Ryan Yu, MD

Syringoid eccrine carcinoma is a rare malignant adnexal tumor with eccrine differentiation that histologically resembles a syringoma.¹ Originally described as eccrine epithelioma by Freeman and Winklemann² in 1969, syringoid eccrine carcinoma has been reported in the literature as eccrine carcinoma, eccrine syringomatous carcinoma, and sclerosing sweat duct carcinoma.³ Clinically, syringoid eccrine carcinoma most 
commonly presents as a tender plaque or nodule on the scalp, and histologic examination generally reveals a dermal-based lesion that rarely shows epidermal connection. It demonstrates 
syringomalike tadpole morphology (epithelial strands 
with lumen formation) composed of basaloid epithelium with uniform hyperchromatic nuclei 
(Figure 1). There usually is an infiltrative growth pattern to the subcutis (Figure 2 [left]) or skeletal muscle as well as remarkable perineural invasion 
(Figure 2 [right]). Mitotic activity is minimal to absent. The tumor cells of syringoid eccrine 
carcinoma typically show positive immuno-staining for high- and low-molecular-weight cytokeratin, while the lumina are highlighted 
by epithelial membrane antigen and carcinoembryonic antigen.⁴ However, immunohistochemistry 
often is not contributory in diagnosing primary eccrine carcinomas.

Figure 1. Dermal infiltrate with tadpole morphology (arrow) characteristic of syringoid eccrine carcinoma (left)(H&E, original magnification ×40). High-power view shows an epithelial infiltrate and tadpole morphology (arrow)(right)(H&E, original magnification ×400).

Figure 2. Syringoid eccrine carcinoma extending to the junction of the reticular dermis and subcutaneous fat (left) (H&E, original magnification ×100). Nerve with adjacent and invasive basaloid nests of syringoid carcinoma (right)(H&E, original magnification ×100). The tumor consists of monomorphic cells with oval hyperchromatic nuclei.

The differential diagnosis of syringoid eccrine carcinoma includes cutaneous adenoid cystic carcinoma, metastatic adenocarcinoma, sclerosing basal cell carcinoma, and syringoma. Cutaneous adenoid cystic carcinoma is a rare, slow-growing, 
flesh-colored tumor that consists of lobules, islands, and cords of basaloid cells with prominent cystic cribriforming (Figure 3). The tumor cells typically are small, cuboidal, and monomorphic. Metastatic adenoid cystic carcinoma, such as from a primary tumor of the salivary glands or breasts, must be excluded before rendering a diagnosis of primary cutaneous disease.

Figure 3. Striking cribriform architecture of cutaneous adenoid cystic carcinoma (H&E, original magnification ×40). The tumor is well circumscribed and consists of multiple cystic spaces lined by flattened to cuboidal basaloid epithelium.

Metastatic adenocarcinoma of the skin usually presents in patients with a clinical history of preexisting disease. The breasts, colon, stomach, and ovaries are common origins of metastases. The histopathologic and immunohistochemical findings depend on the particular site of origin of the metastasis. Compared with primary eccrine carcinomas, metastatic adenocarcinomas of the skin generally are high-grade lesions with prominent atypia, mitosis, and necrosis (Figure 4).

Figure 4. Metastatic adenocarcinoma of the skin with dermal infiltrating glands (H&E, original magnification ×100). The nuclei are highly atypical. The tumor cells are cytokeratin 7 positive, cytokeratin 20 negative, estrogen-receptor positive, and gross cystic disease fluid protein positive, which is consistent with metastasis from a primary carcinoma of the breast (not shown).

Sclerosing basal cell carcinoma shows basaloid tumor cells with deep infiltration. Unlike syringoid eccrine carcinoma, basal cell carcinoma is an epidermal tumor that does not have true lumen formation. Furthermore, other variants of basal cell carcinoma, including nodular, micronodular, or superficial multicentric tumors, often coexist with the sclerosing variant in the same lesion and constitute a useful diagnostic clue (Figure 5). Staining for epithelial membrane antigen may be useful in identifying the absence of lumen formation, and Ber-EP4 highlights the epidermal origin of the lesion.⁵

Figure 5. Deeply invasive tumor with multiple architectures (sclerosing and micronodular) in a case of sclerosing basal cell carcinoma (H&E, original magnification ×40). Basaloid nests without true lumen formation invade subcutaneous adipose tissue.

Syringomas most commonly present as multiple small flesh-colored papules on the eyelids. On histology, syringomas present as small superficial dermal lesions composed of small ducts that may form tadpolelike structures in a fibrotic stroma (Figure 6). The ducts are lined by benign cuboidal cells. In contrast to syringoid eccrine carcinomas, syringomas usually present as multiple lesions that are microscopically superficial without perineural involvement.

Figure 6. Syringoma is composed of dilated ducts in a fibrotic stroma (H&E, original magnification ×40). Careful microscopic examination would reveal no perineural or deep subcutaneous tumor involvement.

Syringoid eccrine carcinoma is a rare malignant adnexal tumor with eccrine differentiation that histologically resembles a syringoma.¹ Originally described as eccrine epithelioma by Freeman and Winklemann² in 1969, syringoid eccrine carcinoma has been reported in the literature as eccrine carcinoma, eccrine syringomatous carcinoma, and sclerosing sweat duct carcinoma.³ Clinically, syringoid eccrine carcinoma most 
commonly presents as a tender plaque or nodule on the scalp, and histologic examination generally reveals a dermal-based lesion that rarely shows epidermal connection. It demonstrates 
syringomalike tadpole morphology (epithelial strands 
with lumen formation) composed of basaloid epithelium with uniform hyperchromatic nuclei 
(Figure 1). There usually is an infiltrative growth pattern to the subcutis (Figure 2 [left]) or skeletal muscle as well as remarkable perineural invasion 
(Figure 2 [right]). Mitotic activity is minimal to absent. The tumor cells of syringoid eccrine 
carcinoma typically show positive immuno-staining for high- and low-molecular-weight cytokeratin, while the lumina are highlighted 
by epithelial membrane antigen and carcinoembryonic antigen.⁴ However, immunohistochemistry 
often is not contributory in diagnosing primary eccrine carcinomas.

Figure 1. Dermal infiltrate with tadpole morphology (arrow) characteristic of syringoid eccrine carcinoma (left)(H&E, original magnification ×40). High-power view shows an epithelial infiltrate and tadpole morphology (arrow)(right)(H&E, original magnification ×400).

Figure 2. Syringoid eccrine carcinoma extending to the junction of the reticular dermis and subcutaneous fat (left) (H&E, original magnification ×100). Nerve with adjacent and invasive basaloid nests of syringoid carcinoma (right)(H&E, original magnification ×100). The tumor consists of monomorphic cells with oval hyperchromatic nuclei.

The differential diagnosis of syringoid eccrine carcinoma includes cutaneous adenoid cystic carcinoma, metastatic adenocarcinoma, sclerosing basal cell carcinoma, and syringoma. Cutaneous adenoid cystic carcinoma is a rare, slow-growing, 
flesh-colored tumor that consists of lobules, islands, and cords of basaloid cells with prominent cystic cribriforming (Figure 3). The tumor cells typically are small, cuboidal, and monomorphic. Metastatic adenoid cystic carcinoma, such as from a primary tumor of the salivary glands or breasts, must be excluded before rendering a diagnosis of primary cutaneous disease.

Figure 3. Striking cribriform architecture of cutaneous adenoid cystic carcinoma (H&E, original magnification ×40). The tumor is well circumscribed and consists of multiple cystic spaces lined by flattened to cuboidal basaloid epithelium.

Metastatic adenocarcinoma of the skin usually presents in patients with a clinical history of preexisting disease. The breasts, colon, stomach, and ovaries are common origins of metastases. The histopathologic and immunohistochemical findings depend on the particular site of origin of the metastasis. Compared with primary eccrine carcinomas, metastatic adenocarcinomas of the skin generally are high-grade lesions with prominent atypia, mitosis, and necrosis (Figure 4).

Figure 4. Metastatic adenocarcinoma of the skin with dermal infiltrating glands (H&E, original magnification ×100). The nuclei are highly atypical. The tumor cells are cytokeratin 7 positive, cytokeratin 20 negative, estrogen-receptor positive, and gross cystic disease fluid protein positive, which is consistent with metastasis from a primary carcinoma of the breast (not shown).

Sclerosing basal cell carcinoma shows basaloid tumor cells with deep infiltration. Unlike syringoid eccrine carcinoma, basal cell carcinoma is an epidermal tumor that does not have true lumen formation. Furthermore, other variants of basal cell carcinoma, including nodular, micronodular, or superficial multicentric tumors, often coexist with the sclerosing variant in the same lesion and constitute a useful diagnostic clue (Figure 5). Staining for epithelial membrane antigen may be useful in identifying the absence of lumen formation, and Ber-EP4 highlights the epidermal origin of the lesion.⁵

Figure 5. Deeply invasive tumor with multiple architectures (sclerosing and micronodular) in a case of sclerosing basal cell carcinoma (H&E, original magnification ×40). Basaloid nests without true lumen formation invade subcutaneous adipose tissue.

Syringomas most commonly present as multiple small flesh-colored papules on the eyelids. On histology, syringomas present as small superficial dermal lesions composed of small ducts that may form tadpolelike structures in a fibrotic stroma (Figure 6). The ducts are lined by benign cuboidal cells. In contrast to syringoid eccrine carcinomas, syringomas usually present as multiple lesions that are microscopically superficial without perineural involvement.

Figure 6. Syringoma is composed of dilated ducts in a fibrotic stroma (H&E, original magnification ×40). Careful microscopic examination would reveal no perineural or deep subcutaneous tumor involvement.

Syringoid eccrine carcinoma is a rare malignant adnexal tumor with eccrine differentiation that histologically resembles a syringoma.¹ Originally described as eccrine epithelioma by Freeman and Winklemann² in 1969, syringoid eccrine carcinoma has been reported in the literature as eccrine carcinoma, eccrine syringomatous carcinoma, and sclerosing sweat duct carcinoma.³ Clinically, syringoid eccrine carcinoma most 
commonly presents as a tender plaque or nodule on the scalp, and histologic examination generally reveals a dermal-based lesion that rarely shows epidermal connection. It demonstrates 
syringomalike tadpole morphology (epithelial strands 
with lumen formation) composed of basaloid epithelium with uniform hyperchromatic nuclei 
(Figure 1). There usually is an infiltrative growth pattern to the subcutis (Figure 2 [left]) or skeletal muscle as well as remarkable perineural invasion 
(Figure 2 [right]). Mitotic activity is minimal to absent. The tumor cells of syringoid eccrine 
carcinoma typically show positive immuno-staining for high- and low-molecular-weight cytokeratin, while the lumina are highlighted 
by epithelial membrane antigen and carcinoembryonic antigen.⁴ However, immunohistochemistry 
often is not contributory in diagnosing primary eccrine carcinomas.

Figure 1. Dermal infiltrate with tadpole morphology (arrow) characteristic of syringoid eccrine carcinoma (left)(H&E, original magnification ×40). High-power view shows an epithelial infiltrate and tadpole morphology (arrow)(right)(H&E, original magnification ×400).

Figure 2. Syringoid eccrine carcinoma extending to the junction of the reticular dermis and subcutaneous fat (left) (H&E, original magnification ×100). Nerve with adjacent and invasive basaloid nests of syringoid carcinoma (right)(H&E, original magnification ×100). The tumor consists of monomorphic cells with oval hyperchromatic nuclei.

The differential diagnosis of syringoid eccrine carcinoma includes cutaneous adenoid cystic carcinoma, metastatic adenocarcinoma, sclerosing basal cell carcinoma, and syringoma. Cutaneous adenoid cystic carcinoma is a rare, slow-growing, 
flesh-colored tumor that consists of lobules, islands, and cords of basaloid cells with prominent cystic cribriforming (Figure 3). The tumor cells typically are small, cuboidal, and monomorphic. Metastatic adenoid cystic carcinoma, such as from a primary tumor of the salivary glands or breasts, must be excluded before rendering a diagnosis of primary cutaneous disease.

Figure 3. Striking cribriform architecture of cutaneous adenoid cystic carcinoma (H&E, original magnification ×40). The tumor is well circumscribed and consists of multiple cystic spaces lined by flattened to cuboidal basaloid epithelium.

Metastatic adenocarcinoma of the skin usually presents in patients with a clinical history of preexisting disease. The breasts, colon, stomach, and ovaries are common origins of metastases. The histopathologic and immunohistochemical findings depend on the particular site of origin of the metastasis. Compared with primary eccrine carcinomas, metastatic adenocarcinomas of the skin generally are high-grade lesions with prominent atypia, mitosis, and necrosis (Figure 4).

Figure 4. Metastatic adenocarcinoma of the skin with dermal infiltrating glands (H&E, original magnification ×100). The nuclei are highly atypical. The tumor cells are cytokeratin 7 positive, cytokeratin 20 negative, estrogen-receptor positive, and gross cystic disease fluid protein positive, which is consistent with metastasis from a primary carcinoma of the breast (not shown).

Sclerosing basal cell carcinoma shows basaloid tumor cells with deep infiltration. Unlike syringoid eccrine carcinoma, basal cell carcinoma is an epidermal tumor that does not have true lumen formation. Furthermore, other variants of basal cell carcinoma, including nodular, micronodular, or superficial multicentric tumors, often coexist with the sclerosing variant in the same lesion and constitute a useful diagnostic clue (Figure 5). Staining for epithelial membrane antigen may be useful in identifying the absence of lumen formation, and Ber-EP4 highlights the epidermal origin of the lesion.⁵

Figure 5. Deeply invasive tumor with multiple architectures (sclerosing and micronodular) in a case of sclerosing basal cell carcinoma (H&E, original magnification ×40). Basaloid nests without true lumen formation invade subcutaneous adipose tissue.

Syringomas most commonly present as multiple small flesh-colored papules on the eyelids. On histology, syringomas present as small superficial dermal lesions composed of small ducts that may form tadpolelike structures in a fibrotic stroma (Figure 6). The ducts are lined by benign cuboidal cells. In contrast to syringoid eccrine carcinomas, syringomas usually present as multiple lesions that are microscopically superficial without perineural involvement.

Figure 6. Syringoma is composed of dilated ducts in a fibrotic stroma (H&E, original magnification ×40). Careful microscopic examination would reveal no perineural or deep subcutaneous tumor involvement.

Squamous cell carcinoma (SCC) is the second most common form of skin cancer. Pseudoglandular SCC, also known as adenoid SCC or acantholytic SCC, is an uncommon variant that was first described by Lever¹ in 1947 as an adenoacanthoma of the sweat glands. Of the many variants of SCC, pseudoglandular SCC generally is considered to behave aggressively with intermediate (3%–10%) risk for metastasis.² The metastatic potential of pseudoglandular SCC may be conferred in part by diminished expression of intercellular adhesion molecules, including desmoglein 3, epithelial cadherin, and syn-decan 1.^3,4 Pseudoglandular SCC presents most often on sun-damaged skin of elderly patients, especially the face and ears, as a pink or red nodule with central ulceration and a raised indurated border. It may be mistaken clinically for basal cell carcinoma (BCC) or keratoacanthoma.

On microscopic examination, the lesion is predominantly located in the dermis and may extend to the subcutis. There usually is connection to the overlying epidermis, which often shows hyperkeratosis and parakeratosis. Epidermal squamous dysplasia may be present. The dermis typically contains nests of squamous cells with a variable degree of central acantholysis. The morphology on low-power magnification consists of tubules of irregular size and shape, which are present either focally or throughout the lesion (Figure 1). The tubules are typically admixed with foci of keratinization. One or more layers of cohesive cells line the tubules. Partial keratinization may be found in the lining of tubules with more than 1 cell layer. The tumor cells are polygonal with eosinophilic cytoplasm, ovoid hyperchromatic or vesicular nuclei, and prominent nucleoli. Mitoses are common. The tubular lumina are filled with acantholytic cells, either singly or in small clusters, which may demonstrate residual bridging to tubular lining cells (Figure 2). The acantholytic cells show some variability in size and may be large, multinucleated, or keratinized. The tubules may contain material that is amorphous, basophilic, periodic acid–Schiff positive, diastase sensitive, and mucicarmine negative.⁵ Eccrine ducts at the periphery of the tumor may show reactive dilatation and proliferation. Tumor cells show positive immunostaining for epithelial membrane antigen, 34βE12, CK5/6, and tumor protein p63.^6-8 There is negative immunostaining for carcinoembryonic antigen, amylase, S-100 protein, and factor VIII.⁵

Figure 1. Glandlike tubular structures admixed with foci of keratinization (H&E, original magnification ×40). Figure 2. Pseudoglandular spaces containing acantholytic cells (H&E, original magnification ×100).

The differential diagnosis includes adenoid BCC, angiosarcoma, eccrine carcinoma, and metastatic adenocarcinoma of the skin. In adenoid BCC, excess stromal mucin imparts pseudoglandular architecture (Figure 3). However, features of conventional BCC, including peripheral nuclear palisading and retraction artifact often are present as well.

Figure 3. Thin strands of basaloid cells in a reticulate pattern with prominent stromal mucin in adenoid basal cell carcinoma. There also is palisading and retraction artifact of conventional basal cell carcinoma (H&E, original magnification ×40).

Angiosarcoma shows slitlike vascular spaces lined by hyperchromatic endothelial cells (Figure 4). Further, there is positive immunostaining for vascular markers CD31 and CD34.

Figure 4. Slitlike vascular spaces lined by hyperchromatic endothelial cells in angiosarcoma (H&E, original magnification ×100).

In eccrine carcinoma, there are invasive ductal structures lined by either a single or double layer of cells that may contain luminal material that is periodic acid–Schiff positive and diastase resistant (Figure 5).⁹ The tumor cells show positive immunostaining for cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, and S-100 protein.¹⁰

Figure 5. Invasive ductal structures of malignant eccrine carcinoma (H&E, original magnification ×100).

Pseudoglandular SCC is susceptible to misdiagnosis as adenocarcinoma by sampling error if biopsies do not capture areas with typical features of SCC, including dysplastic squamous epithelium and keratinization. Metastatic adenocarcinoma of the skin is more likely to present with multiple nodules in older individuals. Lack of epidermal connection of the tumor and minimal to no acantholytic dyskeratosis further support cutaneous metastasis (Figure 6). Review of the patient’s clinical history might be helpful if adenocarcinoma was previously diagnosed. Immunohistochemical evaluation may aid in the prediction of the primary site in patients with metastatic adenocarcinoma of unknown origin.¹¹

Figure 6. The dermis is filled with malignant glandular epithelium that is CK7 positive, CK20 negative, and thyroid transcription factor 1 positive (immunohistochemistry not shown), consistent with metastatic adenocarcinoma of lung origin (H&E, original magnification ×40).

Squamous cell carcinoma (SCC) is the second most common form of skin cancer. Pseudoglandular SCC, also known as adenoid SCC or acantholytic SCC, is an uncommon variant that was first described by Lever¹ in 1947 as an adenoacanthoma of the sweat glands. Of the many variants of SCC, pseudoglandular SCC generally is considered to behave aggressively with intermediate (3%–10%) risk for metastasis.² The metastatic potential of pseudoglandular SCC may be conferred in part by diminished expression of intercellular adhesion molecules, including desmoglein 3, epithelial cadherin, and syn-decan 1.^3,4 Pseudoglandular SCC presents most often on sun-damaged skin of elderly patients, especially the face and ears, as a pink or red nodule with central ulceration and a raised indurated border. It may be mistaken clinically for basal cell carcinoma (BCC) or keratoacanthoma.

On microscopic examination, the lesion is predominantly located in the dermis and may extend to the subcutis. There usually is connection to the overlying epidermis, which often shows hyperkeratosis and parakeratosis. Epidermal squamous dysplasia may be present. The dermis typically contains nests of squamous cells with a variable degree of central acantholysis. The morphology on low-power magnification consists of tubules of irregular size and shape, which are present either focally or throughout the lesion (Figure 1). The tubules are typically admixed with foci of keratinization. One or more layers of cohesive cells line the tubules. Partial keratinization may be found in the lining of tubules with more than 1 cell layer. The tumor cells are polygonal with eosinophilic cytoplasm, ovoid hyperchromatic or vesicular nuclei, and prominent nucleoli. Mitoses are common. The tubular lumina are filled with acantholytic cells, either singly or in small clusters, which may demonstrate residual bridging to tubular lining cells (Figure 2). The acantholytic cells show some variability in size and may be large, multinucleated, or keratinized. The tubules may contain material that is amorphous, basophilic, periodic acid–Schiff positive, diastase sensitive, and mucicarmine negative.⁵ Eccrine ducts at the periphery of the tumor may show reactive dilatation and proliferation. Tumor cells show positive immunostaining for epithelial membrane antigen, 34βE12, CK5/6, and tumor protein p63.^6-8 There is negative immunostaining for carcinoembryonic antigen, amylase, S-100 protein, and factor VIII.⁵

Figure 1. Glandlike tubular structures admixed with foci of keratinization (H&E, original magnification ×40). Figure 2. Pseudoglandular spaces containing acantholytic cells (H&E, original magnification ×100).

The differential diagnosis includes adenoid BCC, angiosarcoma, eccrine carcinoma, and metastatic adenocarcinoma of the skin. In adenoid BCC, excess stromal mucin imparts pseudoglandular architecture (Figure 3). However, features of conventional BCC, including peripheral nuclear palisading and retraction artifact often are present as well.

Figure 3. Thin strands of basaloid cells in a reticulate pattern with prominent stromal mucin in adenoid basal cell carcinoma. There also is palisading and retraction artifact of conventional basal cell carcinoma (H&E, original magnification ×40).

Angiosarcoma shows slitlike vascular spaces lined by hyperchromatic endothelial cells (Figure 4). Further, there is positive immunostaining for vascular markers CD31 and CD34.

Figure 4. Slitlike vascular spaces lined by hyperchromatic endothelial cells in angiosarcoma (H&E, original magnification ×100).

In eccrine carcinoma, there are invasive ductal structures lined by either a single or double layer of cells that may contain luminal material that is periodic acid–Schiff positive and diastase resistant (Figure 5).⁹ The tumor cells show positive immunostaining for cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, and S-100 protein.¹⁰

Figure 5. Invasive ductal structures of malignant eccrine carcinoma (H&E, original magnification ×100).

Pseudoglandular SCC is susceptible to misdiagnosis as adenocarcinoma by sampling error if biopsies do not capture areas with typical features of SCC, including dysplastic squamous epithelium and keratinization. Metastatic adenocarcinoma of the skin is more likely to present with multiple nodules in older individuals. Lack of epidermal connection of the tumor and minimal to no acantholytic dyskeratosis further support cutaneous metastasis (Figure 6). Review of the patient’s clinical history might be helpful if adenocarcinoma was previously diagnosed. Immunohistochemical evaluation may aid in the prediction of the primary site in patients with metastatic adenocarcinoma of unknown origin.¹¹

Figure 6. The dermis is filled with malignant glandular epithelium that is CK7 positive, CK20 negative, and thyroid transcription factor 1 positive (immunohistochemistry not shown), consistent with metastatic adenocarcinoma of lung origin (H&E, original magnification ×40).

Squamous cell carcinoma (SCC) is the second most common form of skin cancer. Pseudoglandular SCC, also known as adenoid SCC or acantholytic SCC, is an uncommon variant that was first described by Lever¹ in 1947 as an adenoacanthoma of the sweat glands. Of the many variants of SCC, pseudoglandular SCC generally is considered to behave aggressively with intermediate (3%–10%) risk for metastasis.² The metastatic potential of pseudoglandular SCC may be conferred in part by diminished expression of intercellular adhesion molecules, including desmoglein 3, epithelial cadherin, and syn-decan 1.^3,4 Pseudoglandular SCC presents most often on sun-damaged skin of elderly patients, especially the face and ears, as a pink or red nodule with central ulceration and a raised indurated border. It may be mistaken clinically for basal cell carcinoma (BCC) or keratoacanthoma.

On microscopic examination, the lesion is predominantly located in the dermis and may extend to the subcutis. There usually is connection to the overlying epidermis, which often shows hyperkeratosis and parakeratosis. Epidermal squamous dysplasia may be present. The dermis typically contains nests of squamous cells with a variable degree of central acantholysis. The morphology on low-power magnification consists of tubules of irregular size and shape, which are present either focally or throughout the lesion (Figure 1). The tubules are typically admixed with foci of keratinization. One or more layers of cohesive cells line the tubules. Partial keratinization may be found in the lining of tubules with more than 1 cell layer. The tumor cells are polygonal with eosinophilic cytoplasm, ovoid hyperchromatic or vesicular nuclei, and prominent nucleoli. Mitoses are common. The tubular lumina are filled with acantholytic cells, either singly or in small clusters, which may demonstrate residual bridging to tubular lining cells (Figure 2). The acantholytic cells show some variability in size and may be large, multinucleated, or keratinized. The tubules may contain material that is amorphous, basophilic, periodic acid–Schiff positive, diastase sensitive, and mucicarmine negative.⁵ Eccrine ducts at the periphery of the tumor may show reactive dilatation and proliferation. Tumor cells show positive immunostaining for epithelial membrane antigen, 34βE12, CK5/6, and tumor protein p63.^6-8 There is negative immunostaining for carcinoembryonic antigen, amylase, S-100 protein, and factor VIII.⁵

Figure 1. Glandlike tubular structures admixed with foci of keratinization (H&E, original magnification ×40). Figure 2. Pseudoglandular spaces containing acantholytic cells (H&E, original magnification ×100).

The differential diagnosis includes adenoid BCC, angiosarcoma, eccrine carcinoma, and metastatic adenocarcinoma of the skin. In adenoid BCC, excess stromal mucin imparts pseudoglandular architecture (Figure 3). However, features of conventional BCC, including peripheral nuclear palisading and retraction artifact often are present as well.

Figure 3. Thin strands of basaloid cells in a reticulate pattern with prominent stromal mucin in adenoid basal cell carcinoma. There also is palisading and retraction artifact of conventional basal cell carcinoma (H&E, original magnification ×40).

Angiosarcoma shows slitlike vascular spaces lined by hyperchromatic endothelial cells (Figure 4). Further, there is positive immunostaining for vascular markers CD31 and CD34.

Figure 4. Slitlike vascular spaces lined by hyperchromatic endothelial cells in angiosarcoma (H&E, original magnification ×100).

In eccrine carcinoma, there are invasive ductal structures lined by either a single or double layer of cells that may contain luminal material that is periodic acid–Schiff positive and diastase resistant (Figure 5).⁹ The tumor cells show positive immunostaining for cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, and S-100 protein.¹⁰

Figure 5. Invasive ductal structures of malignant eccrine carcinoma (H&E, original magnification ×100).

Pseudoglandular SCC is susceptible to misdiagnosis as adenocarcinoma by sampling error if biopsies do not capture areas with typical features of SCC, including dysplastic squamous epithelium and keratinization. Metastatic adenocarcinoma of the skin is more likely to present with multiple nodules in older individuals. Lack of epidermal connection of the tumor and minimal to no acantholytic dyskeratosis further support cutaneous metastasis (Figure 6). Review of the patient’s clinical history might be helpful if adenocarcinoma was previously diagnosed. Immunohistochemical evaluation may aid in the prediction of the primary site in patients with metastatic adenocarcinoma of unknown origin.¹¹

Figure 6. The dermis is filled with malignant glandular epithelium that is CK7 positive, CK20 negative, and thyroid transcription factor 1 positive (immunohistochemistry not shown), consistent with metastatic adenocarcinoma of lung origin (H&E, original magnification ×40).

A fibrous papule is a common benign lesion that usually presents in adults on the face,  especially on the lower portion of the nose. It typically presents as a small (2–5 mm), asymptomatic, flesh-colored, dome-shaped lesion that is firm and nontender. Several histopathologic variants of fibrous papules have been described, including clear cell, granular, epithelioid, hypercellular, pleomorphic, pigmented, and inflammatory.¹ Clear cell fibrous papules are exceedingly rare. On microscopic examination the epidermis may be normal or show some degree of hyperkeratosis and parakeratosis, erosion, ulceration, or crust. The basal layer may show an increase of melanin. The dermis is expanded by a proliferation of clear cells arranged in sheets, clusters, or as single cells (Figure 1). The clear cells show variation in size and shape. The nuclei are small and round without pleomorphism, hyperchromasia, or mitoses. The nuclei may be centrally located or eccentrically displaced by a large intracytoplasmic vacuole (Figure 2). Some clear cells may exhibit finely vacuolated cytoplasm with nuclear scalloping. The surrounding stroma usually consists of sclerotic collagen and dilated blood vessels (Figure 3). Extravasated red blood cells may be present focally. Patchy lymphocytic infiltrates may be found in the stroma at the periphery of the lesion. Periodic acid–Schiff and mucicarmine staining of the clear cells is negative. On immunohistochemistry, the clear cells are diffusely positive for vimentin and negative for cytokeratin AE1/AE3, epithelial membrane antigen, carcinoembryonic antigen, and HMB-45 (human melanoma black 45).^2,3 The clear cells often are positive for CD68, factor XIIIa, and NKI/C3 (anti-CD63) but also may be negative. The S-100 protein often is negative but may be focally positive.

The differential diagnosis for clear cell fibrous papules is broad but reasonably includes balloon cell nevus, clear cell hidradenoma, and cutaneous metastasis of clear cell (conventional) renal cell carcinoma (ccRCC). Balloon cell malignant melanoma is not considered strongly in the differential diagnosis because it usually exhibits invasive growth, cytologic atypia, and mitoses, all of which are not characteristic morphologic features of clear cell fibrous papules.

A balloon cell nevus may be difficult to distinguish from a clear cell fibrous papule on routine hematoxylin and eosin staining (Figure 4); however, the nuclei of a balloon cell nevus tend to be more rounded and centrally located. Any junctional nesting or nests of conventional nevus cells in the dermis also help differentiate a balloon cell nevus from a clear cell fibrous papule. Diffusely positive immunostaining for S-100 protein also is indicative of a balloon cell nevus.

Clear cell hidradenoma consists predominantly of cells with clear cytoplasm and small dark nuclei that may closely mimic a clear cell fibrous papule (Figure 5) but often shows a second population of cells with more vesicular nuclei and dark eosinophilic cytoplasm. Cystic spaces containing hyaline material and foci of squamoid change are common, along with occasional tubular lumina that may be prominent or inconspicuous. Further, the tumor cells of clear cell hidradenoma show positive immunostaining for epithelial markers (eg, cytokeratin AE1/AE3, CAM5.2).

Cutaneous metastasis of ccRCC is rare and usually presents clinically as a larger lesion than a clear cell fibrous papule. The cells of ccRCC have moderate to abundant clear cytoplasm and nuclei with varying degrees of pleomorphism (Figure 6). Periodic acid–Schiff staining demonstrates intracytoplasmic glycogen. The stroma is abundantly vascular and extravasated blood cells are frequently observed. On immunohistochemistry, the tumor cells of ccRCC stain positively for cytokeratin AE1/AE3, CAM5.2, epithelial membrane antigen, CD10, and vimentin.

A fibrous papule is a common benign lesion that usually presents in adults on the face,  especially on the lower portion of the nose. It typically presents as a small (2–5 mm), asymptomatic, flesh-colored, dome-shaped lesion that is firm and nontender. Several histopathologic variants of fibrous papules have been described, including clear cell, granular, epithelioid, hypercellular, pleomorphic, pigmented, and inflammatory.¹ Clear cell fibrous papules are exceedingly rare. On microscopic examination the epidermis may be normal or show some degree of hyperkeratosis and parakeratosis, erosion, ulceration, or crust. The basal layer may show an increase of melanin. The dermis is expanded by a proliferation of clear cells arranged in sheets, clusters, or as single cells (Figure 1). The clear cells show variation in size and shape. The nuclei are small and round without pleomorphism, hyperchromasia, or mitoses. The nuclei may be centrally located or eccentrically displaced by a large intracytoplasmic vacuole (Figure 2). Some clear cells may exhibit finely vacuolated cytoplasm with nuclear scalloping. The surrounding stroma usually consists of sclerotic collagen and dilated blood vessels (Figure 3). Extravasated red blood cells may be present focally. Patchy lymphocytic infiltrates may be found in the stroma at the periphery of the lesion. Periodic acid–Schiff and mucicarmine staining of the clear cells is negative. On immunohistochemistry, the clear cells are diffusely positive for vimentin and negative for cytokeratin AE1/AE3, epithelial membrane antigen, carcinoembryonic antigen, and HMB-45 (human melanoma black 45).^2,3 The clear cells often are positive for CD68, factor XIIIa, and NKI/C3 (anti-CD63) but also may be negative. The S-100 protein often is negative but may be focally positive.

The differential diagnosis for clear cell fibrous papules is broad but reasonably includes balloon cell nevus, clear cell hidradenoma, and cutaneous metastasis of clear cell (conventional) renal cell carcinoma (ccRCC). Balloon cell malignant melanoma is not considered strongly in the differential diagnosis because it usually exhibits invasive growth, cytologic atypia, and mitoses, all of which are not characteristic morphologic features of clear cell fibrous papules.

A balloon cell nevus may be difficult to distinguish from a clear cell fibrous papule on routine hematoxylin and eosin staining (Figure 4); however, the nuclei of a balloon cell nevus tend to be more rounded and centrally located. Any junctional nesting or nests of conventional nevus cells in the dermis also help differentiate a balloon cell nevus from a clear cell fibrous papule. Diffusely positive immunostaining for S-100 protein also is indicative of a balloon cell nevus.

Clear cell hidradenoma consists predominantly of cells with clear cytoplasm and small dark nuclei that may closely mimic a clear cell fibrous papule (Figure 5) but often shows a second population of cells with more vesicular nuclei and dark eosinophilic cytoplasm. Cystic spaces containing hyaline material and foci of squamoid change are common, along with occasional tubular lumina that may be prominent or inconspicuous. Further, the tumor cells of clear cell hidradenoma show positive immunostaining for epithelial markers (eg, cytokeratin AE1/AE3, CAM5.2).

Cutaneous metastasis of ccRCC is rare and usually presents clinically as a larger lesion than a clear cell fibrous papule. The cells of ccRCC have moderate to abundant clear cytoplasm and nuclei with varying degrees of pleomorphism (Figure 6). Periodic acid–Schiff staining demonstrates intracytoplasmic glycogen. The stroma is abundantly vascular and extravasated blood cells are frequently observed. On immunohistochemistry, the tumor cells of ccRCC stain positively for cytokeratin AE1/AE3, CAM5.2, epithelial membrane antigen, CD10, and vimentin.

A fibrous papule is a common benign lesion that usually presents in adults on the face,  especially on the lower portion of the nose. It typically presents as a small (2–5 mm), asymptomatic, flesh-colored, dome-shaped lesion that is firm and nontender. Several histopathologic variants of fibrous papules have been described, including clear cell, granular, epithelioid, hypercellular, pleomorphic, pigmented, and inflammatory.¹ Clear cell fibrous papules are exceedingly rare. On microscopic examination the epidermis may be normal or show some degree of hyperkeratosis and parakeratosis, erosion, ulceration, or crust. The basal layer may show an increase of melanin. The dermis is expanded by a proliferation of clear cells arranged in sheets, clusters, or as single cells (Figure 1). The clear cells show variation in size and shape. The nuclei are small and round without pleomorphism, hyperchromasia, or mitoses. The nuclei may be centrally located or eccentrically displaced by a large intracytoplasmic vacuole (Figure 2). Some clear cells may exhibit finely vacuolated cytoplasm with nuclear scalloping. The surrounding stroma usually consists of sclerotic collagen and dilated blood vessels (Figure 3). Extravasated red blood cells may be present focally. Patchy lymphocytic infiltrates may be found in the stroma at the periphery of the lesion. Periodic acid–Schiff and mucicarmine staining of the clear cells is negative. On immunohistochemistry, the clear cells are diffusely positive for vimentin and negative for cytokeratin AE1/AE3, epithelial membrane antigen, carcinoembryonic antigen, and HMB-45 (human melanoma black 45).^2,3 The clear cells often are positive for CD68, factor XIIIa, and NKI/C3 (anti-CD63) but also may be negative. The S-100 protein often is negative but may be focally positive.

The differential diagnosis for clear cell fibrous papules is broad but reasonably includes balloon cell nevus, clear cell hidradenoma, and cutaneous metastasis of clear cell (conventional) renal cell carcinoma (ccRCC). Balloon cell malignant melanoma is not considered strongly in the differential diagnosis because it usually exhibits invasive growth, cytologic atypia, and mitoses, all of which are not characteristic morphologic features of clear cell fibrous papules.

A balloon cell nevus may be difficult to distinguish from a clear cell fibrous papule on routine hematoxylin and eosin staining (Figure 4); however, the nuclei of a balloon cell nevus tend to be more rounded and centrally located. Any junctional nesting or nests of conventional nevus cells in the dermis also help differentiate a balloon cell nevus from a clear cell fibrous papule. Diffusely positive immunostaining for S-100 protein also is indicative of a balloon cell nevus.

Clear cell hidradenoma consists predominantly of cells with clear cytoplasm and small dark nuclei that may closely mimic a clear cell fibrous papule (Figure 5) but often shows a second population of cells with more vesicular nuclei and dark eosinophilic cytoplasm. Cystic spaces containing hyaline material and foci of squamoid change are common, along with occasional tubular lumina that may be prominent or inconspicuous. Further, the tumor cells of clear cell hidradenoma show positive immunostaining for epithelial markers (eg, cytokeratin AE1/AE3, CAM5.2).

Cutaneous metastasis of ccRCC is rare and usually presents clinically as a larger lesion than a clear cell fibrous papule. The cells of ccRCC have moderate to abundant clear cytoplasm and nuclei with varying degrees of pleomorphism (Figure 6). Periodic acid–Schiff staining demonstrates intracytoplasmic glycogen. The stroma is abundantly vascular and extravasated blood cells are frequently observed. On immunohistochemistry, the tumor cells of ccRCC stain positively for cytokeratin AE1/AE3, CAM5.2, epithelial membrane antigen, CD10, and vimentin.