen or elastin, but sometimes both are present.

In our case, we identified elastin as the perforating substance, which is less common than collagen, the typical perforating substance in APD. Elastin has occasionally been seen to serve as the only perforating substance from APD lesions among patients. Abe et al¹⁸ reported that the biopsy of a Japanese patient with keratotic follicular papules and serpiginous-arranged papules demonstrated elimination of atypical elastin fibers from the transepidermal channels. This patient was diagnosed with APD as well as EPS and perforating folliculitis based on the clinical presentation.¹⁸ Kim et al¹⁹ studied 30 Korean patients with APD. One had serpiginous hyperkeratotic plaques along the upper extremity and trunk that revealed transepidermal channels containing coarse elastic fibers and basophilic debris; however, due to the serpiginous morphology of lesions, both Abe et al¹⁸ and Kim et al¹⁹ favored a diagnosis of acquired EPS. Saray et al²⁰ conducted a retrospective study of 22 Turkish patients with APD; 1 patient had a painful hyperkeratotic papule on the auricle that on histopathology showed degenerated elastin perforating through the keratotic plug, features similar to our case.

Differential Diagnosis
The differential diagnoses include perforating diseases^14,19 as well as other disorders that exhibit the Köbner phenomenon, such as psoriasis, lichen planus, and verruca vulgaris.^21,22 Also, it is not uncommon for patients with APD to have coexisting folliculitis or prurigo nodularis.²²

Treatment
Management is focused on treating the symptoms. For pruritus, sedating antihistamines and other antipruritic agents are efficacious.²³ Topical, intra-lesional, or systemic corticosteroids and topical retinoids have shown variable resolution in APD lesions.²⁴ Some case reports describe topical menthol, salicylic acid, sulfur, benzoyl peroxide, systemic antibiotics (eg, clindamycin, doxycycline), and allopurinol for elevated uric acid levels as effective treatment methods.⁶ Narrowband UVB phototherapy is beneficial for APD and renal disease.^25,26 Renal transplantation has been curative for some patients with APD.²⁷ Given that our patient’s lesions were asymptomatic, no treatment was offered at the time.

Conclusion

Our patient presented with APD localized exclusively to the site of a skin graft, and histologic examination identified elastin as the primary perforating substance. A medical history of DM and chronic kidney disease predisposes patients to APD. This case suggests that skin graft sites may be predisposed to the development of APD.

Case Report

A 57-year-old black woman with a history of dialysis-dependent end-stage renal disease, diabetes mellitus (DM), hypertension, diastolic congestive heart failure, and chronic bronchitis was admitted to Howard University Hospital (Washington, DC) for acute chest pain and shortness of breath. During her hospital stay the dermatology team was consulted for evaluation of two 1.6-cm teardrop-shaped, yellow-white-chalky plaques noted in the center of an atrophic, hyperpigmented, shiny, contracted split-thickness skin graft (STSG) on the right posterior forearm (Figure 1). Twenty years prior, the patient received STSGs on the right and left forearm secondary to caustic burns. Two months before the current admission she noticed 2 adjacent teardrop-shaped white plaques within the center of the STSG on the right forearm. At a 3-month follow-up, she had developed more lesions within both graft sites of the bilateral forearm. There was no notable pruritus associated with the lesions.

A 4-mm punch biopsy showed an orthokeratotic plug with basophilic inflammatory debris adjacent to acanthotic epidermis, necrotic basophilic debris at the superficial dermis with epidermal canals extending from the base of the lesion superiorly, and transepidermal elimination of elastic fibers (Figure 2A). A Verhoeff-van Gieson stain revealed the necrotic basophilic debris located in the superficial dermis admixed with a cluster of black wavy elastic fibers establishing the identity of the perforating substance (Figure 2B). Masson trichrome stain revealed loss of collagen structure within the aggregate of elastic fibers adjacent to the epidermis and no collagen within epidermal canals (Figure 2C). These histopathologic findings together with the clinical presentation were consistent with a diagnosis of acquired perforating dermatosis (APD).

Comment

Presentation
Acquired perforating dermatosis is a dermatologic condition characterized by multiple pruritic, dome-shaped papules and plaques with central keratotic plugs giving a craterlike appearance.^1-4 A green-brown or black crust with an erythematous border typically surrounds the primary lesions.⁴ Acquired perforating dermatosis favors a distribution over the trunk, gluteal region, and the extensor surfaces of the upper and lower extremities. Palmoplantar, intertriginous, and mucous membrane regions typically are spared.⁴ Occasionally, APD may present as generalized nodules and papules. Our case consisting of lesions that were localized to STSGs on the forearms supports the typical distribution; however, the presentation of APD occurring within a skin graft is unique.

From an epidemiologic standpoint, APD is more likely to affect men than women (1.5:1 ratio). Additionally, APD’s affected age range is 29 to 96 years (mean, 56.8 years),⁵ which is consistent with our patient’s age. Acquired perforating dermatosis has no racial predilection, though there is a predominance among black patients with concomitant chronic renal failure, as seen in our patient.³

Pathogenesis
The etiology of APD remains unknown.⁶ Some believe that the uremic or calcium deposits on the skin of patients with chronic kidney disease may trigger chronic pruritus, leading to epithelial hyperplasia and the development of perforating lesions.^1,3 A prominent theory in the literature is that superficial trauma, such as scratching, induces necrosis of tissue, facilitating transepidermal elimination of connective tissue components.⁷ The Köbner phenomenon, which can easily be induced by scratching the skin, supports this idea.⁸ Fujimoto et al⁹ suggested that scratching exposes keratinocytes to advanced glycation end product–modified extracellular matrix proteins, particularly types I and III collagen. This exposure leads to the terminal differentiation of keratinocytes with the advanced glycation end receptor (CD36) followed by the upward movement of keratinocytes with glycated collagen. Others postulate fibronectin, involved in epidermal cell signaling, locomotion, and differentiation, is an antigenic trigger because patients with DM and uremia have increased levels of fibronectin in the serum and at sites of perforating skin lesions.¹⁰

Diseases Associated With APD
Acquired perforating dermatosis is an umbrella term for perforating disease found in adults. It is associated with systemic diseases, such as DM and pruritus of renal failure.¹¹ Our patient had both dialysis-dependent end-stage renal disease and DM. Acquired perforating dermatosis is observed in 4.5% to 11% of patients on hemodialysis^12,13; however, APD may occur prior to or in the absence of dialysis.³ Other examples of systemic conditions associated with APD include obstructive uropathy, chronic nephritis, anuria, and hypertensive nephrosclerosis. Koebnerization also may trigger lesions to manifest in a linear pattern after localized trauma to the skin.⁷ Acquired perforating dermatosis is associated with other types of trauma, such as healing herpes zoster, or following exposure to drugs, such as tumor necrosis factor α inhibitors, bevacizumab, telaprevir, sorafenib, sirolimus, and indinavir.^14-16 Rarely, there have been associations with a history of insect bites, scabies, lymphoma, and hepatobiliary disease.^1-3

Histopathology
Acquired perforating dermatosis is classified as a perforating disease, along with reactive perforating collagenosis, elastosis perforans serpiginosa (EPS), perforating folliculitis, and perforating calcific elastosis. Perforating diseases are histologically characterized by the transepidermal penetration and elimination of altered connective tissue and inflammatory cells.⁵ Each disease differs based on their clinical and histological characteristics.

Histologic sections of APD show a plug of crusting or hyperkeratosis with variable parakeratosis, acanthosis, and occasional dyskeratotic keratinocytes. In the dermis, aggregates of neutrophils, lymphocytes, macrophages, or multinucleated giant cells may be found.¹⁷ The histologic findings vary depending on the stage of evolution of the individual lesion. Early lesions show a concave depression with acanthosis, vacuolation of basal keratinocytes, and dermal inflammation.⁴ Additionally, transepidermal channels filled with keratin, pyknotic nuclear debris, inflammatory cells, elastin, or collagen can be noted.³ Over time, the elastic fibers, as detected by the Verhoeff-van Gieson stain, dissipate and the collagen acquires a basophilic staining. Adjacent to the channels, the basement membrane remains intact in early lesions but later shows discontinuities and electron-dense fibrinlike material.³ Occasionally, amorphous degenerated material within the perforations is the major histologic finding.¹¹ Usually, the material cannot be clearly identified as collagen or elastin, but sometimes both are present.

In our case, we identified elastin as the perforating substance, which is less common than collagen, the typical perforating substance in APD. Elastin has occasionally been seen to serve as the only perforating substance from APD lesions among patients. Abe et al¹⁸ reported that the biopsy of a Japanese patient with keratotic follicular papules and serpiginous-arranged papules demonstrated elimination of atypical elastin fibers from the transepidermal channels. This patient was diagnosed with APD as well as EPS and perforating folliculitis based on the clinical presentation.¹⁸ Kim et al¹⁹ studied 30 Korean patients with APD. One had serpiginous hyperkeratotic plaques along the upper extremity and trunk that revealed transepidermal channels containing coarse elastic fibers and basophilic debris; however, due to the serpiginous morphology of lesions, both Abe et al¹⁸ and Kim et al¹⁹ favored a diagnosis of acquired EPS. Saray et al²⁰ conducted a retrospective study of 22 Turkish patients with APD; 1 patient had a painful hyperkeratotic papule on the auricle that on histopathology showed degenerated elastin perforating through the keratotic plug, features similar to our case.

Differential Diagnosis
The differential diagnoses include perforating diseases^14,19 as well as other disorders that exhibit the Köbner phenomenon, such as psoriasis, lichen planus, and verruca vulgaris.^21,22 Also, it is not uncommon for patients with APD to have coexisting folliculitis or prurigo nodularis.²²

Treatment
Management is focused on treating the symptoms. For pruritus, sedating antihistamines and other antipruritic agents are efficacious.²³ Topical, intra-lesional, or systemic corticosteroids and topical retinoids have shown variable resolution in APD lesions.²⁴ Some case reports describe topical menthol, salicylic acid, sulfur, benzoyl peroxide, systemic antibiotics (eg, clindamycin, doxycycline), and allopurinol for elevated uric acid levels as effective treatment methods.⁶ Narrowband UVB phototherapy is beneficial for APD and renal disease.^25,26 Renal transplantation has been curative for some patients with APD.²⁷ Given that our patient’s lesions were asymptomatic, no treatment was offered at the time.

Conclusion

Our patient presented with APD localized exclusively to the site of a skin graft, and histologic examination identified elastin as the primary perforating substance. A medical history of DM and chronic kidney disease predisposes patients to APD. This case suggests that skin graft sites may be predisposed to the development of APD.

Case Report

A 57-year-old black woman with a history of dialysis-dependent end-stage renal disease, diabetes mellitus (DM), hypertension, diastolic congestive heart failure, and chronic bronchitis was admitted to Howard University Hospital (Washington, DC) for acute chest pain and shortness of breath. During her hospital stay the dermatology team was consulted for evaluation of two 1.6-cm teardrop-shaped, yellow-white-chalky plaques noted in the center of an atrophic, hyperpigmented, shiny, contracted split-thickness skin graft (STSG) on the right posterior forearm (Figure 1). Twenty years prior, the patient received STSGs on the right and left forearm secondary to caustic burns. Two months before the current admission she noticed 2 adjacent teardrop-shaped white plaques within the center of the STSG on the right forearm. At a 3-month follow-up, she had developed more lesions within both graft sites of the bilateral forearm. There was no notable pruritus associated with the lesions.

A 4-mm punch biopsy showed an orthokeratotic plug with basophilic inflammatory debris adjacent to acanthotic epidermis, necrotic basophilic debris at the superficial dermis with epidermal canals extending from the base of the lesion superiorly, and transepidermal elimination of elastic fibers (Figure 2A). A Verhoeff-van Gieson stain revealed the necrotic basophilic debris located in the superficial dermis admixed with a cluster of black wavy elastic fibers establishing the identity of the perforating substance (Figure 2B). Masson trichrome stain revealed loss of collagen structure within the aggregate of elastic fibers adjacent to the epidermis and no collagen within epidermal canals (Figure 2C). These histopathologic findings together with the clinical presentation were consistent with a diagnosis of acquired perforating dermatosis (APD).

Comment

Presentation
Acquired perforating dermatosis is a dermatologic condition characterized by multiple pruritic, dome-shaped papules and plaques with central keratotic plugs giving a craterlike appearance.^1-4 A green-brown or black crust with an erythematous border typically surrounds the primary lesions.⁴ Acquired perforating dermatosis favors a distribution over the trunk, gluteal region, and the extensor surfaces of the upper and lower extremities. Palmoplantar, intertriginous, and mucous membrane regions typically are spared.⁴ Occasionally, APD may present as generalized nodules and papules. Our case consisting of lesions that were localized to STSGs on the forearms supports the typical distribution; however, the presentation of APD occurring within a skin graft is unique.

From an epidemiologic standpoint, APD is more likely to affect men than women (1.5:1 ratio). Additionally, APD’s affected age range is 29 to 96 years (mean, 56.8 years),⁵ which is consistent with our patient’s age. Acquired perforating dermatosis has no racial predilection, though there is a predominance among black patients with concomitant chronic renal failure, as seen in our patient.³

Pathogenesis
The etiology of APD remains unknown.⁶ Some believe that the uremic or calcium deposits on the skin of patients with chronic kidney disease may trigger chronic pruritus, leading to epithelial hyperplasia and the development of perforating lesions.^1,3 A prominent theory in the literature is that superficial trauma, such as scratching, induces necrosis of tissue, facilitating transepidermal elimination of connective tissue components.⁷ The Köbner phenomenon, which can easily be induced by scratching the skin, supports this idea.⁸ Fujimoto et al⁹ suggested that scratching exposes keratinocytes to advanced glycation end product–modified extracellular matrix proteins, particularly types I and III collagen. This exposure leads to the terminal differentiation of keratinocytes with the advanced glycation end receptor (CD36) followed by the upward movement of keratinocytes with glycated collagen. Others postulate fibronectin, involved in epidermal cell signaling, locomotion, and differentiation, is an antigenic trigger because patients with DM and uremia have increased levels of fibronectin in the serum and at sites of perforating skin lesions.¹⁰

Diseases Associated With APD
Acquired perforating dermatosis is an umbrella term for perforating disease found in adults. It is associated with systemic diseases, such as DM and pruritus of renal failure.¹¹ Our patient had both dialysis-dependent end-stage renal disease and DM. Acquired perforating dermatosis is observed in 4.5% to 11% of patients on hemodialysis^12,13; however, APD may occur prior to or in the absence of dialysis.³ Other examples of systemic conditions associated with APD include obstructive uropathy, chronic nephritis, anuria, and hypertensive nephrosclerosis. Koebnerization also may trigger lesions to manifest in a linear pattern after localized trauma to the skin.⁷ Acquired perforating dermatosis is associated with other types of trauma, such as healing herpes zoster, or following exposure to drugs, such as tumor necrosis factor α inhibitors, bevacizumab, telaprevir, sorafenib, sirolimus, and indinavir.^14-16 Rarely, there have been associations with a history of insect bites, scabies, lymphoma, and hepatobiliary disease.^1-3

Histopathology
Acquired perforating dermatosis is classified as a perforating disease, along with reactive perforating collagenosis, elastosis perforans serpiginosa (EPS), perforating folliculitis, and perforating calcific elastosis. Perforating diseases are histologically characterized by the transepidermal penetration and elimination of altered connective tissue and inflammatory cells.⁵ Each disease differs based on their clinical and histological characteristics.

Histologic sections of APD show a plug of crusting or hyperkeratosis with variable parakeratosis, acanthosis, and occasional dyskeratotic keratinocytes. In the dermis, aggregates of neutrophils, lymphocytes, macrophages, or multinucleated giant cells may be found.¹⁷ The histologic findings vary depending on the stage of evolution of the individual lesion. Early lesions show a concave depression with acanthosis, vacuolation of basal keratinocytes, and dermal inflammation.⁴ Additionally, transepidermal channels filled with keratin, pyknotic nuclear debris, inflammatory cells, elastin, or collagen can be noted.³ Over time, the elastic fibers, as detected by the Verhoeff-van Gieson stain, dissipate and the collagen acquires a basophilic staining. Adjacent to the channels, the basement membrane remains intact in early lesions but later shows discontinuities and electron-dense fibrinlike material.³ Occasionally, amorphous degenerated material within the perforations is the major histologic finding.¹¹ Usually, the material cannot be clearly identified as collagen or elastin, but sometimes both are present.

In our case, we identified elastin as the perforating substance, which is less common than collagen, the typical perforating substance in APD. Elastin has occasionally been seen to serve as the only perforating substance from APD lesions among patients. Abe et al¹⁸ reported that the biopsy of a Japanese patient with keratotic follicular papules and serpiginous-arranged papules demonstrated elimination of atypical elastin fibers from the transepidermal channels. This patient was diagnosed with APD as well as EPS and perforating folliculitis based on the clinical presentation.¹⁸ Kim et al¹⁹ studied 30 Korean patients with APD. One had serpiginous hyperkeratotic plaques along the upper extremity and trunk that revealed transepidermal channels containing coarse elastic fibers and basophilic debris; however, due to the serpiginous morphology of lesions, both Abe et al¹⁸ and Kim et al¹⁹ favored a diagnosis of acquired EPS. Saray et al²⁰ conducted a retrospective study of 22 Turkish patients with APD; 1 patient had a painful hyperkeratotic papule on the auricle that on histopathology showed degenerated elastin perforating through the keratotic plug, features similar to our case.

Differential Diagnosis
The differential diagnoses include perforating diseases^14,19 as well as other disorders that exhibit the Köbner phenomenon, such as psoriasis, lichen planus, and verruca vulgaris.^21,22 Also, it is not uncommon for patients with APD to have coexisting folliculitis or prurigo nodularis.²²

Treatment
Management is focused on treating the symptoms. For pruritus, sedating antihistamines and other antipruritic agents are efficacious.²³ Topical, intra-lesional, or systemic corticosteroids and topical retinoids have shown variable resolution in APD lesions.²⁴ Some case reports describe topical menthol, salicylic acid, sulfur, benzoyl peroxide, systemic antibiotics (eg, clindamycin, doxycycline), and allopurinol for elevated uric acid levels as effective treatment methods.⁶ Narrowband UVB phototherapy is beneficial for APD and renal disease.^25,26 Renal transplantation has been curative for some patients with APD.²⁷ Given that our patient’s lesions were asymptomatic, no treatment was offered at the time.

Conclusion

Our patient presented with APD localized exclusively to the site of a skin graft, and histologic examination identified elastin as the primary perforating substance. A medical history of DM and chronic kidney disease predisposes patients to APD. This case suggests that skin graft sites may be predisposed to the development of APD.

The Diagnosis: Cutaneous Metastases

Cutaneous metastases (CMs) can present in an otherwise asymptomatic patient as the only sign of an underlying disease process. In women, the most common cause of CM is breast carcinoma.^1-3 Cutaneous metastases are found in approximately 25% of all patients with breast carcinoma,¹ and breast carcinomas represent approximately 69% of all CMs found in women (Table 1).² Cutaneous metastatic breast carcinoma (CMBC) is associated with a poor prognosis with a mean survival of approximately 6 months at the time of diagnosis.^1,3 It commonly presents as a collection of flesh-colored, firm, asymptomatic, and rapidly appearing papules and nodules that can resemble cysts or fibrous tumors.^1,3,4 They typically are located on the chest wall or abdomen near the site of the underlying malignancy.^1-3 The histologic features of CMBC can include hyperchromatic tumor cells infiltrating between the collagen fibers in a characteristic single file manner,^3,5 giving the appearance of a busy dermis, a nonspecific term to describe a focally hypercellular dermis at low-power magnification (Table 2).^5,6 Cords and clusters of atypical cells with intracytoplasmic vacuoles or well-developed ducts also can be seen (quiz image [inset]). The carcinoma en cuirasse subtype of CMBC is characterized by a fibrotic scarlike plaque on the chest wall.^1,3 If a punch biopsy is obtained, the specimen typically appears rectangular rather than tapered because of the sclerotic dermal collagen.⁶ In contrast, inflammatory carcinoma (carcinoma erysipelatoides) presents as an erythematous plaque resembling cellulitis due to the lymphatics being congested by tumor cells.³ Immunohistochemistry is a valuable tool in diagnosis. Positive staining is seen with cytokeratin 7, gross cystic disease fluid protein-15, mammaglobin, and GATA-3.^1,3,6

Kaposi sarcoma (KS) is a low-grade endothelial malignancy associated with human herpesvirus 8.^3,4 Kaposi sarcoma can be divided into 4 main subtypes: classic KS, African KS, AIDS-related KS, and immunosuppression-associated KS that occurs in patients with diseases such as human immunodeficiency virus. The cutaneous lesions are similar between subtypes and present as dark reddish purple macules that may enlarge or become nodular lesions.^3,4 Histologically, 3 distinct stages of progression are described: patch, plaque, and tumor. The plaque stage has the appearance of a busy dermis due to the rapid proliferation of vascular structures within the dermis.^3,6 A useful histologic feature known as the promontory sign can be seen as the proliferating tumor causes preexisting structures to project into vascular spaces (Figure 1).⁶ Immunohistochemistry for the endothelial and lymphatic markers CD31 and D2-40, respectively, are positive and may aid in the diagnosis.³ Staining for the latent nuclear antigen-1 of human herpesvirus 8 is a highly specific marker used to diagnose KS and can further distinguish it from the other busy dermis lesions.³ 

Granuloma annulare (GA) is characterized by rings of small, firm, pink to flesh-colored papules with a variable disease duration.⁴ Histologically, the interstitial variant of GA is characterized by a scattered inflammatory infiltrate consisting of histiocytes and lymphocytes located between altered collagen fibers in the superficial to mid dermis (Figure 2).^3,6 Occasional eosinophils and increased dermal mucin are useful features to distinguish interstitial GA from other entities in the busy dermis differential.⁷

Scleromyxedema, also known as generalized lichen myxedematosus, is a rare mucinosis.^3,8 Although its pathogenesis is unknown, it has been suggested that paraproteins related to the underlying gammopathy act to stimulate fibroblast proliferation and mucin overproduction.⁸ Clinically, characteristic widespread firm, waxy, dome-shaped papules are present over the head, upper trunk, and extremities.^3,8 Histologically, scleromyxedema is characterized by increased dermal fibroblasts, mucin, and fibrosis, leading to the appearance of a busy dermis (Figure 3).^3,6

Neurofibromas are common benign peripheral nerve sheath tumors that can occur sporadically or in the setting of neurofibromatosis.^3-5 They present as soft, flesh-colored papules or nodules most commonly located on the trunk and limbs.⁴ Histologically, neurofibromas are nonencapsulated tumors composed of abundant spindle cells with comma-shaped nuclei diffusely arranged in a pale myxoid stroma (Figure 4). Scattered mast cells can be visualized at higher magnification.^3,6

The Diagnosis: Cutaneous Metastases

Cutaneous metastases (CMs) can present in an otherwise asymptomatic patient as the only sign of an underlying disease process. In women, the most common cause of CM is breast carcinoma.^1-3 Cutaneous metastases are found in approximately 25% of all patients with breast carcinoma,¹ and breast carcinomas represent approximately 69% of all CMs found in women (Table 1).² Cutaneous metastatic breast carcinoma (CMBC) is associated with a poor prognosis with a mean survival of approximately 6 months at the time of diagnosis.^1,3 It commonly presents as a collection of flesh-colored, firm, asymptomatic, and rapidly appearing papules and nodules that can resemble cysts or fibrous tumors.^1,3,4 They typically are located on the chest wall or abdomen near the site of the underlying malignancy.^1-3 The histologic features of CMBC can include hyperchromatic tumor cells infiltrating between the collagen fibers in a characteristic single file manner,^3,5 giving the appearance of a busy dermis, a nonspecific term to describe a focally hypercellular dermis at low-power magnification (Table 2).^5,6 Cords and clusters of atypical cells with intracytoplasmic vacuoles or well-developed ducts also can be seen (quiz image [inset]). The carcinoma en cuirasse subtype of CMBC is characterized by a fibrotic scarlike plaque on the chest wall.^1,3 If a punch biopsy is obtained, the specimen typically appears rectangular rather than tapered because of the sclerotic dermal collagen.⁶ In contrast, inflammatory carcinoma (carcinoma erysipelatoides) presents as an erythematous plaque resembling cellulitis due to the lymphatics being congested by tumor cells.³ Immunohistochemistry is a valuable tool in diagnosis. Positive staining is seen with cytokeratin 7, gross cystic disease fluid protein-15, mammaglobin, and GATA-3.^1,3,6

Kaposi sarcoma (KS) is a low-grade endothelial malignancy associated with human herpesvirus 8.^3,4 Kaposi sarcoma can be divided into 4 main subtypes: classic KS, African KS, AIDS-related KS, and immunosuppression-associated KS that occurs in patients with diseases such as human immunodeficiency virus. The cutaneous lesions are similar between subtypes and present as dark reddish purple macules that may enlarge or become nodular lesions.^3,4 Histologically, 3 distinct stages of progression are described: patch, plaque, and tumor. The plaque stage has the appearance of a busy dermis due to the rapid proliferation of vascular structures within the dermis.^3,6 A useful histologic feature known as the promontory sign can be seen as the proliferating tumor causes preexisting structures to project into vascular spaces (Figure 1).⁶ Immunohistochemistry for the endothelial and lymphatic markers CD31 and D2-40, respectively, are positive and may aid in the diagnosis.³ Staining for the latent nuclear antigen-1 of human herpesvirus 8 is a highly specific marker used to diagnose KS and can further distinguish it from the other busy dermis lesions.³ 

Granuloma annulare (GA) is characterized by rings of small, firm, pink to flesh-colored papules with a variable disease duration.⁴ Histologically, the interstitial variant of GA is characterized by a scattered inflammatory infiltrate consisting of histiocytes and lymphocytes located between altered collagen fibers in the superficial to mid dermis (Figure 2).^3,6 Occasional eosinophils and increased dermal mucin are useful features to distinguish interstitial GA from other entities in the busy dermis differential.⁷

Scleromyxedema, also known as generalized lichen myxedematosus, is a rare mucinosis.^3,8 Although its pathogenesis is unknown, it has been suggested that paraproteins related to the underlying gammopathy act to stimulate fibroblast proliferation and mucin overproduction.⁸ Clinically, characteristic widespread firm, waxy, dome-shaped papules are present over the head, upper trunk, and extremities.^3,8 Histologically, scleromyxedema is characterized by increased dermal fibroblasts, mucin, and fibrosis, leading to the appearance of a busy dermis (Figure 3).^3,6

Neurofibromas are common benign peripheral nerve sheath tumors that can occur sporadically or in the setting of neurofibromatosis.^3-5 They present as soft, flesh-colored papules or nodules most commonly located on the trunk and limbs.⁴ Histologically, neurofibromas are nonencapsulated tumors composed of abundant spindle cells with comma-shaped nuclei diffusely arranged in a pale myxoid stroma (Figure 4). Scattered mast cells can be visualized at higher magnification.^3,6

The Diagnosis: Cutaneous Metastases

Cutaneous metastases (CMs) can present in an otherwise asymptomatic patient as the only sign of an underlying disease process. In women, the most common cause of CM is breast carcinoma.^1-3 Cutaneous metastases are found in approximately 25% of all patients with breast carcinoma,¹ and breast carcinomas represent approximately 69% of all CMs found in women (Table 1).² Cutaneous metastatic breast carcinoma (CMBC) is associated with a poor prognosis with a mean survival of approximately 6 months at the time of diagnosis.^1,3 It commonly presents as a collection of flesh-colored, firm, asymptomatic, and rapidly appearing papules and nodules that can resemble cysts or fibrous tumors.^1,3,4 They typically are located on the chest wall or abdomen near the site of the underlying malignancy.^1-3 The histologic features of CMBC can include hyperchromatic tumor cells infiltrating between the collagen fibers in a characteristic single file manner,^3,5 giving the appearance of a busy dermis, a nonspecific term to describe a focally hypercellular dermis at low-power magnification (Table 2).^5,6 Cords and clusters of atypical cells with intracytoplasmic vacuoles or well-developed ducts also can be seen (quiz image [inset]). The carcinoma en cuirasse subtype of CMBC is characterized by a fibrotic scarlike plaque on the chest wall.^1,3 If a punch biopsy is obtained, the specimen typically appears rectangular rather than tapered because of the sclerotic dermal collagen.⁶ In contrast, inflammatory carcinoma (carcinoma erysipelatoides) presents as an erythematous plaque resembling cellulitis due to the lymphatics being congested by tumor cells.³ Immunohistochemistry is a valuable tool in diagnosis. Positive staining is seen with cytokeratin 7, gross cystic disease fluid protein-15, mammaglobin, and GATA-3.^1,3,6

Kaposi sarcoma (KS) is a low-grade endothelial malignancy associated with human herpesvirus 8.^3,4 Kaposi sarcoma can be divided into 4 main subtypes: classic KS, African KS, AIDS-related KS, and immunosuppression-associated KS that occurs in patients with diseases such as human immunodeficiency virus. The cutaneous lesions are similar between subtypes and present as dark reddish purple macules that may enlarge or become nodular lesions.^3,4 Histologically, 3 distinct stages of progression are described: patch, plaque, and tumor. The plaque stage has the appearance of a busy dermis due to the rapid proliferation of vascular structures within the dermis.^3,6 A useful histologic feature known as the promontory sign can be seen as the proliferating tumor causes preexisting structures to project into vascular spaces (Figure 1).⁶ Immunohistochemistry for the endothelial and lymphatic markers CD31 and D2-40, respectively, are positive and may aid in the diagnosis.³ Staining for the latent nuclear antigen-1 of human herpesvirus 8 is a highly specific marker used to diagnose KS and can further distinguish it from the other busy dermis lesions.³ 

Granuloma annulare (GA) is characterized by rings of small, firm, pink to flesh-colored papules with a variable disease duration.⁴ Histologically, the interstitial variant of GA is characterized by a scattered inflammatory infiltrate consisting of histiocytes and lymphocytes located between altered collagen fibers in the superficial to mid dermis (Figure 2).^3,6 Occasional eosinophils and increased dermal mucin are useful features to distinguish interstitial GA from other entities in the busy dermis differential.⁷

Scleromyxedema, also known as generalized lichen myxedematosus, is a rare mucinosis.^3,8 Although its pathogenesis is unknown, it has been suggested that paraproteins related to the underlying gammopathy act to stimulate fibroblast proliferation and mucin overproduction.⁸ Clinically, characteristic widespread firm, waxy, dome-shaped papules are present over the head, upper trunk, and extremities.^3,8 Histologically, scleromyxedema is characterized by increased dermal fibroblasts, mucin, and fibrosis, leading to the appearance of a busy dermis (Figure 3).^3,6

Neurofibromas are common benign peripheral nerve sheath tumors that can occur sporadically or in the setting of neurofibromatosis.^3-5 They present as soft, flesh-colored papules or nodules most commonly located on the trunk and limbs.⁴ Histologically, neurofibromas are nonencapsulated tumors composed of abundant spindle cells with comma-shaped nuclei diffusely arranged in a pale myxoid stroma (Figure 4). Scattered mast cells can be visualized at higher magnification.^3,6

Adult-onset Still disease (AOSD) is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, evanescent skin rash, and lymphadenopathy. ¹ The most commonly used criteria for diagnosing AOSD are the Yamaguchi criteria. ² The major criteria include high fever for more than 1 week, arthralgia for more than 2 weeks, leukocytosis, and an evanescent skin rash. The minor criteria consist of sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative rheumatoid factor and antinuclear antibodies. Classically, the skin rash is described as an evanescent, salmon-colored erythema involving the extremities. Nevertheless, unusual cutaneous eruptions have been reported in AOSD, including persistent pruritic papules and plaques. ³ Importantly, this atypical rash demonstrates specific histologic findings that are not found on routine histopathology of a typical evanescent rash. We describe 2 patients with this atypical cutaneous eruption along with the unique histopathologic findings of AOSD.

Case Reports

Patient 1
A 23-year-old Chinese woman presented with periodic fevers, persistent rash, and joint pain of 2 years’ duration. Her medical history included splenectomy for hepatosplenomegaly as well as evaluation by hematology for lymphadenopathy; a cervical lymph node biopsy showed lymphoid and follicular hyperplasia.

Twenty days later, the patient was referred to the dermatology department for evaluation of the persistent rash. The patient described a history of flushing of the face, severe joint pain in both arms and legs, aching muscles, and persistent sore throat. The patient did not report any history of drug ingestion. Physical examination revealed a fever (temperature, 39.2°C); swollen nontender lymph nodes in the neck, axillae, and groin; and salmon-colored and hyperpigmented patches and thin plaques over the neck, chest, abdomen, and arms (Figure 1). A splenectomy scar also was noted. Peripheral blood was collected for laboratory analyses, which revealed transaminitis and moderate hyperferritinemia (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. The patient was admitted to the hospital, and a skin biopsy was performed. Histology showed superficial dyskeratotic keratinocytes and sparse perivascular infiltration of neutrophils in the upper dermis (Figure 2).

The patient was diagnosed with AOSD based on fulfillment of the Yamaguchi criteria.² She was treated with methylprednisolone 60 mg daily and was discharged 14 days later. At 16-month follow-up, the patient demonstrated complete resolution of symptoms with a maintenance dose of prednisolone (7.5 mg daily).

Patient 2
A 23-year-old black woman presented to the emergency department 3 months postpartum with recurrent high fevers, worsening joint pain, and persistent itchy rash of 2 months’ duration. The patient had no history of travel, autoimmune disease, or sick contacts. She occasionally took aspirin for joint pain. Physical examination revealed a fever (temperature, 39.1°C) along with hyperpigmented patches and thin scaly hyperpigmented papules coalescing into a poorly demarcated V-shaped plaque on the upper back and posterior neck, extending to the chest in a shawl-like distribution (Figure 3). Submental lymphadenopathy was present. The spleen was not palpable.

Peripheral blood was collected for laboratory analysis and demonstrated transaminitis and a markedly high ferritin level (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. Skin biopsy was performed and demonstrated many necrotic keratinocytes, singly and in aggregates, distributed from the spinous layer to the stratum corneum. A neutrophilic infiltrate was present in the papillary dermis (Figure 4).

The patient met the Yamaguchi criteria and was subsequently diagnosed with AOSD. She was treated with intravenous methylprednisolone 20 mg every 8 hours and was discharged 1 week later on oral prednisone 60 mg daily to be tapered over a period of months. At 2-week follow-up, the patient continued to experience rash and joint pain; oral methotrexate 10 mg weekly was added to her regimen, as well as vitamin D, calcium, and folic acid supplementation. At the next 2-week follow-up the patient noted improvement in the rash as well as the joint pain, but both still persisted. Prednisone was decreased to 50 mg daily and methotrexate was increased to 15 mg weekly. The patient continued to show improvement over the subsequent 3 months, during which prednisone was tapered to 10 mg daily and methotrexate was increased to 20 mg weekly. The patient showed resolution of symptoms at 3-month follow-up on this regimen, with plans to continue the prednisone taper and maintain methotrexate dosing.

Comment

Adult-onset Still disease is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, salmon-pink evanescent erythema, and lymphadenopathy.² The condition also can cause liver dysfunction, splenomegaly, pericarditis, pleuritis, renal dysfunction, and a reactive hemophagocytic syndrome.¹ Furthermore, one review of the literature described an association with delayed-onset malignancy.⁴ Early diagnosis is important yet challenging, as AOSD is a diagnosis of exclusion. The Yamaguchi criteria are the most widely used method of diagnosis and demonstrate more than 90% sensitivity.In addition to the Yamaguchi criteria, marked hyperferritinemia is characteristic of AOSD and can act as an indicator of disease activity.⁵ Interestingly, both of our patients had elevated ferritin levels, with patient 2 showing marked elevation (Table). In both patients, all major criteria were fulfilled, except the typical skin rash.

The skin rash in AOSD, classically consisting of an evanescent, salmon-pink erythema predominantly involving the extremities, has been observed in up to 87% of AOSD patients.⁵ The histology of the typical evanescent rash is nonspecific, characterized by a relatively sparse, perivascular, mixed inflammatory infiltrate. Notably, other skin manifestations may be found in patients with AOSD.^1,2,5-16 Persistent pruritic papules and plaques are the most commonly reported nonclassical rash, presenting as erythematous, slightly scaly papules and plaques with a linear configuration typically on the trunk.² Both of our patients presented with this atypical eruption. Importantly, the histopathology of this unique rash displays distinctive features, which can aid in early diagnosis. Findings include dyskeratotic keratinocytes in the cornified layers as well as in the epidermis, and a sparse neutrophilic and/or lymphocytic infiltrate in the papillary dermis without vasculitis. These findings were evident in both histopathologic studies of our patients (Figures 2 and 4). Although not present in our patients, dermal mucin deposition has been demonstrated in some reports.^1,13,15

A 2015 review of the literature yielded 30 cases of AOSD with pruritic persistent papules and plaques.⁴ The study confirmed a linear, erythematous or brown rash on the back and neck in the majority of cases. Histologic findings were congruent with those reported in our 2 cases: necrotic keratinocytes in the upper epidermis with a neutrophilic infiltrate in the upper dermis without vasculitis. Most patients showed rapid resolution of the rash and symptoms with the use of prednisone, prednisolone, or intravenous pulsed methylprednisolone. Interestingly, a range of presentations were noted, including prurigo pigmentosalike urticarial papules; lichenoid papules; and dermatographismlike, dermatomyositislike, and lichen amyloidosis–like rashes.⁴ In our report, patient 2 presented with a rash in a dermat-omyositislike shawl distribution. It has been suggested that patients with dermatomyositislike rashes require more potent immunotherapy as compared to patients with other rash morphologies.⁴ The need for methotrexate in addition to a prednisone taper in the clinical course of patient 2 lends further support to this observation.

Conclusion

A clinically and pathologically distinct form of cutaneous disease—AOSD with persistent pruritic papules and plaques—was observed in our 2 patients. These histopathologic findings facilitated timely diagnosis in both patients. A range of clinical morphologies may exist in AOSD, an awareness of which is paramount. Adult-onset Still disease should be included in the differential diagnosis of a dermatomyositislike presentation in a shawl distribution. Prompt diagnosis is essential to ensure adequate therapy.

Adult-onset Still disease (AOSD) is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, evanescent skin rash, and lymphadenopathy. ¹ The most commonly used criteria for diagnosing AOSD are the Yamaguchi criteria. ² The major criteria include high fever for more than 1 week, arthralgia for more than 2 weeks, leukocytosis, and an evanescent skin rash. The minor criteria consist of sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative rheumatoid factor and antinuclear antibodies. Classically, the skin rash is described as an evanescent, salmon-colored erythema involving the extremities. Nevertheless, unusual cutaneous eruptions have been reported in AOSD, including persistent pruritic papules and plaques. ³ Importantly, this atypical rash demonstrates specific histologic findings that are not found on routine histopathology of a typical evanescent rash. We describe 2 patients with this atypical cutaneous eruption along with the unique histopathologic findings of AOSD.

Case Reports

Patient 1
A 23-year-old Chinese woman presented with periodic fevers, persistent rash, and joint pain of 2 years’ duration. Her medical history included splenectomy for hepatosplenomegaly as well as evaluation by hematology for lymphadenopathy; a cervical lymph node biopsy showed lymphoid and follicular hyperplasia.

Twenty days later, the patient was referred to the dermatology department for evaluation of the persistent rash. The patient described a history of flushing of the face, severe joint pain in both arms and legs, aching muscles, and persistent sore throat. The patient did not report any history of drug ingestion. Physical examination revealed a fever (temperature, 39.2°C); swollen nontender lymph nodes in the neck, axillae, and groin; and salmon-colored and hyperpigmented patches and thin plaques over the neck, chest, abdomen, and arms (Figure 1). A splenectomy scar also was noted. Peripheral blood was collected for laboratory analyses, which revealed transaminitis and moderate hyperferritinemia (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. The patient was admitted to the hospital, and a skin biopsy was performed. Histology showed superficial dyskeratotic keratinocytes and sparse perivascular infiltration of neutrophils in the upper dermis (Figure 2).

The patient was diagnosed with AOSD based on fulfillment of the Yamaguchi criteria.² She was treated with methylprednisolone 60 mg daily and was discharged 14 days later. At 16-month follow-up, the patient demonstrated complete resolution of symptoms with a maintenance dose of prednisolone (7.5 mg daily).

Patient 2
A 23-year-old black woman presented to the emergency department 3 months postpartum with recurrent high fevers, worsening joint pain, and persistent itchy rash of 2 months’ duration. The patient had no history of travel, autoimmune disease, or sick contacts. She occasionally took aspirin for joint pain. Physical examination revealed a fever (temperature, 39.1°C) along with hyperpigmented patches and thin scaly hyperpigmented papules coalescing into a poorly demarcated V-shaped plaque on the upper back and posterior neck, extending to the chest in a shawl-like distribution (Figure 3). Submental lymphadenopathy was present. The spleen was not palpable.

Peripheral blood was collected for laboratory analysis and demonstrated transaminitis and a markedly high ferritin level (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. Skin biopsy was performed and demonstrated many necrotic keratinocytes, singly and in aggregates, distributed from the spinous layer to the stratum corneum. A neutrophilic infiltrate was present in the papillary dermis (Figure 4).

The patient met the Yamaguchi criteria and was subsequently diagnosed with AOSD. She was treated with intravenous methylprednisolone 20 mg every 8 hours and was discharged 1 week later on oral prednisone 60 mg daily to be tapered over a period of months. At 2-week follow-up, the patient continued to experience rash and joint pain; oral methotrexate 10 mg weekly was added to her regimen, as well as vitamin D, calcium, and folic acid supplementation. At the next 2-week follow-up the patient noted improvement in the rash as well as the joint pain, but both still persisted. Prednisone was decreased to 50 mg daily and methotrexate was increased to 15 mg weekly. The patient continued to show improvement over the subsequent 3 months, during which prednisone was tapered to 10 mg daily and methotrexate was increased to 20 mg weekly. The patient showed resolution of symptoms at 3-month follow-up on this regimen, with plans to continue the prednisone taper and maintain methotrexate dosing.

Comment

Adult-onset Still disease is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, salmon-pink evanescent erythema, and lymphadenopathy.² The condition also can cause liver dysfunction, splenomegaly, pericarditis, pleuritis, renal dysfunction, and a reactive hemophagocytic syndrome.¹ Furthermore, one review of the literature described an association with delayed-onset malignancy.⁴ Early diagnosis is important yet challenging, as AOSD is a diagnosis of exclusion. The Yamaguchi criteria are the most widely used method of diagnosis and demonstrate more than 90% sensitivity.In addition to the Yamaguchi criteria, marked hyperferritinemia is characteristic of AOSD and can act as an indicator of disease activity.⁵ Interestingly, both of our patients had elevated ferritin levels, with patient 2 showing marked elevation (Table). In both patients, all major criteria were fulfilled, except the typical skin rash.

The skin rash in AOSD, classically consisting of an evanescent, salmon-pink erythema predominantly involving the extremities, has been observed in up to 87% of AOSD patients.⁵ The histology of the typical evanescent rash is nonspecific, characterized by a relatively sparse, perivascular, mixed inflammatory infiltrate. Notably, other skin manifestations may be found in patients with AOSD.^1,2,5-16 Persistent pruritic papules and plaques are the most commonly reported nonclassical rash, presenting as erythematous, slightly scaly papules and plaques with a linear configuration typically on the trunk.² Both of our patients presented with this atypical eruption. Importantly, the histopathology of this unique rash displays distinctive features, which can aid in early diagnosis. Findings include dyskeratotic keratinocytes in the cornified layers as well as in the epidermis, and a sparse neutrophilic and/or lymphocytic infiltrate in the papillary dermis without vasculitis. These findings were evident in both histopathologic studies of our patients (Figures 2 and 4). Although not present in our patients, dermal mucin deposition has been demonstrated in some reports.^1,13,15

A 2015 review of the literature yielded 30 cases of AOSD with pruritic persistent papules and plaques.⁴ The study confirmed a linear, erythematous or brown rash on the back and neck in the majority of cases. Histologic findings were congruent with those reported in our 2 cases: necrotic keratinocytes in the upper epidermis with a neutrophilic infiltrate in the upper dermis without vasculitis. Most patients showed rapid resolution of the rash and symptoms with the use of prednisone, prednisolone, or intravenous pulsed methylprednisolone. Interestingly, a range of presentations were noted, including prurigo pigmentosalike urticarial papules; lichenoid papules; and dermatographismlike, dermatomyositislike, and lichen amyloidosis–like rashes.⁴ In our report, patient 2 presented with a rash in a dermat-omyositislike shawl distribution. It has been suggested that patients with dermatomyositislike rashes require more potent immunotherapy as compared to patients with other rash morphologies.⁴ The need for methotrexate in addition to a prednisone taper in the clinical course of patient 2 lends further support to this observation.

Conclusion

A clinically and pathologically distinct form of cutaneous disease—AOSD with persistent pruritic papules and plaques—was observed in our 2 patients. These histopathologic findings facilitated timely diagnosis in both patients. A range of clinical morphologies may exist in AOSD, an awareness of which is paramount. Adult-onset Still disease should be included in the differential diagnosis of a dermatomyositislike presentation in a shawl distribution. Prompt diagnosis is essential to ensure adequate therapy.

Adult-onset Still disease (AOSD) is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, evanescent skin rash, and lymphadenopathy. ¹ The most commonly used criteria for diagnosing AOSD are the Yamaguchi criteria. ² The major criteria include high fever for more than 1 week, arthralgia for more than 2 weeks, leukocytosis, and an evanescent skin rash. The minor criteria consist of sore throat, lymphadenopathy and/or splenomegaly, liver dysfunction, and negative rheumatoid factor and antinuclear antibodies. Classically, the skin rash is described as an evanescent, salmon-colored erythema involving the extremities. Nevertheless, unusual cutaneous eruptions have been reported in AOSD, including persistent pruritic papules and plaques. ³ Importantly, this atypical rash demonstrates specific histologic findings that are not found on routine histopathology of a typical evanescent rash. We describe 2 patients with this atypical cutaneous eruption along with the unique histopathologic findings of AOSD.

Case Reports

Patient 1
A 23-year-old Chinese woman presented with periodic fevers, persistent rash, and joint pain of 2 years’ duration. Her medical history included splenectomy for hepatosplenomegaly as well as evaluation by hematology for lymphadenopathy; a cervical lymph node biopsy showed lymphoid and follicular hyperplasia.

Twenty days later, the patient was referred to the dermatology department for evaluation of the persistent rash. The patient described a history of flushing of the face, severe joint pain in both arms and legs, aching muscles, and persistent sore throat. The patient did not report any history of drug ingestion. Physical examination revealed a fever (temperature, 39.2°C); swollen nontender lymph nodes in the neck, axillae, and groin; and salmon-colored and hyperpigmented patches and thin plaques over the neck, chest, abdomen, and arms (Figure 1). A splenectomy scar also was noted. Peripheral blood was collected for laboratory analyses, which revealed transaminitis and moderate hyperferritinemia (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. The patient was admitted to the hospital, and a skin biopsy was performed. Histology showed superficial dyskeratotic keratinocytes and sparse perivascular infiltration of neutrophils in the upper dermis (Figure 2).

The patient was diagnosed with AOSD based on fulfillment of the Yamaguchi criteria.² She was treated with methylprednisolone 60 mg daily and was discharged 14 days later. At 16-month follow-up, the patient demonstrated complete resolution of symptoms with a maintenance dose of prednisolone (7.5 mg daily).

Patient 2
A 23-year-old black woman presented to the emergency department 3 months postpartum with recurrent high fevers, worsening joint pain, and persistent itchy rash of 2 months’ duration. The patient had no history of travel, autoimmune disease, or sick contacts. She occasionally took aspirin for joint pain. Physical examination revealed a fever (temperature, 39.1°C) along with hyperpigmented patches and thin scaly hyperpigmented papules coalescing into a poorly demarcated V-shaped plaque on the upper back and posterior neck, extending to the chest in a shawl-like distribution (Figure 3). Submental lymphadenopathy was present. The spleen was not palpable.

Peripheral blood was collected for laboratory analysis and demonstrated transaminitis and a markedly high ferritin level (Table). An autoimmune panel was negative for rheumatoid factor, antinuclear antibodies, and antineutrophil cytoplasmic antibodies. Skin biopsy was performed and demonstrated many necrotic keratinocytes, singly and in aggregates, distributed from the spinous layer to the stratum corneum. A neutrophilic infiltrate was present in the papillary dermis (Figure 4).

The patient met the Yamaguchi criteria and was subsequently diagnosed with AOSD. She was treated with intravenous methylprednisolone 20 mg every 8 hours and was discharged 1 week later on oral prednisone 60 mg daily to be tapered over a period of months. At 2-week follow-up, the patient continued to experience rash and joint pain; oral methotrexate 10 mg weekly was added to her regimen, as well as vitamin D, calcium, and folic acid supplementation. At the next 2-week follow-up the patient noted improvement in the rash as well as the joint pain, but both still persisted. Prednisone was decreased to 50 mg daily and methotrexate was increased to 15 mg weekly. The patient continued to show improvement over the subsequent 3 months, during which prednisone was tapered to 10 mg daily and methotrexate was increased to 20 mg weekly. The patient showed resolution of symptoms at 3-month follow-up on this regimen, with plans to continue the prednisone taper and maintain methotrexate dosing.

Comment

Adult-onset Still disease is a systemic inflammatory condition that clinically manifests as spiking fevers, arthralgia, salmon-pink evanescent erythema, and lymphadenopathy.² The condition also can cause liver dysfunction, splenomegaly, pericarditis, pleuritis, renal dysfunction, and a reactive hemophagocytic syndrome.¹ Furthermore, one review of the literature described an association with delayed-onset malignancy.⁴ Early diagnosis is important yet challenging, as AOSD is a diagnosis of exclusion. The Yamaguchi criteria are the most widely used method of diagnosis and demonstrate more than 90% sensitivity.In addition to the Yamaguchi criteria, marked hyperferritinemia is characteristic of AOSD and can act as an indicator of disease activity.⁵ Interestingly, both of our patients had elevated ferritin levels, with patient 2 showing marked elevation (Table). In both patients, all major criteria were fulfilled, except the typical skin rash.

The skin rash in AOSD, classically consisting of an evanescent, salmon-pink erythema predominantly involving the extremities, has been observed in up to 87% of AOSD patients.⁵ The histology of the typical evanescent rash is nonspecific, characterized by a relatively sparse, perivascular, mixed inflammatory infiltrate. Notably, other skin manifestations may be found in patients with AOSD.^1,2,5-16 Persistent pruritic papules and plaques are the most commonly reported nonclassical rash, presenting as erythematous, slightly scaly papules and plaques with a linear configuration typically on the trunk.² Both of our patients presented with this atypical eruption. Importantly, the histopathology of this unique rash displays distinctive features, which can aid in early diagnosis. Findings include dyskeratotic keratinocytes in the cornified layers as well as in the epidermis, and a sparse neutrophilic and/or lymphocytic infiltrate in the papillary dermis without vasculitis. These findings were evident in both histopathologic studies of our patients (Figures 2 and 4). Although not present in our patients, dermal mucin deposition has been demonstrated in some reports.^1,13,15

A 2015 review of the literature yielded 30 cases of AOSD with pruritic persistent papules and plaques.⁴ The study confirmed a linear, erythematous or brown rash on the back and neck in the majority of cases. Histologic findings were congruent with those reported in our 2 cases: necrotic keratinocytes in the upper epidermis with a neutrophilic infiltrate in the upper dermis without vasculitis. Most patients showed rapid resolution of the rash and symptoms with the use of prednisone, prednisolone, or intravenous pulsed methylprednisolone. Interestingly, a range of presentations were noted, including prurigo pigmentosalike urticarial papules; lichenoid papules; and dermatographismlike, dermatomyositislike, and lichen amyloidosis–like rashes.⁴ In our report, patient 2 presented with a rash in a dermat-omyositislike shawl distribution. It has been suggested that patients with dermatomyositislike rashes require more potent immunotherapy as compared to patients with other rash morphologies.⁴ The need for methotrexate in addition to a prednisone taper in the clinical course of patient 2 lends further support to this observation.

Conclusion

A clinically and pathologically distinct form of cutaneous disease—AOSD with persistent pruritic papules and plaques—was observed in our 2 patients. These histopathologic findings facilitated timely diagnosis in both patients. A range of clinical morphologies may exist in AOSD, an awareness of which is paramount. Adult-onset Still disease should be included in the differential diagnosis of a dermatomyositislike presentation in a shawl distribution. Prompt diagnosis is essential to ensure adequate therapy.