Dermpath Diagnosis

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 

The Diagnosis: Cutaneous Collagenous Vasculopathy 

Cutaneous collagenous vasculopathy (CCV) is an idiopathic microangiopathy of the small vessels in the superficial dermis. A condition first identified by Salama and Rosenthal¹ in 2000, CCV likely is underreported, as its clinical mimickers are not routinely biopsied.² It presents as asymptomatic telangiectatic macules, initially on the lower extremities and often spreading to the trunk. Cutaneous collagenous vasculopathy often is seen in middle-aged adults, and most patients have comorbidities such as hypertension, diabetes mellitus, or cardiovascular disease. The exact etiology of this disease is unknown.^3,4 

Histopathologically, CCV is characterized by dilated superficial vessels with thickened eosinophilic walls. The eosinophilic material is composed of hyalinized type IV collagen, which is periodic acid-Schiff positive and diastase resistant (Figure 1).^3,4 Stains for amyloid are negative.  

Generalized essential telangiectasia (GET) is a condition that presents with symmetric, blanchable, erythematous telangiectases.⁵ These lesions can occur alone or can accompany systemic diseases. Similar to CCV, the telangiectases tend to begin on the legs before gradually spreading to the trunk; however, this process more often is seen in females and occurs at an earlier age. Unlike CCV, GET can occur on mucosal surfaces, with cases of conjunctival and oral involvement reported.⁶ Generalized essential telangiectasia usually is a diagnosis of exclusion.^7,8 It is thought that many CCV lesions have been misclassified clinically as GET, which highlights the importance of biopsy. Microscopically, GET is distinct from CCV in that the superficial dermis lacks thick-walled vessels.^5,7 Although usually not associated with systemic diseases or progressive morbidity, treatment options are limited.⁸ 

Livedoid vasculopathy, also known as atrophie blanche, is caused by fibrin thrombi occlusion of dermal vessels. Clinically, patients have recurrent telangiectatic papules and painful ulcers on the lower extremities that gradually heal, leaving behind white stellate scars. It is caused by an underlying prothrombotic state with a superimposed inflammatory response.⁹ Livedoid vasculopathy primarily affects middle-aged women, and many patients have comorbidities such as scleroderma or systemic lupus erythematosus. Histologically, the epidermis often is ulcerated, and thrombi are visualized within small vessels. Eosinophilic fibrinoid material is deposited in vessel walls, including but not confined to vessels at the base of the epidermal ulcer (Figure 2). The fibrinoid material is periodic acid-Schiff positive and diastase resistant and can be highlighted with immunofluorescence, which may help to distinguish this entity from CCV.^1,9 As the disease progresses, vessels are diffusely hyalinized, and there is epidermal atrophy and dermal sclerosis. Treatment options include antiplatelet and fibrinolytic drugs with a multidisciplinary approach to resolve pain and scarring.⁹ 

Primary systemic amyloidosis is a rare condition, and cutaneous manifestations are seen in approximately one-third of affected individuals. Amyloid deposition results in waxy papules that predominantly affect the face and periorbital areas but also may occur on the neck, flexural areas, and genitalia.⁵ Because the amyloid deposits also can be found within vessel walls, hemorrhagic lesions may occur. Microscopically, amorphous eosinophilic material can be found within the vessel walls, similar to CCV (Figure 3A); however, when stained with Congo red, cutaneous amyloidosis shows waxy red-orange material involving the vessel walls and exhibits apple green birefringence under polarization (Figure 3B).¹⁰ Amyloid also will be negative for type IV collagen, fibronectin, and laminin, whereas CCV will be positive.⁵

The Diagnosis: Cutaneous Collagenous Vasculopathy 

Cutaneous collagenous vasculopathy (CCV) is an idiopathic microangiopathy of the small vessels in the superficial dermis. A condition first identified by Salama and Rosenthal¹ in 2000, CCV likely is underreported, as its clinical mimickers are not routinely biopsied.² It presents as asymptomatic telangiectatic macules, initially on the lower extremities and often spreading to the trunk. Cutaneous collagenous vasculopathy often is seen in middle-aged adults, and most patients have comorbidities such as hypertension, diabetes mellitus, or cardiovascular disease. The exact etiology of this disease is unknown.^3,4 

Histopathologically, CCV is characterized by dilated superficial vessels with thickened eosinophilic walls. The eosinophilic material is composed of hyalinized type IV collagen, which is periodic acid-Schiff positive and diastase resistant (Figure 1).^3,4 Stains for amyloid are negative.  

Generalized essential telangiectasia (GET) is a condition that presents with symmetric, blanchable, erythematous telangiectases.⁵ These lesions can occur alone or can accompany systemic diseases. Similar to CCV, the telangiectases tend to begin on the legs before gradually spreading to the trunk; however, this process more often is seen in females and occurs at an earlier age. Unlike CCV, GET can occur on mucosal surfaces, with cases of conjunctival and oral involvement reported.⁶ Generalized essential telangiectasia usually is a diagnosis of exclusion.^7,8 It is thought that many CCV lesions have been misclassified clinically as GET, which highlights the importance of biopsy. Microscopically, GET is distinct from CCV in that the superficial dermis lacks thick-walled vessels.^5,7 Although usually not associated with systemic diseases or progressive morbidity, treatment options are limited.⁸ 

Livedoid vasculopathy, also known as atrophie blanche, is caused by fibrin thrombi occlusion of dermal vessels. Clinically, patients have recurrent telangiectatic papules and painful ulcers on the lower extremities that gradually heal, leaving behind white stellate scars. It is caused by an underlying prothrombotic state with a superimposed inflammatory response.⁹ Livedoid vasculopathy primarily affects middle-aged women, and many patients have comorbidities such as scleroderma or systemic lupus erythematosus. Histologically, the epidermis often is ulcerated, and thrombi are visualized within small vessels. Eosinophilic fibrinoid material is deposited in vessel walls, including but not confined to vessels at the base of the epidermal ulcer (Figure 2). The fibrinoid material is periodic acid-Schiff positive and diastase resistant and can be highlighted with immunofluorescence, which may help to distinguish this entity from CCV.^1,9 As the disease progresses, vessels are diffusely hyalinized, and there is epidermal atrophy and dermal sclerosis. Treatment options include antiplatelet and fibrinolytic drugs with a multidisciplinary approach to resolve pain and scarring.⁹ 

Primary systemic amyloidosis is a rare condition, and cutaneous manifestations are seen in approximately one-third of affected individuals. Amyloid deposition results in waxy papules that predominantly affect the face and periorbital areas but also may occur on the neck, flexural areas, and genitalia.⁵ Because the amyloid deposits also can be found within vessel walls, hemorrhagic lesions may occur. Microscopically, amorphous eosinophilic material can be found within the vessel walls, similar to CCV (Figure 3A); however, when stained with Congo red, cutaneous amyloidosis shows waxy red-orange material involving the vessel walls and exhibits apple green birefringence under polarization (Figure 3B).¹⁰ Amyloid also will be negative for type IV collagen, fibronectin, and laminin, whereas CCV will be positive.⁵

The Diagnosis: Cutaneous Collagenous Vasculopathy 

Cutaneous collagenous vasculopathy (CCV) is an idiopathic microangiopathy of the small vessels in the superficial dermis. A condition first identified by Salama and Rosenthal¹ in 2000, CCV likely is underreported, as its clinical mimickers are not routinely biopsied.² It presents as asymptomatic telangiectatic macules, initially on the lower extremities and often spreading to the trunk. Cutaneous collagenous vasculopathy often is seen in middle-aged adults, and most patients have comorbidities such as hypertension, diabetes mellitus, or cardiovascular disease. The exact etiology of this disease is unknown.^3,4 

Histopathologically, CCV is characterized by dilated superficial vessels with thickened eosinophilic walls. The eosinophilic material is composed of hyalinized type IV collagen, which is periodic acid-Schiff positive and diastase resistant (Figure 1).^3,4 Stains for amyloid are negative.  

Generalized essential telangiectasia (GET) is a condition that presents with symmetric, blanchable, erythematous telangiectases.⁵ These lesions can occur alone or can accompany systemic diseases. Similar to CCV, the telangiectases tend to begin on the legs before gradually spreading to the trunk; however, this process more often is seen in females and occurs at an earlier age. Unlike CCV, GET can occur on mucosal surfaces, with cases of conjunctival and oral involvement reported.⁶ Generalized essential telangiectasia usually is a diagnosis of exclusion.^7,8 It is thought that many CCV lesions have been misclassified clinically as GET, which highlights the importance of biopsy. Microscopically, GET is distinct from CCV in that the superficial dermis lacks thick-walled vessels.^5,7 Although usually not associated with systemic diseases or progressive morbidity, treatment options are limited.⁸ 

Livedoid vasculopathy, also known as atrophie blanche, is caused by fibrin thrombi occlusion of dermal vessels. Clinically, patients have recurrent telangiectatic papules and painful ulcers on the lower extremities that gradually heal, leaving behind white stellate scars. It is caused by an underlying prothrombotic state with a superimposed inflammatory response.⁹ Livedoid vasculopathy primarily affects middle-aged women, and many patients have comorbidities such as scleroderma or systemic lupus erythematosus. Histologically, the epidermis often is ulcerated, and thrombi are visualized within small vessels. Eosinophilic fibrinoid material is deposited in vessel walls, including but not confined to vessels at the base of the epidermal ulcer (Figure 2). The fibrinoid material is periodic acid-Schiff positive and diastase resistant and can be highlighted with immunofluorescence, which may help to distinguish this entity from CCV.^1,9 As the disease progresses, vessels are diffusely hyalinized, and there is epidermal atrophy and dermal sclerosis. Treatment options include antiplatelet and fibrinolytic drugs with a multidisciplinary approach to resolve pain and scarring.⁹ 

Primary systemic amyloidosis is a rare condition, and cutaneous manifestations are seen in approximately one-third of affected individuals. Amyloid deposition results in waxy papules that predominantly affect the face and periorbital areas but also may occur on the neck, flexural areas, and genitalia.⁵ Because the amyloid deposits also can be found within vessel walls, hemorrhagic lesions may occur. Microscopically, amorphous eosinophilic material can be found within the vessel walls, similar to CCV (Figure 3A); however, when stained with Congo red, cutaneous amyloidosis shows waxy red-orange material involving the vessel walls and exhibits apple green birefringence under polarization (Figure 3B).¹⁰ Amyloid also will be negative for type IV collagen, fibronectin, and laminin, whereas CCV will be positive.⁵

The Diagnosis: Targetoid Hemosiderotic Hemangioma 

Targetoid hemosiderotic hemangioma (THH), also known as hobnail hemangioma, is a benign vascular tumor that usually occurs in young or middle-aged adults. It most commonly presents on the extremities or trunk as an isolated red-brown plaque or papule.^1,2 Histologically, THH is characterized by superficial dilated ectatic vessels with underlying proliferating vascular channels lined by plump hobnail endothelial cells.¹ Targetoid hemosiderotic hemangioma typically involves the dermis and spares the subcutis. The vascular channels may contain erythrocytes as well as pale eosinophilic lymph, as seen in our patient (quiz image). The deeper dermis contains vascular spaces that are more angulated and smaller and appear to be dissecting through the collagen bundles or collapsed.^1,3 A variable amount of hemosiderin deposition and extravasated erythrocytes are seen.^2,3 Histologic features evolve with the age of the lesion. Increasing amounts of hemosiderin deposition and erythrocyte extravasation may correspond histologically to the recent clinical color change reported by the patient.  

Verrucous hemangioma is a rare congenital vascular abnormality that is characterized by dilated vessels in the papillary dermis along with acanthosis, hyperkeratosis, and irregular papillomatosis, as seen in angiokeratoma.⁴ However, the vascular proliferation composed of variably sized, thin-walled capillaries extends into the deep dermis as well as the subcutis (Figure 1). Verrucous hemangioma most commonly is reported on the legs and generally starts as a violaceous patch that progresses into a hyperkeratotic verrucous plaque or nodule.^5,6  

Angiokeratoma is characterized by superficial vascular ectasia of the papillary dermis in association with overlying acanthosis, hyperkeratosis, and rete elongation.⁷ The dilated vascular spaces appear encircled by the epidermis (Figure 2). Intravascular thrombosis can be seen within the ectatic vessels.⁷ In contrast to verrucous hemangioma, angiokeratoma is limited to the papillary dermis. Therefore, obtaining a biopsy of sufficient depth is necessary for differentiation.⁸ There are 5 clinical presentations of angiokeratoma: sporadic, angiokeratoma of Mibelli, angiokeratoma of Fordyce, angiokeratoma circumscriptum, and angiokeratoma corporis diffusum (Fabry disease). Angiokeratomas may present on the lower extremities, tongue, trunk, and scrotum as hyperkeratotic, dark red to purple or black papules.⁷ 

There are 3 clinical stages of Kaposi sarcoma: patch, plaque, and nodular stages. The patch stage is characterized histologically by vascular channels that dissect through the dermis and extend around native vessels (the promontory sign)(Figure 3).^9,10 These features can show histologic overlap with THH. The plaque stage shows a more diffuse dermal vascular proliferation, increased cellularity of spindle cells, and possible extension into the subcutis.^9,10 Focal plasma cells, hemosiderin, and extravasated red blood cells can be seen. The nodular stage is characterized by a proliferation of spindle cells with red blood cells squeezed between slitlike vascular spaces, hyaline globules, and scattered mitotic figures, but not atypical forms.¹⁰ In this stage, plasma cells and hemosiderin are more readily identifiable. A biopsy from the nodular stage is unlikely to enter the histologic differential diagnosis with THH. Clinically, there are 4 variants of Kaposi sarcoma: the classic or sporadic form, an endemic form, iatrogenic, and AIDS associated. Overall, it is more common in males and can occur at any age.¹⁰ Human herpesvirus 8 is seen in all forms, and infected cells can be highlighted by the immunohistochemical stain for latent nuclear antigen 1.^9,10 

Angiosarcoma is a malignant endothelial tumor of soft tissue, skin, bone, and visceral organs.^11,12 Clinically, cutaneous angiosarcoma can present in a variety of ways, including single or multiple bluish red lesions that can ulcerate or bleed; violaceous nodules or plaques; and hematomalike lesions that can mimic epithelial neoplasms including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma.^11,13,14 The cutaneous lesions most commonly occur on sun-exposed skin, particularly on the face and scalp.¹² Other clinical variants that are important to recognize are postradiation angiosarcoma, characterized by MYC gene amplification, and lymphedema-associated angiosarcoma (Stewart-Treves syndrome). Angiosarcoma can have a variety of morphologic features, ranging from well to poorly differentiated. Classically, angiosarcoma is characterized by infiltrating vascular spaces lined by atypical endothelial cells (Figure 4). Poorly differentiated angiosarcoma can demonstrate spindle, epithelioid, or polygonal cells with increased mitotic activity, pleomorphism, and irregular vascular spaces.¹¹ Endothelial markers such as ERG (erythroblast transformation specific-related gene)(nuclear) and CD31 (membranous) can be used to aid in the diagnosis of a poorly differentiated lesion. Epithelioid angiosarcoma also occasionally stains with cytokeratins.^13,14  

The Diagnosis: Targetoid Hemosiderotic Hemangioma 

Targetoid hemosiderotic hemangioma (THH), also known as hobnail hemangioma, is a benign vascular tumor that usually occurs in young or middle-aged adults. It most commonly presents on the extremities or trunk as an isolated red-brown plaque or papule.^1,2 Histologically, THH is characterized by superficial dilated ectatic vessels with underlying proliferating vascular channels lined by plump hobnail endothelial cells.¹ Targetoid hemosiderotic hemangioma typically involves the dermis and spares the subcutis. The vascular channels may contain erythrocytes as well as pale eosinophilic lymph, as seen in our patient (quiz image). The deeper dermis contains vascular spaces that are more angulated and smaller and appear to be dissecting through the collagen bundles or collapsed.^1,3 A variable amount of hemosiderin deposition and extravasated erythrocytes are seen.^2,3 Histologic features evolve with the age of the lesion. Increasing amounts of hemosiderin deposition and erythrocyte extravasation may correspond histologically to the recent clinical color change reported by the patient.  

Verrucous hemangioma is a rare congenital vascular abnormality that is characterized by dilated vessels in the papillary dermis along with acanthosis, hyperkeratosis, and irregular papillomatosis, as seen in angiokeratoma.⁴ However, the vascular proliferation composed of variably sized, thin-walled capillaries extends into the deep dermis as well as the subcutis (Figure 1). Verrucous hemangioma most commonly is reported on the legs and generally starts as a violaceous patch that progresses into a hyperkeratotic verrucous plaque or nodule.^5,6  

Angiokeratoma is characterized by superficial vascular ectasia of the papillary dermis in association with overlying acanthosis, hyperkeratosis, and rete elongation.⁷ The dilated vascular spaces appear encircled by the epidermis (Figure 2). Intravascular thrombosis can be seen within the ectatic vessels.⁷ In contrast to verrucous hemangioma, angiokeratoma is limited to the papillary dermis. Therefore, obtaining a biopsy of sufficient depth is necessary for differentiation.⁸ There are 5 clinical presentations of angiokeratoma: sporadic, angiokeratoma of Mibelli, angiokeratoma of Fordyce, angiokeratoma circumscriptum, and angiokeratoma corporis diffusum (Fabry disease). Angiokeratomas may present on the lower extremities, tongue, trunk, and scrotum as hyperkeratotic, dark red to purple or black papules.⁷ 

There are 3 clinical stages of Kaposi sarcoma: patch, plaque, and nodular stages. The patch stage is characterized histologically by vascular channels that dissect through the dermis and extend around native vessels (the promontory sign)(Figure 3).^9,10 These features can show histologic overlap with THH. The plaque stage shows a more diffuse dermal vascular proliferation, increased cellularity of spindle cells, and possible extension into the subcutis.^9,10 Focal plasma cells, hemosiderin, and extravasated red blood cells can be seen. The nodular stage is characterized by a proliferation of spindle cells with red blood cells squeezed between slitlike vascular spaces, hyaline globules, and scattered mitotic figures, but not atypical forms.¹⁰ In this stage, plasma cells and hemosiderin are more readily identifiable. A biopsy from the nodular stage is unlikely to enter the histologic differential diagnosis with THH. Clinically, there are 4 variants of Kaposi sarcoma: the classic or sporadic form, an endemic form, iatrogenic, and AIDS associated. Overall, it is more common in males and can occur at any age.¹⁰ Human herpesvirus 8 is seen in all forms, and infected cells can be highlighted by the immunohistochemical stain for latent nuclear antigen 1.^9,10 

Angiosarcoma is a malignant endothelial tumor of soft tissue, skin, bone, and visceral organs.^11,12 Clinically, cutaneous angiosarcoma can present in a variety of ways, including single or multiple bluish red lesions that can ulcerate or bleed; violaceous nodules or plaques; and hematomalike lesions that can mimic epithelial neoplasms including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma.^11,13,14 The cutaneous lesions most commonly occur on sun-exposed skin, particularly on the face and scalp.¹² Other clinical variants that are important to recognize are postradiation angiosarcoma, characterized by MYC gene amplification, and lymphedema-associated angiosarcoma (Stewart-Treves syndrome). Angiosarcoma can have a variety of morphologic features, ranging from well to poorly differentiated. Classically, angiosarcoma is characterized by infiltrating vascular spaces lined by atypical endothelial cells (Figure 4). Poorly differentiated angiosarcoma can demonstrate spindle, epithelioid, or polygonal cells with increased mitotic activity, pleomorphism, and irregular vascular spaces.¹¹ Endothelial markers such as ERG (erythroblast transformation specific-related gene)(nuclear) and CD31 (membranous) can be used to aid in the diagnosis of a poorly differentiated lesion. Epithelioid angiosarcoma also occasionally stains with cytokeratins.^13,14  

The Diagnosis: Targetoid Hemosiderotic Hemangioma 

Targetoid hemosiderotic hemangioma (THH), also known as hobnail hemangioma, is a benign vascular tumor that usually occurs in young or middle-aged adults. It most commonly presents on the extremities or trunk as an isolated red-brown plaque or papule.^1,2 Histologically, THH is characterized by superficial dilated ectatic vessels with underlying proliferating vascular channels lined by plump hobnail endothelial cells.¹ Targetoid hemosiderotic hemangioma typically involves the dermis and spares the subcutis. The vascular channels may contain erythrocytes as well as pale eosinophilic lymph, as seen in our patient (quiz image). The deeper dermis contains vascular spaces that are more angulated and smaller and appear to be dissecting through the collagen bundles or collapsed.^1,3 A variable amount of hemosiderin deposition and extravasated erythrocytes are seen.^2,3 Histologic features evolve with the age of the lesion. Increasing amounts of hemosiderin deposition and erythrocyte extravasation may correspond histologically to the recent clinical color change reported by the patient.  

Verrucous hemangioma is a rare congenital vascular abnormality that is characterized by dilated vessels in the papillary dermis along with acanthosis, hyperkeratosis, and irregular papillomatosis, as seen in angiokeratoma.⁴ However, the vascular proliferation composed of variably sized, thin-walled capillaries extends into the deep dermis as well as the subcutis (Figure 1). Verrucous hemangioma most commonly is reported on the legs and generally starts as a violaceous patch that progresses into a hyperkeratotic verrucous plaque or nodule.^5,6  

Angiokeratoma is characterized by superficial vascular ectasia of the papillary dermis in association with overlying acanthosis, hyperkeratosis, and rete elongation.⁷ The dilated vascular spaces appear encircled by the epidermis (Figure 2). Intravascular thrombosis can be seen within the ectatic vessels.⁷ In contrast to verrucous hemangioma, angiokeratoma is limited to the papillary dermis. Therefore, obtaining a biopsy of sufficient depth is necessary for differentiation.⁸ There are 5 clinical presentations of angiokeratoma: sporadic, angiokeratoma of Mibelli, angiokeratoma of Fordyce, angiokeratoma circumscriptum, and angiokeratoma corporis diffusum (Fabry disease). Angiokeratomas may present on the lower extremities, tongue, trunk, and scrotum as hyperkeratotic, dark red to purple or black papules.⁷ 

There are 3 clinical stages of Kaposi sarcoma: patch, plaque, and nodular stages. The patch stage is characterized histologically by vascular channels that dissect through the dermis and extend around native vessels (the promontory sign)(Figure 3).^9,10 These features can show histologic overlap with THH. The plaque stage shows a more diffuse dermal vascular proliferation, increased cellularity of spindle cells, and possible extension into the subcutis.^9,10 Focal plasma cells, hemosiderin, and extravasated red blood cells can be seen. The nodular stage is characterized by a proliferation of spindle cells with red blood cells squeezed between slitlike vascular spaces, hyaline globules, and scattered mitotic figures, but not atypical forms.¹⁰ In this stage, plasma cells and hemosiderin are more readily identifiable. A biopsy from the nodular stage is unlikely to enter the histologic differential diagnosis with THH. Clinically, there are 4 variants of Kaposi sarcoma: the classic or sporadic form, an endemic form, iatrogenic, and AIDS associated. Overall, it is more common in males and can occur at any age.¹⁰ Human herpesvirus 8 is seen in all forms, and infected cells can be highlighted by the immunohistochemical stain for latent nuclear antigen 1.^9,10 

Angiosarcoma is a malignant endothelial tumor of soft tissue, skin, bone, and visceral organs.^11,12 Clinically, cutaneous angiosarcoma can present in a variety of ways, including single or multiple bluish red lesions that can ulcerate or bleed; violaceous nodules or plaques; and hematomalike lesions that can mimic epithelial neoplasms including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma.^11,13,14 The cutaneous lesions most commonly occur on sun-exposed skin, particularly on the face and scalp.¹² Other clinical variants that are important to recognize are postradiation angiosarcoma, characterized by MYC gene amplification, and lymphedema-associated angiosarcoma (Stewart-Treves syndrome). Angiosarcoma can have a variety of morphologic features, ranging from well to poorly differentiated. Classically, angiosarcoma is characterized by infiltrating vascular spaces lined by atypical endothelial cells (Figure 4). Poorly differentiated angiosarcoma can demonstrate spindle, epithelioid, or polygonal cells with increased mitotic activity, pleomorphism, and irregular vascular spaces.¹¹ Endothelial markers such as ERG (erythroblast transformation specific-related gene)(nuclear) and CD31 (membranous) can be used to aid in the diagnosis of a poorly differentiated lesion. Epithelioid angiosarcoma also occasionally stains with cytokeratins.^13,14  

The Diagnosis: Subcutaneous Panniculitislike T-cell Lymphoma 

Subcutaneous panniculitislike T-cell lymphoma (SPTCL) is a rare form of cutaneous lymphoma of mature cytotoxic T cells simulating panniculitis and preferentially infiltrating the subcutaneous tissue.¹ Subcutaneous panniculitislike T-cell lymphoma can affect all ages but predominantly affects younger individuals, with 20% being younger than 20 years.² It is a rare lymphoma that accounts for less than 1% of all non-Hodgkin lymphomas.³ It presents clinically as multiple subcutaneous masses, nodules, or plaques generally on the trunk or extremities.^1,2 The skin surrounding the nodules may be erythematous, and the nodules may become necrotic; however, ulceration typically is not seen. Systemic symptoms such as fever, night sweats, and chills are present in half of cases.¹ According to the World Health Organization, cytopenia and elevated liver function tests are common, and a hemophagocytic syndrome may be present in 15% to 20% of cases.³ The presence of a hemophagocytic syndrome yields a poor prognosis.^1,3 Current guidelines denote that SPTCL T-cell receptor (TCR) αβ; is a distinct entity from the TCRγδ; phenotype, known as cutaneous γδ-positive T-cell lymphoma.^3,4 Cutaneous γδ-positive T-cell lymphoma is associated with rapid decline and a worse prognosis.⁴  

Histology of SPTCL is characteristic for a lobular panniculitislike infiltrate.¹ The heavy subcutaneous lymphoid infiltrate is composed of atypical small- to medium-sized lymphocytes with mature chromatin and inconspicuous nucleoli lining adipocytes. The dense inflammatory infiltrate composed predominantly of neoplastic T cells and macrophages may diffusely invade into the subcutaneous tissue.¹ Admixed histocytes and karyorrhectic debris as well as rimming of the lymphocytes around the fat cells is typical and was seen in our patient (quiz image). The T cells of SPTCL have the following immunophenotype: TCR-beta F1⁺, CD3⁺, CD4^-, CD8⁺, CD56^-. They can express numerous cytotoxic proteins, such as T1a-1, granzyme B, and perforin.^2,3 Although the CD8⁺ T cells may be sparse, they generally surround the adipocytes in a rimming manner and may distort the adipocyte membrane.¹  

Lupus erythematosus profundus (LEP) is a form of chronic cutaneous lupus that affects the deep dermis and fat.⁵ It also can present clinically as tender plaques or nodules. It most frequently involves the upper arms, shoulders, face, or buttocks--areas that are less commonly involved in other panniculitides.⁶ Histologically, LEP is similar to chronic discoid lupus with features such as epidermal atrophy, interface changes, and a thickened basement membrane (Figure 1). Lupus erythematosus profundus can present as a lobular panniculitis with mucin as well as a superficial and deep lymphocytic infiltrate that can involve the septa.⁵ Some cases of LEP have a predominantly lobular lymphocytic panniculitis in the absence of the typical epidermal or dermal changes of lupus erythematosus. Lymphoid follicles with germinal center formation are present in half of cases and reportedly are characteristic of LEP.^6,7 The lymphoid follicles often have plasma cells, can extend into the septa as well as in between collagen bundles, and may have nuclear fragmentation.⁵ Another characteristic feature of LEP is hyaline sclerosis of lobules with focal extension into the interlobular septa. Immunofluorescence studies usually show linear deposition of IgM and C3 at the dermoepidermal junction. Antinuclear antibodies can be present in patients who have LEP but are not entirely specific.⁶  

Lupus erythematosus profundus and SPTCL are part of a spectrum and may have overlapping clinical and histopathologic characteristics; therefore, distinguishing them may be difficult.^6-8 It is important to monitor these patients closely, as their disease may progress to lymphoma.⁶ Patients with SPTCL are more likely to present with advanced symptoms such as fever and hepatosplenomegaly and to succumb to hemophagocytic syndrome than patients with LEP.⁹  

Although SPTCL usually is clonal, several cases of LEP with clonality also have been described. Clonal LEP cases generally are identified in patients who present with fever and cytopenia.⁸ Lymphoid atypia and morphologic abnormalities may be seen in cases of LEP, further complicating the distinction between LEP and SPTCL. An elevated Ki67 level may be seen in cases of SPTCL with periadipocytic rimming.⁹ LeBlanc et al¹⁰ used Ki67 "hot spots" along with CD8 immunohistochemistry to identify atypical lymphocytes associated with SPTCL. Lymphocyte rimming was defined by the presence of CD8⁺ lymphocytes with an elevated Ki67 index. Clinical, histopathologic, and molecular findings all should be used when dealing with challenging cases.  

Fat necrosis can occur in any part of the body where trauma has occurred and can be associated with many disease processes. Patients typically present with a palpable mass, but a clinical history of trauma is not always present. Histopathologic findings include necrotic fat alongside lipid-laden foamy macrophages and scattered inflammatory cells (Figure 2).¹¹ Fragments of normal as well as degenerating adipose tissue and multinucleated giant cells can be present.  

Erythema nodosum (EN) is the most frequently encountered panniculitis and usually is seen in women in early adulthood.¹² Patients present with several tender subcutaneous nodules and plaques that most commonly are present on the anterior surface of the legs.^12,13 Patients may have a constellation of symptoms including fever and leukocytosis, but the disorder generally is self-limited.¹² Erythema nodosum may be associated with a variety of diseases or infections including sarcoidosis, inflammatory bowel disease, and malignancy.¹⁴ The etiology of EN is diverse; therefore, a proper clinical workup may be necessary. Histopathology is that of a septal panniculitis with lymphocytes, histiocytes, and occasional eosinophils (Figure 3).¹³  

Lipodermatosclerosis also occurs on the legs, most commonly in patients with venous insufficiency.^12,15 Patients present clinically with pain, induration, redness, or swelling of the legs. Histopathology predominantly is characterized by membranous fat necrosis, fibrosis, and fatty microcysts that may be lined by a thickened hyaline membrane (Figure 4). Lipodermatosclerosis lesions generally do not resolve spontaneously and may need to be treated.¹⁶ 

The Diagnosis: Subcutaneous Panniculitislike T-cell Lymphoma 

Subcutaneous panniculitislike T-cell lymphoma (SPTCL) is a rare form of cutaneous lymphoma of mature cytotoxic T cells simulating panniculitis and preferentially infiltrating the subcutaneous tissue.¹ Subcutaneous panniculitislike T-cell lymphoma can affect all ages but predominantly affects younger individuals, with 20% being younger than 20 years.² It is a rare lymphoma that accounts for less than 1% of all non-Hodgkin lymphomas.³ It presents clinically as multiple subcutaneous masses, nodules, or plaques generally on the trunk or extremities.^1,2 The skin surrounding the nodules may be erythematous, and the nodules may become necrotic; however, ulceration typically is not seen. Systemic symptoms such as fever, night sweats, and chills are present in half of cases.¹ According to the World Health Organization, cytopenia and elevated liver function tests are common, and a hemophagocytic syndrome may be present in 15% to 20% of cases.³ The presence of a hemophagocytic syndrome yields a poor prognosis.^1,3 Current guidelines denote that SPTCL T-cell receptor (TCR) αβ; is a distinct entity from the TCRγδ; phenotype, known as cutaneous γδ-positive T-cell lymphoma.^3,4 Cutaneous γδ-positive T-cell lymphoma is associated with rapid decline and a worse prognosis.⁴  

Histology of SPTCL is characteristic for a lobular panniculitislike infiltrate.¹ The heavy subcutaneous lymphoid infiltrate is composed of atypical small- to medium-sized lymphocytes with mature chromatin and inconspicuous nucleoli lining adipocytes. The dense inflammatory infiltrate composed predominantly of neoplastic T cells and macrophages may diffusely invade into the subcutaneous tissue.¹ Admixed histocytes and karyorrhectic debris as well as rimming of the lymphocytes around the fat cells is typical and was seen in our patient (quiz image). The T cells of SPTCL have the following immunophenotype: TCR-beta F1⁺, CD3⁺, CD4^-, CD8⁺, CD56^-. They can express numerous cytotoxic proteins, such as T1a-1, granzyme B, and perforin.^2,3 Although the CD8⁺ T cells may be sparse, they generally surround the adipocytes in a rimming manner and may distort the adipocyte membrane.¹  

Lupus erythematosus profundus (LEP) is a form of chronic cutaneous lupus that affects the deep dermis and fat.⁵ It also can present clinically as tender plaques or nodules. It most frequently involves the upper arms, shoulders, face, or buttocks--areas that are less commonly involved in other panniculitides.⁶ Histologically, LEP is similar to chronic discoid lupus with features such as epidermal atrophy, interface changes, and a thickened basement membrane (Figure 1). Lupus erythematosus profundus can present as a lobular panniculitis with mucin as well as a superficial and deep lymphocytic infiltrate that can involve the septa.⁵ Some cases of LEP have a predominantly lobular lymphocytic panniculitis in the absence of the typical epidermal or dermal changes of lupus erythematosus. Lymphoid follicles with germinal center formation are present in half of cases and reportedly are characteristic of LEP.^6,7 The lymphoid follicles often have plasma cells, can extend into the septa as well as in between collagen bundles, and may have nuclear fragmentation.⁵ Another characteristic feature of LEP is hyaline sclerosis of lobules with focal extension into the interlobular septa. Immunofluorescence studies usually show linear deposition of IgM and C3 at the dermoepidermal junction. Antinuclear antibodies can be present in patients who have LEP but are not entirely specific.⁶  

Lupus erythematosus profundus and SPTCL are part of a spectrum and may have overlapping clinical and histopathologic characteristics; therefore, distinguishing them may be difficult.^6-8 It is important to monitor these patients closely, as their disease may progress to lymphoma.⁶ Patients with SPTCL are more likely to present with advanced symptoms such as fever and hepatosplenomegaly and to succumb to hemophagocytic syndrome than patients with LEP.⁹  

Although SPTCL usually is clonal, several cases of LEP with clonality also have been described. Clonal LEP cases generally are identified in patients who present with fever and cytopenia.⁸ Lymphoid atypia and morphologic abnormalities may be seen in cases of LEP, further complicating the distinction between LEP and SPTCL. An elevated Ki67 level may be seen in cases of SPTCL with periadipocytic rimming.⁹ LeBlanc et al¹⁰ used Ki67 "hot spots" along with CD8 immunohistochemistry to identify atypical lymphocytes associated with SPTCL. Lymphocyte rimming was defined by the presence of CD8⁺ lymphocytes with an elevated Ki67 index. Clinical, histopathologic, and molecular findings all should be used when dealing with challenging cases.  

Fat necrosis can occur in any part of the body where trauma has occurred and can be associated with many disease processes. Patients typically present with a palpable mass, but a clinical history of trauma is not always present. Histopathologic findings include necrotic fat alongside lipid-laden foamy macrophages and scattered inflammatory cells (Figure 2).¹¹ Fragments of normal as well as degenerating adipose tissue and multinucleated giant cells can be present.  

Erythema nodosum (EN) is the most frequently encountered panniculitis and usually is seen in women in early adulthood.¹² Patients present with several tender subcutaneous nodules and plaques that most commonly are present on the anterior surface of the legs.^12,13 Patients may have a constellation of symptoms including fever and leukocytosis, but the disorder generally is self-limited.¹² Erythema nodosum may be associated with a variety of diseases or infections including sarcoidosis, inflammatory bowel disease, and malignancy.¹⁴ The etiology of EN is diverse; therefore, a proper clinical workup may be necessary. Histopathology is that of a septal panniculitis with lymphocytes, histiocytes, and occasional eosinophils (Figure 3).¹³  

Lipodermatosclerosis also occurs on the legs, most commonly in patients with venous insufficiency.^12,15 Patients present clinically with pain, induration, redness, or swelling of the legs. Histopathology predominantly is characterized by membranous fat necrosis, fibrosis, and fatty microcysts that may be lined by a thickened hyaline membrane (Figure 4). Lipodermatosclerosis lesions generally do not resolve spontaneously and may need to be treated.¹⁶ 

The Diagnosis: Subcutaneous Panniculitislike T-cell Lymphoma 

Subcutaneous panniculitislike T-cell lymphoma (SPTCL) is a rare form of cutaneous lymphoma of mature cytotoxic T cells simulating panniculitis and preferentially infiltrating the subcutaneous tissue.¹ Subcutaneous panniculitislike T-cell lymphoma can affect all ages but predominantly affects younger individuals, with 20% being younger than 20 years.² It is a rare lymphoma that accounts for less than 1% of all non-Hodgkin lymphomas.³ It presents clinically as multiple subcutaneous masses, nodules, or plaques generally on the trunk or extremities.^1,2 The skin surrounding the nodules may be erythematous, and the nodules may become necrotic; however, ulceration typically is not seen. Systemic symptoms such as fever, night sweats, and chills are present in half of cases.¹ According to the World Health Organization, cytopenia and elevated liver function tests are common, and a hemophagocytic syndrome may be present in 15% to 20% of cases.³ The presence of a hemophagocytic syndrome yields a poor prognosis.^1,3 Current guidelines denote that SPTCL T-cell receptor (TCR) αβ; is a distinct entity from the TCRγδ; phenotype, known as cutaneous γδ-positive T-cell lymphoma.^3,4 Cutaneous γδ-positive T-cell lymphoma is associated with rapid decline and a worse prognosis.⁴  

Histology of SPTCL is characteristic for a lobular panniculitislike infiltrate.¹ The heavy subcutaneous lymphoid infiltrate is composed of atypical small- to medium-sized lymphocytes with mature chromatin and inconspicuous nucleoli lining adipocytes. The dense inflammatory infiltrate composed predominantly of neoplastic T cells and macrophages may diffusely invade into the subcutaneous tissue.¹ Admixed histocytes and karyorrhectic debris as well as rimming of the lymphocytes around the fat cells is typical and was seen in our patient (quiz image). The T cells of SPTCL have the following immunophenotype: TCR-beta F1⁺, CD3⁺, CD4^-, CD8⁺, CD56^-. They can express numerous cytotoxic proteins, such as T1a-1, granzyme B, and perforin.^2,3 Although the CD8⁺ T cells may be sparse, they generally surround the adipocytes in a rimming manner and may distort the adipocyte membrane.¹  

Lupus erythematosus profundus (LEP) is a form of chronic cutaneous lupus that affects the deep dermis and fat.⁵ It also can present clinically as tender plaques or nodules. It most frequently involves the upper arms, shoulders, face, or buttocks--areas that are less commonly involved in other panniculitides.⁶ Histologically, LEP is similar to chronic discoid lupus with features such as epidermal atrophy, interface changes, and a thickened basement membrane (Figure 1). Lupus erythematosus profundus can present as a lobular panniculitis with mucin as well as a superficial and deep lymphocytic infiltrate that can involve the septa.⁵ Some cases of LEP have a predominantly lobular lymphocytic panniculitis in the absence of the typical epidermal or dermal changes of lupus erythematosus. Lymphoid follicles with germinal center formation are present in half of cases and reportedly are characteristic of LEP.^6,7 The lymphoid follicles often have plasma cells, can extend into the septa as well as in between collagen bundles, and may have nuclear fragmentation.⁵ Another characteristic feature of LEP is hyaline sclerosis of lobules with focal extension into the interlobular septa. Immunofluorescence studies usually show linear deposition of IgM and C3 at the dermoepidermal junction. Antinuclear antibodies can be present in patients who have LEP but are not entirely specific.⁶  

Lupus erythematosus profundus and SPTCL are part of a spectrum and may have overlapping clinical and histopathologic characteristics; therefore, distinguishing them may be difficult.^6-8 It is important to monitor these patients closely, as their disease may progress to lymphoma.⁶ Patients with SPTCL are more likely to present with advanced symptoms such as fever and hepatosplenomegaly and to succumb to hemophagocytic syndrome than patients with LEP.⁹  

Although SPTCL usually is clonal, several cases of LEP with clonality also have been described. Clonal LEP cases generally are identified in patients who present with fever and cytopenia.⁸ Lymphoid atypia and morphologic abnormalities may be seen in cases of LEP, further complicating the distinction between LEP and SPTCL. An elevated Ki67 level may be seen in cases of SPTCL with periadipocytic rimming.⁹ LeBlanc et al¹⁰ used Ki67 "hot spots" along with CD8 immunohistochemistry to identify atypical lymphocytes associated with SPTCL. Lymphocyte rimming was defined by the presence of CD8⁺ lymphocytes with an elevated Ki67 index. Clinical, histopathologic, and molecular findings all should be used when dealing with challenging cases.  

Fat necrosis can occur in any part of the body where trauma has occurred and can be associated with many disease processes. Patients typically present with a palpable mass, but a clinical history of trauma is not always present. Histopathologic findings include necrotic fat alongside lipid-laden foamy macrophages and scattered inflammatory cells (Figure 2).¹¹ Fragments of normal as well as degenerating adipose tissue and multinucleated giant cells can be present.  

Erythema nodosum (EN) is the most frequently encountered panniculitis and usually is seen in women in early adulthood.¹² Patients present with several tender subcutaneous nodules and plaques that most commonly are present on the anterior surface of the legs.^12,13 Patients may have a constellation of symptoms including fever and leukocytosis, but the disorder generally is self-limited.¹² Erythema nodosum may be associated with a variety of diseases or infections including sarcoidosis, inflammatory bowel disease, and malignancy.¹⁴ The etiology of EN is diverse; therefore, a proper clinical workup may be necessary. Histopathology is that of a septal panniculitis with lymphocytes, histiocytes, and occasional eosinophils (Figure 3).¹³  

Lipodermatosclerosis also occurs on the legs, most commonly in patients with venous insufficiency.^12,15 Patients present clinically with pain, induration, redness, or swelling of the legs. Histopathology predominantly is characterized by membranous fat necrosis, fibrosis, and fatty microcysts that may be lined by a thickened hyaline membrane (Figure 4). Lipodermatosclerosis lesions generally do not resolve spontaneously and may need to be treated.¹⁶ 

The Diagnosis: Subcutaneous Granuloma Annulare 

Subcutaneous granuloma annulare (SGA), also known as deep GA, is a rare variant of GA that usually occurs in children and young adults. It presents as single or multiple, nontender, deep dermal and/or subcutaneous nodules with normal-appearing skin usually on the anterior lower legs, dorsal aspects of the hands and fingers, scalp, or buttocks.^1-3 The pathogenesis of SGA as well as GA is not fully understood, and proposed inciting factors include trauma, insect bite reactions, tuberculin skin testing, vaccines, UV exposure, medications, and viral infections.^3-6 A cell-mediated, delayed-type hypersensitivity reaction to an unknown antigen also has been postulated as a possible mechanism.⁷ Treatment usually is not necessary, as the nature of the condition is benign and the course often is self-limited. Spontaneous resolution occurs within 2 years in 50% of patients with localized GA.^4,8 Surgery usually is not recommended due to the high recurrence rate (40%-75%).^4,9  

Absence of epidermal change in this entity obfuscates clinical recognition, and accurate diagnosis often depends on punch or excisional biopsies revealing characteristic histopathology. The histology of SGA consists of palisaded granulomas with central areas of necrobiosis composed of degenerated collagen, mucin deposition, and nuclear dust from neutrophils that extend into the deep dermis and subcutis.² The periphery of the granulomas is lined by palisading epithelioid histiocytes with occasional multinucleated giant cells.^10,11 Eosinophils often are present.¹² Colloidal iron and Alcian blue stains can be used to highlight the abundant connective tissue mucin of the granulomas.⁴  

The histologic differential diagnosis of SGA includes rheumatoid nodule, necrobiosis lipoidica, epithelioid sarcoma, and tophaceous gout.² Rheumatoid nodules are the most common dermatologic presentation of rheumatoid arthritis and are found in up to 30% to 40% of patients with the disease.^13-15 They present as firm, painless, subcutaneous papulonodules on the extensor surfaces and at sites of trauma or pressure. Histologically, rheumatoid nodules exhibit a homogenous and eosinophilic central area of necrobiosis with fibrin deposition and absent mucin deep within the dermis and subcutaneous tissue (Figure 1). In contrast, granulomas in SGA usually are pale and basophilic with abundant mucin.²  

Necrobiosis lipoidica is a rare chronic granulomatous disease of the skin that most commonly occurs in young to middle-aged adults and is strongly associated with diabetes mellitus.¹⁶ It clinically presents as yellow to red-brown papules and plaques with a peripheral erythematous to violaceous rim usually on the pretibial area. Over time, lesions become yellowish atrophic patches and plaques that sometimes can ulcerate. Histopathology reveals areas of horizontally arranged, palisaded, and interstitial granulomatous dermatitis intermixed with areas of degenerated collagen and widespread fibrosis extending from the superficial dermis into the subcutis (Figure 2).² These areas lack mucin and have an increased number of plasma cells. Eosinophils and/or lymphoid nodules occasionally can be seen.^17,18 

Epithelioid sarcoma is a rare malignant soft tissue sarcoma that tends to occur on the distal extremities in younger patients, typically aged 20 to 40 years, often with preceding trauma to the area. It usually presents as a solitary, poorly defined, hard, subcutaneous nodule. Histologic analysis shows central areas of necrosis and degenerated collagen surrounded by epithelioid and spindle cells with hyperchromatic and pleomorphic nuclei and mitoses (Figure 3).² These tumor cells express positivity for keratins, vimentin, epithelial membrane antigen, and CD34, while they usually are negative for desmin, S-100, and FLI-1 nuclear transcription factor.^2,4,19  

Tophaceous gout results from the accumulation of monosodium urate crystals in the skin. It clinically presents as firm, white-yellow, dermal and subcutaneous papulonodules on the helix of the ear and the skin overlying joints. Histopathology reveals palisaded granulomas surrounding an amorphous feathery material that corresponds to the urate crystals that were destroyed with formalin fixation (Figure 4). When the tissue is fixed with ethanol or is incompletely fixed in formalin, birefringent urate crystals are evident with polarization.²⁰

The Diagnosis: Subcutaneous Granuloma Annulare 

Subcutaneous granuloma annulare (SGA), also known as deep GA, is a rare variant of GA that usually occurs in children and young adults. It presents as single or multiple, nontender, deep dermal and/or subcutaneous nodules with normal-appearing skin usually on the anterior lower legs, dorsal aspects of the hands and fingers, scalp, or buttocks.^1-3 The pathogenesis of SGA as well as GA is not fully understood, and proposed inciting factors include trauma, insect bite reactions, tuberculin skin testing, vaccines, UV exposure, medications, and viral infections.^3-6 A cell-mediated, delayed-type hypersensitivity reaction to an unknown antigen also has been postulated as a possible mechanism.⁷ Treatment usually is not necessary, as the nature of the condition is benign and the course often is self-limited. Spontaneous resolution occurs within 2 years in 50% of patients with localized GA.^4,8 Surgery usually is not recommended due to the high recurrence rate (40%-75%).^4,9  

Absence of epidermal change in this entity obfuscates clinical recognition, and accurate diagnosis often depends on punch or excisional biopsies revealing characteristic histopathology. The histology of SGA consists of palisaded granulomas with central areas of necrobiosis composed of degenerated collagen, mucin deposition, and nuclear dust from neutrophils that extend into the deep dermis and subcutis.² The periphery of the granulomas is lined by palisading epithelioid histiocytes with occasional multinucleated giant cells.^10,11 Eosinophils often are present.¹² Colloidal iron and Alcian blue stains can be used to highlight the abundant connective tissue mucin of the granulomas.⁴  

The histologic differential diagnosis of SGA includes rheumatoid nodule, necrobiosis lipoidica, epithelioid sarcoma, and tophaceous gout.² Rheumatoid nodules are the most common dermatologic presentation of rheumatoid arthritis and are found in up to 30% to 40% of patients with the disease.^13-15 They present as firm, painless, subcutaneous papulonodules on the extensor surfaces and at sites of trauma or pressure. Histologically, rheumatoid nodules exhibit a homogenous and eosinophilic central area of necrobiosis with fibrin deposition and absent mucin deep within the dermis and subcutaneous tissue (Figure 1). In contrast, granulomas in SGA usually are pale and basophilic with abundant mucin.²  

Necrobiosis lipoidica is a rare chronic granulomatous disease of the skin that most commonly occurs in young to middle-aged adults and is strongly associated with diabetes mellitus.¹⁶ It clinically presents as yellow to red-brown papules and plaques with a peripheral erythematous to violaceous rim usually on the pretibial area. Over time, lesions become yellowish atrophic patches and plaques that sometimes can ulcerate. Histopathology reveals areas of horizontally arranged, palisaded, and interstitial granulomatous dermatitis intermixed with areas of degenerated collagen and widespread fibrosis extending from the superficial dermis into the subcutis (Figure 2).² These areas lack mucin and have an increased number of plasma cells. Eosinophils and/or lymphoid nodules occasionally can be seen.^17,18 

Epithelioid sarcoma is a rare malignant soft tissue sarcoma that tends to occur on the distal extremities in younger patients, typically aged 20 to 40 years, often with preceding trauma to the area. It usually presents as a solitary, poorly defined, hard, subcutaneous nodule. Histologic analysis shows central areas of necrosis and degenerated collagen surrounded by epithelioid and spindle cells with hyperchromatic and pleomorphic nuclei and mitoses (Figure 3).² These tumor cells express positivity for keratins, vimentin, epithelial membrane antigen, and CD34, while they usually are negative for desmin, S-100, and FLI-1 nuclear transcription factor.^2,4,19  

Tophaceous gout results from the accumulation of monosodium urate crystals in the skin. It clinically presents as firm, white-yellow, dermal and subcutaneous papulonodules on the helix of the ear and the skin overlying joints. Histopathology reveals palisaded granulomas surrounding an amorphous feathery material that corresponds to the urate crystals that were destroyed with formalin fixation (Figure 4). When the tissue is fixed with ethanol or is incompletely fixed in formalin, birefringent urate crystals are evident with polarization.²⁰

The Diagnosis: Subcutaneous Granuloma Annulare 

Subcutaneous granuloma annulare (SGA), also known as deep GA, is a rare variant of GA that usually occurs in children and young adults. It presents as single or multiple, nontender, deep dermal and/or subcutaneous nodules with normal-appearing skin usually on the anterior lower legs, dorsal aspects of the hands and fingers, scalp, or buttocks.^1-3 The pathogenesis of SGA as well as GA is not fully understood, and proposed inciting factors include trauma, insect bite reactions, tuberculin skin testing, vaccines, UV exposure, medications, and viral infections.^3-6 A cell-mediated, delayed-type hypersensitivity reaction to an unknown antigen also has been postulated as a possible mechanism.⁷ Treatment usually is not necessary, as the nature of the condition is benign and the course often is self-limited. Spontaneous resolution occurs within 2 years in 50% of patients with localized GA.^4,8 Surgery usually is not recommended due to the high recurrence rate (40%-75%).^4,9  

Absence of epidermal change in this entity obfuscates clinical recognition, and accurate diagnosis often depends on punch or excisional biopsies revealing characteristic histopathology. The histology of SGA consists of palisaded granulomas with central areas of necrobiosis composed of degenerated collagen, mucin deposition, and nuclear dust from neutrophils that extend into the deep dermis and subcutis.² The periphery of the granulomas is lined by palisading epithelioid histiocytes with occasional multinucleated giant cells.^10,11 Eosinophils often are present.¹² Colloidal iron and Alcian blue stains can be used to highlight the abundant connective tissue mucin of the granulomas.⁴  

The histologic differential diagnosis of SGA includes rheumatoid nodule, necrobiosis lipoidica, epithelioid sarcoma, and tophaceous gout.² Rheumatoid nodules are the most common dermatologic presentation of rheumatoid arthritis and are found in up to 30% to 40% of patients with the disease.^13-15 They present as firm, painless, subcutaneous papulonodules on the extensor surfaces and at sites of trauma or pressure. Histologically, rheumatoid nodules exhibit a homogenous and eosinophilic central area of necrobiosis with fibrin deposition and absent mucin deep within the dermis and subcutaneous tissue (Figure 1). In contrast, granulomas in SGA usually are pale and basophilic with abundant mucin.²  

Necrobiosis lipoidica is a rare chronic granulomatous disease of the skin that most commonly occurs in young to middle-aged adults and is strongly associated with diabetes mellitus.¹⁶ It clinically presents as yellow to red-brown papules and plaques with a peripheral erythematous to violaceous rim usually on the pretibial area. Over time, lesions become yellowish atrophic patches and plaques that sometimes can ulcerate. Histopathology reveals areas of horizontally arranged, palisaded, and interstitial granulomatous dermatitis intermixed with areas of degenerated collagen and widespread fibrosis extending from the superficial dermis into the subcutis (Figure 2).² These areas lack mucin and have an increased number of plasma cells. Eosinophils and/or lymphoid nodules occasionally can be seen.^17,18 

Epithelioid sarcoma is a rare malignant soft tissue sarcoma that tends to occur on the distal extremities in younger patients, typically aged 20 to 40 years, often with preceding trauma to the area. It usually presents as a solitary, poorly defined, hard, subcutaneous nodule. Histologic analysis shows central areas of necrosis and degenerated collagen surrounded by epithelioid and spindle cells with hyperchromatic and pleomorphic nuclei and mitoses (Figure 3).² These tumor cells express positivity for keratins, vimentin, epithelial membrane antigen, and CD34, while they usually are negative for desmin, S-100, and FLI-1 nuclear transcription factor.^2,4,19  

Tophaceous gout results from the accumulation of monosodium urate crystals in the skin. It clinically presents as firm, white-yellow, dermal and subcutaneous papulonodules on the helix of the ear and the skin overlying joints. Histopathology reveals palisaded granulomas surrounding an amorphous feathery material that corresponds to the urate crystals that were destroyed with formalin fixation (Figure 4). When the tissue is fixed with ethanol or is incompletely fixed in formalin, birefringent urate crystals are evident with polarization.²⁰

The Diagnosis: Piloleiomyoma 

Leiomyoma cutis, also known as cutaneous leiomyoma, is a benign smooth muscle tumor first described in 1854.¹ Cutaneous leiomyoma is comprised of 3 distinct types that depend on the origin of smooth muscle tumor: piloleiomyoma (arrector pili muscle), angioleiomyoma (tunica media of arteries/veins), and genital leiomyoma (dartos muscle of the scrotum and labia majora, erectile muscle of nipple).² It affects both sexes equally, though some reports have noted an increased prevalence in females. Piloleiomyomas commonly present on the extensor surfaces of the extremities (solitary) and trunk (multiple).¹ Tumors most often present as firm flesh-colored or pink-brown papulonodules. They can be linear, dermatomal, segmental, or diffuse, and often are painful. Clinical differential diagnosis for painful skin tumors is aided by the acronym "BLEND AN EGG": blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor.³ For isolated lesions, surgical excision is the treatment of choice. For numerous lesions in which excision would not be feasible, intralesional corticosteroids, medications (eg, calcium channel blockers, alpha blockers, nitroglycerin), and botulinum toxin have been used for pain relief.⁴  

Notably, multiple cutaneous leiomyomas can be seen in association with uterine leiomyomas in Reed syndrome due to an autosomal-dominant or de novo mutation in the fumarate hydratase gene, FH. Reed syndrome is associated with a lifetime risk for renal cell carcinoma (hereditary leiomyomatosis and renal cell cancer) in 15% of cases with FH mutations.⁵ In our patient, both immunohistochemical staining and blood testing for FH were performed. Immunohistochemistry revealed notably diminished staining with only weak patchy granular cytoplasmic staining present (Figure 1). Genetic testing revealed heterozygosity for a pathogenic variant of the FH gene, consistent with a diagnosis of Reed syndrome.  

Histologically, the differential diagnosis includes other spindle cell tumors, such as dermatofibroma, neurofibroma, and dermatomyofibroma. The histologic appearance varies depending on the type, with piloleiomyoma typically located within the reticular dermis with possible subcutaneous extension. Fascicles of eosinophilic smooth muscle cells in an interlacing arrangement often ramify between neighboring dermal collagen; these smooth muscle cells contain cigar-shaped, blunt-ended nuclei with a perinuclear clear vacuole. Marked epidermal hyperplasia is possible.⁶ A close association with a nearby hair follicle frequently is noted. Although differentiated smooth muscle cells usually are evident on hematoxylin and eosin, positive staining for smooth muscle actin (SMA) and desmin can aid in diagnosis.⁷ Immunohistochemical staining for FH has proven to be highly specific (97.6%) with moderate sensitivity (70.0%).⁸ Angioleiomyomas appear as well-demarcated dermal to subcutaneous tumors composed of smooth muscle cells surrounding thick-walled vaculature.⁹ Scrotal and vulvar leiomyomas are composed of eosinophilic spindle cells, though vulvar leiomyomas have shown epithelioid differentiation.¹⁰ Nipple leiomyomas appear similar to piloleiomyomas on histology with interlacing smooth muscle fiber bundles.  

Eccrine spiradenoma is a relatively uncommon adnexal tumor derived from eccrine sweat glands. It most often presents as a small, painful or tender, intradermal nodule (or rarely as nodules) on the head or ventral trunk.¹¹ There is no sexual predilection. It affects adults at any age but most often from 15 to 35 years. Although rare, malignant transformation is possible. Histologically, eccrine spiradenomas appear as a well-demarcated dermal tumor composed of bland basaloid cells with minimal cytoplasm, often with numerous admixed lymphocytes and variably prominent vasculature (Figure 2). Eosinophilic basement membrane material can be seen within or surrounding the nodules of tumor cells. Multiple spiradenomas can occur in the setting of Brooke-Spiegler syndrome, which is an autosomal-dominant disorder due to an inherited mutation in the CYLD gene. Spiradenomas are benign neoplasms, and surgical excision with clear margins is the treatment of choice.¹²  

Dermatofibroma, also known as cutaneous benign fibrous histiocytoma, is a firm, flesh-colored papule or nodule that most often presents on the lower extremities. It typically is seen in women aged 20 to 40 years.¹³ The etiology is uncertain, and dermatofibromas often spontaneously develop, though there are inconsistent reports of development with local trauma including insect bites and puncture wounds. The dimple sign refers to skin dimpling with lateral pressure.¹³ Most commonly, dermatofibromas consist of a dermal proliferation of bland fibroblastic cells with entrapment of dermal collagen bundles at the periphery of the tumors (Figure 3). The fibroblastic cells often are paler and less eosinophilic than smooth muscle cells seen in cutaneous leiomyomas, with tapered nuclei that lack a perinuclear vacuole. Admixed histocytes and other inflammatory cells often are present. Overlying epidermal hyperplasia and/or hyperpigmentation also may be present. Numerous histologic variants have been described, including cellular, epithelioid, aneurysmal, atypical, and hemosiderotic types.¹⁴ Immunohistochemical stains may show patchy positive staining for SMA, but h-caldesmon and desmin typically are negative.  

Neurofibroma is a tumor derived from neuromesenchymal tissue with nerve axons. They form through neuromesenchyme (eg, Schwann cells, mast cells, perineural cells, endoneural fibroblast) proliferation. Solitary neurofibromas occur most commonly in adults and have no gender predilection. The most common presentation is an asymptomatic, solitary, soft, flesh-colored papulonodule.¹⁵ Clinical variants include pigmented, diffuse, and plexiform, with plexiform neurofibromas almost always being consistent with a diagnosis of neurofibromatosis type 1. Histologically, neurofibromas present as dermal or subcutaneous nodules composed of randomly arranged spindle cells with wavy tapered nuclei within a loose collagenous stroma (Figure 4).¹⁶ The spindle cells in neurofibromas will stain positively for S-100 protein and SOX-10 and negatively for SMA and desmin.  

Angiolipoma is a benign tumor composed of adipocytes that also contains vasculature.¹⁷ The majority of cases are of unknown etiology, though familial cases have been described. They typically present as multiple painful or tender (differentiating from lipomas) subcutaneous swellings over the forearms in individuals aged 20 to 30 years.¹⁸ On histopathology, angiolipomas appear as well-circumscribed subcutaneous tumors containing mature adipocytes intermixed with small capillary vessels, some of which contain luminal fibrin thrombi (Figure 5).  

The Diagnosis: Piloleiomyoma 

Leiomyoma cutis, also known as cutaneous leiomyoma, is a benign smooth muscle tumor first described in 1854.¹ Cutaneous leiomyoma is comprised of 3 distinct types that depend on the origin of smooth muscle tumor: piloleiomyoma (arrector pili muscle), angioleiomyoma (tunica media of arteries/veins), and genital leiomyoma (dartos muscle of the scrotum and labia majora, erectile muscle of nipple).² It affects both sexes equally, though some reports have noted an increased prevalence in females. Piloleiomyomas commonly present on the extensor surfaces of the extremities (solitary) and trunk (multiple).¹ Tumors most often present as firm flesh-colored or pink-brown papulonodules. They can be linear, dermatomal, segmental, or diffuse, and often are painful. Clinical differential diagnosis for painful skin tumors is aided by the acronym "BLEND AN EGG": blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor.³ For isolated lesions, surgical excision is the treatment of choice. For numerous lesions in which excision would not be feasible, intralesional corticosteroids, medications (eg, calcium channel blockers, alpha blockers, nitroglycerin), and botulinum toxin have been used for pain relief.⁴  

Notably, multiple cutaneous leiomyomas can be seen in association with uterine leiomyomas in Reed syndrome due to an autosomal-dominant or de novo mutation in the fumarate hydratase gene, FH. Reed syndrome is associated with a lifetime risk for renal cell carcinoma (hereditary leiomyomatosis and renal cell cancer) in 15% of cases with FH mutations.⁵ In our patient, both immunohistochemical staining and blood testing for FH were performed. Immunohistochemistry revealed notably diminished staining with only weak patchy granular cytoplasmic staining present (Figure 1). Genetic testing revealed heterozygosity for a pathogenic variant of the FH gene, consistent with a diagnosis of Reed syndrome.  

Histologically, the differential diagnosis includes other spindle cell tumors, such as dermatofibroma, neurofibroma, and dermatomyofibroma. The histologic appearance varies depending on the type, with piloleiomyoma typically located within the reticular dermis with possible subcutaneous extension. Fascicles of eosinophilic smooth muscle cells in an interlacing arrangement often ramify between neighboring dermal collagen; these smooth muscle cells contain cigar-shaped, blunt-ended nuclei with a perinuclear clear vacuole. Marked epidermal hyperplasia is possible.⁶ A close association with a nearby hair follicle frequently is noted. Although differentiated smooth muscle cells usually are evident on hematoxylin and eosin, positive staining for smooth muscle actin (SMA) and desmin can aid in diagnosis.⁷ Immunohistochemical staining for FH has proven to be highly specific (97.6%) with moderate sensitivity (70.0%).⁸ Angioleiomyomas appear as well-demarcated dermal to subcutaneous tumors composed of smooth muscle cells surrounding thick-walled vaculature.⁹ Scrotal and vulvar leiomyomas are composed of eosinophilic spindle cells, though vulvar leiomyomas have shown epithelioid differentiation.¹⁰ Nipple leiomyomas appear similar to piloleiomyomas on histology with interlacing smooth muscle fiber bundles.  

Eccrine spiradenoma is a relatively uncommon adnexal tumor derived from eccrine sweat glands. It most often presents as a small, painful or tender, intradermal nodule (or rarely as nodules) on the head or ventral trunk.¹¹ There is no sexual predilection. It affects adults at any age but most often from 15 to 35 years. Although rare, malignant transformation is possible. Histologically, eccrine spiradenomas appear as a well-demarcated dermal tumor composed of bland basaloid cells with minimal cytoplasm, often with numerous admixed lymphocytes and variably prominent vasculature (Figure 2). Eosinophilic basement membrane material can be seen within or surrounding the nodules of tumor cells. Multiple spiradenomas can occur in the setting of Brooke-Spiegler syndrome, which is an autosomal-dominant disorder due to an inherited mutation in the CYLD gene. Spiradenomas are benign neoplasms, and surgical excision with clear margins is the treatment of choice.¹²  

Dermatofibroma, also known as cutaneous benign fibrous histiocytoma, is a firm, flesh-colored papule or nodule that most often presents on the lower extremities. It typically is seen in women aged 20 to 40 years.¹³ The etiology is uncertain, and dermatofibromas often spontaneously develop, though there are inconsistent reports of development with local trauma including insect bites and puncture wounds. The dimple sign refers to skin dimpling with lateral pressure.¹³ Most commonly, dermatofibromas consist of a dermal proliferation of bland fibroblastic cells with entrapment of dermal collagen bundles at the periphery of the tumors (Figure 3). The fibroblastic cells often are paler and less eosinophilic than smooth muscle cells seen in cutaneous leiomyomas, with tapered nuclei that lack a perinuclear vacuole. Admixed histocytes and other inflammatory cells often are present. Overlying epidermal hyperplasia and/or hyperpigmentation also may be present. Numerous histologic variants have been described, including cellular, epithelioid, aneurysmal, atypical, and hemosiderotic types.¹⁴ Immunohistochemical stains may show patchy positive staining for SMA, but h-caldesmon and desmin typically are negative.  

Neurofibroma is a tumor derived from neuromesenchymal tissue with nerve axons. They form through neuromesenchyme (eg, Schwann cells, mast cells, perineural cells, endoneural fibroblast) proliferation. Solitary neurofibromas occur most commonly in adults and have no gender predilection. The most common presentation is an asymptomatic, solitary, soft, flesh-colored papulonodule.¹⁵ Clinical variants include pigmented, diffuse, and plexiform, with plexiform neurofibromas almost always being consistent with a diagnosis of neurofibromatosis type 1. Histologically, neurofibromas present as dermal or subcutaneous nodules composed of randomly arranged spindle cells with wavy tapered nuclei within a loose collagenous stroma (Figure 4).¹⁶ The spindle cells in neurofibromas will stain positively for S-100 protein and SOX-10 and negatively for SMA and desmin.  

Angiolipoma is a benign tumor composed of adipocytes that also contains vasculature.¹⁷ The majority of cases are of unknown etiology, though familial cases have been described. They typically present as multiple painful or tender (differentiating from lipomas) subcutaneous swellings over the forearms in individuals aged 20 to 30 years.¹⁸ On histopathology, angiolipomas appear as well-circumscribed subcutaneous tumors containing mature adipocytes intermixed with small capillary vessels, some of which contain luminal fibrin thrombi (Figure 5).  

The Diagnosis: Piloleiomyoma 

Leiomyoma cutis, also known as cutaneous leiomyoma, is a benign smooth muscle tumor first described in 1854.¹ Cutaneous leiomyoma is comprised of 3 distinct types that depend on the origin of smooth muscle tumor: piloleiomyoma (arrector pili muscle), angioleiomyoma (tunica media of arteries/veins), and genital leiomyoma (dartos muscle of the scrotum and labia majora, erectile muscle of nipple).² It affects both sexes equally, though some reports have noted an increased prevalence in females. Piloleiomyomas commonly present on the extensor surfaces of the extremities (solitary) and trunk (multiple).¹ Tumors most often present as firm flesh-colored or pink-brown papulonodules. They can be linear, dermatomal, segmental, or diffuse, and often are painful. Clinical differential diagnosis for painful skin tumors is aided by the acronym "BLEND AN EGG": blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomangioma, and granular cell tumor.³ For isolated lesions, surgical excision is the treatment of choice. For numerous lesions in which excision would not be feasible, intralesional corticosteroids, medications (eg, calcium channel blockers, alpha blockers, nitroglycerin), and botulinum toxin have been used for pain relief.⁴  

Notably, multiple cutaneous leiomyomas can be seen in association with uterine leiomyomas in Reed syndrome due to an autosomal-dominant or de novo mutation in the fumarate hydratase gene, FH. Reed syndrome is associated with a lifetime risk for renal cell carcinoma (hereditary leiomyomatosis and renal cell cancer) in 15% of cases with FH mutations.⁵ In our patient, both immunohistochemical staining and blood testing for FH were performed. Immunohistochemistry revealed notably diminished staining with only weak patchy granular cytoplasmic staining present (Figure 1). Genetic testing revealed heterozygosity for a pathogenic variant of the FH gene, consistent with a diagnosis of Reed syndrome.  

Histologically, the differential diagnosis includes other spindle cell tumors, such as dermatofibroma, neurofibroma, and dermatomyofibroma. The histologic appearance varies depending on the type, with piloleiomyoma typically located within the reticular dermis with possible subcutaneous extension. Fascicles of eosinophilic smooth muscle cells in an interlacing arrangement often ramify between neighboring dermal collagen; these smooth muscle cells contain cigar-shaped, blunt-ended nuclei with a perinuclear clear vacuole. Marked epidermal hyperplasia is possible.⁶ A close association with a nearby hair follicle frequently is noted. Although differentiated smooth muscle cells usually are evident on hematoxylin and eosin, positive staining for smooth muscle actin (SMA) and desmin can aid in diagnosis.⁷ Immunohistochemical staining for FH has proven to be highly specific (97.6%) with moderate sensitivity (70.0%).⁸ Angioleiomyomas appear as well-demarcated dermal to subcutaneous tumors composed of smooth muscle cells surrounding thick-walled vaculature.⁹ Scrotal and vulvar leiomyomas are composed of eosinophilic spindle cells, though vulvar leiomyomas have shown epithelioid differentiation.¹⁰ Nipple leiomyomas appear similar to piloleiomyomas on histology with interlacing smooth muscle fiber bundles.  

Eccrine spiradenoma is a relatively uncommon adnexal tumor derived from eccrine sweat glands. It most often presents as a small, painful or tender, intradermal nodule (or rarely as nodules) on the head or ventral trunk.¹¹ There is no sexual predilection. It affects adults at any age but most often from 15 to 35 years. Although rare, malignant transformation is possible. Histologically, eccrine spiradenomas appear as a well-demarcated dermal tumor composed of bland basaloid cells with minimal cytoplasm, often with numerous admixed lymphocytes and variably prominent vasculature (Figure 2). Eosinophilic basement membrane material can be seen within or surrounding the nodules of tumor cells. Multiple spiradenomas can occur in the setting of Brooke-Spiegler syndrome, which is an autosomal-dominant disorder due to an inherited mutation in the CYLD gene. Spiradenomas are benign neoplasms, and surgical excision with clear margins is the treatment of choice.¹²  

Dermatofibroma, also known as cutaneous benign fibrous histiocytoma, is a firm, flesh-colored papule or nodule that most often presents on the lower extremities. It typically is seen in women aged 20 to 40 years.¹³ The etiology is uncertain, and dermatofibromas often spontaneously develop, though there are inconsistent reports of development with local trauma including insect bites and puncture wounds. The dimple sign refers to skin dimpling with lateral pressure.¹³ Most commonly, dermatofibromas consist of a dermal proliferation of bland fibroblastic cells with entrapment of dermal collagen bundles at the periphery of the tumors (Figure 3). The fibroblastic cells often are paler and less eosinophilic than smooth muscle cells seen in cutaneous leiomyomas, with tapered nuclei that lack a perinuclear vacuole. Admixed histocytes and other inflammatory cells often are present. Overlying epidermal hyperplasia and/or hyperpigmentation also may be present. Numerous histologic variants have been described, including cellular, epithelioid, aneurysmal, atypical, and hemosiderotic types.¹⁴ Immunohistochemical stains may show patchy positive staining for SMA, but h-caldesmon and desmin typically are negative.  

Neurofibroma is a tumor derived from neuromesenchymal tissue with nerve axons. They form through neuromesenchyme (eg, Schwann cells, mast cells, perineural cells, endoneural fibroblast) proliferation. Solitary neurofibromas occur most commonly in adults and have no gender predilection. The most common presentation is an asymptomatic, solitary, soft, flesh-colored papulonodule.¹⁵ Clinical variants include pigmented, diffuse, and plexiform, with plexiform neurofibromas almost always being consistent with a diagnosis of neurofibromatosis type 1. Histologically, neurofibromas present as dermal or subcutaneous nodules composed of randomly arranged spindle cells with wavy tapered nuclei within a loose collagenous stroma (Figure 4).¹⁶ The spindle cells in neurofibromas will stain positively for S-100 protein and SOX-10 and negatively for SMA and desmin.  

Angiolipoma is a benign tumor composed of adipocytes that also contains vasculature.¹⁷ The majority of cases are of unknown etiology, though familial cases have been described. They typically present as multiple painful or tender (differentiating from lipomas) subcutaneous swellings over the forearms in individuals aged 20 to 30 years.¹⁸ On histopathology, angiolipomas appear as well-circumscribed subcutaneous tumors containing mature adipocytes intermixed with small capillary vessels, some of which contain luminal fibrin thrombi (Figure 5).  

The Diagnosis: Clonal Melanoacanthoma 

Melanoacanthoma (MA) is an extremely rare, benign, epidermal tumor histologically characterized by keratinocytes and large, pigmented, dendritic melanocytes. These lesions are loosely related to seborrheic keratoses, and the term was first coined by Mishima and Pinkus¹ in 1960. It is estimated that the lesion occurs in only 5 of 500,000 individuals and tends to occur in older, light-skinned individuals.² The majority are slow growing and are present on the head, neck, or upper extremities; however, similar lesions also have been reported on the oral mucosa.³ Melanoacanthomas range in size from 2×2 to 15×15 cm; are clinically pigmented; and present as either a papule, plaque, nodule, or horn.² 

Classic histologic findings of MA include papillomatosis, acanthosis, and hyperkeratosis with heavily pigmented dendritic melanocytes diffusely dispersed throughout all layers of the seborrheic keratosis-like epidermis.³ Other features include keratin-filled pseudocysts, Langerhans cells, reactive spindling of keratinocytes, and an inflammatory infiltrate. In our case, the classic histologic findings also were architecturally arranged in oval to round clones within the epidermis (quiz images 1 and 2). A MART-1 (melanoma antigen recognized by T cells) immunostain was obtained that highlighted the numerous but benign-appearing, dendritic melanocytes (quiz image 2 [inset]). A dual MART-1/Ki67 immunostain later was obtained and demonstrated a negligible proliferation index within the dendritic melanocytes. Therefore, the diagnosis of clonal MA was rendered. This formation of epidermal clones also is called the Borst-Jadassohn phenomenon, which rarely occurs in MAs. This subtype is important to recognize because the clonal pattern can more closely mimic malignant neoplasms such as melanoma.  

Hidroacanthoma simplex is an intraepidermal variant of eccrine poroma. It is a rare entity that typically occurs in the extremities of women as a hyperkeratotic plaque. These typically clonal epidermal tumors may be heavily pigmented and rarely contain dendritic melanocytes; therefore, they may be confused with MA. However, classic histology will reveal an intraepidermal clonal proliferation of bland, monotonous, cuboidal cells with ample pink cytoplasm, as well as occasional cuticle-lined ducts (Figure 1).⁴ These ducts will highlight with carcinoembryonic antigen and epithelial membrane antigen immunostaining.  

Malignant melanoma typically presents as a growing pigmented lesion and therefore can clinically mimic MA. Histologically, MA could be confused with melanoma due to the increased number of melanocytes plus the appearance of pagetoid spread resulting from the diffuse presence of melanocytes throughout the neoplasm. However, histologic assessment of melanoma should reveal cytologic atypia such as nuclear enlargement, hyperchromasia, molding, pleomorphism, and mitotic activity (Figure 2). Architectural atypia such as poor lateral circumscription of melanocytes, confluence and pagetoid spread of nondendritic atypical junctional melanocytes, production of pigment in deep dermal nests of melanocytes, and lack of maturation and dispersion of dermal melanocytes also should be seen.⁵ Unlike a melanocytic neoplasm, true melanocytic nests are not seen in MA, and the melanocytes are bland, normal-appearing but heavily pigmented, dendritic melanocytes. Electron microscopy has shown a defect in the transfer of melanin from these highly dendritic melanocytes to the keratinocytes.⁶  

Similar to melanoma, seborrheic keratosis presents as a pigmented growing lesion; therefore, definitive diagnosis often is achieved via skin biopsy. Classic histologic findings include acanthotic or exophytic epidermal growth with a dome-shaped configuration containing multiple cornified hornlike cysts (Figure 3).⁷ Multiple keratin plugs and variably sized concentric keratin islands are common features. There may be varying degrees of melanin pigment deposition among the proliferating cells, and clonal formation may occur. Melanocyte-specific special stains and immunostains can be used to differentiate MA from seborrheic keratosis by highlighting numerous dendritic melanocytes diffusely spread throughout the epidermis in MA vs a normal distribution of occasional junctional melanocytes in seborrheic keratosis.^2,8  

Squamous cell carcinoma in situ presents histologically with cytologically atypical keratinocytes encompassing the full thickness of the epidermis and sometimes crushing the basement membrane zone (Figure 4). There is a loss of the granular layer and overlying parakeratosis that often spares the adnexal ostial epithelium.⁹ Clonal formation can occur as well as increased pigment production. In comparison, bland keratinocytes are seen in MA.  

Establishing the diagnosis of MA based on clinical features alone can be difficult. Dermoscopy can prove to be useful and typically will show a sunburst pattern with ridges and fissures.² However, seborrheic keratoses and melanomas can have similar dermoscopic findings¹⁰; therefore, a biopsy often is necessary to establish the diagnosis. 

The Diagnosis: Clonal Melanoacanthoma 

Melanoacanthoma (MA) is an extremely rare, benign, epidermal tumor histologically characterized by keratinocytes and large, pigmented, dendritic melanocytes. These lesions are loosely related to seborrheic keratoses, and the term was first coined by Mishima and Pinkus¹ in 1960. It is estimated that the lesion occurs in only 5 of 500,000 individuals and tends to occur in older, light-skinned individuals.² The majority are slow growing and are present on the head, neck, or upper extremities; however, similar lesions also have been reported on the oral mucosa.³ Melanoacanthomas range in size from 2×2 to 15×15 cm; are clinically pigmented; and present as either a papule, plaque, nodule, or horn.² 

Classic histologic findings of MA include papillomatosis, acanthosis, and hyperkeratosis with heavily pigmented dendritic melanocytes diffusely dispersed throughout all layers of the seborrheic keratosis-like epidermis.³ Other features include keratin-filled pseudocysts, Langerhans cells, reactive spindling of keratinocytes, and an inflammatory infiltrate. In our case, the classic histologic findings also were architecturally arranged in oval to round clones within the epidermis (quiz images 1 and 2). A MART-1 (melanoma antigen recognized by T cells) immunostain was obtained that highlighted the numerous but benign-appearing, dendritic melanocytes (quiz image 2 [inset]). A dual MART-1/Ki67 immunostain later was obtained and demonstrated a negligible proliferation index within the dendritic melanocytes. Therefore, the diagnosis of clonal MA was rendered. This formation of epidermal clones also is called the Borst-Jadassohn phenomenon, which rarely occurs in MAs. This subtype is important to recognize because the clonal pattern can more closely mimic malignant neoplasms such as melanoma.  

Hidroacanthoma simplex is an intraepidermal variant of eccrine poroma. It is a rare entity that typically occurs in the extremities of women as a hyperkeratotic plaque. These typically clonal epidermal tumors may be heavily pigmented and rarely contain dendritic melanocytes; therefore, they may be confused with MA. However, classic histology will reveal an intraepidermal clonal proliferation of bland, monotonous, cuboidal cells with ample pink cytoplasm, as well as occasional cuticle-lined ducts (Figure 1).⁴ These ducts will highlight with carcinoembryonic antigen and epithelial membrane antigen immunostaining.  

Malignant melanoma typically presents as a growing pigmented lesion and therefore can clinically mimic MA. Histologically, MA could be confused with melanoma due to the increased number of melanocytes plus the appearance of pagetoid spread resulting from the diffuse presence of melanocytes throughout the neoplasm. However, histologic assessment of melanoma should reveal cytologic atypia such as nuclear enlargement, hyperchromasia, molding, pleomorphism, and mitotic activity (Figure 2). Architectural atypia such as poor lateral circumscription of melanocytes, confluence and pagetoid spread of nondendritic atypical junctional melanocytes, production of pigment in deep dermal nests of melanocytes, and lack of maturation and dispersion of dermal melanocytes also should be seen.⁵ Unlike a melanocytic neoplasm, true melanocytic nests are not seen in MA, and the melanocytes are bland, normal-appearing but heavily pigmented, dendritic melanocytes. Electron microscopy has shown a defect in the transfer of melanin from these highly dendritic melanocytes to the keratinocytes.⁶  

Similar to melanoma, seborrheic keratosis presents as a pigmented growing lesion; therefore, definitive diagnosis often is achieved via skin biopsy. Classic histologic findings include acanthotic or exophytic epidermal growth with a dome-shaped configuration containing multiple cornified hornlike cysts (Figure 3).⁷ Multiple keratin plugs and variably sized concentric keratin islands are common features. There may be varying degrees of melanin pigment deposition among the proliferating cells, and clonal formation may occur. Melanocyte-specific special stains and immunostains can be used to differentiate MA from seborrheic keratosis by highlighting numerous dendritic melanocytes diffusely spread throughout the epidermis in MA vs a normal distribution of occasional junctional melanocytes in seborrheic keratosis.^2,8  

Squamous cell carcinoma in situ presents histologically with cytologically atypical keratinocytes encompassing the full thickness of the epidermis and sometimes crushing the basement membrane zone (Figure 4). There is a loss of the granular layer and overlying parakeratosis that often spares the adnexal ostial epithelium.⁹ Clonal formation can occur as well as increased pigment production. In comparison, bland keratinocytes are seen in MA.  

Establishing the diagnosis of MA based on clinical features alone can be difficult. Dermoscopy can prove to be useful and typically will show a sunburst pattern with ridges and fissures.² However, seborrheic keratoses and melanomas can have similar dermoscopic findings¹⁰; therefore, a biopsy often is necessary to establish the diagnosis. 

The Diagnosis: Clonal Melanoacanthoma 

Melanoacanthoma (MA) is an extremely rare, benign, epidermal tumor histologically characterized by keratinocytes and large, pigmented, dendritic melanocytes. These lesions are loosely related to seborrheic keratoses, and the term was first coined by Mishima and Pinkus¹ in 1960. It is estimated that the lesion occurs in only 5 of 500,000 individuals and tends to occur in older, light-skinned individuals.² The majority are slow growing and are present on the head, neck, or upper extremities; however, similar lesions also have been reported on the oral mucosa.³ Melanoacanthomas range in size from 2×2 to 15×15 cm; are clinically pigmented; and present as either a papule, plaque, nodule, or horn.² 

Classic histologic findings of MA include papillomatosis, acanthosis, and hyperkeratosis with heavily pigmented dendritic melanocytes diffusely dispersed throughout all layers of the seborrheic keratosis-like epidermis.³ Other features include keratin-filled pseudocysts, Langerhans cells, reactive spindling of keratinocytes, and an inflammatory infiltrate. In our case, the classic histologic findings also were architecturally arranged in oval to round clones within the epidermis (quiz images 1 and 2). A MART-1 (melanoma antigen recognized by T cells) immunostain was obtained that highlighted the numerous but benign-appearing, dendritic melanocytes (quiz image 2 [inset]). A dual MART-1/Ki67 immunostain later was obtained and demonstrated a negligible proliferation index within the dendritic melanocytes. Therefore, the diagnosis of clonal MA was rendered. This formation of epidermal clones also is called the Borst-Jadassohn phenomenon, which rarely occurs in MAs. This subtype is important to recognize because the clonal pattern can more closely mimic malignant neoplasms such as melanoma.  

Hidroacanthoma simplex is an intraepidermal variant of eccrine poroma. It is a rare entity that typically occurs in the extremities of women as a hyperkeratotic plaque. These typically clonal epidermal tumors may be heavily pigmented and rarely contain dendritic melanocytes; therefore, they may be confused with MA. However, classic histology will reveal an intraepidermal clonal proliferation of bland, monotonous, cuboidal cells with ample pink cytoplasm, as well as occasional cuticle-lined ducts (Figure 1).⁴ These ducts will highlight with carcinoembryonic antigen and epithelial membrane antigen immunostaining.  

Malignant melanoma typically presents as a growing pigmented lesion and therefore can clinically mimic MA. Histologically, MA could be confused with melanoma due to the increased number of melanocytes plus the appearance of pagetoid spread resulting from the diffuse presence of melanocytes throughout the neoplasm. However, histologic assessment of melanoma should reveal cytologic atypia such as nuclear enlargement, hyperchromasia, molding, pleomorphism, and mitotic activity (Figure 2). Architectural atypia such as poor lateral circumscription of melanocytes, confluence and pagetoid spread of nondendritic atypical junctional melanocytes, production of pigment in deep dermal nests of melanocytes, and lack of maturation and dispersion of dermal melanocytes also should be seen.⁵ Unlike a melanocytic neoplasm, true melanocytic nests are not seen in MA, and the melanocytes are bland, normal-appearing but heavily pigmented, dendritic melanocytes. Electron microscopy has shown a defect in the transfer of melanin from these highly dendritic melanocytes to the keratinocytes.⁶  

Similar to melanoma, seborrheic keratosis presents as a pigmented growing lesion; therefore, definitive diagnosis often is achieved via skin biopsy. Classic histologic findings include acanthotic or exophytic epidermal growth with a dome-shaped configuration containing multiple cornified hornlike cysts (Figure 3).⁷ Multiple keratin plugs and variably sized concentric keratin islands are common features. There may be varying degrees of melanin pigment deposition among the proliferating cells, and clonal formation may occur. Melanocyte-specific special stains and immunostains can be used to differentiate MA from seborrheic keratosis by highlighting numerous dendritic melanocytes diffusely spread throughout the epidermis in MA vs a normal distribution of occasional junctional melanocytes in seborrheic keratosis.^2,8  

Squamous cell carcinoma in situ presents histologically with cytologically atypical keratinocytes encompassing the full thickness of the epidermis and sometimes crushing the basement membrane zone (Figure 4). There is a loss of the granular layer and overlying parakeratosis that often spares the adnexal ostial epithelium.⁹ Clonal formation can occur as well as increased pigment production. In comparison, bland keratinocytes are seen in MA.  

Establishing the diagnosis of MA based on clinical features alone can be difficult. Dermoscopy can prove to be useful and typically will show a sunburst pattern with ridges and fissures.² However, seborrheic keratoses and melanomas can have similar dermoscopic findings¹⁰; therefore, a biopsy often is necessary to establish the diagnosis.