Dermatopathology

The Diagnosis: Cutaneous Myxoma

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

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

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

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

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

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

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

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

The Diagnosis: Cutaneous Myxoma

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

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

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

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

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

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

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

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

The Diagnosis: Cutaneous Myxoma

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

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

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

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

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

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

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

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

The Diagnosis: Dermatofibrosarcoma Protuberans

Histopathologic examination showed a dermal tumor composed of spindle cells in a storiform arrangement (Figure 1). Immunohistochemistry demonstrated positive CD34 staining of the tumoral cells (Figure 2). Clinical review, histopathologic examination, and immunohistochemistry confirmed a diagnosis of dermatofibrosarcoma protuberans (DFSP). The patient underwent Mohs micrographic surgery (MMS) with clear margins after 3 stages, followed by repair with a rotation flap. No evidence of recurrence was found at 4-year follow-up.

Dermatofibrosarcoma protuberans is a rare low-grade sarcoma of fibroblast origin with an annual incidence of 0.8 to 5 cases per million individuals.¹ It typically presents in patients aged 30 to 50 years on the trunk, scalp, or proximal extremities as an asymptomatic, flesh-colored, erythematous or brown, indurated plaque or nodule.² Due to its variable presentation, these lesions often may be misdiagnosed as lipomas or epidermoid cysts, preventing proper targeted treatment. Therefore, suspicious enlarging indurated nodules require a lower threshold for biopsy.¹

A definitive diagnosis of DFSP is achieved after a biopsy and histopathologic evaluation. Hematoxylin and eosin staining typically shows diffuse infiltration of the dermis and the subcutaneous fat by densely packed, cytologic, relatively uniform, spindle-shaped tumor cells arranged in a characteristic storiform shape. Tumor cells are spread along the septae of the subcutaneous fatty tissue.³ Immunohistochemistry is characterized by positive CD34 and negative factor XIIIa, with rare exceptions.

The differential diagnosis includes lipoma, epidermoid cyst, plexiform fibrohistiocytic tumor, and malignant peripheral nerve sheath tumor.³ Positive CD34 immunostaining, negative S-100 staining, and a storiform pattern of spindle cells can assist in differentiating DFSP from these possible differential diagnoses; lesions of these other entities are characterized by different pathologic findings. Lipomas are composed of fat tissue, epidermoid cysts have epithelial-lined cysts filled with keratin, plexiform fibrohistiocytic tumors have plexiform rays of fibrous tissue extending into fat with negative CD34 staining, and malignant peripheral nerve sheath tumors have fleshy variegated masses involving the peripheral nerve trunks with partial S-100 staining.^4-7 Additional evaluation to confirm DFSP can be accomplished by analysis of tumor samples by fluorescence in situ hybridization or reverse transcriptase–polymerase chain reaction to detect chromosomal translocations and fusion gene transcripts, as chromosomal translocations may be found in more than 90% of cases.³

Early diagnosis of DFSP is beneficial, as it can help prevent recurrence as well as metastasis. Studies have attempted to document the risk for recurrence as well as metastasis based on characteristic features and treatment strategies of DFSP. In a study of 186 patients, 3 had metastatic disease to the lungs, the most common site of metastasis.⁸ These 3 patients had fibrosarcomatous transformation within DFSP, emphasizing the importance of detailing this finding early in the diagnosis, as it was characterized by a higher degree of cellularity, cytologic atypia, mitotic activity, and negative CD34 immunostaining.⁹ In patients with suspected metastasis, lymph node ultrasonography, chest radiography, and computed tomography may be utilized.³

When treating DFSP, the goal is complete removal of the tumor with clear margins. Mohs micrographic surgery, modified MMS, and wide local excision (WLE) with 2- to 4-cm margins are appropriate treatment options, though MMS is the treatment of choice. A study comparing MMS and WLE demonstrated 3% and 30.8% recurrence rates, respectively.⁸ In MMS, complete margin evaluation on microscopy is performed after each stage to ensure negative surgical margins. The presence of positive surgical margins elicits continued resection until the margins are clear.^10,11

Other treatment modalities may be considered for patients with DFSP. Molecular therapy with imatinib, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor–regulated expression, can be utilized for inoperable tumors; however, additional clinical trials are required to ensure efficacy.³ Surgical removal of the possible remaining tumor is still recommended after molecular therapy. Radiotherapy is an additional method of treatment that may be used for inoperable tumors.³

Dermatofibrosarcoma protuberans is a rare lowgrade sarcoma of fibroblast origin that typically does not metastasize but often has notable subclinical extension and recurrence. Differentiating DFSP from other tumors often may be difficult. A protuberant, flesh-colored, slowgrowing, and asymptomatic lesion often may be confused with lipomas or epidermoid cysts; therefore, biopsies with immunohistostaining for suspicious lesions is required.¹² Mohs micrographic surgery has evolved as the treatment of choice for this tumor, though WLE and new targeted molecular therapies still are considered. Proper diagnosis and treatment of DFSP is paramount in preventing future morbidity.

The Diagnosis: Dermatofibrosarcoma Protuberans

Histopathologic examination showed a dermal tumor composed of spindle cells in a storiform arrangement (Figure 1). Immunohistochemistry demonstrated positive CD34 staining of the tumoral cells (Figure 2). Clinical review, histopathologic examination, and immunohistochemistry confirmed a diagnosis of dermatofibrosarcoma protuberans (DFSP). The patient underwent Mohs micrographic surgery (MMS) with clear margins after 3 stages, followed by repair with a rotation flap. No evidence of recurrence was found at 4-year follow-up.

Dermatofibrosarcoma protuberans is a rare low-grade sarcoma of fibroblast origin with an annual incidence of 0.8 to 5 cases per million individuals.¹ It typically presents in patients aged 30 to 50 years on the trunk, scalp, or proximal extremities as an asymptomatic, flesh-colored, erythematous or brown, indurated plaque or nodule.² Due to its variable presentation, these lesions often may be misdiagnosed as lipomas or epidermoid cysts, preventing proper targeted treatment. Therefore, suspicious enlarging indurated nodules require a lower threshold for biopsy.¹

A definitive diagnosis of DFSP is achieved after a biopsy and histopathologic evaluation. Hematoxylin and eosin staining typically shows diffuse infiltration of the dermis and the subcutaneous fat by densely packed, cytologic, relatively uniform, spindle-shaped tumor cells arranged in a characteristic storiform shape. Tumor cells are spread along the septae of the subcutaneous fatty tissue.³ Immunohistochemistry is characterized by positive CD34 and negative factor XIIIa, with rare exceptions.

The differential diagnosis includes lipoma, epidermoid cyst, plexiform fibrohistiocytic tumor, and malignant peripheral nerve sheath tumor.³ Positive CD34 immunostaining, negative S-100 staining, and a storiform pattern of spindle cells can assist in differentiating DFSP from these possible differential diagnoses; lesions of these other entities are characterized by different pathologic findings. Lipomas are composed of fat tissue, epidermoid cysts have epithelial-lined cysts filled with keratin, plexiform fibrohistiocytic tumors have plexiform rays of fibrous tissue extending into fat with negative CD34 staining, and malignant peripheral nerve sheath tumors have fleshy variegated masses involving the peripheral nerve trunks with partial S-100 staining.^4-7 Additional evaluation to confirm DFSP can be accomplished by analysis of tumor samples by fluorescence in situ hybridization or reverse transcriptase–polymerase chain reaction to detect chromosomal translocations and fusion gene transcripts, as chromosomal translocations may be found in more than 90% of cases.³

Early diagnosis of DFSP is beneficial, as it can help prevent recurrence as well as metastasis. Studies have attempted to document the risk for recurrence as well as metastasis based on characteristic features and treatment strategies of DFSP. In a study of 186 patients, 3 had metastatic disease to the lungs, the most common site of metastasis.⁸ These 3 patients had fibrosarcomatous transformation within DFSP, emphasizing the importance of detailing this finding early in the diagnosis, as it was characterized by a higher degree of cellularity, cytologic atypia, mitotic activity, and negative CD34 immunostaining.⁹ In patients with suspected metastasis, lymph node ultrasonography, chest radiography, and computed tomography may be utilized.³

When treating DFSP, the goal is complete removal of the tumor with clear margins. Mohs micrographic surgery, modified MMS, and wide local excision (WLE) with 2- to 4-cm margins are appropriate treatment options, though MMS is the treatment of choice. A study comparing MMS and WLE demonstrated 3% and 30.8% recurrence rates, respectively.⁸ In MMS, complete margin evaluation on microscopy is performed after each stage to ensure negative surgical margins. The presence of positive surgical margins elicits continued resection until the margins are clear.^10,11

Other treatment modalities may be considered for patients with DFSP. Molecular therapy with imatinib, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor–regulated expression, can be utilized for inoperable tumors; however, additional clinical trials are required to ensure efficacy.³ Surgical removal of the possible remaining tumor is still recommended after molecular therapy. Radiotherapy is an additional method of treatment that may be used for inoperable tumors.³

Dermatofibrosarcoma protuberans is a rare lowgrade sarcoma of fibroblast origin that typically does not metastasize but often has notable subclinical extension and recurrence. Differentiating DFSP from other tumors often may be difficult. A protuberant, flesh-colored, slowgrowing, and asymptomatic lesion often may be confused with lipomas or epidermoid cysts; therefore, biopsies with immunohistostaining for suspicious lesions is required.¹² Mohs micrographic surgery has evolved as the treatment of choice for this tumor, though WLE and new targeted molecular therapies still are considered. Proper diagnosis and treatment of DFSP is paramount in preventing future morbidity.

The Diagnosis: Dermatofibrosarcoma Protuberans

Histopathologic examination showed a dermal tumor composed of spindle cells in a storiform arrangement (Figure 1). Immunohistochemistry demonstrated positive CD34 staining of the tumoral cells (Figure 2). Clinical review, histopathologic examination, and immunohistochemistry confirmed a diagnosis of dermatofibrosarcoma protuberans (DFSP). The patient underwent Mohs micrographic surgery (MMS) with clear margins after 3 stages, followed by repair with a rotation flap. No evidence of recurrence was found at 4-year follow-up.

Dermatofibrosarcoma protuberans is a rare low-grade sarcoma of fibroblast origin with an annual incidence of 0.8 to 5 cases per million individuals.¹ It typically presents in patients aged 30 to 50 years on the trunk, scalp, or proximal extremities as an asymptomatic, flesh-colored, erythematous or brown, indurated plaque or nodule.² Due to its variable presentation, these lesions often may be misdiagnosed as lipomas or epidermoid cysts, preventing proper targeted treatment. Therefore, suspicious enlarging indurated nodules require a lower threshold for biopsy.¹

A definitive diagnosis of DFSP is achieved after a biopsy and histopathologic evaluation. Hematoxylin and eosin staining typically shows diffuse infiltration of the dermis and the subcutaneous fat by densely packed, cytologic, relatively uniform, spindle-shaped tumor cells arranged in a characteristic storiform shape. Tumor cells are spread along the septae of the subcutaneous fatty tissue.³ Immunohistochemistry is characterized by positive CD34 and negative factor XIIIa, with rare exceptions.

The differential diagnosis includes lipoma, epidermoid cyst, plexiform fibrohistiocytic tumor, and malignant peripheral nerve sheath tumor.³ Positive CD34 immunostaining, negative S-100 staining, and a storiform pattern of spindle cells can assist in differentiating DFSP from these possible differential diagnoses; lesions of these other entities are characterized by different pathologic findings. Lipomas are composed of fat tissue, epidermoid cysts have epithelial-lined cysts filled with keratin, plexiform fibrohistiocytic tumors have plexiform rays of fibrous tissue extending into fat with negative CD34 staining, and malignant peripheral nerve sheath tumors have fleshy variegated masses involving the peripheral nerve trunks with partial S-100 staining.^4-7 Additional evaluation to confirm DFSP can be accomplished by analysis of tumor samples by fluorescence in situ hybridization or reverse transcriptase–polymerase chain reaction to detect chromosomal translocations and fusion gene transcripts, as chromosomal translocations may be found in more than 90% of cases.³

Early diagnosis of DFSP is beneficial, as it can help prevent recurrence as well as metastasis. Studies have attempted to document the risk for recurrence as well as metastasis based on characteristic features and treatment strategies of DFSP. In a study of 186 patients, 3 had metastatic disease to the lungs, the most common site of metastasis.⁸ These 3 patients had fibrosarcomatous transformation within DFSP, emphasizing the importance of detailing this finding early in the diagnosis, as it was characterized by a higher degree of cellularity, cytologic atypia, mitotic activity, and negative CD34 immunostaining.⁹ In patients with suspected metastasis, lymph node ultrasonography, chest radiography, and computed tomography may be utilized.³

When treating DFSP, the goal is complete removal of the tumor with clear margins. Mohs micrographic surgery, modified MMS, and wide local excision (WLE) with 2- to 4-cm margins are appropriate treatment options, though MMS is the treatment of choice. A study comparing MMS and WLE demonstrated 3% and 30.8% recurrence rates, respectively.⁸ In MMS, complete margin evaluation on microscopy is performed after each stage to ensure negative surgical margins. The presence of positive surgical margins elicits continued resection until the margins are clear.^10,11

Other treatment modalities may be considered for patients with DFSP. Molecular therapy with imatinib, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor–regulated expression, can be utilized for inoperable tumors; however, additional clinical trials are required to ensure efficacy.³ Surgical removal of the possible remaining tumor is still recommended after molecular therapy. Radiotherapy is an additional method of treatment that may be used for inoperable tumors.³

Dermatofibrosarcoma protuberans is a rare lowgrade sarcoma of fibroblast origin that typically does not metastasize but often has notable subclinical extension and recurrence. Differentiating DFSP from other tumors often may be difficult. A protuberant, flesh-colored, slowgrowing, and asymptomatic lesion often may be confused with lipomas or epidermoid cysts; therefore, biopsies with immunohistostaining for suspicious lesions is required.¹² Mohs micrographic surgery has evolved as the treatment of choice for this tumor, though WLE and new targeted molecular therapies still are considered. Proper diagnosis and treatment of DFSP is paramount in preventing future morbidity.

To the Editor:

Pityriasis lichenoides is a papulosquamous dermatologic disorder that is characterized by recurrent papules.¹ There is a spectrum of disease in pityriasis lichenoides that includes pityriasis lichenoides et varioliformis acuta (PLEVA) at one end and pityriasis lichenoides chronica at the other. Pityriasis lichenoides et varioliformis acuta is more common in younger individuals and is characterized by erythematous papules that often crust; these lesions resolve over weeks. The lesions of pityriasis lichenoides chronica are characteristically scaly, pink to red-brown papules that tend to resolve over months.¹

Histologically, PLEVA exhibits parakeratosis, interface dermatitis, and a wedge-shaped infiltrate.¹ Necrotic keratinocytes and extravasated erythrocytes also are common features. Additionally, monoclonal T cells may be present in the infiltrate.¹

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a rare and severe variant of PLEVA. Febrile ulceronecrotic Mucha-Habermann disease is characterized by ulceronecrotic lesions, fever, and systemic symptoms.² Herein, we present a case of FUMHD.

A 57-year-old man presented with an eruption of painful lesions involving the face, trunk, arms, legs, and genitalia of 1 month’s duration. The patient denied oral and ocular involvement. He had soreness and swelling of the arms and legs. A prior 12-day course of prednisone prescribed by a community dermatologist failed to improve the rash. A biopsy performed by a community dermatologist was nondiagnostic. The patient denied fever but did report chills. He had no preceding illness and was not taking new medications. On physical examination, the patient was afebrile and normotensive with innumerable deep-seated pustules and crusted ulcerations on the face, palms, soles, trunk, extremities, and penis (Figures 1 and 2). There was a background morbilliform eruption on the trunk. The ocular and oral mucosae were spared. The upper and lower extremities had pitting edema.

The patient’s alanine aminotransaminase and aspartate aminotransaminase levels were elevated at 55 and 51 U/L, respectively. His white blood cell count was within reference range; however, there was an elevated absolute neutrophil count (8.7×10³/μL). No eosinophilia was noted. Laboratory evaluation showed a positive antimitochondrial antibody, and magnetic resonance imaging showed evidence of steatohepatitis. Punch biopsies from both the morbilliform eruption and a deep-seated pustule showed epidermal necrosis, parakeratosis, necrotic keratinocytes, and a lichenoid infiltrate of lymphocytes at the dermoepidermal interface. In the dermis, there was a wedge-shaped superficial and deep, perivascular infiltrate with extravasated erythrocytes (Figures 3 and 4). Tissue Gram stain was negative for bacteria. Varicella-zoster virus and herpes simplex virus immunostains were negative. Direct immunofluorescence showed colloid bodies, as can be seen in lichenoid dermatitis.

At the next clinic visit, the patient reported a fever of 39.4 °C. After reviewing the patient’s histopathology and clinical picture, along with the presence of fever, a final diagnosis of FUMHD was made. The patient was started on an oral regimen of prednisone 80 mg once daily, minocycline 100 mg twice daily, and methotrexate 15 mg weekly. Unna boots (specialized compression wraps) with triamcinolone acetonide ointment 0.1% were placed weekly until the leg edema and ulcerations healed. He was maintained on methotrexate 15 mg weekly and 5 to 10 mg of prednisone once daily. The patient demonstrated residual scarring, with only rare new papulonodules that did not ulcerate when attempts were made to taper his medications. He was followed for nearly 3 years, with a recurrence of symptoms 2 years and 3 months after initial presentation to the academic dermatology clinic.

Febrile ulceronecrotic Mucha-Habermann disease is a rare and severe variant of PLEVA that can present with the rapid appearance of necrotic skin lesions, fever, and systemic manifestations, including pulmonary, gastrointestinal, central nervous system, cardiac, hematologic, and rheumatologic symptoms.^2-4 The evolution from PLEVA to FUMHD ranges from days to weeks, and patientsrarely can have an initial presentation of FUMHD.² The duration of illness has been reported to be 1 to 24 months⁵; however, the length of illness still remains unclear, as many studies of FUMHD are case reports with limited follow-up. Our patient had a disease duration of at least 27 months. The lesions of FUMHD usually are generalized with flexural prominence, and mucosal involvement occurs in approximately one-quarter of cases. Hypertrophic scarring may be seen after the ulcerated lesions heal.² The incidence of FUMHD is higher in men than in women, and it is more common in younger individuals.^2,6 There have been reported fatalities associated with FUMHD, mostly in adults.^2,4

The clinical differential diagnosis for PLEVA includes disseminated herpes zoster, varicella-zoster virus or coxsackievirus infections, lymphomatoid papulosis, angiodestructive lymphoma such as extranodal natural killer/T-cell lymphoma, drug eruption, arthropod bite, erythema multiforme, ecthyma, ecthyma gangrenosum, necrotic folliculitis, and cutaneous small vessel vasculitis. To differentiate between these diagnoses and PLEVA or FUMHD, it is important to take a strong clinical history. For example, for varicella-zoster virus and coxsackievirus infections, exposure history to the viruses and vaccination history for varicella-zoster virus can help elucidate the diagnosis.

Skin biopsy can help differentiate between these entities and PLEVA or FUMHD. The histopathology of a nonulcerated lesion of FUMHD shows parakeratosis, spongiosis, and lymphocyte exocytosis, as well as lymphocytic vasculitis—findings commonly seen in PLEVA. With the ulceronecrotic lesions of FUMHD, epidermal necrosis and ulceration can be seen microscopically.² Although skin biopsy is not absolutely necessary for making the diagnosis of PLEVA, it can be helpful.³ However, given the dramatic and extreme clinical impression with an extensive differential diagnosis that includes disorders ranging from infectious to neoplastic, biopsy of FUMHD with clinicopathologic correlation often is required.

It is important to avoid biopsying ulcerated lesions of FUMHD, as the histopathologic findings are more likely to be nonspecific. Additionally, nonspecific features often are seen with immunohistochemistry; abnormal laboratory testing may be seen in FUMHD, but there is no specific test to diagnose FUMHD.² Finally, a predominantly CD8⁺ cell infiltrate was seen in 4 of 6 cases of FUMHD, with 2 cases showing a mixed infiltrate of CD8⁺ and CD4⁺ cells.^5,7-10

Although no unified diagnostic criterion exists for FUMHD, Nofal et al² proposed criteria comprised of constant features, which are found in every case of FUMHD and can confirm the diagnosis alone, and variable features to help ensure that cases of FUMHD are not missed. The constant features include fever, acute onset of generalized ulceronecrotic papules and plaques, a course that is rapid and progressive (without a tendency for spontaneous resolution), and histopathology that is consistent with PLEVA. The variable features include history of PLEVA, involvement of mucous membranes, and systemic involvement.²

No single unifying treatment modality for all cases of FUMHD has been described. Immunosuppressive drugs (eg, systemic steroids, methotrexate), antibiotics, antivirals, phototherapy, intravenous immunoglobulin, and dapsone have been tried in patients with FUMHD.² Combination therapy with an oral medication such as erythromycin or methotrexate and psoralen plus UVA may be effective for FUMHD.³ Additionally, some authors believe that patients with FUMHD should be treated similar to burn victims with intensive supportive care.²

The etiology of PLEVA is unknown, but it is presumed to be associated with an effector cytotoxic T-cell response to either an infectious agent or a drug.¹¹Three studies have shown that most PLEVA cases (100% [3/3]; 65% [13/20]; and 57% [8/14]) demonstrate T-cell clonality,^12-14 and some have suggested that PLEVA may be a T-cell lymphoproliferative disorder.^12,13 Additionally, in a case report of 2 children with PLEVA who progressed to cutaneous T-cell lymphoma, the authors suggested that PLEVA may be related to nonaggressive cutaneous T-cell lymphoma.¹⁵ Of note, T-cell clonality, often found through the analysis of T-cell receptor gene rearrangement, is not an absolute criterion for determining malignancy, as some benign conditions may have clonality.¹⁶ However, in another study, clonality was found in only 1 of 10 cases of PLEVA, suggesting that PLEVA stems from an inflammatory reaction to infectious or other triggering agents.¹⁷

Four cases of FUMHD with monoclonality have been reported,^4,7,8 and some researchers propose that FUMHD may be a subset of cutaneous T-cell lymphoma.⁷ However, 2 other cases of FUMHD did not show monoclonality of T cells,^5,18 suggesting that FUMHD may represent an inflammatory disorder, rather than a lymphoproliferative process of T cells.¹⁸ Given the controversy surrounding the clonality of FUMHD, T-cell gene rearrangement studies were not performed in our case.

To the Editor:

Pityriasis lichenoides is a papulosquamous dermatologic disorder that is characterized by recurrent papules.¹ There is a spectrum of disease in pityriasis lichenoides that includes pityriasis lichenoides et varioliformis acuta (PLEVA) at one end and pityriasis lichenoides chronica at the other. Pityriasis lichenoides et varioliformis acuta is more common in younger individuals and is characterized by erythematous papules that often crust; these lesions resolve over weeks. The lesions of pityriasis lichenoides chronica are characteristically scaly, pink to red-brown papules that tend to resolve over months.¹

Histologically, PLEVA exhibits parakeratosis, interface dermatitis, and a wedge-shaped infiltrate.¹ Necrotic keratinocytes and extravasated erythrocytes also are common features. Additionally, monoclonal T cells may be present in the infiltrate.¹

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a rare and severe variant of PLEVA. Febrile ulceronecrotic Mucha-Habermann disease is characterized by ulceronecrotic lesions, fever, and systemic symptoms.² Herein, we present a case of FUMHD.

A 57-year-old man presented with an eruption of painful lesions involving the face, trunk, arms, legs, and genitalia of 1 month’s duration. The patient denied oral and ocular involvement. He had soreness and swelling of the arms and legs. A prior 12-day course of prednisone prescribed by a community dermatologist failed to improve the rash. A biopsy performed by a community dermatologist was nondiagnostic. The patient denied fever but did report chills. He had no preceding illness and was not taking new medications. On physical examination, the patient was afebrile and normotensive with innumerable deep-seated pustules and crusted ulcerations on the face, palms, soles, trunk, extremities, and penis (Figures 1 and 2). There was a background morbilliform eruption on the trunk. The ocular and oral mucosae were spared. The upper and lower extremities had pitting edema.

The patient’s alanine aminotransaminase and aspartate aminotransaminase levels were elevated at 55 and 51 U/L, respectively. His white blood cell count was within reference range; however, there was an elevated absolute neutrophil count (8.7×10³/μL). No eosinophilia was noted. Laboratory evaluation showed a positive antimitochondrial antibody, and magnetic resonance imaging showed evidence of steatohepatitis. Punch biopsies from both the morbilliform eruption and a deep-seated pustule showed epidermal necrosis, parakeratosis, necrotic keratinocytes, and a lichenoid infiltrate of lymphocytes at the dermoepidermal interface. In the dermis, there was a wedge-shaped superficial and deep, perivascular infiltrate with extravasated erythrocytes (Figures 3 and 4). Tissue Gram stain was negative for bacteria. Varicella-zoster virus and herpes simplex virus immunostains were negative. Direct immunofluorescence showed colloid bodies, as can be seen in lichenoid dermatitis.

At the next clinic visit, the patient reported a fever of 39.4 °C. After reviewing the patient’s histopathology and clinical picture, along with the presence of fever, a final diagnosis of FUMHD was made. The patient was started on an oral regimen of prednisone 80 mg once daily, minocycline 100 mg twice daily, and methotrexate 15 mg weekly. Unna boots (specialized compression wraps) with triamcinolone acetonide ointment 0.1% were placed weekly until the leg edema and ulcerations healed. He was maintained on methotrexate 15 mg weekly and 5 to 10 mg of prednisone once daily. The patient demonstrated residual scarring, with only rare new papulonodules that did not ulcerate when attempts were made to taper his medications. He was followed for nearly 3 years, with a recurrence of symptoms 2 years and 3 months after initial presentation to the academic dermatology clinic.

Febrile ulceronecrotic Mucha-Habermann disease is a rare and severe variant of PLEVA that can present with the rapid appearance of necrotic skin lesions, fever, and systemic manifestations, including pulmonary, gastrointestinal, central nervous system, cardiac, hematologic, and rheumatologic symptoms.^2-4 The evolution from PLEVA to FUMHD ranges from days to weeks, and patientsrarely can have an initial presentation of FUMHD.² The duration of illness has been reported to be 1 to 24 months⁵; however, the length of illness still remains unclear, as many studies of FUMHD are case reports with limited follow-up. Our patient had a disease duration of at least 27 months. The lesions of FUMHD usually are generalized with flexural prominence, and mucosal involvement occurs in approximately one-quarter of cases. Hypertrophic scarring may be seen after the ulcerated lesions heal.² The incidence of FUMHD is higher in men than in women, and it is more common in younger individuals.^2,6 There have been reported fatalities associated with FUMHD, mostly in adults.^2,4

The clinical differential diagnosis for PLEVA includes disseminated herpes zoster, varicella-zoster virus or coxsackievirus infections, lymphomatoid papulosis, angiodestructive lymphoma such as extranodal natural killer/T-cell lymphoma, drug eruption, arthropod bite, erythema multiforme, ecthyma, ecthyma gangrenosum, necrotic folliculitis, and cutaneous small vessel vasculitis. To differentiate between these diagnoses and PLEVA or FUMHD, it is important to take a strong clinical history. For example, for varicella-zoster virus and coxsackievirus infections, exposure history to the viruses and vaccination history for varicella-zoster virus can help elucidate the diagnosis.

Skin biopsy can help differentiate between these entities and PLEVA or FUMHD. The histopathology of a nonulcerated lesion of FUMHD shows parakeratosis, spongiosis, and lymphocyte exocytosis, as well as lymphocytic vasculitis—findings commonly seen in PLEVA. With the ulceronecrotic lesions of FUMHD, epidermal necrosis and ulceration can be seen microscopically.² Although skin biopsy is not absolutely necessary for making the diagnosis of PLEVA, it can be helpful.³ However, given the dramatic and extreme clinical impression with an extensive differential diagnosis that includes disorders ranging from infectious to neoplastic, biopsy of FUMHD with clinicopathologic correlation often is required.

It is important to avoid biopsying ulcerated lesions of FUMHD, as the histopathologic findings are more likely to be nonspecific. Additionally, nonspecific features often are seen with immunohistochemistry; abnormal laboratory testing may be seen in FUMHD, but there is no specific test to diagnose FUMHD.² Finally, a predominantly CD8⁺ cell infiltrate was seen in 4 of 6 cases of FUMHD, with 2 cases showing a mixed infiltrate of CD8⁺ and CD4⁺ cells.^5,7-10

Although no unified diagnostic criterion exists for FUMHD, Nofal et al² proposed criteria comprised of constant features, which are found in every case of FUMHD and can confirm the diagnosis alone, and variable features to help ensure that cases of FUMHD are not missed. The constant features include fever, acute onset of generalized ulceronecrotic papules and plaques, a course that is rapid and progressive (without a tendency for spontaneous resolution), and histopathology that is consistent with PLEVA. The variable features include history of PLEVA, involvement of mucous membranes, and systemic involvement.²

No single unifying treatment modality for all cases of FUMHD has been described. Immunosuppressive drugs (eg, systemic steroids, methotrexate), antibiotics, antivirals, phototherapy, intravenous immunoglobulin, and dapsone have been tried in patients with FUMHD.² Combination therapy with an oral medication such as erythromycin or methotrexate and psoralen plus UVA may be effective for FUMHD.³ Additionally, some authors believe that patients with FUMHD should be treated similar to burn victims with intensive supportive care.²

The etiology of PLEVA is unknown, but it is presumed to be associated with an effector cytotoxic T-cell response to either an infectious agent or a drug.¹¹Three studies have shown that most PLEVA cases (100% [3/3]; 65% [13/20]; and 57% [8/14]) demonstrate T-cell clonality,^12-14 and some have suggested that PLEVA may be a T-cell lymphoproliferative disorder.^12,13 Additionally, in a case report of 2 children with PLEVA who progressed to cutaneous T-cell lymphoma, the authors suggested that PLEVA may be related to nonaggressive cutaneous T-cell lymphoma.¹⁵ Of note, T-cell clonality, often found through the analysis of T-cell receptor gene rearrangement, is not an absolute criterion for determining malignancy, as some benign conditions may have clonality.¹⁶ However, in another study, clonality was found in only 1 of 10 cases of PLEVA, suggesting that PLEVA stems from an inflammatory reaction to infectious or other triggering agents.¹⁷

Four cases of FUMHD with monoclonality have been reported,^4,7,8 and some researchers propose that FUMHD may be a subset of cutaneous T-cell lymphoma.⁷ However, 2 other cases of FUMHD did not show monoclonality of T cells,^5,18 suggesting that FUMHD may represent an inflammatory disorder, rather than a lymphoproliferative process of T cells.¹⁸ Given the controversy surrounding the clonality of FUMHD, T-cell gene rearrangement studies were not performed in our case.

To the Editor:

Pityriasis lichenoides is a papulosquamous dermatologic disorder that is characterized by recurrent papules.¹ There is a spectrum of disease in pityriasis lichenoides that includes pityriasis lichenoides et varioliformis acuta (PLEVA) at one end and pityriasis lichenoides chronica at the other. Pityriasis lichenoides et varioliformis acuta is more common in younger individuals and is characterized by erythematous papules that often crust; these lesions resolve over weeks. The lesions of pityriasis lichenoides chronica are characteristically scaly, pink to red-brown papules that tend to resolve over months.¹

Histologically, PLEVA exhibits parakeratosis, interface dermatitis, and a wedge-shaped infiltrate.¹ Necrotic keratinocytes and extravasated erythrocytes also are common features. Additionally, monoclonal T cells may be present in the infiltrate.¹

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a rare and severe variant of PLEVA. Febrile ulceronecrotic Mucha-Habermann disease is characterized by ulceronecrotic lesions, fever, and systemic symptoms.² Herein, we present a case of FUMHD.

A 57-year-old man presented with an eruption of painful lesions involving the face, trunk, arms, legs, and genitalia of 1 month’s duration. The patient denied oral and ocular involvement. He had soreness and swelling of the arms and legs. A prior 12-day course of prednisone prescribed by a community dermatologist failed to improve the rash. A biopsy performed by a community dermatologist was nondiagnostic. The patient denied fever but did report chills. He had no preceding illness and was not taking new medications. On physical examination, the patient was afebrile and normotensive with innumerable deep-seated pustules and crusted ulcerations on the face, palms, soles, trunk, extremities, and penis (Figures 1 and 2). There was a background morbilliform eruption on the trunk. The ocular and oral mucosae were spared. The upper and lower extremities had pitting edema.

The patient’s alanine aminotransaminase and aspartate aminotransaminase levels were elevated at 55 and 51 U/L, respectively. His white blood cell count was within reference range; however, there was an elevated absolute neutrophil count (8.7×10³/μL). No eosinophilia was noted. Laboratory evaluation showed a positive antimitochondrial antibody, and magnetic resonance imaging showed evidence of steatohepatitis. Punch biopsies from both the morbilliform eruption and a deep-seated pustule showed epidermal necrosis, parakeratosis, necrotic keratinocytes, and a lichenoid infiltrate of lymphocytes at the dermoepidermal interface. In the dermis, there was a wedge-shaped superficial and deep, perivascular infiltrate with extravasated erythrocytes (Figures 3 and 4). Tissue Gram stain was negative for bacteria. Varicella-zoster virus and herpes simplex virus immunostains were negative. Direct immunofluorescence showed colloid bodies, as can be seen in lichenoid dermatitis.

At the next clinic visit, the patient reported a fever of 39.4 °C. After reviewing the patient’s histopathology and clinical picture, along with the presence of fever, a final diagnosis of FUMHD was made. The patient was started on an oral regimen of prednisone 80 mg once daily, minocycline 100 mg twice daily, and methotrexate 15 mg weekly. Unna boots (specialized compression wraps) with triamcinolone acetonide ointment 0.1% were placed weekly until the leg edema and ulcerations healed. He was maintained on methotrexate 15 mg weekly and 5 to 10 mg of prednisone once daily. The patient demonstrated residual scarring, with only rare new papulonodules that did not ulcerate when attempts were made to taper his medications. He was followed for nearly 3 years, with a recurrence of symptoms 2 years and 3 months after initial presentation to the academic dermatology clinic.

Febrile ulceronecrotic Mucha-Habermann disease is a rare and severe variant of PLEVA that can present with the rapid appearance of necrotic skin lesions, fever, and systemic manifestations, including pulmonary, gastrointestinal, central nervous system, cardiac, hematologic, and rheumatologic symptoms.^2-4 The evolution from PLEVA to FUMHD ranges from days to weeks, and patientsrarely can have an initial presentation of FUMHD.² The duration of illness has been reported to be 1 to 24 months⁵; however, the length of illness still remains unclear, as many studies of FUMHD are case reports with limited follow-up. Our patient had a disease duration of at least 27 months. The lesions of FUMHD usually are generalized with flexural prominence, and mucosal involvement occurs in approximately one-quarter of cases. Hypertrophic scarring may be seen after the ulcerated lesions heal.² The incidence of FUMHD is higher in men than in women, and it is more common in younger individuals.^2,6 There have been reported fatalities associated with FUMHD, mostly in adults.^2,4

The clinical differential diagnosis for PLEVA includes disseminated herpes zoster, varicella-zoster virus or coxsackievirus infections, lymphomatoid papulosis, angiodestructive lymphoma such as extranodal natural killer/T-cell lymphoma, drug eruption, arthropod bite, erythema multiforme, ecthyma, ecthyma gangrenosum, necrotic folliculitis, and cutaneous small vessel vasculitis. To differentiate between these diagnoses and PLEVA or FUMHD, it is important to take a strong clinical history. For example, for varicella-zoster virus and coxsackievirus infections, exposure history to the viruses and vaccination history for varicella-zoster virus can help elucidate the diagnosis.

Skin biopsy can help differentiate between these entities and PLEVA or FUMHD. The histopathology of a nonulcerated lesion of FUMHD shows parakeratosis, spongiosis, and lymphocyte exocytosis, as well as lymphocytic vasculitis—findings commonly seen in PLEVA. With the ulceronecrotic lesions of FUMHD, epidermal necrosis and ulceration can be seen microscopically.² Although skin biopsy is not absolutely necessary for making the diagnosis of PLEVA, it can be helpful.³ However, given the dramatic and extreme clinical impression with an extensive differential diagnosis that includes disorders ranging from infectious to neoplastic, biopsy of FUMHD with clinicopathologic correlation often is required.

It is important to avoid biopsying ulcerated lesions of FUMHD, as the histopathologic findings are more likely to be nonspecific. Additionally, nonspecific features often are seen with immunohistochemistry; abnormal laboratory testing may be seen in FUMHD, but there is no specific test to diagnose FUMHD.² Finally, a predominantly CD8⁺ cell infiltrate was seen in 4 of 6 cases of FUMHD, with 2 cases showing a mixed infiltrate of CD8⁺ and CD4⁺ cells.^5,7-10

Although no unified diagnostic criterion exists for FUMHD, Nofal et al² proposed criteria comprised of constant features, which are found in every case of FUMHD and can confirm the diagnosis alone, and variable features to help ensure that cases of FUMHD are not missed. The constant features include fever, acute onset of generalized ulceronecrotic papules and plaques, a course that is rapid and progressive (without a tendency for spontaneous resolution), and histopathology that is consistent with PLEVA. The variable features include history of PLEVA, involvement of mucous membranes, and systemic involvement.²

No single unifying treatment modality for all cases of FUMHD has been described. Immunosuppressive drugs (eg, systemic steroids, methotrexate), antibiotics, antivirals, phototherapy, intravenous immunoglobulin, and dapsone have been tried in patients with FUMHD.² Combination therapy with an oral medication such as erythromycin or methotrexate and psoralen plus UVA may be effective for FUMHD.³ Additionally, some authors believe that patients with FUMHD should be treated similar to burn victims with intensive supportive care.²

The etiology of PLEVA is unknown, but it is presumed to be associated with an effector cytotoxic T-cell response to either an infectious agent or a drug.¹¹Three studies have shown that most PLEVA cases (100% [3/3]; 65% [13/20]; and 57% [8/14]) demonstrate T-cell clonality,^12-14 and some have suggested that PLEVA may be a T-cell lymphoproliferative disorder.^12,13 Additionally, in a case report of 2 children with PLEVA who progressed to cutaneous T-cell lymphoma, the authors suggested that PLEVA may be related to nonaggressive cutaneous T-cell lymphoma.¹⁵ Of note, T-cell clonality, often found through the analysis of T-cell receptor gene rearrangement, is not an absolute criterion for determining malignancy, as some benign conditions may have clonality.¹⁶ However, in another study, clonality was found in only 1 of 10 cases of PLEVA, suggesting that PLEVA stems from an inflammatory reaction to infectious or other triggering agents.¹⁷

Four cases of FUMHD with monoclonality have been reported,^4,7,8 and some researchers propose that FUMHD may be a subset of cutaneous T-cell lymphoma.⁷ However, 2 other cases of FUMHD did not show monoclonality of T cells,^5,18 suggesting that FUMHD may represent an inflammatory disorder, rather than a lymphoproliferative process of T cells.¹⁸ Given the controversy surrounding the clonality of FUMHD, T-cell gene rearrangement studies were not performed in our case.

The Diagnosis: Actinomycetoma

Histopathology revealed evidence of an actinomycete organism within the suppuration, consistent with actinomycosis (quiz image [inset]). Given the clinical presentation and histopathologic findings, our patient was diagnosed with actinomycetoma.

Actinomycetoma is an indolent, progressive, subcutaneous infection characterized by a well-known clinical triad of tumefaction/subcutaneous mass, draining sinuses, and an exudate containing grains on microscopy. The sinus tracts are formed from the chronic infectious process that destroys tissue, creating tunnels. This infectious disease of soft tissue is a clinical subset of mycetoma, which is categorized as eumycetoma (fungal) and actinomycetoma (bacterial). Actinomycetoma resembles the behavior of insidious and chronic fungal infections; however, most mycetoma infections are bacterial.^1,2 Actinomycetoma may be confused with actinomycosis, which is caused by Actinomycoses species, commensal organisms commonly located on the teeth and oral mucosa in association with other microorganisms that may pathogenically cause cervicofacial actinomycosis.^3,4 Actinomycetoma can be caused by Nocardia, Streptomyces, and Actinomadura. ^2,5 The foot is the most common location of involvement followed by the thoracic region. It is more common in tropical or equatorial locations and may be contracted through exposure to soil or wood.⁵ Mycetoma is considered a neglected tropical disease by the World Health Organization.1 In tropical countries, this disease may go undiagnosed or untreated for so long that surgical amputation may be the only effective treatment.

Actinomycetoma commonly is identifiable by direct microscopy, Gram stain, or bacterial culture, with Gram stain being more sensitive than bacterial culture.³ It is important to indicate the suspected organism to the microbiology laboratory because common bacterial pathogens are detected within 24 to 48 hours, but the causative microorganism in actinomycetoma may require up to 4 weeks for culture,² leading to possible false negatives due to inadequate culture time.³ Histopathology of actinomycotic infections will demonstrate granulomatous inflammation, focal suppuration, and the presence of grains (ie, a colony of filamentous bacteria in a stellate shaped mass)(quiz image [inset]).

The gold standard of treatment is trimethoprim-sulfamethoxazole for up to several years.^4,5 Amoxicillin–clavulanic acid, dapsone, amikacin, streptomycin, and beta-lactams have been used successfully.^2,5 The treatment course is dependent on clinical severity and location of the disease. The cure rate with appropriate antibiotics can be as high as 90%,^2,5 and thus surgical intervention can be avoided.

In the differential, cutaneous tuberculosis would show tuberculoid granulomas with epithelioid histiocytes with possible caseation on histopathology, typically alongside positive tuberculosis screening. Botryomycosis has a similar clinical presentation of a swollen or indurated lesion with draining sinus tracts, but it less commonly occurs on the trunk. Histopathology also is a close mimic of actinomycetoma with a small grain inside a suppurative infiltrate; however, it has no filamentous bacteria. A foreign body reaction would not histologically present with suppuration or grains, and draining sinuses typically would not be seen on clinical presentation. Sarcoma is a neoplastic process and most commonly would show a proliferation of cells with soft tissue or bone origin on histopathology and not primarily an inflammatory cell process.⁶

The Diagnosis: Actinomycetoma

Histopathology revealed evidence of an actinomycete organism within the suppuration, consistent with actinomycosis (quiz image [inset]). Given the clinical presentation and histopathologic findings, our patient was diagnosed with actinomycetoma.

Actinomycetoma is an indolent, progressive, subcutaneous infection characterized by a well-known clinical triad of tumefaction/subcutaneous mass, draining sinuses, and an exudate containing grains on microscopy. The sinus tracts are formed from the chronic infectious process that destroys tissue, creating tunnels. This infectious disease of soft tissue is a clinical subset of mycetoma, which is categorized as eumycetoma (fungal) and actinomycetoma (bacterial). Actinomycetoma resembles the behavior of insidious and chronic fungal infections; however, most mycetoma infections are bacterial.^1,2 Actinomycetoma may be confused with actinomycosis, which is caused by Actinomycoses species, commensal organisms commonly located on the teeth and oral mucosa in association with other microorganisms that may pathogenically cause cervicofacial actinomycosis.^3,4 Actinomycetoma can be caused by Nocardia, Streptomyces, and Actinomadura. ^2,5 The foot is the most common location of involvement followed by the thoracic region. It is more common in tropical or equatorial locations and may be contracted through exposure to soil or wood.⁵ Mycetoma is considered a neglected tropical disease by the World Health Organization.1 In tropical countries, this disease may go undiagnosed or untreated for so long that surgical amputation may be the only effective treatment.

Actinomycetoma commonly is identifiable by direct microscopy, Gram stain, or bacterial culture, with Gram stain being more sensitive than bacterial culture.³ It is important to indicate the suspected organism to the microbiology laboratory because common bacterial pathogens are detected within 24 to 48 hours, but the causative microorganism in actinomycetoma may require up to 4 weeks for culture,² leading to possible false negatives due to inadequate culture time.³ Histopathology of actinomycotic infections will demonstrate granulomatous inflammation, focal suppuration, and the presence of grains (ie, a colony of filamentous bacteria in a stellate shaped mass)(quiz image [inset]).

The gold standard of treatment is trimethoprim-sulfamethoxazole for up to several years.^4,5 Amoxicillin–clavulanic acid, dapsone, amikacin, streptomycin, and beta-lactams have been used successfully.^2,5 The treatment course is dependent on clinical severity and location of the disease. The cure rate with appropriate antibiotics can be as high as 90%,^2,5 and thus surgical intervention can be avoided.

In the differential, cutaneous tuberculosis would show tuberculoid granulomas with epithelioid histiocytes with possible caseation on histopathology, typically alongside positive tuberculosis screening. Botryomycosis has a similar clinical presentation of a swollen or indurated lesion with draining sinus tracts, but it less commonly occurs on the trunk. Histopathology also is a close mimic of actinomycetoma with a small grain inside a suppurative infiltrate; however, it has no filamentous bacteria. A foreign body reaction would not histologically present with suppuration or grains, and draining sinuses typically would not be seen on clinical presentation. Sarcoma is a neoplastic process and most commonly would show a proliferation of cells with soft tissue or bone origin on histopathology and not primarily an inflammatory cell process.⁶

The Diagnosis: Actinomycetoma

Histopathology revealed evidence of an actinomycete organism within the suppuration, consistent with actinomycosis (quiz image [inset]). Given the clinical presentation and histopathologic findings, our patient was diagnosed with actinomycetoma.

Actinomycetoma is an indolent, progressive, subcutaneous infection characterized by a well-known clinical triad of tumefaction/subcutaneous mass, draining sinuses, and an exudate containing grains on microscopy. The sinus tracts are formed from the chronic infectious process that destroys tissue, creating tunnels. This infectious disease of soft tissue is a clinical subset of mycetoma, which is categorized as eumycetoma (fungal) and actinomycetoma (bacterial). Actinomycetoma resembles the behavior of insidious and chronic fungal infections; however, most mycetoma infections are bacterial.^1,2 Actinomycetoma may be confused with actinomycosis, which is caused by Actinomycoses species, commensal organisms commonly located on the teeth and oral mucosa in association with other microorganisms that may pathogenically cause cervicofacial actinomycosis.^3,4 Actinomycetoma can be caused by Nocardia, Streptomyces, and Actinomadura. ^2,5 The foot is the most common location of involvement followed by the thoracic region. It is more common in tropical or equatorial locations and may be contracted through exposure to soil or wood.⁵ Mycetoma is considered a neglected tropical disease by the World Health Organization.1 In tropical countries, this disease may go undiagnosed or untreated for so long that surgical amputation may be the only effective treatment.

Actinomycetoma commonly is identifiable by direct microscopy, Gram stain, or bacterial culture, with Gram stain being more sensitive than bacterial culture.³ It is important to indicate the suspected organism to the microbiology laboratory because common bacterial pathogens are detected within 24 to 48 hours, but the causative microorganism in actinomycetoma may require up to 4 weeks for culture,² leading to possible false negatives due to inadequate culture time.³ Histopathology of actinomycotic infections will demonstrate granulomatous inflammation, focal suppuration, and the presence of grains (ie, a colony of filamentous bacteria in a stellate shaped mass)(quiz image [inset]).

The gold standard of treatment is trimethoprim-sulfamethoxazole for up to several years.^4,5 Amoxicillin–clavulanic acid, dapsone, amikacin, streptomycin, and beta-lactams have been used successfully.^2,5 The treatment course is dependent on clinical severity and location of the disease. The cure rate with appropriate antibiotics can be as high as 90%,^2,5 and thus surgical intervention can be avoided.

In the differential, cutaneous tuberculosis would show tuberculoid granulomas with epithelioid histiocytes with possible caseation on histopathology, typically alongside positive tuberculosis screening. Botryomycosis has a similar clinical presentation of a swollen or indurated lesion with draining sinus tracts, but it less commonly occurs on the trunk. Histopathology also is a close mimic of actinomycetoma with a small grain inside a suppurative infiltrate; however, it has no filamentous bacteria. A foreign body reaction would not histologically present with suppuration or grains, and draining sinuses typically would not be seen on clinical presentation. Sarcoma is a neoplastic process and most commonly would show a proliferation of cells with soft tissue or bone origin on histopathology and not primarily an inflammatory cell process.⁶

THE DIAGNOSIS:

Acquired Perforating Disorder of Renal Disease

A papule with the central plug removed left a pitlike depression, representing Kyrle disease (Figure 1). A punch biopsy of the left forearm revealed epidermal hyperplasia (Figure 2A) surrounding a keratin plug that contained degenerated basophilic material (Figure 2B), confirming the diagnosis of acquired perforating disorder of renal disease (APDRD), classically described as Kyrle disease.

Acquired perforating disorder of renal disease is an uncommon condition in the general population. It is associated with systemic disease, commonly diabetes mellitus and chronic renal failure, and is seen in up to 10% patients receiving hemodialysis.¹ The underlying etiology and pathogenesis of APDRD remains unknown. It has been proposed to be a variant of prurigo nodularis, representing end-stage excoriated folliculitis.¹ Given that most cases appear in patients with systemic disease and metabolic abnormalities, APDRD also has been classified under the spectrum of acquired perforating dermatoses, a group of disorders defined by transepithelial elimination of dermal connective tissue. Elevated levels of serum and tissue fibronectin, uremia, and hyperphosphatemia have been observed in patients with APDRD.^1,2 Fibronectin stimulates epithelial migration and proliferation and may lead to expulsion of keratin. Furthermore, dermal deposition of excess urea and/or phosphate could initiate transepithelial elimination of material. Alternative hypotheses implicate abnormal keratinization or an imbalance between the rates of epidermal proliferation/ differentiation and keratin production, whereby keratin production outpaces the former. Keratin deposited within the dermis subsequently elicits an inflammatory response along with alterations in the local dermis and connective tissue. These components become intermixed and are extruded through the plug opening.³ Lastly, immune dysregulation resulting from systemic disease could contribute to APDRD through increased expression of IL-31, a cytokine thought to play a role in several pruritic inflammatory skin diseases.⁴

Although standardized treatment guidelines for APDRD have not been established, the mainstay of therapy is control of the underlying systemic disorder. Intense pruritus and repeated scratching may contribute to microtrauma and subsequent koebnerization of new lesions.³ Thus, ameliorating pruritus can provide both symptomatic relief and prevent the development of new lesions. Retinoids, UV light, oral antibiotics, antihistamines, corticosteroids, keratolytic agents, and immunosuppressants (eg, allopurinol, tacrolimus) have shown some benefit.⁴

The differential diagnoses for APDRD include arthropod hypersensitivity reactions, eruptive keratoacanthomas, keratosis pilaris, and prurigo nodularis. Arthropod hypersensitivity reactions are seen in patients with a history of a bite or sting from arthropods such as bees, fleas, mites, ticks, and spiders. These reactions cause symptoms of pain, burning, or pruritus and present heterogeneously. They can be edematous and appear as single or multiple papules, pustules, plaques, vesicles, and/or bullae. A central punctum or crusting also may be present. Eruptive keratoacanthomas are seen in Grzybowski syndrome and Ferguson-Smith disease. Grzybowski syndrome arises in the fifth to seventh decades of life and is characterized by the eruptive onset of hundreds to thousands of pruritic, dome-shaped, follicular papules with or without central keratin plugs. Ectropion, mucosal lesions, and masklike facies are other clinical characteristics of Grzybowski syndrome. Ferguson-Smith disease begins in the second decade of life. The eruption of multiple keratoacanthomas and/or squamous cell carcinomas occurs in crops, rapidly growing over 2 to 4 weeks, and then self-resolves. This disease is inherited in an autosomal-dominant manner and is associated with chromosome 9q22. Keratosis pilaris is a benign condition of follicular hyperkeratosis that can appear in any age group and usually is absent of symptoms. It is not associated with any systemic disease. Clinically, the condition appears as folliculocentric keratotic papules with varying degrees of perifollicular erythema located along the extensor surfaces. Keratosis pilaris and APDRD share features of a follicular hyperkeratosis and dilated infundibulum; however, perforation is absent in keratosis pilaris. Lastly, prurigo nodularis is another intensely pruritic dermatosis associated with renal disease that presents as papulonodules on the extensor surfaces of the arms and legs. A biopsy can help to distinguish prurigo nodularis from APDRD.

THE DIAGNOSIS:

Acquired Perforating Disorder of Renal Disease

A papule with the central plug removed left a pitlike depression, representing Kyrle disease (Figure 1). A punch biopsy of the left forearm revealed epidermal hyperplasia (Figure 2A) surrounding a keratin plug that contained degenerated basophilic material (Figure 2B), confirming the diagnosis of acquired perforating disorder of renal disease (APDRD), classically described as Kyrle disease.

Acquired perforating disorder of renal disease is an uncommon condition in the general population. It is associated with systemic disease, commonly diabetes mellitus and chronic renal failure, and is seen in up to 10% patients receiving hemodialysis.¹ The underlying etiology and pathogenesis of APDRD remains unknown. It has been proposed to be a variant of prurigo nodularis, representing end-stage excoriated folliculitis.¹ Given that most cases appear in patients with systemic disease and metabolic abnormalities, APDRD also has been classified under the spectrum of acquired perforating dermatoses, a group of disorders defined by transepithelial elimination of dermal connective tissue. Elevated levels of serum and tissue fibronectin, uremia, and hyperphosphatemia have been observed in patients with APDRD.^1,2 Fibronectin stimulates epithelial migration and proliferation and may lead to expulsion of keratin. Furthermore, dermal deposition of excess urea and/or phosphate could initiate transepithelial elimination of material. Alternative hypotheses implicate abnormal keratinization or an imbalance between the rates of epidermal proliferation/ differentiation and keratin production, whereby keratin production outpaces the former. Keratin deposited within the dermis subsequently elicits an inflammatory response along with alterations in the local dermis and connective tissue. These components become intermixed and are extruded through the plug opening.³ Lastly, immune dysregulation resulting from systemic disease could contribute to APDRD through increased expression of IL-31, a cytokine thought to play a role in several pruritic inflammatory skin diseases.⁴

Although standardized treatment guidelines for APDRD have not been established, the mainstay of therapy is control of the underlying systemic disorder. Intense pruritus and repeated scratching may contribute to microtrauma and subsequent koebnerization of new lesions.³ Thus, ameliorating pruritus can provide both symptomatic relief and prevent the development of new lesions. Retinoids, UV light, oral antibiotics, antihistamines, corticosteroids, keratolytic agents, and immunosuppressants (eg, allopurinol, tacrolimus) have shown some benefit.⁴

The differential diagnoses for APDRD include arthropod hypersensitivity reactions, eruptive keratoacanthomas, keratosis pilaris, and prurigo nodularis. Arthropod hypersensitivity reactions are seen in patients with a history of a bite or sting from arthropods such as bees, fleas, mites, ticks, and spiders. These reactions cause symptoms of pain, burning, or pruritus and present heterogeneously. They can be edematous and appear as single or multiple papules, pustules, plaques, vesicles, and/or bullae. A central punctum or crusting also may be present. Eruptive keratoacanthomas are seen in Grzybowski syndrome and Ferguson-Smith disease. Grzybowski syndrome arises in the fifth to seventh decades of life and is characterized by the eruptive onset of hundreds to thousands of pruritic, dome-shaped, follicular papules with or without central keratin plugs. Ectropion, mucosal lesions, and masklike facies are other clinical characteristics of Grzybowski syndrome. Ferguson-Smith disease begins in the second decade of life. The eruption of multiple keratoacanthomas and/or squamous cell carcinomas occurs in crops, rapidly growing over 2 to 4 weeks, and then self-resolves. This disease is inherited in an autosomal-dominant manner and is associated with chromosome 9q22. Keratosis pilaris is a benign condition of follicular hyperkeratosis that can appear in any age group and usually is absent of symptoms. It is not associated with any systemic disease. Clinically, the condition appears as folliculocentric keratotic papules with varying degrees of perifollicular erythema located along the extensor surfaces. Keratosis pilaris and APDRD share features of a follicular hyperkeratosis and dilated infundibulum; however, perforation is absent in keratosis pilaris. Lastly, prurigo nodularis is another intensely pruritic dermatosis associated with renal disease that presents as papulonodules on the extensor surfaces of the arms and legs. A biopsy can help to distinguish prurigo nodularis from APDRD.

THE DIAGNOSIS:

Acquired Perforating Disorder of Renal Disease

A papule with the central plug removed left a pitlike depression, representing Kyrle disease (Figure 1). A punch biopsy of the left forearm revealed epidermal hyperplasia (Figure 2A) surrounding a keratin plug that contained degenerated basophilic material (Figure 2B), confirming the diagnosis of acquired perforating disorder of renal disease (APDRD), classically described as Kyrle disease.

Acquired perforating disorder of renal disease is an uncommon condition in the general population. It is associated with systemic disease, commonly diabetes mellitus and chronic renal failure, and is seen in up to 10% patients receiving hemodialysis.¹ The underlying etiology and pathogenesis of APDRD remains unknown. It has been proposed to be a variant of prurigo nodularis, representing end-stage excoriated folliculitis.¹ Given that most cases appear in patients with systemic disease and metabolic abnormalities, APDRD also has been classified under the spectrum of acquired perforating dermatoses, a group of disorders defined by transepithelial elimination of dermal connective tissue. Elevated levels of serum and tissue fibronectin, uremia, and hyperphosphatemia have been observed in patients with APDRD.^1,2 Fibronectin stimulates epithelial migration and proliferation and may lead to expulsion of keratin. Furthermore, dermal deposition of excess urea and/or phosphate could initiate transepithelial elimination of material. Alternative hypotheses implicate abnormal keratinization or an imbalance between the rates of epidermal proliferation/ differentiation and keratin production, whereby keratin production outpaces the former. Keratin deposited within the dermis subsequently elicits an inflammatory response along with alterations in the local dermis and connective tissue. These components become intermixed and are extruded through the plug opening.³ Lastly, immune dysregulation resulting from systemic disease could contribute to APDRD through increased expression of IL-31, a cytokine thought to play a role in several pruritic inflammatory skin diseases.⁴

Although standardized treatment guidelines for APDRD have not been established, the mainstay of therapy is control of the underlying systemic disorder. Intense pruritus and repeated scratching may contribute to microtrauma and subsequent koebnerization of new lesions.³ Thus, ameliorating pruritus can provide both symptomatic relief and prevent the development of new lesions. Retinoids, UV light, oral antibiotics, antihistamines, corticosteroids, keratolytic agents, and immunosuppressants (eg, allopurinol, tacrolimus) have shown some benefit.⁴

The differential diagnoses for APDRD include arthropod hypersensitivity reactions, eruptive keratoacanthomas, keratosis pilaris, and prurigo nodularis. Arthropod hypersensitivity reactions are seen in patients with a history of a bite or sting from arthropods such as bees, fleas, mites, ticks, and spiders. These reactions cause symptoms of pain, burning, or pruritus and present heterogeneously. They can be edematous and appear as single or multiple papules, pustules, plaques, vesicles, and/or bullae. A central punctum or crusting also may be present. Eruptive keratoacanthomas are seen in Grzybowski syndrome and Ferguson-Smith disease. Grzybowski syndrome arises in the fifth to seventh decades of life and is characterized by the eruptive onset of hundreds to thousands of pruritic, dome-shaped, follicular papules with or without central keratin plugs. Ectropion, mucosal lesions, and masklike facies are other clinical characteristics of Grzybowski syndrome. Ferguson-Smith disease begins in the second decade of life. The eruption of multiple keratoacanthomas and/or squamous cell carcinomas occurs in crops, rapidly growing over 2 to 4 weeks, and then self-resolves. This disease is inherited in an autosomal-dominant manner and is associated with chromosome 9q22. Keratosis pilaris is a benign condition of follicular hyperkeratosis that can appear in any age group and usually is absent of symptoms. It is not associated with any systemic disease. Clinically, the condition appears as folliculocentric keratotic papules with varying degrees of perifollicular erythema located along the extensor surfaces. Keratosis pilaris and APDRD share features of a follicular hyperkeratosis and dilated infundibulum; however, perforation is absent in keratosis pilaris. Lastly, prurigo nodularis is another intensely pruritic dermatosis associated with renal disease that presents as papulonodules on the extensor surfaces of the arms and legs. A biopsy can help to distinguish prurigo nodularis from APDRD.

THE DIAGNOSIS:

Cutaneous Metastatic Mesothelioma

Biopsies of the larger erythematous papules revealed an infiltrate of atypical tumor cells with mitoses (Figure 1) that were immunoreactive for calretinin (Figure 2) and lacked nuclear BRCA1 associated protein-1, BAP1, expression (not shown). The patient’s prior mesothelioma was re-reviewed, and the cutaneous tumor cells were similar to the primary mesothelioma. A diagnosis of cutaneous metastatic mesothelioma (CMM) was made.

Mesothelioma is a rare neoplasm arising from the pleura, pericardium, peritoneum, and tunica vaginalis,¹ with an estimated annual incidence of 2500 cases.² The predominant risk factor for the development of pleural mesothelioma is asbestos exposure, which has been identified in up to 90% of cases. Mesothelioma can give rise to local and less frequently distant hematogenous metastases. Cutaneous involvement of mesothelioma is rare.³ More than 80% of CMM cases are attributed to seeding the skin at procedure sites or by direct infiltration of scars. Distant CMM is rare and typically presents as subcutaneous nodules.⁴ Few cases of inflammatory CMM have been published,^1,4,5 with even fewer mimicking herpes zoster infection (HZI), as seen in our patient.

The most specific stain for mesothelioma is calretinin, which strongly and diffusely stains both the nucleus and cytoplasm. Other markers include Wilms tumor 1, cytokeratin 5/6, thrombomodulin, and HBME-1. Immunohistochemistry to detect the loss of BAP1 staining in the nucleus is important for differentiating between mesothelioma and mesothelial hyperplasia.³

Cutaneous metastases occur in 0.7% to 9% of patients with internal malignant disease. Most commonly, cutaneous metastases present as cutaneous nodules, though other reported inflammatory presentations include erysipeloides, generalized erythematous patches, telangiectasia, and zosteriform distributions.⁶ Zosteriform distributions are particularly rare and most commonly are due to breast carcinomas or lymphomas. The mechanism of zosteriform metastasis is unknown, but theories include tumoral spread along vessels, invasion of the thoracic perineural sheaths, localized spread of tumor cells from a surgical site, or a Koebner-like reaction at the site of an existing HZI. Regardless of primary tumor type or presentation, cutaneous metastasis is a poor prognostic sign, with survival rates varying based on primary tumor type.⁷

Other differential diagnoses include herpes zoster granulomatous dermatitis, radiation recall dermatitis, cutaneous Rosai-Dorfman disease, and zosteriform lichen planus, all of which have been reported after HZI.^8-10 Herpes zoster granulomatous dermatitis typically presents weeks to years after acute HZI with erythematous to violaceous papules and plaques at the site of the prior HZI. A biopsy reveals interstitial granulomatous dermatitis and multinucleated giant cells.⁸ Radiation recall dermatitis is a cutaneous inflammatory reaction limited to regions of prior radiation exposure after the administration of a triggering medication. Radiation recall dermatitis can present days to many years after the completion of treatment.⁹ Although the eruption in our patient was at the site of prior radiation, the pathologic and clinical presentation was not consistent with radiation recall dermatitis. Cutaneous Rosai-Dorfman disease is a non-Langerhans cell histiocytosis that may present as either solitary or numerous papules, plaques, or nodules and has been reported to occur after HZI. Biopsy reveals a diffuse dermal histiocytic infiltration with plasma cells and lymphocytes. In contrast to metastatic disease, mitoses and nuclear atypia are rare in cutaneous RosaiDorfman disease.¹¹ Lichen planus is an inflammatory disease of unknown etiology presenting as flat-topped, violaceous, pruritic papules¹² that may present in a zosteriform pattern.¹³

Although it is uncommon, metastatic spread should be considered in patients with known malignancy presenting with zosteriform eruptions.² Our patient remained on treatment with immunotherapy, as he was unable to undergo additional radiation and had failed multiple other lines of therapy. He died 3 months after presentation.

THE DIAGNOSIS:

Cutaneous Metastatic Mesothelioma

Biopsies of the larger erythematous papules revealed an infiltrate of atypical tumor cells with mitoses (Figure 1) that were immunoreactive for calretinin (Figure 2) and lacked nuclear BRCA1 associated protein-1, BAP1, expression (not shown). The patient’s prior mesothelioma was re-reviewed, and the cutaneous tumor cells were similar to the primary mesothelioma. A diagnosis of cutaneous metastatic mesothelioma (CMM) was made.

Mesothelioma is a rare neoplasm arising from the pleura, pericardium, peritoneum, and tunica vaginalis,¹ with an estimated annual incidence of 2500 cases.² The predominant risk factor for the development of pleural mesothelioma is asbestos exposure, which has been identified in up to 90% of cases. Mesothelioma can give rise to local and less frequently distant hematogenous metastases. Cutaneous involvement of mesothelioma is rare.³ More than 80% of CMM cases are attributed to seeding the skin at procedure sites or by direct infiltration of scars. Distant CMM is rare and typically presents as subcutaneous nodules.⁴ Few cases of inflammatory CMM have been published,^1,4,5 with even fewer mimicking herpes zoster infection (HZI), as seen in our patient.

The most specific stain for mesothelioma is calretinin, which strongly and diffusely stains both the nucleus and cytoplasm. Other markers include Wilms tumor 1, cytokeratin 5/6, thrombomodulin, and HBME-1. Immunohistochemistry to detect the loss of BAP1 staining in the nucleus is important for differentiating between mesothelioma and mesothelial hyperplasia.³

Cutaneous metastases occur in 0.7% to 9% of patients with internal malignant disease. Most commonly, cutaneous metastases present as cutaneous nodules, though other reported inflammatory presentations include erysipeloides, generalized erythematous patches, telangiectasia, and zosteriform distributions.⁶ Zosteriform distributions are particularly rare and most commonly are due to breast carcinomas or lymphomas. The mechanism of zosteriform metastasis is unknown, but theories include tumoral spread along vessels, invasion of the thoracic perineural sheaths, localized spread of tumor cells from a surgical site, or a Koebner-like reaction at the site of an existing HZI. Regardless of primary tumor type or presentation, cutaneous metastasis is a poor prognostic sign, with survival rates varying based on primary tumor type.⁷

Other differential diagnoses include herpes zoster granulomatous dermatitis, radiation recall dermatitis, cutaneous Rosai-Dorfman disease, and zosteriform lichen planus, all of which have been reported after HZI.^8-10 Herpes zoster granulomatous dermatitis typically presents weeks to years after acute HZI with erythematous to violaceous papules and plaques at the site of the prior HZI. A biopsy reveals interstitial granulomatous dermatitis and multinucleated giant cells.⁸ Radiation recall dermatitis is a cutaneous inflammatory reaction limited to regions of prior radiation exposure after the administration of a triggering medication. Radiation recall dermatitis can present days to many years after the completion of treatment.⁹ Although the eruption in our patient was at the site of prior radiation, the pathologic and clinical presentation was not consistent with radiation recall dermatitis. Cutaneous Rosai-Dorfman disease is a non-Langerhans cell histiocytosis that may present as either solitary or numerous papules, plaques, or nodules and has been reported to occur after HZI. Biopsy reveals a diffuse dermal histiocytic infiltration with plasma cells and lymphocytes. In contrast to metastatic disease, mitoses and nuclear atypia are rare in cutaneous RosaiDorfman disease.¹¹ Lichen planus is an inflammatory disease of unknown etiology presenting as flat-topped, violaceous, pruritic papules¹² that may present in a zosteriform pattern.¹³

Although it is uncommon, metastatic spread should be considered in patients with known malignancy presenting with zosteriform eruptions.² Our patient remained on treatment with immunotherapy, as he was unable to undergo additional radiation and had failed multiple other lines of therapy. He died 3 months after presentation.

THE DIAGNOSIS:

Cutaneous Metastatic Mesothelioma

Biopsies of the larger erythematous papules revealed an infiltrate of atypical tumor cells with mitoses (Figure 1) that were immunoreactive for calretinin (Figure 2) and lacked nuclear BRCA1 associated protein-1, BAP1, expression (not shown). The patient’s prior mesothelioma was re-reviewed, and the cutaneous tumor cells were similar to the primary mesothelioma. A diagnosis of cutaneous metastatic mesothelioma (CMM) was made.

Mesothelioma is a rare neoplasm arising from the pleura, pericardium, peritoneum, and tunica vaginalis,¹ with an estimated annual incidence of 2500 cases.² The predominant risk factor for the development of pleural mesothelioma is asbestos exposure, which has been identified in up to 90% of cases. Mesothelioma can give rise to local and less frequently distant hematogenous metastases. Cutaneous involvement of mesothelioma is rare.³ More than 80% of CMM cases are attributed to seeding the skin at procedure sites or by direct infiltration of scars. Distant CMM is rare and typically presents as subcutaneous nodules.⁴ Few cases of inflammatory CMM have been published,^1,4,5 with even fewer mimicking herpes zoster infection (HZI), as seen in our patient.

The most specific stain for mesothelioma is calretinin, which strongly and diffusely stains both the nucleus and cytoplasm. Other markers include Wilms tumor 1, cytokeratin 5/6, thrombomodulin, and HBME-1. Immunohistochemistry to detect the loss of BAP1 staining in the nucleus is important for differentiating between mesothelioma and mesothelial hyperplasia.³

Cutaneous metastases occur in 0.7% to 9% of patients with internal malignant disease. Most commonly, cutaneous metastases present as cutaneous nodules, though other reported inflammatory presentations include erysipeloides, generalized erythematous patches, telangiectasia, and zosteriform distributions.⁶ Zosteriform distributions are particularly rare and most commonly are due to breast carcinomas or lymphomas. The mechanism of zosteriform metastasis is unknown, but theories include tumoral spread along vessels, invasion of the thoracic perineural sheaths, localized spread of tumor cells from a surgical site, or a Koebner-like reaction at the site of an existing HZI. Regardless of primary tumor type or presentation, cutaneous metastasis is a poor prognostic sign, with survival rates varying based on primary tumor type.⁷

Other differential diagnoses include herpes zoster granulomatous dermatitis, radiation recall dermatitis, cutaneous Rosai-Dorfman disease, and zosteriform lichen planus, all of which have been reported after HZI.^8-10 Herpes zoster granulomatous dermatitis typically presents weeks to years after acute HZI with erythematous to violaceous papules and plaques at the site of the prior HZI. A biopsy reveals interstitial granulomatous dermatitis and multinucleated giant cells.⁸ Radiation recall dermatitis is a cutaneous inflammatory reaction limited to regions of prior radiation exposure after the administration of a triggering medication. Radiation recall dermatitis can present days to many years after the completion of treatment.⁹ Although the eruption in our patient was at the site of prior radiation, the pathologic and clinical presentation was not consistent with radiation recall dermatitis. Cutaneous Rosai-Dorfman disease is a non-Langerhans cell histiocytosis that may present as either solitary or numerous papules, plaques, or nodules and has been reported to occur after HZI. Biopsy reveals a diffuse dermal histiocytic infiltration with plasma cells and lymphocytes. In contrast to metastatic disease, mitoses and nuclear atypia are rare in cutaneous RosaiDorfman disease.¹¹ Lichen planus is an inflammatory disease of unknown etiology presenting as flat-topped, violaceous, pruritic papules¹² that may present in a zosteriform pattern.¹³

Although it is uncommon, metastatic spread should be considered in patients with known malignancy presenting with zosteriform eruptions.² Our patient remained on treatment with immunotherapy, as he was unable to undergo additional radiation and had failed multiple other lines of therapy. He died 3 months after presentation.

THE DIAGNOSIS: Vegetative Majocchi Granuloma

A biopsy and tissue culture showed acute dermal inflammation with granulomatous features and numerous fungal hyphae within the stratum corneum (Figure 1A), which were confirmed on GrocottGomori methenamine-silver staining (Figure 1B). Gram and Fite stains were negative for bacteria. A tissue culture speciated Trichophyton rubrum, which led to a diagnosis of deep dermatophyte infection (Majocchi granuloma) with a highly unusual clinical presentation of vegetative plaques. Predisposing factors included treatment with topical corticosteroids and possibly poor health and nutritional status at baseline. Our patient was treated with fluconazole 200 mg daily for 6 weeks, with near resolution of lesions at 3-week follow-up (Figure 2).

Dermatophytes are a common cause of superficial skin infections. The classic morphology consists of an annular scaly plaque; however, a wide variety of presentations have been observed (eg, verrucous, vesicular, pustular, granulomatous). Therefore, dermatophyte infections often mimic other dermatologic conditions, including atopic dermatitis, rosacea, psoriasis, bacterial abscess, erythema gyratum repens, lupus, granuloma annulare, cutaneous lymphoma, Hailey-Hailey disease, scarring alopecia, and syphilis.¹

Notably, when dermatophytes grow downward along hair follicles causing deeper infection, disruption of the follicular wall can lead to an excessive inflammatory response with granulomatous features.² Risk factors include cutaneous trauma, long-standing infection, immunocompromise, and treatment with topical corticosteroids.³ This disease evolution clinically appears as a nodule or infiltrated plaque, often without scale. The most well-known example is a kerion on the scalp. Elsewhere on the body, lesions often are termed Majocchi granulomas.²

Vegetative plaques, as seen in our patient, are a highly unusual morphology for deep tinea infection. Guanziroli et al⁴ reported a case of vegetative lesions on the forearm of a 67-year-old immunocompromised man that were successfully treated with a 3-month course of oral terbinafine after Trichophyton verrucosum was isolated. Skorepova et al⁵ reported a case of pyoderma vegetans triggered by recurrent Trichophyton mentagrophytes on the dorsal hands of a 64-year-old man with immunoglobulin deficiency of unknown etiology. The lesions were successfully treated with a prolonged course of doxycycline, topical triamcinolone, and intravenous immunoglobulin following 2 initial courses of terbinafine.

The differential diagnosis for vegetative lesions includes pemphigus vegetans, a vegetative variant of pyoderma gangrenosum; halogenoderma; and a variety of infections, including dimorphic fungi (histoplasmosis, blastomycosis), blastomycosislike pyoderma (bacterial), and candidiasis.⁶ These conditions usually can be distinguished based on histopathology. Clinically, pemphigus vegetans presents with pustules and vegetative lesions, as in our patient, but usually is more diffuse and favors the intertriginous areas. Histology likely would reveal foci of acantholysis and eosinophils. Vegetative pyoderma gangrenosum favors the trunk, particularly in sites of surgical trauma. In our patient, no lesions were present near the abdominal surgical sites, and there was no antecedent cribriform ulceration. Halogenoderma was a strong initial consideration given the localization, presence of large pustules, and history of numerous contrast computed tomography studies; however, our patient’s iodine levels were normal. Infectious etiologies including dimorphic fungi and blastomycosislike pyoderma generally are not restricted to the head and neck, and tissue culture helps exclude them. Vegetative lesions may occur in the setting of other infections, and tissue culture may be necessary to differentiate them if histopathology is not suggestive.

Deep dermatophyte infections require treatment with oral antifungals, as topicals do not penetrate adequately into the hair follicles. Exact regimens vary, but generally oral terbinafine or an oral azole (except ketoconazole) is administered for 2 to 6 weeks, with immunocompromise necessitating longer courses.

We present a rare case of vegetative Majocchi granuloma secondary to T rubrum infection. A dermatophyte infection should be included in the differential for vegetative lesions, especially in dense hair-bearing areas such as the beard. Treatment generally is straightforward with oral antifungals.

THE DIAGNOSIS: Vegetative Majocchi Granuloma

A biopsy and tissue culture showed acute dermal inflammation with granulomatous features and numerous fungal hyphae within the stratum corneum (Figure 1A), which were confirmed on GrocottGomori methenamine-silver staining (Figure 1B). Gram and Fite stains were negative for bacteria. A tissue culture speciated Trichophyton rubrum, which led to a diagnosis of deep dermatophyte infection (Majocchi granuloma) with a highly unusual clinical presentation of vegetative plaques. Predisposing factors included treatment with topical corticosteroids and possibly poor health and nutritional status at baseline. Our patient was treated with fluconazole 200 mg daily for 6 weeks, with near resolution of lesions at 3-week follow-up (Figure 2).

Dermatophytes are a common cause of superficial skin infections. The classic morphology consists of an annular scaly plaque; however, a wide variety of presentations have been observed (eg, verrucous, vesicular, pustular, granulomatous). Therefore, dermatophyte infections often mimic other dermatologic conditions, including atopic dermatitis, rosacea, psoriasis, bacterial abscess, erythema gyratum repens, lupus, granuloma annulare, cutaneous lymphoma, Hailey-Hailey disease, scarring alopecia, and syphilis.¹

Notably, when dermatophytes grow downward along hair follicles causing deeper infection, disruption of the follicular wall can lead to an excessive inflammatory response with granulomatous features.² Risk factors include cutaneous trauma, long-standing infection, immunocompromise, and treatment with topical corticosteroids.³ This disease evolution clinically appears as a nodule or infiltrated plaque, often without scale. The most well-known example is a kerion on the scalp. Elsewhere on the body, lesions often are termed Majocchi granulomas.²

Vegetative plaques, as seen in our patient, are a highly unusual morphology for deep tinea infection. Guanziroli et al⁴ reported a case of vegetative lesions on the forearm of a 67-year-old immunocompromised man that were successfully treated with a 3-month course of oral terbinafine after Trichophyton verrucosum was isolated. Skorepova et al⁵ reported a case of pyoderma vegetans triggered by recurrent Trichophyton mentagrophytes on the dorsal hands of a 64-year-old man with immunoglobulin deficiency of unknown etiology. The lesions were successfully treated with a prolonged course of doxycycline, topical triamcinolone, and intravenous immunoglobulin following 2 initial courses of terbinafine.

The differential diagnosis for vegetative lesions includes pemphigus vegetans, a vegetative variant of pyoderma gangrenosum; halogenoderma; and a variety of infections, including dimorphic fungi (histoplasmosis, blastomycosis), blastomycosislike pyoderma (bacterial), and candidiasis.⁶ These conditions usually can be distinguished based on histopathology. Clinically, pemphigus vegetans presents with pustules and vegetative lesions, as in our patient, but usually is more diffuse and favors the intertriginous areas. Histology likely would reveal foci of acantholysis and eosinophils. Vegetative pyoderma gangrenosum favors the trunk, particularly in sites of surgical trauma. In our patient, no lesions were present near the abdominal surgical sites, and there was no antecedent cribriform ulceration. Halogenoderma was a strong initial consideration given the localization, presence of large pustules, and history of numerous contrast computed tomography studies; however, our patient’s iodine levels were normal. Infectious etiologies including dimorphic fungi and blastomycosislike pyoderma generally are not restricted to the head and neck, and tissue culture helps exclude them. Vegetative lesions may occur in the setting of other infections, and tissue culture may be necessary to differentiate them if histopathology is not suggestive.

Deep dermatophyte infections require treatment with oral antifungals, as topicals do not penetrate adequately into the hair follicles. Exact regimens vary, but generally oral terbinafine or an oral azole (except ketoconazole) is administered for 2 to 6 weeks, with immunocompromise necessitating longer courses.

We present a rare case of vegetative Majocchi granuloma secondary to T rubrum infection. A dermatophyte infection should be included in the differential for vegetative lesions, especially in dense hair-bearing areas such as the beard. Treatment generally is straightforward with oral antifungals.

THE DIAGNOSIS: Vegetative Majocchi Granuloma

A biopsy and tissue culture showed acute dermal inflammation with granulomatous features and numerous fungal hyphae within the stratum corneum (Figure 1A), which were confirmed on GrocottGomori methenamine-silver staining (Figure 1B). Gram and Fite stains were negative for bacteria. A tissue culture speciated Trichophyton rubrum, which led to a diagnosis of deep dermatophyte infection (Majocchi granuloma) with a highly unusual clinical presentation of vegetative plaques. Predisposing factors included treatment with topical corticosteroids and possibly poor health and nutritional status at baseline. Our patient was treated with fluconazole 200 mg daily for 6 weeks, with near resolution of lesions at 3-week follow-up (Figure 2).

Dermatophytes are a common cause of superficial skin infections. The classic morphology consists of an annular scaly plaque; however, a wide variety of presentations have been observed (eg, verrucous, vesicular, pustular, granulomatous). Therefore, dermatophyte infections often mimic other dermatologic conditions, including atopic dermatitis, rosacea, psoriasis, bacterial abscess, erythema gyratum repens, lupus, granuloma annulare, cutaneous lymphoma, Hailey-Hailey disease, scarring alopecia, and syphilis.¹

Notably, when dermatophytes grow downward along hair follicles causing deeper infection, disruption of the follicular wall can lead to an excessive inflammatory response with granulomatous features.² Risk factors include cutaneous trauma, long-standing infection, immunocompromise, and treatment with topical corticosteroids.³ This disease evolution clinically appears as a nodule or infiltrated plaque, often without scale. The most well-known example is a kerion on the scalp. Elsewhere on the body, lesions often are termed Majocchi granulomas.²

Vegetative plaques, as seen in our patient, are a highly unusual morphology for deep tinea infection. Guanziroli et al⁴ reported a case of vegetative lesions on the forearm of a 67-year-old immunocompromised man that were successfully treated with a 3-month course of oral terbinafine after Trichophyton verrucosum was isolated. Skorepova et al⁵ reported a case of pyoderma vegetans triggered by recurrent Trichophyton mentagrophytes on the dorsal hands of a 64-year-old man with immunoglobulin deficiency of unknown etiology. The lesions were successfully treated with a prolonged course of doxycycline, topical triamcinolone, and intravenous immunoglobulin following 2 initial courses of terbinafine.

The differential diagnosis for vegetative lesions includes pemphigus vegetans, a vegetative variant of pyoderma gangrenosum; halogenoderma; and a variety of infections, including dimorphic fungi (histoplasmosis, blastomycosis), blastomycosislike pyoderma (bacterial), and candidiasis.⁶ These conditions usually can be distinguished based on histopathology. Clinically, pemphigus vegetans presents with pustules and vegetative lesions, as in our patient, but usually is more diffuse and favors the intertriginous areas. Histology likely would reveal foci of acantholysis and eosinophils. Vegetative pyoderma gangrenosum favors the trunk, particularly in sites of surgical trauma. In our patient, no lesions were present near the abdominal surgical sites, and there was no antecedent cribriform ulceration. Halogenoderma was a strong initial consideration given the localization, presence of large pustules, and history of numerous contrast computed tomography studies; however, our patient’s iodine levels were normal. Infectious etiologies including dimorphic fungi and blastomycosislike pyoderma generally are not restricted to the head and neck, and tissue culture helps exclude them. Vegetative lesions may occur in the setting of other infections, and tissue culture may be necessary to differentiate them if histopathology is not suggestive.

Deep dermatophyte infections require treatment with oral antifungals, as topicals do not penetrate adequately into the hair follicles. Exact regimens vary, but generally oral terbinafine or an oral azole (except ketoconazole) is administered for 2 to 6 weeks, with immunocompromise necessitating longer courses.

We present a rare case of vegetative Majocchi granuloma secondary to T rubrum infection. A dermatophyte infection should be included in the differential for vegetative lesions, especially in dense hair-bearing areas such as the beard. Treatment generally is straightforward with oral antifungals.

The Diagnosis: Dermatomyofibroma

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

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

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

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

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

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

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

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

The Diagnosis: Dermatomyofibroma

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

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

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

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

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

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

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

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

The Diagnosis: Dermatomyofibroma

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

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

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

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

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

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

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

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

The Diagnosis: Multicentric Reticulohistiocytosis

Te patient presented with pink papules coalescing into plaques on the upper chest and lower back (Figure 1) as well as a characteristic finding of periungual papules with a coral bead appearance. Histopathologic examination revealed a dense infiltrate of epithelioid histiocytes with amphophilic ground-glass cytoplasm in a nodular configuration (Figure 2). This pattern in conjunction with the clinical features seen in our patient was consistent with a diagnosis of multicentric reticulohistiocytosis (MRH).^1-3 The cutaneous symptoms were managed with triamcinolone ointment 0.1% twice daily and oral hydroxyzine 10 mg 3 times daily as needed for itching with moderate improvement. She was referred to rheumatology for arthritis management, and the initial cancer screening was negative.

Multicentric reticulohistiocytosis is a rare granulomatous disease characterized by papulonodular cutaneous lesions and severe erosive arthritis. It has an insidious onset and most commonly affects middle-aged women.¹ Multicentric reticulohistiocytosis typically presents as rounded pruritic papules or nodules that may be pink, red, or brown primarily affecting the face and distal upper extremities.^1,3 Mucosal involvement occurs in more than half of patients and is characterized by multiple erythematous papules and nodules on the oral and nasopharyngeal mucosae that rarely can produce leonine facies.² A hallmark feature of MRH is the presence of multiple shiny erythematous papules along the proximal and lateral nail folds that take on a coral bead appearance.^1,3,4 Furthermore, nail changes such as atrophy, longitudinal ridging, brittleness, and hyperpigmentation can occur secondary to a synovial reaction that disturbs the nail matrix.^4,5

Joint involvement precedes cutaneous involvement in most cases of MRH.^1,5 Multicentric reticulohistiocytosis is associated with a symmetric destructive arthritis affecting the hands, knees, shoulders, and hips that often is associated with pain, stiffness, and swelling.^1,3 The arthritis rapidly progresses in the early stages of the disease but then becomes less active over the subsequent 8 to 10 years.¹ It has the potential to develop into arthritis mutilans, an end-stage form of arthritis also seen in psoriatic and rheumatoid arthritis that leads to severe joint deformity and debilitation.^1,2

The etiology of MRH still is unknown, but it has an association with underlying malignancy in up to 25% of patients.⁶ Multicentric reticulohistiocytosis has been reported in the context of a wide variety of malignancies including melanoma; sarcoma; lymphoma; leukemia; and carcinomas of the breast, colon, and lung. In some cases, the diagnosis of MRH may even precede the diagnosis of cancer.³ Multicentric reticulohistiocytosis also may be associated with autoimmune conditions,³ as seen in our patient who had a history of both hypothyroidism and vitiligo.

Histopathologic examination is essential in distinguishing MRH from other autoimmune disorders associated with hand lesions, rash, and arthralgia. Erythema elevatum diutinum is associated with symmetric, violaceous, red or brown papules and plaques located on the extensor surfaces of the extremities and hands; however, histology reveals a leukocytoclastic vasculitis with a mixture of polymorphonuclear leukocytes and lymphocytes.⁷ Dermatomyositis may present with arthralgia, flattopped, erythematous (Gottron) papules localized over the proximal interphalangeal and distal interphalangeal joints, as well as proximal nail findings. The latter generally presents with periungual erythema associated with dilated capillary loops rather than the discrete orderly papules seen in MRH. Histologic examination of dermatomyositis shows mild epidermal atrophy, vacuolar changes in the basal keratinocyte layer, and a dermal perivascular lymphocytic infiltrate.⁸ Because MRH initially can present with joint symptoms and hand nodules, it may be confused with rheumatoid arthritis. However, rheumatoid arthritis typically is associated with severe osteopenia and tends to affect the metacarpophalangeal and proximal interphalangeal joints rather than the distal interphalangeal joints that most often are affected in MRH.¹ Histologic examination of rheumatoid nodules reveals palisading granulomas surrounding a central area of fibrinoid necrosis.⁹ Sarcoidosis is a multisystem disease that can present with cutaneous involvement including erythema nodosum, skin plaques, subcutaneous nodules, and papular eruptions in addition to joint lesions.¹⁰ Sarcoidosis most frequently involves the lungs, manifesting as diffuse interstitial lung disease with bilateral hilar lymphadenopathy. Furthermore, histologic examination of lesions demonstrates classic noncaseating granulomas containing epithelioid cells, multinucleated giant cells with inclusion bodies, and lymphocytes.¹¹

A skin biopsy is required to establish the diagnosis of MRH. In general, patients with MRH and no underlying malignancy have a good prognosis and respond to anti-inflammatory therapies such as nonsteroidal antiinflammatory drugs and corticosteroids. Other agents including methotrexate, cyclophosphamide, and tumor necrosis factor α inhibitors also have been effective in more severe cases.^1,3,12 Finally, in addition to treating the cutaneous manifestations of MRH, it is important to screen patients for underlying malignancies and other autoimmune conditions.

The Diagnosis: Multicentric Reticulohistiocytosis

Te patient presented with pink papules coalescing into plaques on the upper chest and lower back (Figure 1) as well as a characteristic finding of periungual papules with a coral bead appearance. Histopathologic examination revealed a dense infiltrate of epithelioid histiocytes with amphophilic ground-glass cytoplasm in a nodular configuration (Figure 2). This pattern in conjunction with the clinical features seen in our patient was consistent with a diagnosis of multicentric reticulohistiocytosis (MRH).^1-3 The cutaneous symptoms were managed with triamcinolone ointment 0.1% twice daily and oral hydroxyzine 10 mg 3 times daily as needed for itching with moderate improvement. She was referred to rheumatology for arthritis management, and the initial cancer screening was negative.

Multicentric reticulohistiocytosis is a rare granulomatous disease characterized by papulonodular cutaneous lesions and severe erosive arthritis. It has an insidious onset and most commonly affects middle-aged women.¹ Multicentric reticulohistiocytosis typically presents as rounded pruritic papules or nodules that may be pink, red, or brown primarily affecting the face and distal upper extremities.^1,3 Mucosal involvement occurs in more than half of patients and is characterized by multiple erythematous papules and nodules on the oral and nasopharyngeal mucosae that rarely can produce leonine facies.² A hallmark feature of MRH is the presence of multiple shiny erythematous papules along the proximal and lateral nail folds that take on a coral bead appearance.^1,3,4 Furthermore, nail changes such as atrophy, longitudinal ridging, brittleness, and hyperpigmentation can occur secondary to a synovial reaction that disturbs the nail matrix.^4,5

Joint involvement precedes cutaneous involvement in most cases of MRH.^1,5 Multicentric reticulohistiocytosis is associated with a symmetric destructive arthritis affecting the hands, knees, shoulders, and hips that often is associated with pain, stiffness, and swelling.^1,3 The arthritis rapidly progresses in the early stages of the disease but then becomes less active over the subsequent 8 to 10 years.¹ It has the potential to develop into arthritis mutilans, an end-stage form of arthritis also seen in psoriatic and rheumatoid arthritis that leads to severe joint deformity and debilitation.^1,2

The etiology of MRH still is unknown, but it has an association with underlying malignancy in up to 25% of patients.⁶ Multicentric reticulohistiocytosis has been reported in the context of a wide variety of malignancies including melanoma; sarcoma; lymphoma; leukemia; and carcinomas of the breast, colon, and lung. In some cases, the diagnosis of MRH may even precede the diagnosis of cancer.³ Multicentric reticulohistiocytosis also may be associated with autoimmune conditions,³ as seen in our patient who had a history of both hypothyroidism and vitiligo.

Histopathologic examination is essential in distinguishing MRH from other autoimmune disorders associated with hand lesions, rash, and arthralgia. Erythema elevatum diutinum is associated with symmetric, violaceous, red or brown papules and plaques located on the extensor surfaces of the extremities and hands; however, histology reveals a leukocytoclastic vasculitis with a mixture of polymorphonuclear leukocytes and lymphocytes.⁷ Dermatomyositis may present with arthralgia, flattopped, erythematous (Gottron) papules localized over the proximal interphalangeal and distal interphalangeal joints, as well as proximal nail findings. The latter generally presents with periungual erythema associated with dilated capillary loops rather than the discrete orderly papules seen in MRH. Histologic examination of dermatomyositis shows mild epidermal atrophy, vacuolar changes in the basal keratinocyte layer, and a dermal perivascular lymphocytic infiltrate.⁸ Because MRH initially can present with joint symptoms and hand nodules, it may be confused with rheumatoid arthritis. However, rheumatoid arthritis typically is associated with severe osteopenia and tends to affect the metacarpophalangeal and proximal interphalangeal joints rather than the distal interphalangeal joints that most often are affected in MRH.¹ Histologic examination of rheumatoid nodules reveals palisading granulomas surrounding a central area of fibrinoid necrosis.⁹ Sarcoidosis is a multisystem disease that can present with cutaneous involvement including erythema nodosum, skin plaques, subcutaneous nodules, and papular eruptions in addition to joint lesions.¹⁰ Sarcoidosis most frequently involves the lungs, manifesting as diffuse interstitial lung disease with bilateral hilar lymphadenopathy. Furthermore, histologic examination of lesions demonstrates classic noncaseating granulomas containing epithelioid cells, multinucleated giant cells with inclusion bodies, and lymphocytes.¹¹

A skin biopsy is required to establish the diagnosis of MRH. In general, patients with MRH and no underlying malignancy have a good prognosis and respond to anti-inflammatory therapies such as nonsteroidal antiinflammatory drugs and corticosteroids. Other agents including methotrexate, cyclophosphamide, and tumor necrosis factor α inhibitors also have been effective in more severe cases.^1,3,12 Finally, in addition to treating the cutaneous manifestations of MRH, it is important to screen patients for underlying malignancies and other autoimmune conditions.

The Diagnosis: Multicentric Reticulohistiocytosis

Te patient presented with pink papules coalescing into plaques on the upper chest and lower back (Figure 1) as well as a characteristic finding of periungual papules with a coral bead appearance. Histopathologic examination revealed a dense infiltrate of epithelioid histiocytes with amphophilic ground-glass cytoplasm in a nodular configuration (Figure 2). This pattern in conjunction with the clinical features seen in our patient was consistent with a diagnosis of multicentric reticulohistiocytosis (MRH).^1-3 The cutaneous symptoms were managed with triamcinolone ointment 0.1% twice daily and oral hydroxyzine 10 mg 3 times daily as needed for itching with moderate improvement. She was referred to rheumatology for arthritis management, and the initial cancer screening was negative.

Multicentric reticulohistiocytosis is a rare granulomatous disease characterized by papulonodular cutaneous lesions and severe erosive arthritis. It has an insidious onset and most commonly affects middle-aged women.¹ Multicentric reticulohistiocytosis typically presents as rounded pruritic papules or nodules that may be pink, red, or brown primarily affecting the face and distal upper extremities.^1,3 Mucosal involvement occurs in more than half of patients and is characterized by multiple erythematous papules and nodules on the oral and nasopharyngeal mucosae that rarely can produce leonine facies.² A hallmark feature of MRH is the presence of multiple shiny erythematous papules along the proximal and lateral nail folds that take on a coral bead appearance.^1,3,4 Furthermore, nail changes such as atrophy, longitudinal ridging, brittleness, and hyperpigmentation can occur secondary to a synovial reaction that disturbs the nail matrix.^4,5

Joint involvement precedes cutaneous involvement in most cases of MRH.^1,5 Multicentric reticulohistiocytosis is associated with a symmetric destructive arthritis affecting the hands, knees, shoulders, and hips that often is associated with pain, stiffness, and swelling.^1,3 The arthritis rapidly progresses in the early stages of the disease but then becomes less active over the subsequent 8 to 10 years.¹ It has the potential to develop into arthritis mutilans, an end-stage form of arthritis also seen in psoriatic and rheumatoid arthritis that leads to severe joint deformity and debilitation.^1,2

The etiology of MRH still is unknown, but it has an association with underlying malignancy in up to 25% of patients.⁶ Multicentric reticulohistiocytosis has been reported in the context of a wide variety of malignancies including melanoma; sarcoma; lymphoma; leukemia; and carcinomas of the breast, colon, and lung. In some cases, the diagnosis of MRH may even precede the diagnosis of cancer.³ Multicentric reticulohistiocytosis also may be associated with autoimmune conditions,³ as seen in our patient who had a history of both hypothyroidism and vitiligo.

Histopathologic examination is essential in distinguishing MRH from other autoimmune disorders associated with hand lesions, rash, and arthralgia. Erythema elevatum diutinum is associated with symmetric, violaceous, red or brown papules and plaques located on the extensor surfaces of the extremities and hands; however, histology reveals a leukocytoclastic vasculitis with a mixture of polymorphonuclear leukocytes and lymphocytes.⁷ Dermatomyositis may present with arthralgia, flattopped, erythematous (Gottron) papules localized over the proximal interphalangeal and distal interphalangeal joints, as well as proximal nail findings. The latter generally presents with periungual erythema associated with dilated capillary loops rather than the discrete orderly papules seen in MRH. Histologic examination of dermatomyositis shows mild epidermal atrophy, vacuolar changes in the basal keratinocyte layer, and a dermal perivascular lymphocytic infiltrate.⁸ Because MRH initially can present with joint symptoms and hand nodules, it may be confused with rheumatoid arthritis. However, rheumatoid arthritis typically is associated with severe osteopenia and tends to affect the metacarpophalangeal and proximal interphalangeal joints rather than the distal interphalangeal joints that most often are affected in MRH.¹ Histologic examination of rheumatoid nodules reveals palisading granulomas surrounding a central area of fibrinoid necrosis.⁹ Sarcoidosis is a multisystem disease that can present with cutaneous involvement including erythema nodosum, skin plaques, subcutaneous nodules, and papular eruptions in addition to joint lesions.¹⁰ Sarcoidosis most frequently involves the lungs, manifesting as diffuse interstitial lung disease with bilateral hilar lymphadenopathy. Furthermore, histologic examination of lesions demonstrates classic noncaseating granulomas containing epithelioid cells, multinucleated giant cells with inclusion bodies, and lymphocytes.¹¹

A skin biopsy is required to establish the diagnosis of MRH. In general, patients with MRH and no underlying malignancy have a good prognosis and respond to anti-inflammatory therapies such as nonsteroidal antiinflammatory drugs and corticosteroids. Other agents including methotrexate, cyclophosphamide, and tumor necrosis factor α inhibitors also have been effective in more severe cases.^1,3,12 Finally, in addition to treating the cutaneous manifestations of MRH, it is important to screen patients for underlying malignancies and other autoimmune conditions.

Direct immunofluorescence (DIF) is the go-to diagnostic test when evaluating vesiculobullous eruptions, connective tissue disease, and vasculitis. This specialized test allows visualization of autoantibodies and their reaction products in the epidermis and dermis (skin) and epithelium and subepithelium (mucosa). Indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) are additional tests that can help in the diagnosis of autoimmune blistering disease. In the blistering autoimmune diseases, the autoantibodies target components in skin and mucous membranes that are essential for cell-cell and cell-matrix adhesion causing separation within or beneath the epidermis, depending on where the target components are located. This article is intended to serve as a helpful primer for immunofluorescence testing in dermatology, with an overview of the tests available as well as pragmatic tips for optimal biopsy sites and specimen transport.

Direct Immunofluorescence

Immunofluorescence techniques date back to 1941 when Albert Coons, an American physician, pathologist, and immunologist, fluorescently labelled antibodies to visualize pneumococcal antigens in infected tissues.^1-3 In dermatology, similar methodology was used to visualize the deposition of immunoglobulins and complement in the skin of patients with systemic lupus erythematosus in 1963.⁴ Basement membrane zone antibodies were first visualized via DIF in bullous pemphigoid in 1967.⁵ This elegant test utilizes specific antibodies labeled with fluorophores that are then incubated with the patient’s tissue, ultimately forming antibody-antigen conjugates that can be visualized with a fluorescent microscope. Antibodies usually include IgG, IgM, IgA, fibrinogen, and C3. Some institutions also evaluate for IgG4.

Transport medium is critical for proper evaluation of tissues using DIF. Inappropriate storage of tissue can degrade the antigen and confuse the interpretation of specimens. An acceptable medium for DIF includes Michel transport medium, which allows tissue to be stored for days while being transported at ambient temperature without loss of signal.^6,7 Zeus medium also can be used and is more readily available. Alternatively, biopsy tissue can be snap frozen using liquid nitrogen. Specimens also may be stored on saline gauze but should be analyzed within 24 to 48 hours.⁸ Most importantly, do not place the specimen in formalin; even a brief soak in formalin can greatly alter results, especially when trying to diagnose pemphigus.⁹ Proper transport conditions are critical to prevent autolysis, mitigate putrefaction, and preserve morphology while maintaining antigenicity.¹⁰

Indirect Immunofluorescence

Indirect immunofluorescence can be helpful for detecting antibodies circulating in patient serum. Indirect immunofluorescence can be used to help diagnose pemphigoid, pemphigus, epidermolysis bullosa acquisita, bullous lupus erythematosus, and dermatitis herpetiformis. Serum testing also can be a helpful alternative when obtaining tissue is difficult, such as in children.

Indirect immunofluorescence is a 2-part technique that takes a bit longer to assay than DIF.¹¹ The first step involves incubating prepared tissue substrates with patient serum. Unlabeled antibodies in the patient serum are allowed to bind to antigens in the substrate tissue for about 30 minutes. Doubling dilutions of patient serum can be performed to titer antibody levels. The second step uses fluorescein-labeled antihuman antibodies to recognize the antigen-antibody conjugates. Normal whole tissues (eg, monkey esophagus for pemphigus vulgaris, rat bladder for paraneoplastic pemphigus, salt-split normal human skin substrate for pemphigoid and epidermolysis bullosa) are the usual substrates for testing.^11,12 Again, this test requires serum and should be collected in a red-top tube or serum-separator tube. Usually, a minimum of 0.5 mL is required for testing, but check with your preferred immunodermatology send-out laboratory before collecting.¹³

Indirect immunofluorescence usually involves an initial screening panel using 1 or 2 tissue substrates followed by individual antigen-specific assays that correspond to the clinical suspicion and IIF screening results.¹¹ Salt-split skin is used to localize basement membrane zone autoantibodies to either the epidermal (roof) or dermal (floor) side. Although many dermatopathology laboratories offer DIF testing, IIF is more specialized and may be a send-out test at your institution.

Enzyme-linked Immunosorbent Assays

Another tool in the immunodermatology armamentarium is ELISA. Commercial ELISA systems are available for the detection of autoantibodies against bullous pemphigoid (BP) antigen 180, BP230, type VII collagen, desmoglein (Dsg) 1, Dsg3, and envoplakin.¹¹ This test allows semiquantitative measurement of antibody levels and thus can be used to monitor response to treatment or identify relapse and treatment failure.¹¹ For example, in BP, significantly increased baseline anti-BP180 IgG levels correlate with 1-year mortality rates (P=.001) and relapse rates (P=.041).^14,15 Numerous additional studies support the observation that monitoring anti-BP180 as a potential marker of disease relapse can be helpful.^16,17 In pemphigus, the presence or increase of autoantibodies at remission, either anti-Dsg3 or anti-Dsg1, may be a useful tool in predicting disease relapse.¹⁸ It is important for physicians to be aware of this to be able to offer guidance on prognosis.

Knowing where to biopsy can be confusing when beginning residency. But the short answer is, it depends. Let your clinical suspicion guide your specimen site. The Figure provides a quick reference for which location will give you the highest yield for a specific diagnosis.

A few cardinal rules should guide which site is biopsied. Avoid obtaining specimens from the lower extremities as much as possible, as this site has been linked with false-negative results, especially in bullous pemphigoid.^19,20 As a dependent area prone to stasis, this site gets a lot of abuse and inflammatory changes secondary to everyday insults that can theoretically alter DIF findings, especially fibrinogen deposition.

Although tissue sent for hematoxylin and eosin staining should be lesional, biopsy for DIF ideally should not contain a new or active blister, ulcer, erosion, or bulla. Immunoreactants are more likely to be degraded in these areas, and DIF may be falsely negative.²¹

It is worthwhile to briefly discuss the definitions of the terms perilesional and nonlesional. Perilesional skin most frequently refers to skin adjacent to a bulla or vesicle. This skin can be erythematous/inflamed or appear normal. When obtaining tissue for a diagnosis of blistering disease, the general recommendation is to obtain the biopsy from lesional nonbullous skin or perilesional uninvolved skin within 1 cm of the bulla.^22-24 The only exception to this is dermatitis herpetiformis, which is best diagnosed on tissue obtained from normal-appearing perilesional skin within 1 cm of an active lesion.²⁵ Additionally, if your patient has oral disease, the recommendation is to obtain the biopsy from nonlesional buccal mucosa, especially if there is desquamative gingivitis.^26,27

The ideal biopsy size is 4 or 5 mm. If considering both DIF and histopathology, it is best to procure 2 separate specimens. One larger biopsy can be carefully bisected in 2 but often is subject to more handling artifacts, which can affect findings. In the case of 1 biopsy bisected into 2 specimens, the punch should be at least 6 mm. Shave biopsies also can be performed as long as they extend into the reticular dermis.²³

For vasculitis, biopsies for DIF should be taken from lesions that are less than 24 hours old for highest yield, as the level of tissue immunoreactants tends to decline over time.²⁸ This guideline does differ from hematoxylin and eosin specimens sent for evaluation of vasculitis, which ideally should be lesional tissue over 72 hours old. When evaluating for lupus (including subacute cutaneous lupus, discoid lupus, and systemic lupus), DIF is more likely to be positive in well-established, active lesions.

Which Test Should I Order?

The answer to this question depends, but the use of all 3 tests has a specificity close to 100% when evaluating for autoantibody-associated diseases.²³ For autoimmune blistering disease, DIF is considered the diagnostic standard. The sensitivity of DIF for diagnosing BP is in the range of 82% to 90.5%, while specificity is 98%.^29-31 Other autoimmune blistering diseases, such as pemphigus or dermatitis herpetiformis, have even higher sensitivities and specificities. Direct immunofluorescence often is used as a screening test, but false negatives do occur.^32,33 Although rare, false positives also can occur, especially in cases of infection, and should be suspected when there is a lack of clinicopathologic correlation.³⁴ If DIF is negative but clinical suspicion remains high, IIF should be ordered to directly evaluate a patient’s serum for autoantibodies.

In acute cutaneous lupus, subacute cutaneous lupus, and discoid lupus, DIF of active lesions may be helpful if histopathologic examination of a cutaneous lupus erythematosus lesion is nondiagnostic. However, histopathologic examination of formalin-fixed tissue remains the standard for these diagnoses. In vasculitis, while DIF is not used for diagnosis, it is useful to evaluate for IgA deposition. This is important in adults, as IgA deposition has been associated with a greater risk for developing end-stage renal disease.³⁵

Final Thoughts

This is an overview of the tests available for diagnosing autoimmune blistering diseases. Residents should keep in mind that these tests are just one part of the puzzle when it comes to diagnosing these diseases. Results of DIF, IIF, and ELISA testing should be considered in conjunction with patient history and physical examination as well as histopathologic examination of lesional tissue when evaluating for dermatologic diseases with autoantibodies.

Direct immunofluorescence (DIF) is the go-to diagnostic test when evaluating vesiculobullous eruptions, connective tissue disease, and vasculitis. This specialized test allows visualization of autoantibodies and their reaction products in the epidermis and dermis (skin) and epithelium and subepithelium (mucosa). Indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) are additional tests that can help in the diagnosis of autoimmune blistering disease. In the blistering autoimmune diseases, the autoantibodies target components in skin and mucous membranes that are essential for cell-cell and cell-matrix adhesion causing separation within or beneath the epidermis, depending on where the target components are located. This article is intended to serve as a helpful primer for immunofluorescence testing in dermatology, with an overview of the tests available as well as pragmatic tips for optimal biopsy sites and specimen transport.

Direct Immunofluorescence

Immunofluorescence techniques date back to 1941 when Albert Coons, an American physician, pathologist, and immunologist, fluorescently labelled antibodies to visualize pneumococcal antigens in infected tissues.^1-3 In dermatology, similar methodology was used to visualize the deposition of immunoglobulins and complement in the skin of patients with systemic lupus erythematosus in 1963.⁴ Basement membrane zone antibodies were first visualized via DIF in bullous pemphigoid in 1967.⁵ This elegant test utilizes specific antibodies labeled with fluorophores that are then incubated with the patient’s tissue, ultimately forming antibody-antigen conjugates that can be visualized with a fluorescent microscope. Antibodies usually include IgG, IgM, IgA, fibrinogen, and C3. Some institutions also evaluate for IgG4.

Transport medium is critical for proper evaluation of tissues using DIF. Inappropriate storage of tissue can degrade the antigen and confuse the interpretation of specimens. An acceptable medium for DIF includes Michel transport medium, which allows tissue to be stored for days while being transported at ambient temperature without loss of signal.^6,7 Zeus medium also can be used and is more readily available. Alternatively, biopsy tissue can be snap frozen using liquid nitrogen. Specimens also may be stored on saline gauze but should be analyzed within 24 to 48 hours.⁸ Most importantly, do not place the specimen in formalin; even a brief soak in formalin can greatly alter results, especially when trying to diagnose pemphigus.⁹ Proper transport conditions are critical to prevent autolysis, mitigate putrefaction, and preserve morphology while maintaining antigenicity.¹⁰

Indirect Immunofluorescence

Indirect immunofluorescence can be helpful for detecting antibodies circulating in patient serum. Indirect immunofluorescence can be used to help diagnose pemphigoid, pemphigus, epidermolysis bullosa acquisita, bullous lupus erythematosus, and dermatitis herpetiformis. Serum testing also can be a helpful alternative when obtaining tissue is difficult, such as in children.

Indirect immunofluorescence is a 2-part technique that takes a bit longer to assay than DIF.¹¹ The first step involves incubating prepared tissue substrates with patient serum. Unlabeled antibodies in the patient serum are allowed to bind to antigens in the substrate tissue for about 30 minutes. Doubling dilutions of patient serum can be performed to titer antibody levels. The second step uses fluorescein-labeled antihuman antibodies to recognize the antigen-antibody conjugates. Normal whole tissues (eg, monkey esophagus for pemphigus vulgaris, rat bladder for paraneoplastic pemphigus, salt-split normal human skin substrate for pemphigoid and epidermolysis bullosa) are the usual substrates for testing.^11,12 Again, this test requires serum and should be collected in a red-top tube or serum-separator tube. Usually, a minimum of 0.5 mL is required for testing, but check with your preferred immunodermatology send-out laboratory before collecting.¹³

Indirect immunofluorescence usually involves an initial screening panel using 1 or 2 tissue substrates followed by individual antigen-specific assays that correspond to the clinical suspicion and IIF screening results.¹¹ Salt-split skin is used to localize basement membrane zone autoantibodies to either the epidermal (roof) or dermal (floor) side. Although many dermatopathology laboratories offer DIF testing, IIF is more specialized and may be a send-out test at your institution.

Enzyme-linked Immunosorbent Assays

Another tool in the immunodermatology armamentarium is ELISA. Commercial ELISA systems are available for the detection of autoantibodies against bullous pemphigoid (BP) antigen 180, BP230, type VII collagen, desmoglein (Dsg) 1, Dsg3, and envoplakin.¹¹ This test allows semiquantitative measurement of antibody levels and thus can be used to monitor response to treatment or identify relapse and treatment failure.¹¹ For example, in BP, significantly increased baseline anti-BP180 IgG levels correlate with 1-year mortality rates (P=.001) and relapse rates (P=.041).^14,15 Numerous additional studies support the observation that monitoring anti-BP180 as a potential marker of disease relapse can be helpful.^16,17 In pemphigus, the presence or increase of autoantibodies at remission, either anti-Dsg3 or anti-Dsg1, may be a useful tool in predicting disease relapse.¹⁸ It is important for physicians to be aware of this to be able to offer guidance on prognosis.

Knowing where to biopsy can be confusing when beginning residency. But the short answer is, it depends. Let your clinical suspicion guide your specimen site. The Figure provides a quick reference for which location will give you the highest yield for a specific diagnosis.

A few cardinal rules should guide which site is biopsied. Avoid obtaining specimens from the lower extremities as much as possible, as this site has been linked with false-negative results, especially in bullous pemphigoid.^19,20 As a dependent area prone to stasis, this site gets a lot of abuse and inflammatory changes secondary to everyday insults that can theoretically alter DIF findings, especially fibrinogen deposition.

Although tissue sent for hematoxylin and eosin staining should be lesional, biopsy for DIF ideally should not contain a new or active blister, ulcer, erosion, or bulla. Immunoreactants are more likely to be degraded in these areas, and DIF may be falsely negative.²¹

It is worthwhile to briefly discuss the definitions of the terms perilesional and nonlesional. Perilesional skin most frequently refers to skin adjacent to a bulla or vesicle. This skin can be erythematous/inflamed or appear normal. When obtaining tissue for a diagnosis of blistering disease, the general recommendation is to obtain the biopsy from lesional nonbullous skin or perilesional uninvolved skin within 1 cm of the bulla.^22-24 The only exception to this is dermatitis herpetiformis, which is best diagnosed on tissue obtained from normal-appearing perilesional skin within 1 cm of an active lesion.²⁵ Additionally, if your patient has oral disease, the recommendation is to obtain the biopsy from nonlesional buccal mucosa, especially if there is desquamative gingivitis.^26,27

The ideal biopsy size is 4 or 5 mm. If considering both DIF and histopathology, it is best to procure 2 separate specimens. One larger biopsy can be carefully bisected in 2 but often is subject to more handling artifacts, which can affect findings. In the case of 1 biopsy bisected into 2 specimens, the punch should be at least 6 mm. Shave biopsies also can be performed as long as they extend into the reticular dermis.²³

For vasculitis, biopsies for DIF should be taken from lesions that are less than 24 hours old for highest yield, as the level of tissue immunoreactants tends to decline over time.²⁸ This guideline does differ from hematoxylin and eosin specimens sent for evaluation of vasculitis, which ideally should be lesional tissue over 72 hours old. When evaluating for lupus (including subacute cutaneous lupus, discoid lupus, and systemic lupus), DIF is more likely to be positive in well-established, active lesions.

Which Test Should I Order?

The answer to this question depends, but the use of all 3 tests has a specificity close to 100% when evaluating for autoantibody-associated diseases.²³ For autoimmune blistering disease, DIF is considered the diagnostic standard. The sensitivity of DIF for diagnosing BP is in the range of 82% to 90.5%, while specificity is 98%.^29-31 Other autoimmune blistering diseases, such as pemphigus or dermatitis herpetiformis, have even higher sensitivities and specificities. Direct immunofluorescence often is used as a screening test, but false negatives do occur.^32,33 Although rare, false positives also can occur, especially in cases of infection, and should be suspected when there is a lack of clinicopathologic correlation.³⁴ If DIF is negative but clinical suspicion remains high, IIF should be ordered to directly evaluate a patient’s serum for autoantibodies.

In acute cutaneous lupus, subacute cutaneous lupus, and discoid lupus, DIF of active lesions may be helpful if histopathologic examination of a cutaneous lupus erythematosus lesion is nondiagnostic. However, histopathologic examination of formalin-fixed tissue remains the standard for these diagnoses. In vasculitis, while DIF is not used for diagnosis, it is useful to evaluate for IgA deposition. This is important in adults, as IgA deposition has been associated with a greater risk for developing end-stage renal disease.³⁵

Final Thoughts

This is an overview of the tests available for diagnosing autoimmune blistering diseases. Residents should keep in mind that these tests are just one part of the puzzle when it comes to diagnosing these diseases. Results of DIF, IIF, and ELISA testing should be considered in conjunction with patient history and physical examination as well as histopathologic examination of lesional tissue when evaluating for dermatologic diseases with autoantibodies.

Direct immunofluorescence (DIF) is the go-to diagnostic test when evaluating vesiculobullous eruptions, connective tissue disease, and vasculitis. This specialized test allows visualization of autoantibodies and their reaction products in the epidermis and dermis (skin) and epithelium and subepithelium (mucosa). Indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) are additional tests that can help in the diagnosis of autoimmune blistering disease. In the blistering autoimmune diseases, the autoantibodies target components in skin and mucous membranes that are essential for cell-cell and cell-matrix adhesion causing separation within or beneath the epidermis, depending on where the target components are located. This article is intended to serve as a helpful primer for immunofluorescence testing in dermatology, with an overview of the tests available as well as pragmatic tips for optimal biopsy sites and specimen transport.

Direct Immunofluorescence

Immunofluorescence techniques date back to 1941 when Albert Coons, an American physician, pathologist, and immunologist, fluorescently labelled antibodies to visualize pneumococcal antigens in infected tissues.^1-3 In dermatology, similar methodology was used to visualize the deposition of immunoglobulins and complement in the skin of patients with systemic lupus erythematosus in 1963.⁴ Basement membrane zone antibodies were first visualized via DIF in bullous pemphigoid in 1967.⁵ This elegant test utilizes specific antibodies labeled with fluorophores that are then incubated with the patient’s tissue, ultimately forming antibody-antigen conjugates that can be visualized with a fluorescent microscope. Antibodies usually include IgG, IgM, IgA, fibrinogen, and C3. Some institutions also evaluate for IgG4.

Transport medium is critical for proper evaluation of tissues using DIF. Inappropriate storage of tissue can degrade the antigen and confuse the interpretation of specimens. An acceptable medium for DIF includes Michel transport medium, which allows tissue to be stored for days while being transported at ambient temperature without loss of signal.^6,7 Zeus medium also can be used and is more readily available. Alternatively, biopsy tissue can be snap frozen using liquid nitrogen. Specimens also may be stored on saline gauze but should be analyzed within 24 to 48 hours.⁸ Most importantly, do not place the specimen in formalin; even a brief soak in formalin can greatly alter results, especially when trying to diagnose pemphigus.⁹ Proper transport conditions are critical to prevent autolysis, mitigate putrefaction, and preserve morphology while maintaining antigenicity.¹⁰

Indirect Immunofluorescence

Indirect immunofluorescence can be helpful for detecting antibodies circulating in patient serum. Indirect immunofluorescence can be used to help diagnose pemphigoid, pemphigus, epidermolysis bullosa acquisita, bullous lupus erythematosus, and dermatitis herpetiformis. Serum testing also can be a helpful alternative when obtaining tissue is difficult, such as in children.

Indirect immunofluorescence is a 2-part technique that takes a bit longer to assay than DIF.¹¹ The first step involves incubating prepared tissue substrates with patient serum. Unlabeled antibodies in the patient serum are allowed to bind to antigens in the substrate tissue for about 30 minutes. Doubling dilutions of patient serum can be performed to titer antibody levels. The second step uses fluorescein-labeled antihuman antibodies to recognize the antigen-antibody conjugates. Normal whole tissues (eg, monkey esophagus for pemphigus vulgaris, rat bladder for paraneoplastic pemphigus, salt-split normal human skin substrate for pemphigoid and epidermolysis bullosa) are the usual substrates for testing.^11,12 Again, this test requires serum and should be collected in a red-top tube or serum-separator tube. Usually, a minimum of 0.5 mL is required for testing, but check with your preferred immunodermatology send-out laboratory before collecting.¹³

Indirect immunofluorescence usually involves an initial screening panel using 1 or 2 tissue substrates followed by individual antigen-specific assays that correspond to the clinical suspicion and IIF screening results.¹¹ Salt-split skin is used to localize basement membrane zone autoantibodies to either the epidermal (roof) or dermal (floor) side. Although many dermatopathology laboratories offer DIF testing, IIF is more specialized and may be a send-out test at your institution.

Enzyme-linked Immunosorbent Assays

Another tool in the immunodermatology armamentarium is ELISA. Commercial ELISA systems are available for the detection of autoantibodies against bullous pemphigoid (BP) antigen 180, BP230, type VII collagen, desmoglein (Dsg) 1, Dsg3, and envoplakin.¹¹ This test allows semiquantitative measurement of antibody levels and thus can be used to monitor response to treatment or identify relapse and treatment failure.¹¹ For example, in BP, significantly increased baseline anti-BP180 IgG levels correlate with 1-year mortality rates (P=.001) and relapse rates (P=.041).^14,15 Numerous additional studies support the observation that monitoring anti-BP180 as a potential marker of disease relapse can be helpful.^16,17 In pemphigus, the presence or increase of autoantibodies at remission, either anti-Dsg3 or anti-Dsg1, may be a useful tool in predicting disease relapse.¹⁸ It is important for physicians to be aware of this to be able to offer guidance on prognosis.

Knowing where to biopsy can be confusing when beginning residency. But the short answer is, it depends. Let your clinical suspicion guide your specimen site. The Figure provides a quick reference for which location will give you the highest yield for a specific diagnosis.

A few cardinal rules should guide which site is biopsied. Avoid obtaining specimens from the lower extremities as much as possible, as this site has been linked with false-negative results, especially in bullous pemphigoid.^19,20 As a dependent area prone to stasis, this site gets a lot of abuse and inflammatory changes secondary to everyday insults that can theoretically alter DIF findings, especially fibrinogen deposition.

Although tissue sent for hematoxylin and eosin staining should be lesional, biopsy for DIF ideally should not contain a new or active blister, ulcer, erosion, or bulla. Immunoreactants are more likely to be degraded in these areas, and DIF may be falsely negative.²¹

It is worthwhile to briefly discuss the definitions of the terms perilesional and nonlesional. Perilesional skin most frequently refers to skin adjacent to a bulla or vesicle. This skin can be erythematous/inflamed or appear normal. When obtaining tissue for a diagnosis of blistering disease, the general recommendation is to obtain the biopsy from lesional nonbullous skin or perilesional uninvolved skin within 1 cm of the bulla.^22-24 The only exception to this is dermatitis herpetiformis, which is best diagnosed on tissue obtained from normal-appearing perilesional skin within 1 cm of an active lesion.²⁵ Additionally, if your patient has oral disease, the recommendation is to obtain the biopsy from nonlesional buccal mucosa, especially if there is desquamative gingivitis.^26,27

The ideal biopsy size is 4 or 5 mm. If considering both DIF and histopathology, it is best to procure 2 separate specimens. One larger biopsy can be carefully bisected in 2 but often is subject to more handling artifacts, which can affect findings. In the case of 1 biopsy bisected into 2 specimens, the punch should be at least 6 mm. Shave biopsies also can be performed as long as they extend into the reticular dermis.²³

For vasculitis, biopsies for DIF should be taken from lesions that are less than 24 hours old for highest yield, as the level of tissue immunoreactants tends to decline over time.²⁸ This guideline does differ from hematoxylin and eosin specimens sent for evaluation of vasculitis, which ideally should be lesional tissue over 72 hours old. When evaluating for lupus (including subacute cutaneous lupus, discoid lupus, and systemic lupus), DIF is more likely to be positive in well-established, active lesions.

Which Test Should I Order?

The answer to this question depends, but the use of all 3 tests has a specificity close to 100% when evaluating for autoantibody-associated diseases.²³ For autoimmune blistering disease, DIF is considered the diagnostic standard. The sensitivity of DIF for diagnosing BP is in the range of 82% to 90.5%, while specificity is 98%.^29-31 Other autoimmune blistering diseases, such as pemphigus or dermatitis herpetiformis, have even higher sensitivities and specificities. Direct immunofluorescence often is used as a screening test, but false negatives do occur.^32,33 Although rare, false positives also can occur, especially in cases of infection, and should be suspected when there is a lack of clinicopathologic correlation.³⁴ If DIF is negative but clinical suspicion remains high, IIF should be ordered to directly evaluate a patient’s serum for autoantibodies.

In acute cutaneous lupus, subacute cutaneous lupus, and discoid lupus, DIF of active lesions may be helpful if histopathologic examination of a cutaneous lupus erythematosus lesion is nondiagnostic. However, histopathologic examination of formalin-fixed tissue remains the standard for these diagnoses. In vasculitis, while DIF is not used for diagnosis, it is useful to evaluate for IgA deposition. This is important in adults, as IgA deposition has been associated with a greater risk for developing end-stage renal disease.³⁵

Final Thoughts

This is an overview of the tests available for diagnosing autoimmune blistering diseases. Residents should keep in mind that these tests are just one part of the puzzle when it comes to diagnosing these diseases. Results of DIF, IIF, and ELISA testing should be considered in conjunction with patient history and physical examination as well as histopathologic examination of lesional tissue when evaluating for dermatologic diseases with autoantibodies.