Dermpath Diagnosis

The Diagnosis: Cutaneous Myxoma

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

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

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

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

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

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

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

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

The Diagnosis: Cutaneous Myxoma

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

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

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

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

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

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

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

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

The Diagnosis: Cutaneous Myxoma

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

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

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

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

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

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

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

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

The Diagnosis: Dermatomyofibroma

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

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

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

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

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

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

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

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

The Diagnosis: Dermatomyofibroma

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

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

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

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

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

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

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

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

The Diagnosis: Dermatomyofibroma

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

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

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

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

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

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

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

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

The Diagnosis: Infantile Digital Fibromatosis

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

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

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

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

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

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

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

The Diagnosis: Infantile Digital Fibromatosis

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

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

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

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

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

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

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

The Diagnosis: Infantile Digital Fibromatosis

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

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

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

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

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

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

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

The Diagnosis: Schwannoma

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

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

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

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

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

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

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

The Diagnosis: Schwannoma

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

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

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

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

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

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

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

The Diagnosis: Schwannoma

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

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

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

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

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

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

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

The Diagnosis: Primary Cutaneous Carcinosarcoma

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

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

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

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

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

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

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

The Diagnosis: Primary Cutaneous Carcinosarcoma

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

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

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

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

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

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

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

The Diagnosis: Primary Cutaneous Carcinosarcoma

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

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

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

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

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

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

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

The Diagnosis: Levamisole-Induced Vasculopathy

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

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

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

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

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

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

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

The Diagnosis: Levamisole-Induced Vasculopathy

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

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

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

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

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

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

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

The Diagnosis: Levamisole-Induced Vasculopathy

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

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

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

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

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

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

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

The Diagnosis: Cystic Panfolliculoma 

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

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

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

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

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

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

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

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

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

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

The Diagnosis: Cystic Panfolliculoma 

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

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

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

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

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

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

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

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

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

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

The Diagnosis: Cystic Panfolliculoma 

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

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

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

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

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

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

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

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

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

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

The Diagnosis: Degos Disease 

The pathophysiology of Degos disease (malignant atrophic papulosis) is unknown.¹ Histopathology demonstrates a wedge-shaped area of dermal necrosis with edema and mucin deposition extending from the papillary dermis to the deep reticular dermis. Occluded vessels, thrombosis, and perivascular lymphocytic infiltrates also may be seen, particularly at the dermal subcutaneous junction and at the periphery of the wedge-shaped infarction. The vascular damage that occurs may be the result of vasculitis, coagulopathy, or endothelial cell dysfunction.¹  

Patients typically present with small, round, erythematous papules that eventually develop atrophic porcelain white centers and telangiectatic rims. These lesions most commonly occur on the trunk and arms. In the benign form of atrophic papulosis, only the skin is involved; however, systemic involvement of the gastrointestinal tract and central nervous system can occur, resulting in bowel perforation and stroke, respectively.¹ Although there is no definitive treatment of Degos disease, successful therapy with aspirin or dipyridamole has been reported.¹ Eculizumab, a monoclonal antibody that binds C5, and treprostinil, a prostacyclin analog, are emerging treatment options.^2,3 The differential diagnosis of Degos disease may include granuloma annulare, guttate extragenital lichen sclerosus, livedoid vasculopathy, and lymphomatoid papulosis.  

Granuloma annulare may clinically mimic the erythematous papules seen in early Degos disease, and histopathology can be used to distinguish between these two disease processes. Localized granuloma annulare is the most common variant and clinically presents as pink papules and plaques in an annular configuration.⁴ Histopathology demonstrates an unremarkable epidermis; however, the dermis contains degenerated collagen surrounded by palisading histiocytes as well as lymphocytes. Similar to Degos disease, increased mucin is seen within these areas of degeneration, but occluded vessels and thrombosis typically are not seen (Figure 1).^4,5  

Guttate extragenital lichen sclerosus initially presents as polygonal, bluish white papules that coalesce into plaques.⁶ Over time, these lesions become more atrophic and may mimic Degos disease but appear differently on histopathology. Histopathology of lichen sclerosus classically demonstrates atrophy of the epidermis with loss of the rete ridges and vacuolar surface changes. Homogenization of the superficial/papillary dermis with an underlying bandlike lymphocytic infiltrate also is seen (Figure 2).⁶

Livedoid vasculopathy is characterized by chronic recurrent ulceration of the legs secondary to thrombosis and subsequent ischemia. In the initial phase of this disease, livedo reticularis is seen followed by the development of ulcerations. As these ulcerations heal, they leave behind porcelain white scars referred to as atrophie blanche.⁷ The areas of scarring in livedoid vasculopathy are broad and angulated, differentiating them from the small, round, porcelain white macules in end-stage Degos disease. Histopathology demonstrates thrombosis and fibrin occlusion of the upper and mid dermal vessels. Very minimal perivascular infiltrate typically is seen, but when it is present, the infiltrate mostly is lymphocytic. Hyalinization of the vessel walls also is seen, particularly in the atrophie blanche stage (Figure 3).⁷  

Lymphomatoid papulosis classically presents with pruritic red papules that often spontaneously involute. After resolution of the primary lesions, atrophic varioliform scars may be left behind that can resemble Degos disease.⁸ Classically, there are 5 histopathologic subtypes: A, B, C, D, and E. Type A is the most common type of lymphomatoid papulosis, and histopathology demonstrates a dermal lymphocytic infiltrate that consists of cells arranged in small clusters. Numerous medium- to large-sized atypical lymphocytes with prominent nucleoli and abundant cytoplasm are seen, and mitotic figures are common (Figure 4).⁸ 

Our case was particularly interesting because the patient was 2 to 3 weeks pregnant. Degos disease in pregnancy appears to be quite exceptional. A PubMed search of articles indexed for MEDLINE using the terms Degos disease and pregnancy revealed only 4 other cases reported in the literature.^9-12 With the exception of a single case that was complicated by severe abdominal pain requiring labor induction, the other reported cases resulted in uncomplicated pregnancies.^9-12 Conversely, our patient's pregnancy was complicated by gestational hypertension and fetal hydrops requiring a preterm cesarean delivery. Furthermore, the infant had multiple complications, which were attributed to both placental insufficiency and a coagulopathic state.  

Our patient also was found to have a heterozygous factor V Leiden mutation on workup. A PubMed search using the terms factor V Leiden mutation and Degos disease revealed 2 other cases of factor V Leiden mutation-associated Degos disease.^13,14 The importance of factor V Leiden mutations in patients with Degos disease currently is unclear. 

The Diagnosis: Degos Disease 

The pathophysiology of Degos disease (malignant atrophic papulosis) is unknown.¹ Histopathology demonstrates a wedge-shaped area of dermal necrosis with edema and mucin deposition extending from the papillary dermis to the deep reticular dermis. Occluded vessels, thrombosis, and perivascular lymphocytic infiltrates also may be seen, particularly at the dermal subcutaneous junction and at the periphery of the wedge-shaped infarction. The vascular damage that occurs may be the result of vasculitis, coagulopathy, or endothelial cell dysfunction.¹  

Patients typically present with small, round, erythematous papules that eventually develop atrophic porcelain white centers and telangiectatic rims. These lesions most commonly occur on the trunk and arms. In the benign form of atrophic papulosis, only the skin is involved; however, systemic involvement of the gastrointestinal tract and central nervous system can occur, resulting in bowel perforation and stroke, respectively.¹ Although there is no definitive treatment of Degos disease, successful therapy with aspirin or dipyridamole has been reported.¹ Eculizumab, a monoclonal antibody that binds C5, and treprostinil, a prostacyclin analog, are emerging treatment options.^2,3 The differential diagnosis of Degos disease may include granuloma annulare, guttate extragenital lichen sclerosus, livedoid vasculopathy, and lymphomatoid papulosis.  

Granuloma annulare may clinically mimic the erythematous papules seen in early Degos disease, and histopathology can be used to distinguish between these two disease processes. Localized granuloma annulare is the most common variant and clinically presents as pink papules and plaques in an annular configuration.⁴ Histopathology demonstrates an unremarkable epidermis; however, the dermis contains degenerated collagen surrounded by palisading histiocytes as well as lymphocytes. Similar to Degos disease, increased mucin is seen within these areas of degeneration, but occluded vessels and thrombosis typically are not seen (Figure 1).^4,5  

Guttate extragenital lichen sclerosus initially presents as polygonal, bluish white papules that coalesce into plaques.⁶ Over time, these lesions become more atrophic and may mimic Degos disease but appear differently on histopathology. Histopathology of lichen sclerosus classically demonstrates atrophy of the epidermis with loss of the rete ridges and vacuolar surface changes. Homogenization of the superficial/papillary dermis with an underlying bandlike lymphocytic infiltrate also is seen (Figure 2).⁶

Livedoid vasculopathy is characterized by chronic recurrent ulceration of the legs secondary to thrombosis and subsequent ischemia. In the initial phase of this disease, livedo reticularis is seen followed by the development of ulcerations. As these ulcerations heal, they leave behind porcelain white scars referred to as atrophie blanche.⁷ The areas of scarring in livedoid vasculopathy are broad and angulated, differentiating them from the small, round, porcelain white macules in end-stage Degos disease. Histopathology demonstrates thrombosis and fibrin occlusion of the upper and mid dermal vessels. Very minimal perivascular infiltrate typically is seen, but when it is present, the infiltrate mostly is lymphocytic. Hyalinization of the vessel walls also is seen, particularly in the atrophie blanche stage (Figure 3).⁷  

Lymphomatoid papulosis classically presents with pruritic red papules that often spontaneously involute. After resolution of the primary lesions, atrophic varioliform scars may be left behind that can resemble Degos disease.⁸ Classically, there are 5 histopathologic subtypes: A, B, C, D, and E. Type A is the most common type of lymphomatoid papulosis, and histopathology demonstrates a dermal lymphocytic infiltrate that consists of cells arranged in small clusters. Numerous medium- to large-sized atypical lymphocytes with prominent nucleoli and abundant cytoplasm are seen, and mitotic figures are common (Figure 4).⁸ 

Our case was particularly interesting because the patient was 2 to 3 weeks pregnant. Degos disease in pregnancy appears to be quite exceptional. A PubMed search of articles indexed for MEDLINE using the terms Degos disease and pregnancy revealed only 4 other cases reported in the literature.^9-12 With the exception of a single case that was complicated by severe abdominal pain requiring labor induction, the other reported cases resulted in uncomplicated pregnancies.^9-12 Conversely, our patient's pregnancy was complicated by gestational hypertension and fetal hydrops requiring a preterm cesarean delivery. Furthermore, the infant had multiple complications, which were attributed to both placental insufficiency and a coagulopathic state.  

Our patient also was found to have a heterozygous factor V Leiden mutation on workup. A PubMed search using the terms factor V Leiden mutation and Degos disease revealed 2 other cases of factor V Leiden mutation-associated Degos disease.^13,14 The importance of factor V Leiden mutations in patients with Degos disease currently is unclear. 

The Diagnosis: Degos Disease 

The pathophysiology of Degos disease (malignant atrophic papulosis) is unknown.¹ Histopathology demonstrates a wedge-shaped area of dermal necrosis with edema and mucin deposition extending from the papillary dermis to the deep reticular dermis. Occluded vessels, thrombosis, and perivascular lymphocytic infiltrates also may be seen, particularly at the dermal subcutaneous junction and at the periphery of the wedge-shaped infarction. The vascular damage that occurs may be the result of vasculitis, coagulopathy, or endothelial cell dysfunction.¹  

Patients typically present with small, round, erythematous papules that eventually develop atrophic porcelain white centers and telangiectatic rims. These lesions most commonly occur on the trunk and arms. In the benign form of atrophic papulosis, only the skin is involved; however, systemic involvement of the gastrointestinal tract and central nervous system can occur, resulting in bowel perforation and stroke, respectively.¹ Although there is no definitive treatment of Degos disease, successful therapy with aspirin or dipyridamole has been reported.¹ Eculizumab, a monoclonal antibody that binds C5, and treprostinil, a prostacyclin analog, are emerging treatment options.^2,3 The differential diagnosis of Degos disease may include granuloma annulare, guttate extragenital lichen sclerosus, livedoid vasculopathy, and lymphomatoid papulosis.  

Granuloma annulare may clinically mimic the erythematous papules seen in early Degos disease, and histopathology can be used to distinguish between these two disease processes. Localized granuloma annulare is the most common variant and clinically presents as pink papules and plaques in an annular configuration.⁴ Histopathology demonstrates an unremarkable epidermis; however, the dermis contains degenerated collagen surrounded by palisading histiocytes as well as lymphocytes. Similar to Degos disease, increased mucin is seen within these areas of degeneration, but occluded vessels and thrombosis typically are not seen (Figure 1).^4,5  

Guttate extragenital lichen sclerosus initially presents as polygonal, bluish white papules that coalesce into plaques.⁶ Over time, these lesions become more atrophic and may mimic Degos disease but appear differently on histopathology. Histopathology of lichen sclerosus classically demonstrates atrophy of the epidermis with loss of the rete ridges and vacuolar surface changes. Homogenization of the superficial/papillary dermis with an underlying bandlike lymphocytic infiltrate also is seen (Figure 2).⁶

Livedoid vasculopathy is characterized by chronic recurrent ulceration of the legs secondary to thrombosis and subsequent ischemia. In the initial phase of this disease, livedo reticularis is seen followed by the development of ulcerations. As these ulcerations heal, they leave behind porcelain white scars referred to as atrophie blanche.⁷ The areas of scarring in livedoid vasculopathy are broad and angulated, differentiating them from the small, round, porcelain white macules in end-stage Degos disease. Histopathology demonstrates thrombosis and fibrin occlusion of the upper and mid dermal vessels. Very minimal perivascular infiltrate typically is seen, but when it is present, the infiltrate mostly is lymphocytic. Hyalinization of the vessel walls also is seen, particularly in the atrophie blanche stage (Figure 3).⁷  

Lymphomatoid papulosis classically presents with pruritic red papules that often spontaneously involute. After resolution of the primary lesions, atrophic varioliform scars may be left behind that can resemble Degos disease.⁸ Classically, there are 5 histopathologic subtypes: A, B, C, D, and E. Type A is the most common type of lymphomatoid papulosis, and histopathology demonstrates a dermal lymphocytic infiltrate that consists of cells arranged in small clusters. Numerous medium- to large-sized atypical lymphocytes with prominent nucleoli and abundant cytoplasm are seen, and mitotic figures are common (Figure 4).⁸ 

Our case was particularly interesting because the patient was 2 to 3 weeks pregnant. Degos disease in pregnancy appears to be quite exceptional. A PubMed search of articles indexed for MEDLINE using the terms Degos disease and pregnancy revealed only 4 other cases reported in the literature.^9-12 With the exception of a single case that was complicated by severe abdominal pain requiring labor induction, the other reported cases resulted in uncomplicated pregnancies.^9-12 Conversely, our patient's pregnancy was complicated by gestational hypertension and fetal hydrops requiring a preterm cesarean delivery. Furthermore, the infant had multiple complications, which were attributed to both placental insufficiency and a coagulopathic state.  

Our patient also was found to have a heterozygous factor V Leiden mutation on workup. A PubMed search using the terms factor V Leiden mutation and Degos disease revealed 2 other cases of factor V Leiden mutation-associated Degos disease.^13,14 The importance of factor V Leiden mutations in patients with Degos disease currently is unclear. 

The Diagnosis: Granular Cell Tumor 

Histopathologic analysis from the axillary excision demonstrated cords and sheets of large polygonal cells in the dermis with uniform, oval, hyperchromatic nuclei and ample pink granular-staining cytoplasm (quiz images). An infiltrative growth pattern was noted; however, there was no evidence of conspicuous mitoses, nuclear pleomorphism, or necrosis. These results in conjunction with the immunohistochemistry findings were consistent with a benign granular cell tumor (GCT), a rare neoplasm considered to have neural/Schwann cell origin.^1-3 

Our case demonstrates the difficulty in clinically diagnosing cutaneous GCTs. The tumor often presents as a solitary, 0.5- to 3-cm, asymptomatic, firm nodule^4,5; however, GCTs also can appear verrucous, eroded, or with other variable morphologies, which can create diagnostic challenges.^5,6 Accordingly, a 1980 study of 110 patients with GCTs found that the preoperative clinical diagnosis was incorrect in all but 3 cases,⁷ emphasizing the need for histologic evaluation. Benign GCTs tend to exhibit sheets of polygonal tumor cells with eosinophilic granular cytoplasm and small central nuclei.^3,5 The cytoplasmic granules are periodic acid-Schiff positive and diastase resistant.⁶ Many cases feature pseudoepitheliomatous hyperplasia, which can misleadingly resemble squamous cell carcinoma.^3,5,6 Of note, invasive growth patterns on histology can occur with benign GCTs, as in our patient's case, and do not impact prognosis.^3,4 On immunohistochemistry, benign, atypical, and malignant GCTs often stain positive for S-100 protein, vimentin, neuron-specific enolase, SOX10, and CD68.^1,3  

Although our patient's GCTs were benign, an estimated 1% to 2% are malignant.^1,4 In 1998, Fanburg-Smith et al¹ defined 6 histologic criteria that characterize malignant GCTs: necrosis, tumor cell spindling, vesicular nuclei with large nucleoli, high nuclear to cytoplasmic ratio, increased mitosis, and pleomorphism. Neoplasms with 3 or more of these features are classified as malignant, those with 1 or 2 are considered atypical, and those with only pleomorphism or no other criteria met are diagnosed as benign.¹  

Multiple GCTs have been reported in 10% to 25% of cases and, as highlighted in our case, can occur in both a metachronous and synchronous manner.^2-4,6 Our patient developed a solitary GCT on the inferior lip 3 years prior to the appearance of 2 additional GCTs within 6 months of each other. The presence of multiple GCTs has been associated with genetic syndromes, such as neurofibromatosis type 1 and Noonan syndrome with multiple lentigines^3,8; however, as our case demonstrates, multiple GCTs can occur in nonsyndromic patients as well. When multiple GCTs develop at distant sites, they can resemble metastasis.³ To differentiate these clinical scenarios, Machado et al³ proposed utilizing histology and anatomic location. Multiple tumors with benign characteristics on histology likely represent multiple GCTs, whereas tumors arising at sites common to GCT metastasis, such as lymph node, bone, or viscera, are more concerning for metastatic disease. It has been suggested that patients with multiple GCTs should be monitored with physical examination and repeat magnetic resonance imaging or computed tomography every 6 to 12 months.² Given our patient's presentation with new tumors arising within 6 months of one another, we recommended a 6-month follow-up interval rather than 1 year. Due to the rarity of GCTs, clinical trials to define treatment guidelines and recommendations have not been performed.³ However, the most commonly utilized treatment modality is wide local excision, as performed in our patient.^2,4 

Melanoma, atypical fibroxanthoma (AFX), xanthoma, and leiomyosarcoma may be difficult to distinguish from GCT.^1,3,4 Melanoma incidence has increased dramatically over the last several decades, with rates in the United States rising from 6.8 cases per 100,000 individuals in the 1970s to 20.¹ in the early 2000s. Risk factors for its development include UV radiation exposure and particularly severe sunburns during childhood, along with a number of host risk factors such as total number of melanocytic nevi, family history, and fair complexion.⁹ Histologically, it often demonstrates irregularly distributed, poorly defined melanocytes with pagetoid spread and dyscohesive nests (Figure 1).¹⁰ Melanoma metastasis occasionally can present as a soft-tissue mass and often stains positive for S-100 and vimentin, thus resembling GCT^1,4; however, unlike melanoma, GCTs lack melanosomes and stain negative for more specific melanocyte markers, such as melanoma antigen recognized by T cells 1 (MART-1).^1,3,4 
Atypical fibroxanthoma is a cutaneous neoplasm with fibrohistiocytic mesenchymal origin.¹¹ These tumors typically arise on the head and neck in elderly individuals, particularly men with sun-damaged skin. They often present as superficial, rapidly growing nodules with the potential to ulcerate and bleed.^11,12 Histologic features include pleomorphic spindle and epithelioid cells, whose nuclei appear hyperchromatic with atypical mitoses (Figure 2).¹² Granular cell changes occur infrequently with AFXs, but in such cases immunohistochemistry can readily distinguish AFX from GCT. Although both tend to stain positive for CD68 and vimentin, AFXs lack S-100 protein and SOX10 expression that frequently is observed in GCTs.^3,12  

Xanthomas are localized lipid deposits in the connective tissue of the skin that often arise in association with dyslipidemia.¹³ They typically present as soft to semisolid yellow papules, plaques, or nodules. Their clinical appearance can resemble GCTs; however, histologic analysis enables differentiation with ease, as xanthomas demonstrate characteristic foam cells, consisting of lipid-laden macrophages (Figure 3).¹³  

Cutaneous leiomyosarcoma is a rare dermal neoplasm, accounting for 2% to 3% of all sarcomas.¹⁴ They typically occur in White males during the fifth to seventh decades of life and often present as asymptomatic lesions on the lower extremities. They frequently arise from pilar smooth muscle. Unlike uterine and soft-tissue leiomyosarcoma, cutaneous leiomyosarcoma tends to follow an indolent course and rarely metastasizes.¹⁴ Histologically, these tumors display intersecting, well-defined, spindle-cell fascicles with abundant eosinophilic cytoplasm and cigar-shaped, blunt-ended nuclei (Figure 4).¹⁵ Occasionally, leiomyosarcomas can demonstrate cytoplasmic granularity due to lysosome accumulation⁴; nevertheless, the diagnosis usually can be elucidated by examining more typical histologic areas and utilizing immunohistochemistry, which often stains positive for α-smooth muscle actin, desmin, and h-caldesmon.^4,15 

The Diagnosis: Granular Cell Tumor 

Histopathologic analysis from the axillary excision demonstrated cords and sheets of large polygonal cells in the dermis with uniform, oval, hyperchromatic nuclei and ample pink granular-staining cytoplasm (quiz images). An infiltrative growth pattern was noted; however, there was no evidence of conspicuous mitoses, nuclear pleomorphism, or necrosis. These results in conjunction with the immunohistochemistry findings were consistent with a benign granular cell tumor (GCT), a rare neoplasm considered to have neural/Schwann cell origin.^1-3 

Our case demonstrates the difficulty in clinically diagnosing cutaneous GCTs. The tumor often presents as a solitary, 0.5- to 3-cm, asymptomatic, firm nodule^4,5; however, GCTs also can appear verrucous, eroded, or with other variable morphologies, which can create diagnostic challenges.^5,6 Accordingly, a 1980 study of 110 patients with GCTs found that the preoperative clinical diagnosis was incorrect in all but 3 cases,⁷ emphasizing the need for histologic evaluation. Benign GCTs tend to exhibit sheets of polygonal tumor cells with eosinophilic granular cytoplasm and small central nuclei.^3,5 The cytoplasmic granules are periodic acid-Schiff positive and diastase resistant.⁶ Many cases feature pseudoepitheliomatous hyperplasia, which can misleadingly resemble squamous cell carcinoma.^3,5,6 Of note, invasive growth patterns on histology can occur with benign GCTs, as in our patient's case, and do not impact prognosis.^3,4 On immunohistochemistry, benign, atypical, and malignant GCTs often stain positive for S-100 protein, vimentin, neuron-specific enolase, SOX10, and CD68.^1,3  

Although our patient's GCTs were benign, an estimated 1% to 2% are malignant.^1,4 In 1998, Fanburg-Smith et al¹ defined 6 histologic criteria that characterize malignant GCTs: necrosis, tumor cell spindling, vesicular nuclei with large nucleoli, high nuclear to cytoplasmic ratio, increased mitosis, and pleomorphism. Neoplasms with 3 or more of these features are classified as malignant, those with 1 or 2 are considered atypical, and those with only pleomorphism or no other criteria met are diagnosed as benign.¹  

Multiple GCTs have been reported in 10% to 25% of cases and, as highlighted in our case, can occur in both a metachronous and synchronous manner.^2-4,6 Our patient developed a solitary GCT on the inferior lip 3 years prior to the appearance of 2 additional GCTs within 6 months of each other. The presence of multiple GCTs has been associated with genetic syndromes, such as neurofibromatosis type 1 and Noonan syndrome with multiple lentigines^3,8; however, as our case demonstrates, multiple GCTs can occur in nonsyndromic patients as well. When multiple GCTs develop at distant sites, they can resemble metastasis.³ To differentiate these clinical scenarios, Machado et al³ proposed utilizing histology and anatomic location. Multiple tumors with benign characteristics on histology likely represent multiple GCTs, whereas tumors arising at sites common to GCT metastasis, such as lymph node, bone, or viscera, are more concerning for metastatic disease. It has been suggested that patients with multiple GCTs should be monitored with physical examination and repeat magnetic resonance imaging or computed tomography every 6 to 12 months.² Given our patient's presentation with new tumors arising within 6 months of one another, we recommended a 6-month follow-up interval rather than 1 year. Due to the rarity of GCTs, clinical trials to define treatment guidelines and recommendations have not been performed.³ However, the most commonly utilized treatment modality is wide local excision, as performed in our patient.^2,4 

Melanoma, atypical fibroxanthoma (AFX), xanthoma, and leiomyosarcoma may be difficult to distinguish from GCT.^1,3,4 Melanoma incidence has increased dramatically over the last several decades, with rates in the United States rising from 6.8 cases per 100,000 individuals in the 1970s to 20.¹ in the early 2000s. Risk factors for its development include UV radiation exposure and particularly severe sunburns during childhood, along with a number of host risk factors such as total number of melanocytic nevi, family history, and fair complexion.⁹ Histologically, it often demonstrates irregularly distributed, poorly defined melanocytes with pagetoid spread and dyscohesive nests (Figure 1).¹⁰ Melanoma metastasis occasionally can present as a soft-tissue mass and often stains positive for S-100 and vimentin, thus resembling GCT^1,4; however, unlike melanoma, GCTs lack melanosomes and stain negative for more specific melanocyte markers, such as melanoma antigen recognized by T cells 1 (MART-1).^1,3,4 
Atypical fibroxanthoma is a cutaneous neoplasm with fibrohistiocytic mesenchymal origin.¹¹ These tumors typically arise on the head and neck in elderly individuals, particularly men with sun-damaged skin. They often present as superficial, rapidly growing nodules with the potential to ulcerate and bleed.^11,12 Histologic features include pleomorphic spindle and epithelioid cells, whose nuclei appear hyperchromatic with atypical mitoses (Figure 2).¹² Granular cell changes occur infrequently with AFXs, but in such cases immunohistochemistry can readily distinguish AFX from GCT. Although both tend to stain positive for CD68 and vimentin, AFXs lack S-100 protein and SOX10 expression that frequently is observed in GCTs.^3,12  

Xanthomas are localized lipid deposits in the connective tissue of the skin that often arise in association with dyslipidemia.¹³ They typically present as soft to semisolid yellow papules, plaques, or nodules. Their clinical appearance can resemble GCTs; however, histologic analysis enables differentiation with ease, as xanthomas demonstrate characteristic foam cells, consisting of lipid-laden macrophages (Figure 3).¹³  

Cutaneous leiomyosarcoma is a rare dermal neoplasm, accounting for 2% to 3% of all sarcomas.¹⁴ They typically occur in White males during the fifth to seventh decades of life and often present as asymptomatic lesions on the lower extremities. They frequently arise from pilar smooth muscle. Unlike uterine and soft-tissue leiomyosarcoma, cutaneous leiomyosarcoma tends to follow an indolent course and rarely metastasizes.¹⁴ Histologically, these tumors display intersecting, well-defined, spindle-cell fascicles with abundant eosinophilic cytoplasm and cigar-shaped, blunt-ended nuclei (Figure 4).¹⁵ Occasionally, leiomyosarcomas can demonstrate cytoplasmic granularity due to lysosome accumulation⁴; nevertheless, the diagnosis usually can be elucidated by examining more typical histologic areas and utilizing immunohistochemistry, which often stains positive for α-smooth muscle actin, desmin, and h-caldesmon.^4,15 

The Diagnosis: Granular Cell Tumor 

Histopathologic analysis from the axillary excision demonstrated cords and sheets of large polygonal cells in the dermis with uniform, oval, hyperchromatic nuclei and ample pink granular-staining cytoplasm (quiz images). An infiltrative growth pattern was noted; however, there was no evidence of conspicuous mitoses, nuclear pleomorphism, or necrosis. These results in conjunction with the immunohistochemistry findings were consistent with a benign granular cell tumor (GCT), a rare neoplasm considered to have neural/Schwann cell origin.^1-3 

Our case demonstrates the difficulty in clinically diagnosing cutaneous GCTs. The tumor often presents as a solitary, 0.5- to 3-cm, asymptomatic, firm nodule^4,5; however, GCTs also can appear verrucous, eroded, or with other variable morphologies, which can create diagnostic challenges.^5,6 Accordingly, a 1980 study of 110 patients with GCTs found that the preoperative clinical diagnosis was incorrect in all but 3 cases,⁷ emphasizing the need for histologic evaluation. Benign GCTs tend to exhibit sheets of polygonal tumor cells with eosinophilic granular cytoplasm and small central nuclei.^3,5 The cytoplasmic granules are periodic acid-Schiff positive and diastase resistant.⁶ Many cases feature pseudoepitheliomatous hyperplasia, which can misleadingly resemble squamous cell carcinoma.^3,5,6 Of note, invasive growth patterns on histology can occur with benign GCTs, as in our patient's case, and do not impact prognosis.^3,4 On immunohistochemistry, benign, atypical, and malignant GCTs often stain positive for S-100 protein, vimentin, neuron-specific enolase, SOX10, and CD68.^1,3  

Although our patient's GCTs were benign, an estimated 1% to 2% are malignant.^1,4 In 1998, Fanburg-Smith et al¹ defined 6 histologic criteria that characterize malignant GCTs: necrosis, tumor cell spindling, vesicular nuclei with large nucleoli, high nuclear to cytoplasmic ratio, increased mitosis, and pleomorphism. Neoplasms with 3 or more of these features are classified as malignant, those with 1 or 2 are considered atypical, and those with only pleomorphism or no other criteria met are diagnosed as benign.¹  

Multiple GCTs have been reported in 10% to 25% of cases and, as highlighted in our case, can occur in both a metachronous and synchronous manner.^2-4,6 Our patient developed a solitary GCT on the inferior lip 3 years prior to the appearance of 2 additional GCTs within 6 months of each other. The presence of multiple GCTs has been associated with genetic syndromes, such as neurofibromatosis type 1 and Noonan syndrome with multiple lentigines^3,8; however, as our case demonstrates, multiple GCTs can occur in nonsyndromic patients as well. When multiple GCTs develop at distant sites, they can resemble metastasis.³ To differentiate these clinical scenarios, Machado et al³ proposed utilizing histology and anatomic location. Multiple tumors with benign characteristics on histology likely represent multiple GCTs, whereas tumors arising at sites common to GCT metastasis, such as lymph node, bone, or viscera, are more concerning for metastatic disease. It has been suggested that patients with multiple GCTs should be monitored with physical examination and repeat magnetic resonance imaging or computed tomography every 6 to 12 months.² Given our patient's presentation with new tumors arising within 6 months of one another, we recommended a 6-month follow-up interval rather than 1 year. Due to the rarity of GCTs, clinical trials to define treatment guidelines and recommendations have not been performed.³ However, the most commonly utilized treatment modality is wide local excision, as performed in our patient.^2,4 

Melanoma, atypical fibroxanthoma (AFX), xanthoma, and leiomyosarcoma may be difficult to distinguish from GCT.^1,3,4 Melanoma incidence has increased dramatically over the last several decades, with rates in the United States rising from 6.8 cases per 100,000 individuals in the 1970s to 20.¹ in the early 2000s. Risk factors for its development include UV radiation exposure and particularly severe sunburns during childhood, along with a number of host risk factors such as total number of melanocytic nevi, family history, and fair complexion.⁹ Histologically, it often demonstrates irregularly distributed, poorly defined melanocytes with pagetoid spread and dyscohesive nests (Figure 1).¹⁰ Melanoma metastasis occasionally can present as a soft-tissue mass and often stains positive for S-100 and vimentin, thus resembling GCT^1,4; however, unlike melanoma, GCTs lack melanosomes and stain negative for more specific melanocyte markers, such as melanoma antigen recognized by T cells 1 (MART-1).^1,3,4 
Atypical fibroxanthoma is a cutaneous neoplasm with fibrohistiocytic mesenchymal origin.¹¹ These tumors typically arise on the head and neck in elderly individuals, particularly men with sun-damaged skin. They often present as superficial, rapidly growing nodules with the potential to ulcerate and bleed.^11,12 Histologic features include pleomorphic spindle and epithelioid cells, whose nuclei appear hyperchromatic with atypical mitoses (Figure 2).¹² Granular cell changes occur infrequently with AFXs, but in such cases immunohistochemistry can readily distinguish AFX from GCT. Although both tend to stain positive for CD68 and vimentin, AFXs lack S-100 protein and SOX10 expression that frequently is observed in GCTs.^3,12  

Xanthomas are localized lipid deposits in the connective tissue of the skin that often arise in association with dyslipidemia.¹³ They typically present as soft to semisolid yellow papules, plaques, or nodules. Their clinical appearance can resemble GCTs; however, histologic analysis enables differentiation with ease, as xanthomas demonstrate characteristic foam cells, consisting of lipid-laden macrophages (Figure 3).¹³  

Cutaneous leiomyosarcoma is a rare dermal neoplasm, accounting for 2% to 3% of all sarcomas.¹⁴ They typically occur in White males during the fifth to seventh decades of life and often present as asymptomatic lesions on the lower extremities. They frequently arise from pilar smooth muscle. Unlike uterine and soft-tissue leiomyosarcoma, cutaneous leiomyosarcoma tends to follow an indolent course and rarely metastasizes.¹⁴ Histologically, these tumors display intersecting, well-defined, spindle-cell fascicles with abundant eosinophilic cytoplasm and cigar-shaped, blunt-ended nuclei (Figure 4).¹⁵ Occasionally, leiomyosarcomas can demonstrate cytoplasmic granularity due to lysosome accumulation⁴; nevertheless, the diagnosis usually can be elucidated by examining more typical histologic areas and utilizing immunohistochemistry, which often stains positive for α-smooth muscle actin, desmin, and h-caldesmon.^4,15 

The Diagnosis: Sweet Syndrome 

Sweet syndrome, alternatively known as acute febrile neutrophilic dermatosis, typically presents with variably tender, erythematous papules, plaques, or nodules in middle-aged adults.¹ Systemic symptoms such as fever, fatigue, and arthralgia often accompany these cutaneous findings.^1,2 Although the pathophysiology has not been fully elucidated, this syndrome frequently is associated with infections, especially upper respiratory illnesses; medications; and malignancies. Among cases of malignancy-associated Sweet syndrome, hematologic malignancies, particularly acute myeloid leukemia and myelodysplastic syndrome, are more common than solid organ malignancies.^1,2 Sweet syndrome may precede the associated malignancy by several months; thus, patients without an identifiable trigger for Sweet syndrome should be closely followed.² Treatment with systemic steroids typically is effective.^1,3 Typical histologic features include papillary dermal edema and a brisk neutrophilic infiltrate in the superficial to mid dermis (quiz image).⁴ Overlying epidermal spongiosis with or without vesiculation also can be seen.⁴ Leukocytoclasia and endothelial swelling without fibrinoid necrosis are typical, though full-blown leukocytoclastic vasculitis can be seen.^3,4 A histiocytoid variant also has been described in which the dermal infiltrate is composed of mononuclear cells reminiscent of histiocytes that are thought to be immature cells of myeloid origin. This variant histologically can simulate leukemia cutis.⁵  

Perniosis, also known as chilblains, typically presents with red to violaceous macules or papules on acral sites, particularly the distal fingers and toes.^6,7 It tends to affect young women more frequently than other demographic groups. Although the pathophysiology is not fully understood, perniosis is thought to represent an abnormal inflammatory response to cold environmental conditions. It can occur as an idiopathic disorder or in association with various systemic illnesses including lupus erythematosus.^6,7 The typical histologic findings include papillary dermal edema and a lymphocytic infiltrate in the superficial to deep dermis, often with perivascular and perieccrine accentuation (Figure 1).^3,6 Other less common microscopic findings include sparse keratinocyte necrosis, basal layer vacuolar change, swelling of endothelial cells, and lymphocytic vasculitis.⁶ The lesions typically resolve spontaneously within a few weeks, but in some cases they may be chronic.³ 

Polymorphous light eruption, a common photodermatosis induced by UV light exposure, typically presents in adolescence or early adulthood with a female predominance. Patients usually develop this pruritic rash on sun-exposed skin other than the face and dorsal aspects of the hands in the spring or early summer upon increased sun exposure after the winter season.^3,8 Consistent sunlight exposure throughout the summer months results in decreased flares. Various cutaneous morphologies including papules, vesicles, and plaques can be seen.^3,8 Histologic findings include papillary dermal edema and a perivascular lymphocytic infiltrate in the superficial to deep dermis (Figure 2).⁴  

Tinea corporis, a superficial cutaneous dermatophyte infection, typically presents as annular scaly plaques with central clearing. Vesicles and pustules also can be seen.³ The diagnosis can be confirmed via fungal culture, identification of hyphae on microscopic examination of skin scrapings using potassium hydroxide, or cutaneous biopsy. Histologic clues to diagnosis include a "compact stratum corneum (either uniform or forming a layer beneath a basket weave stratum corneum), parakeratosis, mild spongiosis, and neutrophils in the stratum corneum" (Figure 3).⁹ Papillary dermal edema also may be present, though this finding less commonly is reported.^9,10 Because fungal hyphae can be difficult to identify on hematoxylin and eosin-stained slides, special stains such as periodic acid-Schiff or Grocott-Gomori methenamine-silver may be helpful.⁹ These infections are managed with topical or oral antifungal medications.  

Wells syndrome, also known as eosinophilic cellulitis, presents with an acute eruption that can clinically resemble bacterial cellulitis.³ It has been described in children and adults with various clinical morphologies including plaques, bullae, papulovesicles, and papulonodules. Peripheral eosinophilia may be present.¹¹ The clinical lesions usually resolve spontaneously in a few weeks to months, but recurrences are typical.^3,11 Histologic findings include papillary dermal edema with or without subepidermal bulla formation and epidermal spongiosis as well as a mixed inflammatory infiltrate with a predominance of eosinophils and flame figures (Figure 4).⁴ Flame figures are collagen fibers coated with major basic protein and other constituents of degranulated eosinophils.³ Although flame figures often are present in Wells syndrome, they are not specific to this condition.^3,4 Some consider Wells syndrome an exaggerated reaction pattern rather than a specific entity.³ 

The Diagnosis: Sweet Syndrome 

Sweet syndrome, alternatively known as acute febrile neutrophilic dermatosis, typically presents with variably tender, erythematous papules, plaques, or nodules in middle-aged adults.¹ Systemic symptoms such as fever, fatigue, and arthralgia often accompany these cutaneous findings.^1,2 Although the pathophysiology has not been fully elucidated, this syndrome frequently is associated with infections, especially upper respiratory illnesses; medications; and malignancies. Among cases of malignancy-associated Sweet syndrome, hematologic malignancies, particularly acute myeloid leukemia and myelodysplastic syndrome, are more common than solid organ malignancies.^1,2 Sweet syndrome may precede the associated malignancy by several months; thus, patients without an identifiable trigger for Sweet syndrome should be closely followed.² Treatment with systemic steroids typically is effective.^1,3 Typical histologic features include papillary dermal edema and a brisk neutrophilic infiltrate in the superficial to mid dermis (quiz image).⁴ Overlying epidermal spongiosis with or without vesiculation also can be seen.⁴ Leukocytoclasia and endothelial swelling without fibrinoid necrosis are typical, though full-blown leukocytoclastic vasculitis can be seen.^3,4 A histiocytoid variant also has been described in which the dermal infiltrate is composed of mononuclear cells reminiscent of histiocytes that are thought to be immature cells of myeloid origin. This variant histologically can simulate leukemia cutis.⁵  

Perniosis, also known as chilblains, typically presents with red to violaceous macules or papules on acral sites, particularly the distal fingers and toes.^6,7 It tends to affect young women more frequently than other demographic groups. Although the pathophysiology is not fully understood, perniosis is thought to represent an abnormal inflammatory response to cold environmental conditions. It can occur as an idiopathic disorder or in association with various systemic illnesses including lupus erythematosus.^6,7 The typical histologic findings include papillary dermal edema and a lymphocytic infiltrate in the superficial to deep dermis, often with perivascular and perieccrine accentuation (Figure 1).^3,6 Other less common microscopic findings include sparse keratinocyte necrosis, basal layer vacuolar change, swelling of endothelial cells, and lymphocytic vasculitis.⁶ The lesions typically resolve spontaneously within a few weeks, but in some cases they may be chronic.³ 

Polymorphous light eruption, a common photodermatosis induced by UV light exposure, typically presents in adolescence or early adulthood with a female predominance. Patients usually develop this pruritic rash on sun-exposed skin other than the face and dorsal aspects of the hands in the spring or early summer upon increased sun exposure after the winter season.^3,8 Consistent sunlight exposure throughout the summer months results in decreased flares. Various cutaneous morphologies including papules, vesicles, and plaques can be seen.^3,8 Histologic findings include papillary dermal edema and a perivascular lymphocytic infiltrate in the superficial to deep dermis (Figure 2).⁴  

Tinea corporis, a superficial cutaneous dermatophyte infection, typically presents as annular scaly plaques with central clearing. Vesicles and pustules also can be seen.³ The diagnosis can be confirmed via fungal culture, identification of hyphae on microscopic examination of skin scrapings using potassium hydroxide, or cutaneous biopsy. Histologic clues to diagnosis include a "compact stratum corneum (either uniform or forming a layer beneath a basket weave stratum corneum), parakeratosis, mild spongiosis, and neutrophils in the stratum corneum" (Figure 3).⁹ Papillary dermal edema also may be present, though this finding less commonly is reported.^9,10 Because fungal hyphae can be difficult to identify on hematoxylin and eosin-stained slides, special stains such as periodic acid-Schiff or Grocott-Gomori methenamine-silver may be helpful.⁹ These infections are managed with topical or oral antifungal medications.  

Wells syndrome, also known as eosinophilic cellulitis, presents with an acute eruption that can clinically resemble bacterial cellulitis.³ It has been described in children and adults with various clinical morphologies including plaques, bullae, papulovesicles, and papulonodules. Peripheral eosinophilia may be present.¹¹ The clinical lesions usually resolve spontaneously in a few weeks to months, but recurrences are typical.^3,11 Histologic findings include papillary dermal edema with or without subepidermal bulla formation and epidermal spongiosis as well as a mixed inflammatory infiltrate with a predominance of eosinophils and flame figures (Figure 4).⁴ Flame figures are collagen fibers coated with major basic protein and other constituents of degranulated eosinophils.³ Although flame figures often are present in Wells syndrome, they are not specific to this condition.^3,4 Some consider Wells syndrome an exaggerated reaction pattern rather than a specific entity.³ 

The Diagnosis: Sweet Syndrome 

Sweet syndrome, alternatively known as acute febrile neutrophilic dermatosis, typically presents with variably tender, erythematous papules, plaques, or nodules in middle-aged adults.¹ Systemic symptoms such as fever, fatigue, and arthralgia often accompany these cutaneous findings.^1,2 Although the pathophysiology has not been fully elucidated, this syndrome frequently is associated with infections, especially upper respiratory illnesses; medications; and malignancies. Among cases of malignancy-associated Sweet syndrome, hematologic malignancies, particularly acute myeloid leukemia and myelodysplastic syndrome, are more common than solid organ malignancies.^1,2 Sweet syndrome may precede the associated malignancy by several months; thus, patients without an identifiable trigger for Sweet syndrome should be closely followed.² Treatment with systemic steroids typically is effective.^1,3 Typical histologic features include papillary dermal edema and a brisk neutrophilic infiltrate in the superficial to mid dermis (quiz image).⁴ Overlying epidermal spongiosis with or without vesiculation also can be seen.⁴ Leukocytoclasia and endothelial swelling without fibrinoid necrosis are typical, though full-blown leukocytoclastic vasculitis can be seen.^3,4 A histiocytoid variant also has been described in which the dermal infiltrate is composed of mononuclear cells reminiscent of histiocytes that are thought to be immature cells of myeloid origin. This variant histologically can simulate leukemia cutis.⁵  

Perniosis, also known as chilblains, typically presents with red to violaceous macules or papules on acral sites, particularly the distal fingers and toes.^6,7 It tends to affect young women more frequently than other demographic groups. Although the pathophysiology is not fully understood, perniosis is thought to represent an abnormal inflammatory response to cold environmental conditions. It can occur as an idiopathic disorder or in association with various systemic illnesses including lupus erythematosus.^6,7 The typical histologic findings include papillary dermal edema and a lymphocytic infiltrate in the superficial to deep dermis, often with perivascular and perieccrine accentuation (Figure 1).^3,6 Other less common microscopic findings include sparse keratinocyte necrosis, basal layer vacuolar change, swelling of endothelial cells, and lymphocytic vasculitis.⁶ The lesions typically resolve spontaneously within a few weeks, but in some cases they may be chronic.³ 

Polymorphous light eruption, a common photodermatosis induced by UV light exposure, typically presents in adolescence or early adulthood with a female predominance. Patients usually develop this pruritic rash on sun-exposed skin other than the face and dorsal aspects of the hands in the spring or early summer upon increased sun exposure after the winter season.^3,8 Consistent sunlight exposure throughout the summer months results in decreased flares. Various cutaneous morphologies including papules, vesicles, and plaques can be seen.^3,8 Histologic findings include papillary dermal edema and a perivascular lymphocytic infiltrate in the superficial to deep dermis (Figure 2).⁴  

Tinea corporis, a superficial cutaneous dermatophyte infection, typically presents as annular scaly plaques with central clearing. Vesicles and pustules also can be seen.³ The diagnosis can be confirmed via fungal culture, identification of hyphae on microscopic examination of skin scrapings using potassium hydroxide, or cutaneous biopsy. Histologic clues to diagnosis include a "compact stratum corneum (either uniform or forming a layer beneath a basket weave stratum corneum), parakeratosis, mild spongiosis, and neutrophils in the stratum corneum" (Figure 3).⁹ Papillary dermal edema also may be present, though this finding less commonly is reported.^9,10 Because fungal hyphae can be difficult to identify on hematoxylin and eosin-stained slides, special stains such as periodic acid-Schiff or Grocott-Gomori methenamine-silver may be helpful.⁹ These infections are managed with topical or oral antifungal medications.  

Wells syndrome, also known as eosinophilic cellulitis, presents with an acute eruption that can clinically resemble bacterial cellulitis.³ It has been described in children and adults with various clinical morphologies including plaques, bullae, papulovesicles, and papulonodules. Peripheral eosinophilia may be present.¹¹ The clinical lesions usually resolve spontaneously in a few weeks to months, but recurrences are typical.^3,11 Histologic findings include papillary dermal edema with or without subepidermal bulla formation and epidermal spongiosis as well as a mixed inflammatory infiltrate with a predominance of eosinophils and flame figures (Figure 4).⁴ Flame figures are collagen fibers coated with major basic protein and other constituents of degranulated eosinophils.³ Although flame figures often are present in Wells syndrome, they are not specific to this condition.^3,4 Some consider Wells syndrome an exaggerated reaction pattern rather than a specific entity.³