B. Joel Tjarks, MD

The Diagnosis: Lichen Planus Pemphigoides 

Lichen planus pemphigoides (LPP) is a rare autoimmune subepithelial blistering disorder with clinical, pathologic, and immunologic features of lichen planus (LP) and bullous pemphigoid (BP).¹ It mainly arises in adults and usually is idiopathic but has been associated with certain infections,² drugs such as angiotensin-converting enzyme inhibitors,³ phototherapy,⁴ and malignancy.⁵ Patients classically present with lichenoid lesions, tense vesiculobullae, and erosions.⁶ Vesiculobullae formation usually follows the development of lichenoid lesions, occurs on both lichenoid lesions and unaffected skin, and predominantly involves the lower extremities, as in our patient.^1,6 

The pathogenesis of LPP is not fully understood but likely represents a distinct entity rather than a subtype of BP or the simultaneous occurrence of LP and BP. Lichen planus pemphigoides generally has an earlier onset and better treatment response compared to BP.⁷ Further, autoantibodies in patients with LPP react to a novel epitope within the C-terminal portion of the BP-180 NC16A domain. Accordingly, it has been postulated that an inflammatory cutaneous process resulting from infection, phototherapy, or LP itself leads to damage of the epidermis and triggers a secondary blistering autoimmune dermatosis mediated by antibody formation against basement membrane (BM) antigens, such as BP-180.⁷ 

The diagnosis of LPP ultimately is confirmed with immunohistologic analysis. Biopsy of LPP shows findings consistent with both LP and BP (quiz image [top]). In the lichenoid portion, biopsy reveals orthohyperkeratosis, hypergranulosis, and acanthosis of the epidermis; a bandlike infiltrate consisting primarily of lymphocytes in the upper dermis; and apoptotic keratinocytes (colloid bodies) and vacuolar degeneration at the dermoepidermal junction (DEJ).¹ Biopsy of bullae reveals eosinophilic spongiosis, a subepithelial blister plane with eosinophils, and a mixed superficial inflammatory cell infiltrate. Direct immunofluorescence from perilesional skin reveals linear deposition of IgG and/or C3 at the DEJ (quiz image [bottom]).¹ Measurement of anti-BM antibodies against BP-180 and BP-230 can be useful in suspected cases, as 50% to 60% of patients have circulating antibodies against these antigens.⁶ Remission usually is achieved with topical and systemic corticosteroids and/or steroid-sparing agents, with rare recurrence following lesion resolution.¹ More recently, successful treatment with biologics such as ustekinumab has been reported.⁸ 

The predominant differential diagnosis for LPP is bullous LP, a variant of LP in which vesiculobullous disease occurs exclusively on preexisting LP lesions, commonly on the legs due to severe vacuolar degeneration at the DEJ. On histopathology, the characteristic features of LP (eg, orthohyperkeratosis, hypergranulosis, acanthosis, bandlike lymphocytic infiltrate, colloid bodies) along with subepidermal clefting will be seen. However, in bullous LP (Figure 1) there is an absence of linear IgG and/or C3 deposition at the DEJ on direct immunofluorescence. Furthermore, patients lack circulating antibodies against BP-180 and BP-230.⁹ 

Lichen planus pemphigoides also can be confused with BP. Bullous pemphigoid is the most common autoimmune blistering disorder; typically arises in older adults; and is caused by autoantibody formation against hemidesmosomal proteins, particularly BP-180 and BP-230. Patients classically present with tense bullae and erosions on an erythematous, urticarial, or normal base. These lesions often are pruritic and concentrated on the trunk, axillary and inguinal folds, and extremity flexures. Histopathologic examination of a bulla edge reveals the classic findings seen in BP (eg, eosinophilic spongiosis, subepithelial blister plane with eosinophils)(Figure 2). Direct immunofluorescence of perilesional skin reveals linear IgG and/or C3 deposition along the DEJ. A large subset of patients also has circulating antibodies against BP-180 and BP-230. In contrast to LPP, however, patients with BP do not develop lichenoid lesions clinically or a lichenoid tissue reaction histopathologically.¹⁰ 

Bullous systemic lupus erythematosus (SLE), a rare cutaneous manifestation of SLE, typically arises in young women of African descent and is due to autoantibody formation against type VII collagen and other BM-zone antigens. Patients generally present with acute onset of tense vesiculobullae on a normal or erythematous base, which often are transient and heal without milia or scarring. Common sites of involvement include the trunk, arms, neck, face, and vermilion border, as well as the oral mucosa. The diagnosis of bullous SLE requires that patients fulfill the criteria for SLE and is confirmed by immunohistologic analysis. Biopsy of a bulla edge reveals a subepidermal blister containing neutrophils and increased mucin within the reticular dermis (Figure 3). Direct immunofluorescence of perilesional skin most commonly reveals linear and/or granular deposition of IgG, IgA, C3, and IgM at the DEJ.¹¹ 

Bullous tinea is a manifestation of cutaneous dermatophytosis that usually occurs in the setting of tinea pedis. Common causative dermatophytes include Trichophyton mentagrophytes, Trichophyton rubrum, and Epidermophyton floccosum. Diagnosis is made by demonstration of fungal hyphae on potassium hydroxide preparation of the blister roof, biopsy with periodic acid-Schiff stain, or fungal culture. If routine histopathologic analysis is performed, epidermal spongiosis with varying degrees of papillary dermal edema is seen, along with abundant fungal elements in the stratum corneum (Figure 4). Direct immunofluorescence of perilesional skin usually is negative, but C3 deposition in a linear and/or granular pattern along the DEJ has been reported.¹² 

Lichen planus pemphigoides is a rare disease entity and often presents a diagnostic challenge to clinicians. The differential for LPP includes bullous LP as well as other bullous disorders. Ultimately, the diagnosis is confirmed through immunohistologic analysis. Timely diagnosis of LPP is crucial, as most patients can achieve long-term remission with appropriate treatment. 

The Diagnosis: Lichen Planus Pemphigoides 

Lichen planus pemphigoides (LPP) is a rare autoimmune subepithelial blistering disorder with clinical, pathologic, and immunologic features of lichen planus (LP) and bullous pemphigoid (BP).¹ It mainly arises in adults and usually is idiopathic but has been associated with certain infections,² drugs such as angiotensin-converting enzyme inhibitors,³ phototherapy,⁴ and malignancy.⁵ Patients classically present with lichenoid lesions, tense vesiculobullae, and erosions.⁶ Vesiculobullae formation usually follows the development of lichenoid lesions, occurs on both lichenoid lesions and unaffected skin, and predominantly involves the lower extremities, as in our patient.^1,6 

The pathogenesis of LPP is not fully understood but likely represents a distinct entity rather than a subtype of BP or the simultaneous occurrence of LP and BP. Lichen planus pemphigoides generally has an earlier onset and better treatment response compared to BP.⁷ Further, autoantibodies in patients with LPP react to a novel epitope within the C-terminal portion of the BP-180 NC16A domain. Accordingly, it has been postulated that an inflammatory cutaneous process resulting from infection, phototherapy, or LP itself leads to damage of the epidermis and triggers a secondary blistering autoimmune dermatosis mediated by antibody formation against basement membrane (BM) antigens, such as BP-180.⁷ 

The diagnosis of LPP ultimately is confirmed with immunohistologic analysis. Biopsy of LPP shows findings consistent with both LP and BP (quiz image [top]). In the lichenoid portion, biopsy reveals orthohyperkeratosis, hypergranulosis, and acanthosis of the epidermis; a bandlike infiltrate consisting primarily of lymphocytes in the upper dermis; and apoptotic keratinocytes (colloid bodies) and vacuolar degeneration at the dermoepidermal junction (DEJ).¹ Biopsy of bullae reveals eosinophilic spongiosis, a subepithelial blister plane with eosinophils, and a mixed superficial inflammatory cell infiltrate. Direct immunofluorescence from perilesional skin reveals linear deposition of IgG and/or C3 at the DEJ (quiz image [bottom]).¹ Measurement of anti-BM antibodies against BP-180 and BP-230 can be useful in suspected cases, as 50% to 60% of patients have circulating antibodies against these antigens.⁶ Remission usually is achieved with topical and systemic corticosteroids and/or steroid-sparing agents, with rare recurrence following lesion resolution.¹ More recently, successful treatment with biologics such as ustekinumab has been reported.⁸ 

The predominant differential diagnosis for LPP is bullous LP, a variant of LP in which vesiculobullous disease occurs exclusively on preexisting LP lesions, commonly on the legs due to severe vacuolar degeneration at the DEJ. On histopathology, the characteristic features of LP (eg, orthohyperkeratosis, hypergranulosis, acanthosis, bandlike lymphocytic infiltrate, colloid bodies) along with subepidermal clefting will be seen. However, in bullous LP (Figure 1) there is an absence of linear IgG and/or C3 deposition at the DEJ on direct immunofluorescence. Furthermore, patients lack circulating antibodies against BP-180 and BP-230.⁹ 

Lichen planus pemphigoides also can be confused with BP. Bullous pemphigoid is the most common autoimmune blistering disorder; typically arises in older adults; and is caused by autoantibody formation against hemidesmosomal proteins, particularly BP-180 and BP-230. Patients classically present with tense bullae and erosions on an erythematous, urticarial, or normal base. These lesions often are pruritic and concentrated on the trunk, axillary and inguinal folds, and extremity flexures. Histopathologic examination of a bulla edge reveals the classic findings seen in BP (eg, eosinophilic spongiosis, subepithelial blister plane with eosinophils)(Figure 2). Direct immunofluorescence of perilesional skin reveals linear IgG and/or C3 deposition along the DEJ. A large subset of patients also has circulating antibodies against BP-180 and BP-230. In contrast to LPP, however, patients with BP do not develop lichenoid lesions clinically or a lichenoid tissue reaction histopathologically.¹⁰ 

Bullous systemic lupus erythematosus (SLE), a rare cutaneous manifestation of SLE, typically arises in young women of African descent and is due to autoantibody formation against type VII collagen and other BM-zone antigens. Patients generally present with acute onset of tense vesiculobullae on a normal or erythematous base, which often are transient and heal without milia or scarring. Common sites of involvement include the trunk, arms, neck, face, and vermilion border, as well as the oral mucosa. The diagnosis of bullous SLE requires that patients fulfill the criteria for SLE and is confirmed by immunohistologic analysis. Biopsy of a bulla edge reveals a subepidermal blister containing neutrophils and increased mucin within the reticular dermis (Figure 3). Direct immunofluorescence of perilesional skin most commonly reveals linear and/or granular deposition of IgG, IgA, C3, and IgM at the DEJ.¹¹ 

Bullous tinea is a manifestation of cutaneous dermatophytosis that usually occurs in the setting of tinea pedis. Common causative dermatophytes include Trichophyton mentagrophytes, Trichophyton rubrum, and Epidermophyton floccosum. Diagnosis is made by demonstration of fungal hyphae on potassium hydroxide preparation of the blister roof, biopsy with periodic acid-Schiff stain, or fungal culture. If routine histopathologic analysis is performed, epidermal spongiosis with varying degrees of papillary dermal edema is seen, along with abundant fungal elements in the stratum corneum (Figure 4). Direct immunofluorescence of perilesional skin usually is negative, but C3 deposition in a linear and/or granular pattern along the DEJ has been reported.¹² 

Lichen planus pemphigoides is a rare disease entity and often presents a diagnostic challenge to clinicians. The differential for LPP includes bullous LP as well as other bullous disorders. Ultimately, the diagnosis is confirmed through immunohistologic analysis. Timely diagnosis of LPP is crucial, as most patients can achieve long-term remission with appropriate treatment. 

The Diagnosis: Lichen Planus Pemphigoides 

Lichen planus pemphigoides (LPP) is a rare autoimmune subepithelial blistering disorder with clinical, pathologic, and immunologic features of lichen planus (LP) and bullous pemphigoid (BP).¹ It mainly arises in adults and usually is idiopathic but has been associated with certain infections,² drugs such as angiotensin-converting enzyme inhibitors,³ phototherapy,⁴ and malignancy.⁵ Patients classically present with lichenoid lesions, tense vesiculobullae, and erosions.⁶ Vesiculobullae formation usually follows the development of lichenoid lesions, occurs on both lichenoid lesions and unaffected skin, and predominantly involves the lower extremities, as in our patient.^1,6 

The pathogenesis of LPP is not fully understood but likely represents a distinct entity rather than a subtype of BP or the simultaneous occurrence of LP and BP. Lichen planus pemphigoides generally has an earlier onset and better treatment response compared to BP.⁷ Further, autoantibodies in patients with LPP react to a novel epitope within the C-terminal portion of the BP-180 NC16A domain. Accordingly, it has been postulated that an inflammatory cutaneous process resulting from infection, phototherapy, or LP itself leads to damage of the epidermis and triggers a secondary blistering autoimmune dermatosis mediated by antibody formation against basement membrane (BM) antigens, such as BP-180.⁷ 

The diagnosis of LPP ultimately is confirmed with immunohistologic analysis. Biopsy of LPP shows findings consistent with both LP and BP (quiz image [top]). In the lichenoid portion, biopsy reveals orthohyperkeratosis, hypergranulosis, and acanthosis of the epidermis; a bandlike infiltrate consisting primarily of lymphocytes in the upper dermis; and apoptotic keratinocytes (colloid bodies) and vacuolar degeneration at the dermoepidermal junction (DEJ).¹ Biopsy of bullae reveals eosinophilic spongiosis, a subepithelial blister plane with eosinophils, and a mixed superficial inflammatory cell infiltrate. Direct immunofluorescence from perilesional skin reveals linear deposition of IgG and/or C3 at the DEJ (quiz image [bottom]).¹ Measurement of anti-BM antibodies against BP-180 and BP-230 can be useful in suspected cases, as 50% to 60% of patients have circulating antibodies against these antigens.⁶ Remission usually is achieved with topical and systemic corticosteroids and/or steroid-sparing agents, with rare recurrence following lesion resolution.¹ More recently, successful treatment with biologics such as ustekinumab has been reported.⁸ 

The predominant differential diagnosis for LPP is bullous LP, a variant of LP in which vesiculobullous disease occurs exclusively on preexisting LP lesions, commonly on the legs due to severe vacuolar degeneration at the DEJ. On histopathology, the characteristic features of LP (eg, orthohyperkeratosis, hypergranulosis, acanthosis, bandlike lymphocytic infiltrate, colloid bodies) along with subepidermal clefting will be seen. However, in bullous LP (Figure 1) there is an absence of linear IgG and/or C3 deposition at the DEJ on direct immunofluorescence. Furthermore, patients lack circulating antibodies against BP-180 and BP-230.⁹ 

Lichen planus pemphigoides also can be confused with BP. Bullous pemphigoid is the most common autoimmune blistering disorder; typically arises in older adults; and is caused by autoantibody formation against hemidesmosomal proteins, particularly BP-180 and BP-230. Patients classically present with tense bullae and erosions on an erythematous, urticarial, or normal base. These lesions often are pruritic and concentrated on the trunk, axillary and inguinal folds, and extremity flexures. Histopathologic examination of a bulla edge reveals the classic findings seen in BP (eg, eosinophilic spongiosis, subepithelial blister plane with eosinophils)(Figure 2). Direct immunofluorescence of perilesional skin reveals linear IgG and/or C3 deposition along the DEJ. A large subset of patients also has circulating antibodies against BP-180 and BP-230. In contrast to LPP, however, patients with BP do not develop lichenoid lesions clinically or a lichenoid tissue reaction histopathologically.¹⁰ 

Bullous systemic lupus erythematosus (SLE), a rare cutaneous manifestation of SLE, typically arises in young women of African descent and is due to autoantibody formation against type VII collagen and other BM-zone antigens. Patients generally present with acute onset of tense vesiculobullae on a normal or erythematous base, which often are transient and heal without milia or scarring. Common sites of involvement include the trunk, arms, neck, face, and vermilion border, as well as the oral mucosa. The diagnosis of bullous SLE requires that patients fulfill the criteria for SLE and is confirmed by immunohistologic analysis. Biopsy of a bulla edge reveals a subepidermal blister containing neutrophils and increased mucin within the reticular dermis (Figure 3). Direct immunofluorescence of perilesional skin most commonly reveals linear and/or granular deposition of IgG, IgA, C3, and IgM at the DEJ.¹¹ 

Bullous tinea is a manifestation of cutaneous dermatophytosis that usually occurs in the setting of tinea pedis. Common causative dermatophytes include Trichophyton mentagrophytes, Trichophyton rubrum, and Epidermophyton floccosum. Diagnosis is made by demonstration of fungal hyphae on potassium hydroxide preparation of the blister roof, biopsy with periodic acid-Schiff stain, or fungal culture. If routine histopathologic analysis is performed, epidermal spongiosis with varying degrees of papillary dermal edema is seen, along with abundant fungal elements in the stratum corneum (Figure 4). Direct immunofluorescence of perilesional skin usually is negative, but C3 deposition in a linear and/or granular pattern along the DEJ has been reported.¹² 

Lichen planus pemphigoides is a rare disease entity and often presents a diagnostic challenge to clinicians. The differential for LPP includes bullous LP as well as other bullous disorders. Ultimately, the diagnosis is confirmed through immunohistologic analysis. Timely diagnosis of LPP is crucial, as most patients can achieve long-term remission with appropriate treatment. 

The Diagnosis: Metastatic Adenocarcinoma of the Colon 

Cutaneous adenocarcinomas are uncommon, whether they present as a primary lesion or metastatic disease. In our patient, the histologic findings and immunohistochemical staining pattern were consistent with metastatic adenocarcinoma of the colon, an uncommon clinical presentation.  

Colonic adenocarcinoma can cause cutaneous metastasis in 3% of cases. The most common sites of metastases include the abdomen, chest, and back.¹ On histologic examination, hematoxylin and eosin (H&E)-stained sections of cutaneous metastatic adenocarcinoma illustrate a malignant gland-forming neoplasm in the dermis with luminal mucin and necrotic debris (quiz image). The glands are lined by tall columnar epithelial cells with hyperchromatic nuclei. Alternatively, poorly differentiated morphology can be seen with fewer glands and more infiltrating nests of tumor cells.² Immunohistochemically, colonic adenocarcinoma typically is negative for cytokeratin (CK) 7 and positive for CK20 and caudal type homeobox transcription factor 2 (CDX-2).³  

Primary cutaneous mucinous carcinoma is characterized by islands of neoplastic cells floating in pools of mucin (Figure 1). It may be indistinguishable from metastatic mucinous carcinomas of the colon or breast. Immunohistochemistry can be helpful in differentiating metastatic breast vs colon carcinoma. Cytokeratin 7, GATA binding protein 3, gross cystic disease fluid protein 15, and estrogen receptor will be positive in carcinomas of the breast and will be negative in colonic adenocarcinomas.^4-6 Furthermore, lesional cells in metastatic adenocarcinoma of the colon are positive for CDX-2 and CK20, while those in metastatic carcinoma of the breast are negative.² Immunohistochemistry also can differentiate primary cutaneous carcinoma from metastatic adenocarcinoma. When used in combination, p63 and podoplanin (D2-40) offer a highly sensitive and specific indicator of a primary cutaneous neoplasm, as both demonstrate either focal or diffuse positivity in this setting. In contrast, these stains typically are negative in metastatic adenocarcinomas of the skin.⁷ 

Endometriosis affects 1% to 2% of all reproductive-age females, of which extrapelvic manifestations account for only 0.5% to 1.0% of cases.⁸ Histologically, extrapelvic endometriosis is characterized by the triad of endometrial-type glands, endometrial stroma, and hemorrhage or hemosiderin deposition (Figure 2). The glands can enlarge and demonstrate architectural distortion with partial lack of polarity. These features initially can be concerning for adenocarcinoma, but on closer examination, nuclear morphology is regular and mitoses are absent.^8,9 The diagnosis usually can be rendered with H&E alone; however, immunohistochemical stains for CD10 and estrogen receptor can highlight the endometrial stroma.¹⁰ Furthermore, endometrial glands will stain positive for paired box gene 8 (PAX8), a marker that is not expressed within the gastrointestinal tract and associated malignancies.¹¹  

Primary cutaneous angiosarcoma may mimic adenocarcinoma, as the endothelial-lined vessels can be confused as malignant glands (Figure 3). Angiosarcoma often is seen in 1 of 3 clinical presentations: the head and neck of elderly patients, postradiation treatment, and chronic lymphedema.^12,13 Regardless of the location, the disease carries a poor prognosis, with a 5-year survival rate of 12% following initial diagnosis.¹³ Angiosarcoma is characterized by malignant endothelial cells dissecting through the dermis. Although the histology can be deceptively bland in some cases, the neoplasm most commonly demonstrates notable atypia with a multilayered endothelium and occasional intravascular atypical cells ("fish in the creek appearance").^13,14 There can be frequent mitoses, and the atypical cells may show intracytoplasmic lumina containing red blood cells. The lesional cells are positive for endothelial markers such as erythroblast transformation specific related gene (ERG), CD31, CD34, and friend leukemia integration factor 1 (FLI-1).^15,16  

Breast cancer also can cause cutaneous metastases in approximately 20% of cases, with the most common presenting site being the anterior chest wall.¹⁷ Macroscopically, these lesions appear most commonly as painless nodules but also as telangiectatic, erysipeloid, fibrotic, and alopecic lesions.^17-19 The histologic findings from H&E-stained sections of a cutaneous metastasis of breast cancer are variable and depend on the specific tumor subtype (eg, ductal, lobular, mucinous). However, the classic histologic presentation is that of nests and cords of malignant epithelial cells with variable gland formation. Often, tumor cells infiltrate in a single-file fashion (Figure 4).¹⁷ Although inflammatory breast carcinoma is a strictly clinical diagnosis, the presence of tumor cells in the lymphovascular spaces is a histologic clue to this diagnosis. Immunohistochemically, GATA binding protein 3 is helpful in identifying both hormone receptor-positive and -negative breast cancer subtypes that have metastasized.²⁰ 

Within the histologic differential diagnoses, the most useful tool to diagnose metastatic adenocarcinoma of the colon often is a thorough clinical history. In the absence of a clinical history of adenocarcinoma, immunohistochemistry can be a useful adjunct to aid in the correct characterization and classification of a malignant gland-forming tumor.^2,3,6 

The Diagnosis: Metastatic Adenocarcinoma of the Colon 

Cutaneous adenocarcinomas are uncommon, whether they present as a primary lesion or metastatic disease. In our patient, the histologic findings and immunohistochemical staining pattern were consistent with metastatic adenocarcinoma of the colon, an uncommon clinical presentation.  

Colonic adenocarcinoma can cause cutaneous metastasis in 3% of cases. The most common sites of metastases include the abdomen, chest, and back.¹ On histologic examination, hematoxylin and eosin (H&E)-stained sections of cutaneous metastatic adenocarcinoma illustrate a malignant gland-forming neoplasm in the dermis with luminal mucin and necrotic debris (quiz image). The glands are lined by tall columnar epithelial cells with hyperchromatic nuclei. Alternatively, poorly differentiated morphology can be seen with fewer glands and more infiltrating nests of tumor cells.² Immunohistochemically, colonic adenocarcinoma typically is negative for cytokeratin (CK) 7 and positive for CK20 and caudal type homeobox transcription factor 2 (CDX-2).³  

Primary cutaneous mucinous carcinoma is characterized by islands of neoplastic cells floating in pools of mucin (Figure 1). It may be indistinguishable from metastatic mucinous carcinomas of the colon or breast. Immunohistochemistry can be helpful in differentiating metastatic breast vs colon carcinoma. Cytokeratin 7, GATA binding protein 3, gross cystic disease fluid protein 15, and estrogen receptor will be positive in carcinomas of the breast and will be negative in colonic adenocarcinomas.^4-6 Furthermore, lesional cells in metastatic adenocarcinoma of the colon are positive for CDX-2 and CK20, while those in metastatic carcinoma of the breast are negative.² Immunohistochemistry also can differentiate primary cutaneous carcinoma from metastatic adenocarcinoma. When used in combination, p63 and podoplanin (D2-40) offer a highly sensitive and specific indicator of a primary cutaneous neoplasm, as both demonstrate either focal or diffuse positivity in this setting. In contrast, these stains typically are negative in metastatic adenocarcinomas of the skin.⁷ 

Endometriosis affects 1% to 2% of all reproductive-age females, of which extrapelvic manifestations account for only 0.5% to 1.0% of cases.⁸ Histologically, extrapelvic endometriosis is characterized by the triad of endometrial-type glands, endometrial stroma, and hemorrhage or hemosiderin deposition (Figure 2). The glands can enlarge and demonstrate architectural distortion with partial lack of polarity. These features initially can be concerning for adenocarcinoma, but on closer examination, nuclear morphology is regular and mitoses are absent.^8,9 The diagnosis usually can be rendered with H&E alone; however, immunohistochemical stains for CD10 and estrogen receptor can highlight the endometrial stroma.¹⁰ Furthermore, endometrial glands will stain positive for paired box gene 8 (PAX8), a marker that is not expressed within the gastrointestinal tract and associated malignancies.¹¹  

Primary cutaneous angiosarcoma may mimic adenocarcinoma, as the endothelial-lined vessels can be confused as malignant glands (Figure 3). Angiosarcoma often is seen in 1 of 3 clinical presentations: the head and neck of elderly patients, postradiation treatment, and chronic lymphedema.^12,13 Regardless of the location, the disease carries a poor prognosis, with a 5-year survival rate of 12% following initial diagnosis.¹³ Angiosarcoma is characterized by malignant endothelial cells dissecting through the dermis. Although the histology can be deceptively bland in some cases, the neoplasm most commonly demonstrates notable atypia with a multilayered endothelium and occasional intravascular atypical cells ("fish in the creek appearance").^13,14 There can be frequent mitoses, and the atypical cells may show intracytoplasmic lumina containing red blood cells. The lesional cells are positive for endothelial markers such as erythroblast transformation specific related gene (ERG), CD31, CD34, and friend leukemia integration factor 1 (FLI-1).^15,16  

Breast cancer also can cause cutaneous metastases in approximately 20% of cases, with the most common presenting site being the anterior chest wall.¹⁷ Macroscopically, these lesions appear most commonly as painless nodules but also as telangiectatic, erysipeloid, fibrotic, and alopecic lesions.^17-19 The histologic findings from H&E-stained sections of a cutaneous metastasis of breast cancer are variable and depend on the specific tumor subtype (eg, ductal, lobular, mucinous). However, the classic histologic presentation is that of nests and cords of malignant epithelial cells with variable gland formation. Often, tumor cells infiltrate in a single-file fashion (Figure 4).¹⁷ Although inflammatory breast carcinoma is a strictly clinical diagnosis, the presence of tumor cells in the lymphovascular spaces is a histologic clue to this diagnosis. Immunohistochemically, GATA binding protein 3 is helpful in identifying both hormone receptor-positive and -negative breast cancer subtypes that have metastasized.²⁰ 

Within the histologic differential diagnoses, the most useful tool to diagnose metastatic adenocarcinoma of the colon often is a thorough clinical history. In the absence of a clinical history of adenocarcinoma, immunohistochemistry can be a useful adjunct to aid in the correct characterization and classification of a malignant gland-forming tumor.^2,3,6 

The Diagnosis: Metastatic Adenocarcinoma of the Colon 

Cutaneous adenocarcinomas are uncommon, whether they present as a primary lesion or metastatic disease. In our patient, the histologic findings and immunohistochemical staining pattern were consistent with metastatic adenocarcinoma of the colon, an uncommon clinical presentation.  

Colonic adenocarcinoma can cause cutaneous metastasis in 3% of cases. The most common sites of metastases include the abdomen, chest, and back.¹ On histologic examination, hematoxylin and eosin (H&E)-stained sections of cutaneous metastatic adenocarcinoma illustrate a malignant gland-forming neoplasm in the dermis with luminal mucin and necrotic debris (quiz image). The glands are lined by tall columnar epithelial cells with hyperchromatic nuclei. Alternatively, poorly differentiated morphology can be seen with fewer glands and more infiltrating nests of tumor cells.² Immunohistochemically, colonic adenocarcinoma typically is negative for cytokeratin (CK) 7 and positive for CK20 and caudal type homeobox transcription factor 2 (CDX-2).³  

Primary cutaneous mucinous carcinoma is characterized by islands of neoplastic cells floating in pools of mucin (Figure 1). It may be indistinguishable from metastatic mucinous carcinomas of the colon or breast. Immunohistochemistry can be helpful in differentiating metastatic breast vs colon carcinoma. Cytokeratin 7, GATA binding protein 3, gross cystic disease fluid protein 15, and estrogen receptor will be positive in carcinomas of the breast and will be negative in colonic adenocarcinomas.^4-6 Furthermore, lesional cells in metastatic adenocarcinoma of the colon are positive for CDX-2 and CK20, while those in metastatic carcinoma of the breast are negative.² Immunohistochemistry also can differentiate primary cutaneous carcinoma from metastatic adenocarcinoma. When used in combination, p63 and podoplanin (D2-40) offer a highly sensitive and specific indicator of a primary cutaneous neoplasm, as both demonstrate either focal or diffuse positivity in this setting. In contrast, these stains typically are negative in metastatic adenocarcinomas of the skin.⁷ 

Endometriosis affects 1% to 2% of all reproductive-age females, of which extrapelvic manifestations account for only 0.5% to 1.0% of cases.⁸ Histologically, extrapelvic endometriosis is characterized by the triad of endometrial-type glands, endometrial stroma, and hemorrhage or hemosiderin deposition (Figure 2). The glands can enlarge and demonstrate architectural distortion with partial lack of polarity. These features initially can be concerning for adenocarcinoma, but on closer examination, nuclear morphology is regular and mitoses are absent.^8,9 The diagnosis usually can be rendered with H&E alone; however, immunohistochemical stains for CD10 and estrogen receptor can highlight the endometrial stroma.¹⁰ Furthermore, endometrial glands will stain positive for paired box gene 8 (PAX8), a marker that is not expressed within the gastrointestinal tract and associated malignancies.¹¹  

Primary cutaneous angiosarcoma may mimic adenocarcinoma, as the endothelial-lined vessels can be confused as malignant glands (Figure 3). Angiosarcoma often is seen in 1 of 3 clinical presentations: the head and neck of elderly patients, postradiation treatment, and chronic lymphedema.^12,13 Regardless of the location, the disease carries a poor prognosis, with a 5-year survival rate of 12% following initial diagnosis.¹³ Angiosarcoma is characterized by malignant endothelial cells dissecting through the dermis. Although the histology can be deceptively bland in some cases, the neoplasm most commonly demonstrates notable atypia with a multilayered endothelium and occasional intravascular atypical cells ("fish in the creek appearance").^13,14 There can be frequent mitoses, and the atypical cells may show intracytoplasmic lumina containing red blood cells. The lesional cells are positive for endothelial markers such as erythroblast transformation specific related gene (ERG), CD31, CD34, and friend leukemia integration factor 1 (FLI-1).^15,16  

Breast cancer also can cause cutaneous metastases in approximately 20% of cases, with the most common presenting site being the anterior chest wall.¹⁷ Macroscopically, these lesions appear most commonly as painless nodules but also as telangiectatic, erysipeloid, fibrotic, and alopecic lesions.^17-19 The histologic findings from H&E-stained sections of a cutaneous metastasis of breast cancer are variable and depend on the specific tumor subtype (eg, ductal, lobular, mucinous). However, the classic histologic presentation is that of nests and cords of malignant epithelial cells with variable gland formation. Often, tumor cells infiltrate in a single-file fashion (Figure 4).¹⁷ Although inflammatory breast carcinoma is a strictly clinical diagnosis, the presence of tumor cells in the lymphovascular spaces is a histologic clue to this diagnosis. Immunohistochemically, GATA binding protein 3 is helpful in identifying both hormone receptor-positive and -negative breast cancer subtypes that have metastasized.²⁰ 

Within the histologic differential diagnoses, the most useful tool to diagnose metastatic adenocarcinoma of the colon often is a thorough clinical history. In the absence of a clinical history of adenocarcinoma, immunohistochemistry can be a useful adjunct to aid in the correct characterization and classification of a malignant gland-forming tumor.^2,3,6 

The Diagnosis: Monsel Solution Reaction

Exogenous substances can cause interesting incongruities in cutaneous biopsies of which pathologists and dermatologists should be cognizant. Exogenous lesions are caused by externally introduced foreign bodies, substances, or materials, such as sterile compressed sponges, aluminum chloride hexahydrate and anhydrous ethyl alcohol, silica, paraffin, and Monsel solution. Monsel solution reaction is a florid fibrohistiocytic proliferation stimulated by the application of Monsel solution. Monsel solution is a ferric subsulfate that often is used to achieve hemostasis after shave biopsies. Hemostasis is thought to result from the ability of ferric ions to denature and agglutinate proteins such as fibrinogen.^1,2 Application of Monsel solution likely causes ferrugination of fibrin, dermal collagen, and striated muscle fibers. Some ferruginated collagen fibers are eliminated through the epidermis as the epidermis regenerates, while some fibers become calcified. Siderophages (iron-containing macrophages) are present in these areas. The ferrugination of collagen fibers becomes less pronounced as the biopsy sites heal and the iron pigment subsequently is absorbed by macrophages. Ferruginated skeletal muscles can act as foreign bodies and may elicit granulomatous reactions.²

It is currently unclear why fibrohistiocytic responses occur in some instances but not others. Iron stains (eg, Perls Prussian blue stain) make interpretation clear, provided the pathologist is familiar with Monsel solution. The primary differential diagnosis of these lesions centers on heavily pigmented melanocytic proliferations. It is critical to review prior biopsy sections or to have definite knowledge of the prior biopsy diagnosis. Histologically, the epidermis may demonstrate nonspecific reactive changes such as hyperkeratosis with foci of irregular acanthosis. The prominent features are present in the dermis where there is a proliferation of spindle- and polyhedral-shaped cells that may show cytologic atypia and occasional mitotic figures. The cells contain refractile brown pigment scattered in the dermis and deposited on collagen fibers (quiz images). Occasional large black or brown encrustations may be identified. Monsel-containing cells may indiscernibly blend with foci of more blatantly fibrohistiocytic differentiation, in which case iron stains are strongly positive (Figure 1). If the clinician uses Monsel solution for hemostasis during the removal of a nevomelanocytic neoplasm, it might be necessary to use melanin stains or immunohistochemistry on the reexcision specimen to distinguish between residual nevomelanocytic and fibrohistiocytic cells.³

Common blue nevus is a benign, typically intradermal melanocytic lesion. It most frequently occurs in young adults and has a predilection for females. Clinically, it can be found anywhere on the body as a single, asymptomatic, well-circumscribed, blue-black, dome-shaped papule measuring less than 1 cm in diameter. Histologically, it is characterized by pigmented, dendritic, spindle-shaped melanocytes that typically are separated by thick collagen bundles (Figure 2). The melanocytes typically have small nuclei with occasional basophilic nucleolus. Melanocytes typically are diffusely positive for melanocytic markers including human melanoma black (HMB) 45, S-100, Melan-A, and microphthalmia transcription factor 1. In contrast to most other benign melanocytic nevi, HMB-45 strongly stains the entire lesion in blue nevi.⁴

Desmoplastic melanoma accounts for 1% to 4% of all melanomas. The median age at diagnosis is 62 years and, as in other types of melanoma, men are more commonly affected.⁵ Clinically, desmoplastic melanoma typically presents on the head and neck as a painless indurated plaque, though it can present as a small papule or nodule. Nearly half of desmoplastic melanomas lack obvious pigmentation, which may lead to the misdiagnosis of basal cell carcinoma or a scar. Histologically, desmoplastic melanomas are composed of spindled melanocytes separated by collagen fibers or fibrous stroma (Figure 3). Histology displays variable cytologic atypia and stromal fibrosis. Characteristically there are small islands of lymphocytes and plasma cells within or at the edge of the tumor. The spindle cells stain positive with S-100 and Sry-related HMg-box gene 10, SOX10. Type IV collagen and laminin often are expressed in desmoplastic melanoma. In contrast to many other subtypes of melanoma, HMB-45 and Melan-A usually are negative.⁶

Animal-type melanoma is a rare neoplasm that differs from other subtypes of melanoma both clinically and histologically. Most frequently, animal-type melanoma affects younger adults (median age, 27 years) and arises on the arms and legs, head and neck, or trunk; men and women are affected equally.7 It most commonly presents with a blue or blue-black nodule with a blue-white veil or irregular white areas. Histologically, animal-type melanoma is a predominantly dermal-based melanocytic proliferation with heavily pigmented epithelioid and spindled melanocytes (Figure 4). The pigmentation pattern ranges widely from fine, granular, light brown deposits to coarse dark brown deposits with malignant cells often arranged in fascicles or sheets. Frequently, there is periadnexal and perieccrine spread. Often, there is epidermal hyperplasia above the dermis. As with conventional melanoma, the immunohistochemistry of animal-type melanoma is positive for S-100 protein, HMB-45, SOX10, and Melan-A.⁷

Recurrent nevi typically arise within 6 months of a previously biopsied melanocytic nevus. Most recurrent nevi originate from common banal nevi (most often a compound nevus). Recurrent nevi also may arise from congenital, atypical/dysplastic, and Spitz nevi. Most often they are found on the back of women aged 20 to 30 years.⁸ Clinically, they manifest as a macular area of scar with variegated hyperpigmentation and hypopigmentation as well as linear streaking. They may demonstrate variable diffuse, stippled, and halo pigmentation patterns. Classically, recurrent nevi present with a trizonal histologic pattern. Within the epidermis there is a proliferation of melanocytes along the dermoepidermal junction, which may show varying degrees of atypia and pagetoid migration. The melanocytes often are described as epithelioid with round nuclei and even chromatin (Figure 5). The atypical features should be confined to the epidermis overlying the prior biopsy site. Within the dermis there is dense dermal collagen and fibrosis with vertically oriented blood vessels. Finally, features of the original nevus may be seen at the base of the lesion. Although immunohistochemistry may be helpful in some cases, an appropriate clinical history and comparison to the prior biopsy can be invaluable.⁸

Host tissue reactions resulting in artefactual changes caused by foreign bodies or substances may confound the untrained eye. Monsel solution reaction may be confused for a blue nevus, desmoplastic melanoma, animal-type melanoma, and a residual/recurrent nevus. This confusion could lead to serious diagnostic errors that could cause an unfavorable outcome for the patient. It is critical to know the salient points in the patient's clinical history. Knowledge of the Monsel solution reaction and other exogenous lesions as well as the subsequent unique tissue reaction patterns can aid in facilitating an accurate and prompt pathologic diagnosis.

The Diagnosis: Monsel Solution Reaction

Exogenous substances can cause interesting incongruities in cutaneous biopsies of which pathologists and dermatologists should be cognizant. Exogenous lesions are caused by externally introduced foreign bodies, substances, or materials, such as sterile compressed sponges, aluminum chloride hexahydrate and anhydrous ethyl alcohol, silica, paraffin, and Monsel solution. Monsel solution reaction is a florid fibrohistiocytic proliferation stimulated by the application of Monsel solution. Monsel solution is a ferric subsulfate that often is used to achieve hemostasis after shave biopsies. Hemostasis is thought to result from the ability of ferric ions to denature and agglutinate proteins such as fibrinogen.^1,2 Application of Monsel solution likely causes ferrugination of fibrin, dermal collagen, and striated muscle fibers. Some ferruginated collagen fibers are eliminated through the epidermis as the epidermis regenerates, while some fibers become calcified. Siderophages (iron-containing macrophages) are present in these areas. The ferrugination of collagen fibers becomes less pronounced as the biopsy sites heal and the iron pigment subsequently is absorbed by macrophages. Ferruginated skeletal muscles can act as foreign bodies and may elicit granulomatous reactions.²

It is currently unclear why fibrohistiocytic responses occur in some instances but not others. Iron stains (eg, Perls Prussian blue stain) make interpretation clear, provided the pathologist is familiar with Monsel solution. The primary differential diagnosis of these lesions centers on heavily pigmented melanocytic proliferations. It is critical to review prior biopsy sections or to have definite knowledge of the prior biopsy diagnosis. Histologically, the epidermis may demonstrate nonspecific reactive changes such as hyperkeratosis with foci of irregular acanthosis. The prominent features are present in the dermis where there is a proliferation of spindle- and polyhedral-shaped cells that may show cytologic atypia and occasional mitotic figures. The cells contain refractile brown pigment scattered in the dermis and deposited on collagen fibers (quiz images). Occasional large black or brown encrustations may be identified. Monsel-containing cells may indiscernibly blend with foci of more blatantly fibrohistiocytic differentiation, in which case iron stains are strongly positive (Figure 1). If the clinician uses Monsel solution for hemostasis during the removal of a nevomelanocytic neoplasm, it might be necessary to use melanin stains or immunohistochemistry on the reexcision specimen to distinguish between residual nevomelanocytic and fibrohistiocytic cells.³

Common blue nevus is a benign, typically intradermal melanocytic lesion. It most frequently occurs in young adults and has a predilection for females. Clinically, it can be found anywhere on the body as a single, asymptomatic, well-circumscribed, blue-black, dome-shaped papule measuring less than 1 cm in diameter. Histologically, it is characterized by pigmented, dendritic, spindle-shaped melanocytes that typically are separated by thick collagen bundles (Figure 2). The melanocytes typically have small nuclei with occasional basophilic nucleolus. Melanocytes typically are diffusely positive for melanocytic markers including human melanoma black (HMB) 45, S-100, Melan-A, and microphthalmia transcription factor 1. In contrast to most other benign melanocytic nevi, HMB-45 strongly stains the entire lesion in blue nevi.⁴

Desmoplastic melanoma accounts for 1% to 4% of all melanomas. The median age at diagnosis is 62 years and, as in other types of melanoma, men are more commonly affected.⁵ Clinically, desmoplastic melanoma typically presents on the head and neck as a painless indurated plaque, though it can present as a small papule or nodule. Nearly half of desmoplastic melanomas lack obvious pigmentation, which may lead to the misdiagnosis of basal cell carcinoma or a scar. Histologically, desmoplastic melanomas are composed of spindled melanocytes separated by collagen fibers or fibrous stroma (Figure 3). Histology displays variable cytologic atypia and stromal fibrosis. Characteristically there are small islands of lymphocytes and plasma cells within or at the edge of the tumor. The spindle cells stain positive with S-100 and Sry-related HMg-box gene 10, SOX10. Type IV collagen and laminin often are expressed in desmoplastic melanoma. In contrast to many other subtypes of melanoma, HMB-45 and Melan-A usually are negative.⁶

Animal-type melanoma is a rare neoplasm that differs from other subtypes of melanoma both clinically and histologically. Most frequently, animal-type melanoma affects younger adults (median age, 27 years) and arises on the arms and legs, head and neck, or trunk; men and women are affected equally.7 It most commonly presents with a blue or blue-black nodule with a blue-white veil or irregular white areas. Histologically, animal-type melanoma is a predominantly dermal-based melanocytic proliferation with heavily pigmented epithelioid and spindled melanocytes (Figure 4). The pigmentation pattern ranges widely from fine, granular, light brown deposits to coarse dark brown deposits with malignant cells often arranged in fascicles or sheets. Frequently, there is periadnexal and perieccrine spread. Often, there is epidermal hyperplasia above the dermis. As with conventional melanoma, the immunohistochemistry of animal-type melanoma is positive for S-100 protein, HMB-45, SOX10, and Melan-A.⁷

Recurrent nevi typically arise within 6 months of a previously biopsied melanocytic nevus. Most recurrent nevi originate from common banal nevi (most often a compound nevus). Recurrent nevi also may arise from congenital, atypical/dysplastic, and Spitz nevi. Most often they are found on the back of women aged 20 to 30 years.⁸ Clinically, they manifest as a macular area of scar with variegated hyperpigmentation and hypopigmentation as well as linear streaking. They may demonstrate variable diffuse, stippled, and halo pigmentation patterns. Classically, recurrent nevi present with a trizonal histologic pattern. Within the epidermis there is a proliferation of melanocytes along the dermoepidermal junction, which may show varying degrees of atypia and pagetoid migration. The melanocytes often are described as epithelioid with round nuclei and even chromatin (Figure 5). The atypical features should be confined to the epidermis overlying the prior biopsy site. Within the dermis there is dense dermal collagen and fibrosis with vertically oriented blood vessels. Finally, features of the original nevus may be seen at the base of the lesion. Although immunohistochemistry may be helpful in some cases, an appropriate clinical history and comparison to the prior biopsy can be invaluable.⁸

Host tissue reactions resulting in artefactual changes caused by foreign bodies or substances may confound the untrained eye. Monsel solution reaction may be confused for a blue nevus, desmoplastic melanoma, animal-type melanoma, and a residual/recurrent nevus. This confusion could lead to serious diagnostic errors that could cause an unfavorable outcome for the patient. It is critical to know the salient points in the patient's clinical history. Knowledge of the Monsel solution reaction and other exogenous lesions as well as the subsequent unique tissue reaction patterns can aid in facilitating an accurate and prompt pathologic diagnosis.

The Diagnosis: Monsel Solution Reaction

Exogenous substances can cause interesting incongruities in cutaneous biopsies of which pathologists and dermatologists should be cognizant. Exogenous lesions are caused by externally introduced foreign bodies, substances, or materials, such as sterile compressed sponges, aluminum chloride hexahydrate and anhydrous ethyl alcohol, silica, paraffin, and Monsel solution. Monsel solution reaction is a florid fibrohistiocytic proliferation stimulated by the application of Monsel solution. Monsel solution is a ferric subsulfate that often is used to achieve hemostasis after shave biopsies. Hemostasis is thought to result from the ability of ferric ions to denature and agglutinate proteins such as fibrinogen.^1,2 Application of Monsel solution likely causes ferrugination of fibrin, dermal collagen, and striated muscle fibers. Some ferruginated collagen fibers are eliminated through the epidermis as the epidermis regenerates, while some fibers become calcified. Siderophages (iron-containing macrophages) are present in these areas. The ferrugination of collagen fibers becomes less pronounced as the biopsy sites heal and the iron pigment subsequently is absorbed by macrophages. Ferruginated skeletal muscles can act as foreign bodies and may elicit granulomatous reactions.²

It is currently unclear why fibrohistiocytic responses occur in some instances but not others. Iron stains (eg, Perls Prussian blue stain) make interpretation clear, provided the pathologist is familiar with Monsel solution. The primary differential diagnosis of these lesions centers on heavily pigmented melanocytic proliferations. It is critical to review prior biopsy sections or to have definite knowledge of the prior biopsy diagnosis. Histologically, the epidermis may demonstrate nonspecific reactive changes such as hyperkeratosis with foci of irregular acanthosis. The prominent features are present in the dermis where there is a proliferation of spindle- and polyhedral-shaped cells that may show cytologic atypia and occasional mitotic figures. The cells contain refractile brown pigment scattered in the dermis and deposited on collagen fibers (quiz images). Occasional large black or brown encrustations may be identified. Monsel-containing cells may indiscernibly blend with foci of more blatantly fibrohistiocytic differentiation, in which case iron stains are strongly positive (Figure 1). If the clinician uses Monsel solution for hemostasis during the removal of a nevomelanocytic neoplasm, it might be necessary to use melanin stains or immunohistochemistry on the reexcision specimen to distinguish between residual nevomelanocytic and fibrohistiocytic cells.³

Common blue nevus is a benign, typically intradermal melanocytic lesion. It most frequently occurs in young adults and has a predilection for females. Clinically, it can be found anywhere on the body as a single, asymptomatic, well-circumscribed, blue-black, dome-shaped papule measuring less than 1 cm in diameter. Histologically, it is characterized by pigmented, dendritic, spindle-shaped melanocytes that typically are separated by thick collagen bundles (Figure 2). The melanocytes typically have small nuclei with occasional basophilic nucleolus. Melanocytes typically are diffusely positive for melanocytic markers including human melanoma black (HMB) 45, S-100, Melan-A, and microphthalmia transcription factor 1. In contrast to most other benign melanocytic nevi, HMB-45 strongly stains the entire lesion in blue nevi.⁴

Desmoplastic melanoma accounts for 1% to 4% of all melanomas. The median age at diagnosis is 62 years and, as in other types of melanoma, men are more commonly affected.⁵ Clinically, desmoplastic melanoma typically presents on the head and neck as a painless indurated plaque, though it can present as a small papule or nodule. Nearly half of desmoplastic melanomas lack obvious pigmentation, which may lead to the misdiagnosis of basal cell carcinoma or a scar. Histologically, desmoplastic melanomas are composed of spindled melanocytes separated by collagen fibers or fibrous stroma (Figure 3). Histology displays variable cytologic atypia and stromal fibrosis. Characteristically there are small islands of lymphocytes and plasma cells within or at the edge of the tumor. The spindle cells stain positive with S-100 and Sry-related HMg-box gene 10, SOX10. Type IV collagen and laminin often are expressed in desmoplastic melanoma. In contrast to many other subtypes of melanoma, HMB-45 and Melan-A usually are negative.⁶

Animal-type melanoma is a rare neoplasm that differs from other subtypes of melanoma both clinically and histologically. Most frequently, animal-type melanoma affects younger adults (median age, 27 years) and arises on the arms and legs, head and neck, or trunk; men and women are affected equally.7 It most commonly presents with a blue or blue-black nodule with a blue-white veil or irregular white areas. Histologically, animal-type melanoma is a predominantly dermal-based melanocytic proliferation with heavily pigmented epithelioid and spindled melanocytes (Figure 4). The pigmentation pattern ranges widely from fine, granular, light brown deposits to coarse dark brown deposits with malignant cells often arranged in fascicles or sheets. Frequently, there is periadnexal and perieccrine spread. Often, there is epidermal hyperplasia above the dermis. As with conventional melanoma, the immunohistochemistry of animal-type melanoma is positive for S-100 protein, HMB-45, SOX10, and Melan-A.⁷

Recurrent nevi typically arise within 6 months of a previously biopsied melanocytic nevus. Most recurrent nevi originate from common banal nevi (most often a compound nevus). Recurrent nevi also may arise from congenital, atypical/dysplastic, and Spitz nevi. Most often they are found on the back of women aged 20 to 30 years.⁸ Clinically, they manifest as a macular area of scar with variegated hyperpigmentation and hypopigmentation as well as linear streaking. They may demonstrate variable diffuse, stippled, and halo pigmentation patterns. Classically, recurrent nevi present with a trizonal histologic pattern. Within the epidermis there is a proliferation of melanocytes along the dermoepidermal junction, which may show varying degrees of atypia and pagetoid migration. The melanocytes often are described as epithelioid with round nuclei and even chromatin (Figure 5). The atypical features should be confined to the epidermis overlying the prior biopsy site. Within the dermis there is dense dermal collagen and fibrosis with vertically oriented blood vessels. Finally, features of the original nevus may be seen at the base of the lesion. Although immunohistochemistry may be helpful in some cases, an appropriate clinical history and comparison to the prior biopsy can be invaluable.⁸

Host tissue reactions resulting in artefactual changes caused by foreign bodies or substances may confound the untrained eye. Monsel solution reaction may be confused for a blue nevus, desmoplastic melanoma, animal-type melanoma, and a residual/recurrent nevus. This confusion could lead to serious diagnostic errors that could cause an unfavorable outcome for the patient. It is critical to know the salient points in the patient's clinical history. Knowledge of the Monsel solution reaction and other exogenous lesions as well as the subsequent unique tissue reaction patterns can aid in facilitating an accurate and prompt pathologic diagnosis.

Cutaneous angiosarcoma is a rare malignant tumor of vascular endothelial cells that has the propensity to arise in various clinical settings. This tumor predominantly occurs in the head and neck region in elderly patients, but it also has been reported to develop postradiotherapy or in the setting of chronic lymphedema in the extremities.^1-3 In all settings, the diagnosis carries a very poor prognosis with a high likelihood of local recurrence and rapid dissemination. The mortality rate typically is 80% or higher.^2,4-6

Making the correct clinical diagnosis of cutaneous angiosarcoma may be difficult given the variety of patient symptoms and clinical appearances that can be demonstrated on presentation. Lesions can appear as bluish or violaceous plaques, macules, or nodules, and ulceration may be present in some advanced cases.^5,7 Clinical misdiagnosis is common, as cutaneous angiosarcomas may be mistaken for infectious processes, benign vascular malformations, and other cutaneous malignancies.¹ Biopsy often is delayed given the initial benign appearance of the lesions, and this frequently results in aggressive and extensive disease at the time of diagnosis, which is unfortunate given that small tumor size has been shown to be one of the only favorable prognostic indicators in cutaneous angiosarcoma.^1,2,6,8

Microscopically, diagnosis of cutaneous angiosarcoma can present a challenge, as the histology varies between a well-differentiated vascular neoplasm and a considerably anaplastic and poorly differentiated malignancy. On low power, some areas may appear as benign hemangiomas with other areas showing frank sarcomatous features.⁹ As a result, these tumors can be mistaken for a variety of other diseases including melanomas, carcinomas, or other vascular tumors.^6,8,9 Previously, electron microscopy has been utilized on undifferentiated tumors to help distinguish cutaneous angiosarcomas from other potential diagnoses. The atypical tumor cells of cutaneous angiosarcoma display common features of endothelial cells (eg, pinocytotic vesicles, tubulated bodies).⁷ Historically, it has been noted that the histologic findings and tumor grade provide little evidence regarding the aggressiveness of the tumor, and all cutaneous angiosarcoma diagnoses receive a poor prognosis.^6,8

Classically, the histologic findings of cutaneous angiosarcoma include a highly infiltrative neoplasm forming irregular vascular channels that penetrate through the cutaneous soft tissues and frequently extend into the subcutaneous fat. The vascular spaces are lined by hyperchromatic endothelial cells with varying degrees of atypia.^1,2,4,6,7,10 Occasionally, prominent endothelial cells lining a papillary structure within the lumen of the neoformed vessel may also be observed. Currently, immunohistochemical staining for MYC, Ki-67, D2-40, and various other markers complement the histologic findings to aid in the diagnosis of cutaneous angiosarcoma.^11,12 An additional diagnostic clue that has been described in cases of postirradiation cutaneous angiosarcoma shows free-floating or tufted pleomorphic spindle cells within the vascular lumen (Figure). This finding has been described as “fish in the creek.”¹¹ In this study, we aimed to determine the frequency and subsequent diagnostic utility of the fish-in-the-creek finding in cases of cutaneous angiosarcoma.

Methods

A natural language search of our institutional archives over a 20-year period (1997–2017) using the term angiosarcoma was performed. Fifteen cases of cutaneous angiosarcoma were identified. Fifteen additional benign and malignant vascular tumors with cutaneous angiosarcoma in the histologic differential diagnosis were selected from the archives over a similar time frame. The additional lesions included Kaposi sarcoma (n=3), atypical vascular lesion (n=6), atypical hemangioma (n=1), tufted angioma (n=1), epithelioid hemangioma (n=1), epithelioid hemangioendothelioma (n=1), sinusoidal hemangioma (n=1), and angiofibroma (n=1). The pathologists were blinded to the original diagnosis of each case and were instructed to evaluate the histology slides for the sole feature of free-floating intraluminal spindle cells or spindle cells tufting off the endothelium. Epithelial cells lining papillae found within the vessel lumen were not counted as a positive finding, as they do not fit the criteria described for the histologic pattern of fish in the creek. Following microscopic evaluation, the original diagnoses were reassigned to their respective cases to evaluate the diagnostic utility of this feature.

Results

The histologic pattern of fish in the creek was identified in all 15 cases of cutaneous angiosarcoma and was absent in the other 15 malignancies examined in this study. This finding shows the potential for the fish-in-the-creek pattern to be used as an additional diagnostic tool for dermatopathologists.

Comment

Cutaneous angiosarcoma is a rare but aggressive malignancy that proves difficult to diagnose both clinically and histologically as well as to treat effectively.^1,5-8 Our results indicate that fish in the creek may be a useful and salient histologic feature in cutaneous angiosarcoma. It is important to recognize, however, that this finding should not be the sole feature upon which a diagnosis of cutaneous angiosarcoma is made, as it requires corroboration with positivity of MYC and D2-40 as well as a high Ki-67 proliferation index (>20%).^11,12 Finding a fish-in-the-creek pattern should prompt dermatopathologists to consider a diagnosis of cutaneous angiosarcoma in the appropriate clinical and histologic settings.

The chief limitation of this study was the small sample size, with only 15 cases of cutaneous angiosarcoma available in the last 20 years at our institution. The limited sample size did not allow us to make claims on sensitivity and specificity regarding this histologic feature; however, with a larger sample size, the true diagnostic potential could be elucidated. Although the pathologists were blinded to the original diagnoses as they examined it for fish in the creek, it is possible they were able to make the correct diagnosis based on other histopathologic clues and therefore were biased.

Although the fish-in-the-creek pattern is present in cutaneous angiosarcoma, there may be other mimickers to consider. Intraluminal papillary projections lined by endothelial cells may be sectioned in a manner imitating this finding.³ In such a case, these endothelial cells must be differentiated from the free-floating or tufted spindle cells in order to have a positive finding for fish in the creek. There can be confusion if the biopsy cuts through a section of spindled cells, resulting in difficulty differentiating cutaneous angiosarcoma from other spindle tumors such as spindle cell melanoma or spindle cell squamous cell carcinoma.⁶ In such cases, immunohistochemistry may be helpful, as spindle cell melanoma would stain positive for S100 and SOX10 and spindle cell squamous cell carcinoma would stain positive for p63 and cytokeratin.

Various treatment strategies for cutaneous angiosarcoma have been employed, with the majority still resulting in poor outcomes.^2,4-6 The recommended treatment is radical surgical excision of the primary tumor with lymph node clearance if possible. Following excision, the patient should undergo high-dose, wide-field radiotherapy to the region.^5,8 Cutaneous angiosarcomas also have the ability to spread extensively through the dermis and can result in subclinical or clinically obvious widespread disease with multifocal or satellite lesions present. Distant metastases occur most frequently in the cervical lymph nodes and lungs.⁷ In cases where the disease is too extensive for surgery, palliative radiation monotherapy can be used.^5,6

As atypical vascular lesions are considered to be a precursor to cutaneous angiosarcoma, it is important to note that the fish-in-the-creek feature was absent in all 6 of the atypical vascular lesions observed in the study. The differentiation generally is made based on MYC, which is present in cutaneous angiosarcomas and absent in atypical vascular lesions.¹⁰ The feature of fish in the creek may now be an additional clue for dermatopathologists to differentiate between angiosarcomas and other similar-appearing tumors.

Conclusion

Our study aimed to highlight an important histologic feature of cutaneous angiosarcomas that can aid in the diagnosis of this deceptive malignancy. Our findings warrant further study of the fish-in-the-creek histologic pattern in a larger sample size to determine its success as a diagnostic tool for cutaneous angiosarcomas. As noted previously, tumor grade does not impact survival outcome, but small tumor size has been one of the only features found to result in a more favorable prognosis.^1,6,8 Future studies to identify a correlation between the histologic finding of fish in the creek and disease outcome in cutaneous angiosarcoma may be helpful to determine if these histologic findings provide prognostic significance in cases of cutaneous angiosarcoma.

Cutaneous angiosarcoma is a rare malignant tumor of vascular endothelial cells that has the propensity to arise in various clinical settings. This tumor predominantly occurs in the head and neck region in elderly patients, but it also has been reported to develop postradiotherapy or in the setting of chronic lymphedema in the extremities.^1-3 In all settings, the diagnosis carries a very poor prognosis with a high likelihood of local recurrence and rapid dissemination. The mortality rate typically is 80% or higher.^2,4-6

Making the correct clinical diagnosis of cutaneous angiosarcoma may be difficult given the variety of patient symptoms and clinical appearances that can be demonstrated on presentation. Lesions can appear as bluish or violaceous plaques, macules, or nodules, and ulceration may be present in some advanced cases.^5,7 Clinical misdiagnosis is common, as cutaneous angiosarcomas may be mistaken for infectious processes, benign vascular malformations, and other cutaneous malignancies.¹ Biopsy often is delayed given the initial benign appearance of the lesions, and this frequently results in aggressive and extensive disease at the time of diagnosis, which is unfortunate given that small tumor size has been shown to be one of the only favorable prognostic indicators in cutaneous angiosarcoma.^1,2,6,8

Microscopically, diagnosis of cutaneous angiosarcoma can present a challenge, as the histology varies between a well-differentiated vascular neoplasm and a considerably anaplastic and poorly differentiated malignancy. On low power, some areas may appear as benign hemangiomas with other areas showing frank sarcomatous features.⁹ As a result, these tumors can be mistaken for a variety of other diseases including melanomas, carcinomas, or other vascular tumors.^6,8,9 Previously, electron microscopy has been utilized on undifferentiated tumors to help distinguish cutaneous angiosarcomas from other potential diagnoses. The atypical tumor cells of cutaneous angiosarcoma display common features of endothelial cells (eg, pinocytotic vesicles, tubulated bodies).⁷ Historically, it has been noted that the histologic findings and tumor grade provide little evidence regarding the aggressiveness of the tumor, and all cutaneous angiosarcoma diagnoses receive a poor prognosis.^6,8

Classically, the histologic findings of cutaneous angiosarcoma include a highly infiltrative neoplasm forming irregular vascular channels that penetrate through the cutaneous soft tissues and frequently extend into the subcutaneous fat. The vascular spaces are lined by hyperchromatic endothelial cells with varying degrees of atypia.^1,2,4,6,7,10 Occasionally, prominent endothelial cells lining a papillary structure within the lumen of the neoformed vessel may also be observed. Currently, immunohistochemical staining for MYC, Ki-67, D2-40, and various other markers complement the histologic findings to aid in the diagnosis of cutaneous angiosarcoma.^11,12 An additional diagnostic clue that has been described in cases of postirradiation cutaneous angiosarcoma shows free-floating or tufted pleomorphic spindle cells within the vascular lumen (Figure). This finding has been described as “fish in the creek.”¹¹ In this study, we aimed to determine the frequency and subsequent diagnostic utility of the fish-in-the-creek finding in cases of cutaneous angiosarcoma.

Methods

A natural language search of our institutional archives over a 20-year period (1997–2017) using the term angiosarcoma was performed. Fifteen cases of cutaneous angiosarcoma were identified. Fifteen additional benign and malignant vascular tumors with cutaneous angiosarcoma in the histologic differential diagnosis were selected from the archives over a similar time frame. The additional lesions included Kaposi sarcoma (n=3), atypical vascular lesion (n=6), atypical hemangioma (n=1), tufted angioma (n=1), epithelioid hemangioma (n=1), epithelioid hemangioendothelioma (n=1), sinusoidal hemangioma (n=1), and angiofibroma (n=1). The pathologists were blinded to the original diagnosis of each case and were instructed to evaluate the histology slides for the sole feature of free-floating intraluminal spindle cells or spindle cells tufting off the endothelium. Epithelial cells lining papillae found within the vessel lumen were not counted as a positive finding, as they do not fit the criteria described for the histologic pattern of fish in the creek. Following microscopic evaluation, the original diagnoses were reassigned to their respective cases to evaluate the diagnostic utility of this feature.

Results

The histologic pattern of fish in the creek was identified in all 15 cases of cutaneous angiosarcoma and was absent in the other 15 malignancies examined in this study. This finding shows the potential for the fish-in-the-creek pattern to be used as an additional diagnostic tool for dermatopathologists.

Comment

Cutaneous angiosarcoma is a rare but aggressive malignancy that proves difficult to diagnose both clinically and histologically as well as to treat effectively.^1,5-8 Our results indicate that fish in the creek may be a useful and salient histologic feature in cutaneous angiosarcoma. It is important to recognize, however, that this finding should not be the sole feature upon which a diagnosis of cutaneous angiosarcoma is made, as it requires corroboration with positivity of MYC and D2-40 as well as a high Ki-67 proliferation index (>20%).^11,12 Finding a fish-in-the-creek pattern should prompt dermatopathologists to consider a diagnosis of cutaneous angiosarcoma in the appropriate clinical and histologic settings.

The chief limitation of this study was the small sample size, with only 15 cases of cutaneous angiosarcoma available in the last 20 years at our institution. The limited sample size did not allow us to make claims on sensitivity and specificity regarding this histologic feature; however, with a larger sample size, the true diagnostic potential could be elucidated. Although the pathologists were blinded to the original diagnoses as they examined it for fish in the creek, it is possible they were able to make the correct diagnosis based on other histopathologic clues and therefore were biased.

Although the fish-in-the-creek pattern is present in cutaneous angiosarcoma, there may be other mimickers to consider. Intraluminal papillary projections lined by endothelial cells may be sectioned in a manner imitating this finding.³ In such a case, these endothelial cells must be differentiated from the free-floating or tufted spindle cells in order to have a positive finding for fish in the creek. There can be confusion if the biopsy cuts through a section of spindled cells, resulting in difficulty differentiating cutaneous angiosarcoma from other spindle tumors such as spindle cell melanoma or spindle cell squamous cell carcinoma.⁶ In such cases, immunohistochemistry may be helpful, as spindle cell melanoma would stain positive for S100 and SOX10 and spindle cell squamous cell carcinoma would stain positive for p63 and cytokeratin.

Various treatment strategies for cutaneous angiosarcoma have been employed, with the majority still resulting in poor outcomes.^2,4-6 The recommended treatment is radical surgical excision of the primary tumor with lymph node clearance if possible. Following excision, the patient should undergo high-dose, wide-field radiotherapy to the region.^5,8 Cutaneous angiosarcomas also have the ability to spread extensively through the dermis and can result in subclinical or clinically obvious widespread disease with multifocal or satellite lesions present. Distant metastases occur most frequently in the cervical lymph nodes and lungs.⁷ In cases where the disease is too extensive for surgery, palliative radiation monotherapy can be used.^5,6

As atypical vascular lesions are considered to be a precursor to cutaneous angiosarcoma, it is important to note that the fish-in-the-creek feature was absent in all 6 of the atypical vascular lesions observed in the study. The differentiation generally is made based on MYC, which is present in cutaneous angiosarcomas and absent in atypical vascular lesions.¹⁰ The feature of fish in the creek may now be an additional clue for dermatopathologists to differentiate between angiosarcomas and other similar-appearing tumors.

Conclusion

Our study aimed to highlight an important histologic feature of cutaneous angiosarcomas that can aid in the diagnosis of this deceptive malignancy. Our findings warrant further study of the fish-in-the-creek histologic pattern in a larger sample size to determine its success as a diagnostic tool for cutaneous angiosarcomas. As noted previously, tumor grade does not impact survival outcome, but small tumor size has been one of the only features found to result in a more favorable prognosis.^1,6,8 Future studies to identify a correlation between the histologic finding of fish in the creek and disease outcome in cutaneous angiosarcoma may be helpful to determine if these histologic findings provide prognostic significance in cases of cutaneous angiosarcoma.

Cutaneous angiosarcoma is a rare malignant tumor of vascular endothelial cells that has the propensity to arise in various clinical settings. This tumor predominantly occurs in the head and neck region in elderly patients, but it also has been reported to develop postradiotherapy or in the setting of chronic lymphedema in the extremities.^1-3 In all settings, the diagnosis carries a very poor prognosis with a high likelihood of local recurrence and rapid dissemination. The mortality rate typically is 80% or higher.^2,4-6

Making the correct clinical diagnosis of cutaneous angiosarcoma may be difficult given the variety of patient symptoms and clinical appearances that can be demonstrated on presentation. Lesions can appear as bluish or violaceous plaques, macules, or nodules, and ulceration may be present in some advanced cases.^5,7 Clinical misdiagnosis is common, as cutaneous angiosarcomas may be mistaken for infectious processes, benign vascular malformations, and other cutaneous malignancies.¹ Biopsy often is delayed given the initial benign appearance of the lesions, and this frequently results in aggressive and extensive disease at the time of diagnosis, which is unfortunate given that small tumor size has been shown to be one of the only favorable prognostic indicators in cutaneous angiosarcoma.^1,2,6,8

Microscopically, diagnosis of cutaneous angiosarcoma can present a challenge, as the histology varies between a well-differentiated vascular neoplasm and a considerably anaplastic and poorly differentiated malignancy. On low power, some areas may appear as benign hemangiomas with other areas showing frank sarcomatous features.⁹ As a result, these tumors can be mistaken for a variety of other diseases including melanomas, carcinomas, or other vascular tumors.^6,8,9 Previously, electron microscopy has been utilized on undifferentiated tumors to help distinguish cutaneous angiosarcomas from other potential diagnoses. The atypical tumor cells of cutaneous angiosarcoma display common features of endothelial cells (eg, pinocytotic vesicles, tubulated bodies).⁷ Historically, it has been noted that the histologic findings and tumor grade provide little evidence regarding the aggressiveness of the tumor, and all cutaneous angiosarcoma diagnoses receive a poor prognosis.^6,8

Classically, the histologic findings of cutaneous angiosarcoma include a highly infiltrative neoplasm forming irregular vascular channels that penetrate through the cutaneous soft tissues and frequently extend into the subcutaneous fat. The vascular spaces are lined by hyperchromatic endothelial cells with varying degrees of atypia.^1,2,4,6,7,10 Occasionally, prominent endothelial cells lining a papillary structure within the lumen of the neoformed vessel may also be observed. Currently, immunohistochemical staining for MYC, Ki-67, D2-40, and various other markers complement the histologic findings to aid in the diagnosis of cutaneous angiosarcoma.^11,12 An additional diagnostic clue that has been described in cases of postirradiation cutaneous angiosarcoma shows free-floating or tufted pleomorphic spindle cells within the vascular lumen (Figure). This finding has been described as “fish in the creek.”¹¹ In this study, we aimed to determine the frequency and subsequent diagnostic utility of the fish-in-the-creek finding in cases of cutaneous angiosarcoma.

Methods

A natural language search of our institutional archives over a 20-year period (1997–2017) using the term angiosarcoma was performed. Fifteen cases of cutaneous angiosarcoma were identified. Fifteen additional benign and malignant vascular tumors with cutaneous angiosarcoma in the histologic differential diagnosis were selected from the archives over a similar time frame. The additional lesions included Kaposi sarcoma (n=3), atypical vascular lesion (n=6), atypical hemangioma (n=1), tufted angioma (n=1), epithelioid hemangioma (n=1), epithelioid hemangioendothelioma (n=1), sinusoidal hemangioma (n=1), and angiofibroma (n=1). The pathologists were blinded to the original diagnosis of each case and were instructed to evaluate the histology slides for the sole feature of free-floating intraluminal spindle cells or spindle cells tufting off the endothelium. Epithelial cells lining papillae found within the vessel lumen were not counted as a positive finding, as they do not fit the criteria described for the histologic pattern of fish in the creek. Following microscopic evaluation, the original diagnoses were reassigned to their respective cases to evaluate the diagnostic utility of this feature.

Results

The histologic pattern of fish in the creek was identified in all 15 cases of cutaneous angiosarcoma and was absent in the other 15 malignancies examined in this study. This finding shows the potential for the fish-in-the-creek pattern to be used as an additional diagnostic tool for dermatopathologists.

Comment

Cutaneous angiosarcoma is a rare but aggressive malignancy that proves difficult to diagnose both clinically and histologically as well as to treat effectively.^1,5-8 Our results indicate that fish in the creek may be a useful and salient histologic feature in cutaneous angiosarcoma. It is important to recognize, however, that this finding should not be the sole feature upon which a diagnosis of cutaneous angiosarcoma is made, as it requires corroboration with positivity of MYC and D2-40 as well as a high Ki-67 proliferation index (>20%).^11,12 Finding a fish-in-the-creek pattern should prompt dermatopathologists to consider a diagnosis of cutaneous angiosarcoma in the appropriate clinical and histologic settings.

The chief limitation of this study was the small sample size, with only 15 cases of cutaneous angiosarcoma available in the last 20 years at our institution. The limited sample size did not allow us to make claims on sensitivity and specificity regarding this histologic feature; however, with a larger sample size, the true diagnostic potential could be elucidated. Although the pathologists were blinded to the original diagnoses as they examined it for fish in the creek, it is possible they were able to make the correct diagnosis based on other histopathologic clues and therefore were biased.

Although the fish-in-the-creek pattern is present in cutaneous angiosarcoma, there may be other mimickers to consider. Intraluminal papillary projections lined by endothelial cells may be sectioned in a manner imitating this finding.³ In such a case, these endothelial cells must be differentiated from the free-floating or tufted spindle cells in order to have a positive finding for fish in the creek. There can be confusion if the biopsy cuts through a section of spindled cells, resulting in difficulty differentiating cutaneous angiosarcoma from other spindle tumors such as spindle cell melanoma or spindle cell squamous cell carcinoma.⁶ In such cases, immunohistochemistry may be helpful, as spindle cell melanoma would stain positive for S100 and SOX10 and spindle cell squamous cell carcinoma would stain positive for p63 and cytokeratin.

Various treatment strategies for cutaneous angiosarcoma have been employed, with the majority still resulting in poor outcomes.^2,4-6 The recommended treatment is radical surgical excision of the primary tumor with lymph node clearance if possible. Following excision, the patient should undergo high-dose, wide-field radiotherapy to the region.^5,8 Cutaneous angiosarcomas also have the ability to spread extensively through the dermis and can result in subclinical or clinically obvious widespread disease with multifocal or satellite lesions present. Distant metastases occur most frequently in the cervical lymph nodes and lungs.⁷ In cases where the disease is too extensive for surgery, palliative radiation monotherapy can be used.^5,6

As atypical vascular lesions are considered to be a precursor to cutaneous angiosarcoma, it is important to note that the fish-in-the-creek feature was absent in all 6 of the atypical vascular lesions observed in the study. The differentiation generally is made based on MYC, which is present in cutaneous angiosarcomas and absent in atypical vascular lesions.¹⁰ The feature of fish in the creek may now be an additional clue for dermatopathologists to differentiate between angiosarcomas and other similar-appearing tumors.

Conclusion

Our study aimed to highlight an important histologic feature of cutaneous angiosarcomas that can aid in the diagnosis of this deceptive malignancy. Our findings warrant further study of the fish-in-the-creek histologic pattern in a larger sample size to determine its success as a diagnostic tool for cutaneous angiosarcomas. As noted previously, tumor grade does not impact survival outcome, but small tumor size has been one of the only features found to result in a more favorable prognosis.^1,6,8 Future studies to identify a correlation between the histologic finding of fish in the creek and disease outcome in cutaneous angiosarcoma may be helpful to determine if these histologic findings provide prognostic significance in cases of cutaneous angiosarcoma.

The Diagnosis: Dermatofibroma

Dermatofibroma (DF) is a commonly encountered lesion. Although usually a straightforward clinical diagnosis, histopathological diagnosis is sometimes required. Conventional histologic findings of DF are hyperkeratosis, induction of the epidermis with acanthosis, and basal layer hyperpigmentation.^1,2 Within the dermis there usually is proliferation of fibroblasts, histiocytes, and blood vessels that sometimes spares the overlying papillary dermis. Nomenclature of specific variants may be assigned based on the predominant component (eg, nodular subepidermal fibrosis, histiocytoma, sclerosing hemangioma) or histologic findings (eg, fibrocollagenous, sclerotic, cellular, histiocytic, lipidized, angiomatous, aneurysmal, clear cell, monster cell, myxoid, keloidal, palisading, osteoclastic, epithelioid).^3-5 Of the histologic variants, fibrocollagenous is most common, but knowledge of other variants is important for accurate diagnosis, especially to exclude malignancy.

The sclerosing hemangioma variant of DF may pre-sent a diagnostic dilemma. In addition to typical features of DF, pseudovascular spaces, abundant hemosiderin, and reactive-appearing spindled cells are histologically demonstrated. The marked sclerosis and pigment deposition may mimic a blue nevus, and the dilated pseudovascular spaces may be reminiscent of a vascular neoplasm such as angiosarcoma or Kaposi sarcoma. However, the presence of characteristic features such as peripheral collagen trapping and overlying epidermal hyperplasia provide important clues for correct diagnosis. 

Angiosarcomas (Figure 1) are malignant neoplasms with vascular differentiation. Cutaneous angiosarcomas present as purple plaques or nodules on the head and/or neck in elderly individuals as well as in patients with chronic lymphedema or prior radiation exposure.^6-9 They are aggressive neoplasms with high rates of recurrence and metastases. Microscopically, the tumor is composed of anastomosing vascular channels lined by atypical endothelial cells with a multilayered appearance. There is frequent red blood cell extravasation, and substantial hemosiderin deposition may be noted in long-standing lesions. Neoplastic cells are positive for vascular markers (CD34, CD31, ETS-related gene transcription factor). Notably, cases associated with radiation exposure and chronic lymphedema are positive for MYC.¹⁰

Blue nevi (Figure 2) are benign melanocytic tumors that occur most frequently in children but may pre-sent in any age group. Clinical presentation is a blue to black, slightly raised papule that may be found on any site of the body. Biopsy typically shows a wedge-shaped infiltrate of spindled melanocytes with elongated dendritic processes in a sclerotic collagenous stroma. There frequently is a striking population of heavily pigmented melanophages. The melanocytes are positive for melanoma antigen recognized by T cells (MART-1)/melan-A, S-100, and transcription factor SOX-10. In contrast to other benign nevi, human melanoma black-45 will be positive in the dermal component.

Dermatofibrosarcoma protuberans (Figure 3) is a dermal-based tumor of intermediate malignant potential with a high rate of local recurrence and potential for sarcomatous transformation. Dermatofibrosarcoma protuberans most commonly presents in young adults as firm, pink to brown plaques and can occur on any site of the body. Histologically, they show a dermal proliferation of spindled cells that infiltrate in a storiform fashion into the subcutaneous adipose tissue,¹¹ which imparts a honeycomb or Swiss cheese pattern. The tumor characteristically demonstrates positive staining for CD34. Loss of CD34 staining, increased mitoses, nuclear atypia, and fascicular growth are features suggestive of sarcomatous transformation.^11,12 Dermatofibrosarcoma protuberans is associated with chromosomal abnormalities of chromosomes 17 and 22, resulting in COL1A1 (collagen type 1 alpha 1 chain) and PDGF-β (platelet-derived growth factor subunit B) gene fusion.¹³

Sclerotic fibromas (also known as storiform collagenomas)(Figure 4) may represent regressed DFs and are frequently associated with prior trauma to the affected area.^14,15 They usually appear as flesh-colored papules or nodules on the face and trunk. The presence of multiple sclerotic fibromas is associated with Cowden syndrome.^16,17 Histologically, the lesions present as well-demarcated, nonencapsulated, dermal nodules composed of a storiform or whorled arrangement of collagen with spindled fibroblasts. The sclerotic collagen bundles often are separated by small clefts imparting a plywoodlike pattern.¹⁶

The differential diagnosis for DF expands once atypical clinical and histopathological findings are present. In this case, the nodule was much larger and darker than the usual appearance of DF (3-10 mm).^2,4 Given the lesion's nodularity, the clinical dimple sign on lateral compression could not be seen. On biopsy, the predominance of blood vessels and sclerosis further complicated the diagnostic picture. In unusual cases such as this one, correlation of clinical history, histology, and immunophenotype is ever important.

The Diagnosis: Dermatofibroma

Dermatofibroma (DF) is a commonly encountered lesion. Although usually a straightforward clinical diagnosis, histopathological diagnosis is sometimes required. Conventional histologic findings of DF are hyperkeratosis, induction of the epidermis with acanthosis, and basal layer hyperpigmentation.^1,2 Within the dermis there usually is proliferation of fibroblasts, histiocytes, and blood vessels that sometimes spares the overlying papillary dermis. Nomenclature of specific variants may be assigned based on the predominant component (eg, nodular subepidermal fibrosis, histiocytoma, sclerosing hemangioma) or histologic findings (eg, fibrocollagenous, sclerotic, cellular, histiocytic, lipidized, angiomatous, aneurysmal, clear cell, monster cell, myxoid, keloidal, palisading, osteoclastic, epithelioid).^3-5 Of the histologic variants, fibrocollagenous is most common, but knowledge of other variants is important for accurate diagnosis, especially to exclude malignancy.

The sclerosing hemangioma variant of DF may pre-sent a diagnostic dilemma. In addition to typical features of DF, pseudovascular spaces, abundant hemosiderin, and reactive-appearing spindled cells are histologically demonstrated. The marked sclerosis and pigment deposition may mimic a blue nevus, and the dilated pseudovascular spaces may be reminiscent of a vascular neoplasm such as angiosarcoma or Kaposi sarcoma. However, the presence of characteristic features such as peripheral collagen trapping and overlying epidermal hyperplasia provide important clues for correct diagnosis. 

Angiosarcomas (Figure 1) are malignant neoplasms with vascular differentiation. Cutaneous angiosarcomas present as purple plaques or nodules on the head and/or neck in elderly individuals as well as in patients with chronic lymphedema or prior radiation exposure.^6-9 They are aggressive neoplasms with high rates of recurrence and metastases. Microscopically, the tumor is composed of anastomosing vascular channels lined by atypical endothelial cells with a multilayered appearance. There is frequent red blood cell extravasation, and substantial hemosiderin deposition may be noted in long-standing lesions. Neoplastic cells are positive for vascular markers (CD34, CD31, ETS-related gene transcription factor). Notably, cases associated with radiation exposure and chronic lymphedema are positive for MYC.¹⁰

Blue nevi (Figure 2) are benign melanocytic tumors that occur most frequently in children but may pre-sent in any age group. Clinical presentation is a blue to black, slightly raised papule that may be found on any site of the body. Biopsy typically shows a wedge-shaped infiltrate of spindled melanocytes with elongated dendritic processes in a sclerotic collagenous stroma. There frequently is a striking population of heavily pigmented melanophages. The melanocytes are positive for melanoma antigen recognized by T cells (MART-1)/melan-A, S-100, and transcription factor SOX-10. In contrast to other benign nevi, human melanoma black-45 will be positive in the dermal component.

Dermatofibrosarcoma protuberans (Figure 3) is a dermal-based tumor of intermediate malignant potential with a high rate of local recurrence and potential for sarcomatous transformation. Dermatofibrosarcoma protuberans most commonly presents in young adults as firm, pink to brown plaques and can occur on any site of the body. Histologically, they show a dermal proliferation of spindled cells that infiltrate in a storiform fashion into the subcutaneous adipose tissue,¹¹ which imparts a honeycomb or Swiss cheese pattern. The tumor characteristically demonstrates positive staining for CD34. Loss of CD34 staining, increased mitoses, nuclear atypia, and fascicular growth are features suggestive of sarcomatous transformation.^11,12 Dermatofibrosarcoma protuberans is associated with chromosomal abnormalities of chromosomes 17 and 22, resulting in COL1A1 (collagen type 1 alpha 1 chain) and PDGF-β (platelet-derived growth factor subunit B) gene fusion.¹³

Sclerotic fibromas (also known as storiform collagenomas)(Figure 4) may represent regressed DFs and are frequently associated with prior trauma to the affected area.^14,15 They usually appear as flesh-colored papules or nodules on the face and trunk. The presence of multiple sclerotic fibromas is associated with Cowden syndrome.^16,17 Histologically, the lesions present as well-demarcated, nonencapsulated, dermal nodules composed of a storiform or whorled arrangement of collagen with spindled fibroblasts. The sclerotic collagen bundles often are separated by small clefts imparting a plywoodlike pattern.¹⁶

The differential diagnosis for DF expands once atypical clinical and histopathological findings are present. In this case, the nodule was much larger and darker than the usual appearance of DF (3-10 mm).^2,4 Given the lesion's nodularity, the clinical dimple sign on lateral compression could not be seen. On biopsy, the predominance of blood vessels and sclerosis further complicated the diagnostic picture. In unusual cases such as this one, correlation of clinical history, histology, and immunophenotype is ever important.

The Diagnosis: Dermatofibroma

Dermatofibroma (DF) is a commonly encountered lesion. Although usually a straightforward clinical diagnosis, histopathological diagnosis is sometimes required. Conventional histologic findings of DF are hyperkeratosis, induction of the epidermis with acanthosis, and basal layer hyperpigmentation.^1,2 Within the dermis there usually is proliferation of fibroblasts, histiocytes, and blood vessels that sometimes spares the overlying papillary dermis. Nomenclature of specific variants may be assigned based on the predominant component (eg, nodular subepidermal fibrosis, histiocytoma, sclerosing hemangioma) or histologic findings (eg, fibrocollagenous, sclerotic, cellular, histiocytic, lipidized, angiomatous, aneurysmal, clear cell, monster cell, myxoid, keloidal, palisading, osteoclastic, epithelioid).^3-5 Of the histologic variants, fibrocollagenous is most common, but knowledge of other variants is important for accurate diagnosis, especially to exclude malignancy.

The sclerosing hemangioma variant of DF may pre-sent a diagnostic dilemma. In addition to typical features of DF, pseudovascular spaces, abundant hemosiderin, and reactive-appearing spindled cells are histologically demonstrated. The marked sclerosis and pigment deposition may mimic a blue nevus, and the dilated pseudovascular spaces may be reminiscent of a vascular neoplasm such as angiosarcoma or Kaposi sarcoma. However, the presence of characteristic features such as peripheral collagen trapping and overlying epidermal hyperplasia provide important clues for correct diagnosis. 

Angiosarcomas (Figure 1) are malignant neoplasms with vascular differentiation. Cutaneous angiosarcomas present as purple plaques or nodules on the head and/or neck in elderly individuals as well as in patients with chronic lymphedema or prior radiation exposure.^6-9 They are aggressive neoplasms with high rates of recurrence and metastases. Microscopically, the tumor is composed of anastomosing vascular channels lined by atypical endothelial cells with a multilayered appearance. There is frequent red blood cell extravasation, and substantial hemosiderin deposition may be noted in long-standing lesions. Neoplastic cells are positive for vascular markers (CD34, CD31, ETS-related gene transcription factor). Notably, cases associated with radiation exposure and chronic lymphedema are positive for MYC.¹⁰

Blue nevi (Figure 2) are benign melanocytic tumors that occur most frequently in children but may pre-sent in any age group. Clinical presentation is a blue to black, slightly raised papule that may be found on any site of the body. Biopsy typically shows a wedge-shaped infiltrate of spindled melanocytes with elongated dendritic processes in a sclerotic collagenous stroma. There frequently is a striking population of heavily pigmented melanophages. The melanocytes are positive for melanoma antigen recognized by T cells (MART-1)/melan-A, S-100, and transcription factor SOX-10. In contrast to other benign nevi, human melanoma black-45 will be positive in the dermal component.

Dermatofibrosarcoma protuberans (Figure 3) is a dermal-based tumor of intermediate malignant potential with a high rate of local recurrence and potential for sarcomatous transformation. Dermatofibrosarcoma protuberans most commonly presents in young adults as firm, pink to brown plaques and can occur on any site of the body. Histologically, they show a dermal proliferation of spindled cells that infiltrate in a storiform fashion into the subcutaneous adipose tissue,¹¹ which imparts a honeycomb or Swiss cheese pattern. The tumor characteristically demonstrates positive staining for CD34. Loss of CD34 staining, increased mitoses, nuclear atypia, and fascicular growth are features suggestive of sarcomatous transformation.^11,12 Dermatofibrosarcoma protuberans is associated with chromosomal abnormalities of chromosomes 17 and 22, resulting in COL1A1 (collagen type 1 alpha 1 chain) and PDGF-β (platelet-derived growth factor subunit B) gene fusion.¹³

Sclerotic fibromas (also known as storiform collagenomas)(Figure 4) may represent regressed DFs and are frequently associated with prior trauma to the affected area.^14,15 They usually appear as flesh-colored papules or nodules on the face and trunk. The presence of multiple sclerotic fibromas is associated with Cowden syndrome.^16,17 Histologically, the lesions present as well-demarcated, nonencapsulated, dermal nodules composed of a storiform or whorled arrangement of collagen with spindled fibroblasts. The sclerotic collagen bundles often are separated by small clefts imparting a plywoodlike pattern.¹⁶

The differential diagnosis for DF expands once atypical clinical and histopathological findings are present. In this case, the nodule was much larger and darker than the usual appearance of DF (3-10 mm).^2,4 Given the lesion's nodularity, the clinical dimple sign on lateral compression could not be seen. On biopsy, the predominance of blood vessels and sclerosis further complicated the diagnostic picture. In unusual cases such as this one, correlation of clinical history, histology, and immunophenotype is ever important.

Metastatic Clear Cell Renal Cell Carcinoma

The differential diagnosis of cutaneous neoplasms with clear cells is broad. Clear cell features can be seen in primary tumors arising from the epidermis and cutaneous adnexa as well as in mesenchymal and melanocytic neoplasms. Furthermore, metastatic disease should be considered in the histologic differential diagnosis, as many visceral malignancies have clear cell features. This patient was subsequently found to have a large renal mass with metastasis to the lungs, spleen, and bone. The histologic findings support the diagnosis of metastatic clear cell renal cell carcinoma (RCC) to the skin.

Approximately 30% of patients with clear cell RCC present with metastatic disease with approximately 8% of those involving the skin.^1,2 Cutaneous RCC metastases show a predilection for the head, especially the scalp. The clinical presentation is variable, but there often is a history of a rapidly growing brown, black, or purple nodule or plaque. A thorough review of the patient's history should be conducted if metastatic RCC is in the differential diagnosis, as it has been reported to occur up to 20 years after initial diagnosis.³

Histologically, clear cell RCC (quiz image) is composed of nests of tumor cells with clear cytoplasm and centrally located nuclei with prominent nucleoli. The clear cell features result from abundant cytoplasmic glycogen and lipid but may not be present in every case. One of the most important histologic features is the presence of delicate branching blood vessels (Figure 1). Numerous extravasated red blood cells also may be present. Positive immunohistochemical staining for PAX8, CD10, and RCC antigens support the diagnosis.⁴

Balloon cell nevi (Figure 2) most commonly occur on the head and neck in adolescents and young adults but clinically are indistinguishable from other banal nevi. The nevus cells are large with foamy to finely vacuolated cytoplasm and lack atypia. The clear cell change is the result of melanosome degeneration and may be extensive. The presence of melanin pigment, nests of typical nevus cells, and positive staining with MART-1 can help distinguish the tumor from xanthomas and RCC.⁵

Clear cell hidradenoma (Figure 3) is a well-circumscribed tumor of sweat gland origin that arises in the dermis. The architecture usually is solid, cystic, or a combination of both. The cytology is classically bland with poroid, squamoid, or clear cell morphology. Clear cells that are positive on periodic acid-Schiff staining predominate in up to one-third of cases. Carcinoembryonic antigen and epithelial membrane antigen can be used to highlight the eosinophilic cuticles of ducts within solid areas.⁶

Sebaceous carcinoma (Figure 4) most frequently arises in a periorbital distribution, although extraocular lesions are known to occur. Histologically, there is a proliferation of both mature sebocytes and basaloid cells in the dermis, occasionally involving the epidermis. The mature sebocytes demonstrate clear cell features with foamy to vacuolated cytoplasm and large nuclei with scalloped borders. The clear cells may vary greatly in number and often are sparse in poorly differentiated tumors in which pleomorphic basaloid cells may predominate. The basaloid cells may resemble those of squamous or basal cell carcinoma, leading to a diagnostic dilemma in some cases. Special staining with Sudan black B and oil red O highlights the cytoplasmic lipid but must be performed on frozen section specimens. Although not entirely specific, immunohistochemical expression of epithelial membrane antigen, androgen receptor, and membranous vesicular adipophilin staining in sebaceous carcinoma can assist in the diagnosis.⁷

Cutaneous xanthomas (Figure 5) may arise in patients of any age and represent deposition of lipid-laden macrophages. Classification often is dependent on the clinical presentation; however, some subtypes demonstrate unique morphologic features (eg, verruciform xanthomas). Xanthomas classically arise in association with elevated serum lipids, but they also may occur in normolipemic patients. Individuals with Erdheim-Chester disease have an increased propensity to develop xanthelasma. Similarly, plane xanthomas have been associated with monoclonal gammopathy. Histologically, xanthomas are characterized by sheets of foamy macrophages within the dermis and subcutis. Positive immunohistochemical staining for CD68 highlighting the histiocytic nature of the cells and the absence of a delicate vascular network aid in the differentiation from RCC.

Metastatic Clear Cell Renal Cell Carcinoma

The differential diagnosis of cutaneous neoplasms with clear cells is broad. Clear cell features can be seen in primary tumors arising from the epidermis and cutaneous adnexa as well as in mesenchymal and melanocytic neoplasms. Furthermore, metastatic disease should be considered in the histologic differential diagnosis, as many visceral malignancies have clear cell features. This patient was subsequently found to have a large renal mass with metastasis to the lungs, spleen, and bone. The histologic findings support the diagnosis of metastatic clear cell renal cell carcinoma (RCC) to the skin.

Approximately 30% of patients with clear cell RCC present with metastatic disease with approximately 8% of those involving the skin.^1,2 Cutaneous RCC metastases show a predilection for the head, especially the scalp. The clinical presentation is variable, but there often is a history of a rapidly growing brown, black, or purple nodule or plaque. A thorough review of the patient's history should be conducted if metastatic RCC is in the differential diagnosis, as it has been reported to occur up to 20 years after initial diagnosis.³

Histologically, clear cell RCC (quiz image) is composed of nests of tumor cells with clear cytoplasm and centrally located nuclei with prominent nucleoli. The clear cell features result from abundant cytoplasmic glycogen and lipid but may not be present in every case. One of the most important histologic features is the presence of delicate branching blood vessels (Figure 1). Numerous extravasated red blood cells also may be present. Positive immunohistochemical staining for PAX8, CD10, and RCC antigens support the diagnosis.⁴

Balloon cell nevi (Figure 2) most commonly occur on the head and neck in adolescents and young adults but clinically are indistinguishable from other banal nevi. The nevus cells are large with foamy to finely vacuolated cytoplasm and lack atypia. The clear cell change is the result of melanosome degeneration and may be extensive. The presence of melanin pigment, nests of typical nevus cells, and positive staining with MART-1 can help distinguish the tumor from xanthomas and RCC.⁵

Clear cell hidradenoma (Figure 3) is a well-circumscribed tumor of sweat gland origin that arises in the dermis. The architecture usually is solid, cystic, or a combination of both. The cytology is classically bland with poroid, squamoid, or clear cell morphology. Clear cells that are positive on periodic acid-Schiff staining predominate in up to one-third of cases. Carcinoembryonic antigen and epithelial membrane antigen can be used to highlight the eosinophilic cuticles of ducts within solid areas.⁶

Sebaceous carcinoma (Figure 4) most frequently arises in a periorbital distribution, although extraocular lesions are known to occur. Histologically, there is a proliferation of both mature sebocytes and basaloid cells in the dermis, occasionally involving the epidermis. The mature sebocytes demonstrate clear cell features with foamy to vacuolated cytoplasm and large nuclei with scalloped borders. The clear cells may vary greatly in number and often are sparse in poorly differentiated tumors in which pleomorphic basaloid cells may predominate. The basaloid cells may resemble those of squamous or basal cell carcinoma, leading to a diagnostic dilemma in some cases. Special staining with Sudan black B and oil red O highlights the cytoplasmic lipid but must be performed on frozen section specimens. Although not entirely specific, immunohistochemical expression of epithelial membrane antigen, androgen receptor, and membranous vesicular adipophilin staining in sebaceous carcinoma can assist in the diagnosis.⁷

Cutaneous xanthomas (Figure 5) may arise in patients of any age and represent deposition of lipid-laden macrophages. Classification often is dependent on the clinical presentation; however, some subtypes demonstrate unique morphologic features (eg, verruciform xanthomas). Xanthomas classically arise in association with elevated serum lipids, but they also may occur in normolipemic patients. Individuals with Erdheim-Chester disease have an increased propensity to develop xanthelasma. Similarly, plane xanthomas have been associated with monoclonal gammopathy. Histologically, xanthomas are characterized by sheets of foamy macrophages within the dermis and subcutis. Positive immunohistochemical staining for CD68 highlighting the histiocytic nature of the cells and the absence of a delicate vascular network aid in the differentiation from RCC.

Metastatic Clear Cell Renal Cell Carcinoma

The differential diagnosis of cutaneous neoplasms with clear cells is broad. Clear cell features can be seen in primary tumors arising from the epidermis and cutaneous adnexa as well as in mesenchymal and melanocytic neoplasms. Furthermore, metastatic disease should be considered in the histologic differential diagnosis, as many visceral malignancies have clear cell features. This patient was subsequently found to have a large renal mass with metastasis to the lungs, spleen, and bone. The histologic findings support the diagnosis of metastatic clear cell renal cell carcinoma (RCC) to the skin.

Approximately 30% of patients with clear cell RCC present with metastatic disease with approximately 8% of those involving the skin.^1,2 Cutaneous RCC metastases show a predilection for the head, especially the scalp. The clinical presentation is variable, but there often is a history of a rapidly growing brown, black, or purple nodule or plaque. A thorough review of the patient's history should be conducted if metastatic RCC is in the differential diagnosis, as it has been reported to occur up to 20 years after initial diagnosis.³

Histologically, clear cell RCC (quiz image) is composed of nests of tumor cells with clear cytoplasm and centrally located nuclei with prominent nucleoli. The clear cell features result from abundant cytoplasmic glycogen and lipid but may not be present in every case. One of the most important histologic features is the presence of delicate branching blood vessels (Figure 1). Numerous extravasated red blood cells also may be present. Positive immunohistochemical staining for PAX8, CD10, and RCC antigens support the diagnosis.⁴

Balloon cell nevi (Figure 2) most commonly occur on the head and neck in adolescents and young adults but clinically are indistinguishable from other banal nevi. The nevus cells are large with foamy to finely vacuolated cytoplasm and lack atypia. The clear cell change is the result of melanosome degeneration and may be extensive. The presence of melanin pigment, nests of typical nevus cells, and positive staining with MART-1 can help distinguish the tumor from xanthomas and RCC.⁵

Clear cell hidradenoma (Figure 3) is a well-circumscribed tumor of sweat gland origin that arises in the dermis. The architecture usually is solid, cystic, or a combination of both. The cytology is classically bland with poroid, squamoid, or clear cell morphology. Clear cells that are positive on periodic acid-Schiff staining predominate in up to one-third of cases. Carcinoembryonic antigen and epithelial membrane antigen can be used to highlight the eosinophilic cuticles of ducts within solid areas.⁶

Sebaceous carcinoma (Figure 4) most frequently arises in a periorbital distribution, although extraocular lesions are known to occur. Histologically, there is a proliferation of both mature sebocytes and basaloid cells in the dermis, occasionally involving the epidermis. The mature sebocytes demonstrate clear cell features with foamy to vacuolated cytoplasm and large nuclei with scalloped borders. The clear cells may vary greatly in number and often are sparse in poorly differentiated tumors in which pleomorphic basaloid cells may predominate. The basaloid cells may resemble those of squamous or basal cell carcinoma, leading to a diagnostic dilemma in some cases. Special staining with Sudan black B and oil red O highlights the cytoplasmic lipid but must be performed on frozen section specimens. Although not entirely specific, immunohistochemical expression of epithelial membrane antigen, androgen receptor, and membranous vesicular adipophilin staining in sebaceous carcinoma can assist in the diagnosis.⁷

Cutaneous xanthomas (Figure 5) may arise in patients of any age and represent deposition of lipid-laden macrophages. Classification often is dependent on the clinical presentation; however, some subtypes demonstrate unique morphologic features (eg, verruciform xanthomas). Xanthomas classically arise in association with elevated serum lipids, but they also may occur in normolipemic patients. Individuals with Erdheim-Chester disease have an increased propensity to develop xanthelasma. Similarly, plane xanthomas have been associated with monoclonal gammopathy. Histologically, xanthomas are characterized by sheets of foamy macrophages within the dermis and subcutis. Positive immunohistochemical staining for CD68 highlighting the histiocytic nature of the cells and the absence of a delicate vascular network aid in the differentiation from RCC.