Dermpath Diagnosis

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare benign histioproliferative disorder of unknown etiology.¹ Clinically, it is most frequently characterized by massive painless cervical lymphadenopathy with other systemic manifestations, including fever, night sweats, and weight loss. Accompanying laboratory findings include leukocytosis with neutrophilia, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Extranodal involvement has been noted in more than 40% of cases, and cutaneous lesions represent the most common form of extranodal disease.² Cutaneous RDD is a distinct and rare entity limited to the skin without lymphadenopathy or other extracutaneous involvement.³ Patients with cutaneous RDD typically present with papules and plaques that can grow to form nodules with satellite lesions that resolve into fibrotic plaques before spontaneous regression.⁴

Histologic examination of cutaneous lesions of RDD reveals a dense nodular dermal and often subcutaneous infiltrate of characteristic large polygonal histiocytes termed Rosai-Dorfman cells, which feature abundant pale to eosinophilic cytoplasm, indistinct borders, and large vesicular nuclei with prominent nucleoli (Figure 1).^4,5 Some multinucleate forms may be seen. These Rosai-Dorfman cells display positive staining for CD68 and S-100, and negative staining for CD1a on immunohistochemistry. Lymphocytes and plasma cells often are admixed with the Rosai-Dorfman cells, and neutrophils and eosinophils also may be present in the infiltrate.⁴ The histologic hallmark of RDD is emperipolesis, a phenomenon whereby inflammatory cells such as lymphocytes and plasma cells reside intact within the cytoplasm of histiocytes (Figure 2).⁵

Figure 1. Sheets of large polygonal histiocytes with admixed lymphocytes and plasma cells seen in Rosai-Dorfman disease (H&E, original magnification ×200).

Figure 2. Emperipolesis (histiocyte-engulfing lymphocytes) demonstrated in Rosai-Dorfman disease (H&E, original magnification ×600).

The histologic differential diagnosis of cutaneous lesions of RDD includes other histiocytic and xanthomatous diseases, including eruptive xanthoma, juvenile xanthogranuloma, Langerhans cell histiocytosis, and solitary reticulohistiocytoma, which should not display emperipolesis. Eruptive xanthomas display collections of foamy histiocytes in the dermis and typically contain extracellular lipid. They may contain infiltrates of lymphocytes (Figure 3). Juvenile xanthogranuloma also features a dense infiltrate of histiocytes in the papillary and reticular dermis but distinctly shows Touton giant cells and lipidization of histiocytes (Figure 4). Both eruptive xanthomas and juvenile xanthogranulomas typically stain negatively for S-100. Langerhans cell histiocytosis is histologically characterized by a dermal infiltrate of Langerhans cells that have their own distinctive morphologic features. They are uniformly ovoid with abundant eosinophilic cytoplasm. Their nuclei are smaller than those of Rosai-Dorfman cells and have a kidney bean shape with inconspicuous nucleoli (Figure 5). Epidermotropism of these cells can be observed. Immunohistochemically, Langerhans cell histiocytosis typically is S-100 positive, CD1a positive, and langerin positive. Reticulohistiocytoma features histiocytes that have a characteristic dusty rose or ground glass cytoplasm with two-toned darker and lighter areas (Figure 6). Reticulohistiocytoma cells stain positively for CD68 but typically stain negatively for both CD1a and S-100.

Figure 3. Lipid-laden macrophages with foamy cytoplasm and extracellular lipid seen in eruptive xanthoma (H&E, original magnification ×400).			Figure 4. Touton giant cell (wreath of nuclei surrounded by foamy cytoplasm) featured in juvenile xanthogranuloma (H&E, original magnification ×600).
Figure 5. Dermal infiltrate of ovoid Langerhans cells with reniform nuclei in Langerhans cell histiocytosis (H&E, original magnification ×600).			Figure 6. Histiocytes with dusty rose–colored cytoplasm and admixed lymphocytes in a reticulohistiocytoma (H&E, original magnification ×400).

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare benign histioproliferative disorder of unknown etiology.¹ Clinically, it is most frequently characterized by massive painless cervical lymphadenopathy with other systemic manifestations, including fever, night sweats, and weight loss. Accompanying laboratory findings include leukocytosis with neutrophilia, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Extranodal involvement has been noted in more than 40% of cases, and cutaneous lesions represent the most common form of extranodal disease.² Cutaneous RDD is a distinct and rare entity limited to the skin without lymphadenopathy or other extracutaneous involvement.³ Patients with cutaneous RDD typically present with papules and plaques that can grow to form nodules with satellite lesions that resolve into fibrotic plaques before spontaneous regression.⁴

Histologic examination of cutaneous lesions of RDD reveals a dense nodular dermal and often subcutaneous infiltrate of characteristic large polygonal histiocytes termed Rosai-Dorfman cells, which feature abundant pale to eosinophilic cytoplasm, indistinct borders, and large vesicular nuclei with prominent nucleoli (Figure 1).^4,5 Some multinucleate forms may be seen. These Rosai-Dorfman cells display positive staining for CD68 and S-100, and negative staining for CD1a on immunohistochemistry. Lymphocytes and plasma cells often are admixed with the Rosai-Dorfman cells, and neutrophils and eosinophils also may be present in the infiltrate.⁴ The histologic hallmark of RDD is emperipolesis, a phenomenon whereby inflammatory cells such as lymphocytes and plasma cells reside intact within the cytoplasm of histiocytes (Figure 2).⁵

Figure 1. Sheets of large polygonal histiocytes with admixed lymphocytes and plasma cells seen in Rosai-Dorfman disease (H&E, original magnification ×200).

Figure 2. Emperipolesis (histiocyte-engulfing lymphocytes) demonstrated in Rosai-Dorfman disease (H&E, original magnification ×600).

The histologic differential diagnosis of cutaneous lesions of RDD includes other histiocytic and xanthomatous diseases, including eruptive xanthoma, juvenile xanthogranuloma, Langerhans cell histiocytosis, and solitary reticulohistiocytoma, which should not display emperipolesis. Eruptive xanthomas display collections of foamy histiocytes in the dermis and typically contain extracellular lipid. They may contain infiltrates of lymphocytes (Figure 3). Juvenile xanthogranuloma also features a dense infiltrate of histiocytes in the papillary and reticular dermis but distinctly shows Touton giant cells and lipidization of histiocytes (Figure 4). Both eruptive xanthomas and juvenile xanthogranulomas typically stain negatively for S-100. Langerhans cell histiocytosis is histologically characterized by a dermal infiltrate of Langerhans cells that have their own distinctive morphologic features. They are uniformly ovoid with abundant eosinophilic cytoplasm. Their nuclei are smaller than those of Rosai-Dorfman cells and have a kidney bean shape with inconspicuous nucleoli (Figure 5). Epidermotropism of these cells can be observed. Immunohistochemically, Langerhans cell histiocytosis typically is S-100 positive, CD1a positive, and langerin positive. Reticulohistiocytoma features histiocytes that have a characteristic dusty rose or ground glass cytoplasm with two-toned darker and lighter areas (Figure 6). Reticulohistiocytoma cells stain positively for CD68 but typically stain negatively for both CD1a and S-100.

Figure 3. Lipid-laden macrophages with foamy cytoplasm and extracellular lipid seen in eruptive xanthoma (H&E, original magnification ×400).			Figure 4. Touton giant cell (wreath of nuclei surrounded by foamy cytoplasm) featured in juvenile xanthogranuloma (H&E, original magnification ×600).
Figure 5. Dermal infiltrate of ovoid Langerhans cells with reniform nuclei in Langerhans cell histiocytosis (H&E, original magnification ×600).			Figure 6. Histiocytes with dusty rose–colored cytoplasm and admixed lymphocytes in a reticulohistiocytoma (H&E, original magnification ×400).

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare benign histioproliferative disorder of unknown etiology.¹ Clinically, it is most frequently characterized by massive painless cervical lymphadenopathy with other systemic manifestations, including fever, night sweats, and weight loss. Accompanying laboratory findings include leukocytosis with neutrophilia, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Extranodal involvement has been noted in more than 40% of cases, and cutaneous lesions represent the most common form of extranodal disease.² Cutaneous RDD is a distinct and rare entity limited to the skin without lymphadenopathy or other extracutaneous involvement.³ Patients with cutaneous RDD typically present with papules and plaques that can grow to form nodules with satellite lesions that resolve into fibrotic plaques before spontaneous regression.⁴

Histologic examination of cutaneous lesions of RDD reveals a dense nodular dermal and often subcutaneous infiltrate of characteristic large polygonal histiocytes termed Rosai-Dorfman cells, which feature abundant pale to eosinophilic cytoplasm, indistinct borders, and large vesicular nuclei with prominent nucleoli (Figure 1).^4,5 Some multinucleate forms may be seen. These Rosai-Dorfman cells display positive staining for CD68 and S-100, and negative staining for CD1a on immunohistochemistry. Lymphocytes and plasma cells often are admixed with the Rosai-Dorfman cells, and neutrophils and eosinophils also may be present in the infiltrate.⁴ The histologic hallmark of RDD is emperipolesis, a phenomenon whereby inflammatory cells such as lymphocytes and plasma cells reside intact within the cytoplasm of histiocytes (Figure 2).⁵

Figure 1. Sheets of large polygonal histiocytes with admixed lymphocytes and plasma cells seen in Rosai-Dorfman disease (H&E, original magnification ×200).

Figure 2. Emperipolesis (histiocyte-engulfing lymphocytes) demonstrated in Rosai-Dorfman disease (H&E, original magnification ×600).

The histologic differential diagnosis of cutaneous lesions of RDD includes other histiocytic and xanthomatous diseases, including eruptive xanthoma, juvenile xanthogranuloma, Langerhans cell histiocytosis, and solitary reticulohistiocytoma, which should not display emperipolesis. Eruptive xanthomas display collections of foamy histiocytes in the dermis and typically contain extracellular lipid. They may contain infiltrates of lymphocytes (Figure 3). Juvenile xanthogranuloma also features a dense infiltrate of histiocytes in the papillary and reticular dermis but distinctly shows Touton giant cells and lipidization of histiocytes (Figure 4). Both eruptive xanthomas and juvenile xanthogranulomas typically stain negatively for S-100. Langerhans cell histiocytosis is histologically characterized by a dermal infiltrate of Langerhans cells that have their own distinctive morphologic features. They are uniformly ovoid with abundant eosinophilic cytoplasm. Their nuclei are smaller than those of Rosai-Dorfman cells and have a kidney bean shape with inconspicuous nucleoli (Figure 5). Epidermotropism of these cells can be observed. Immunohistochemically, Langerhans cell histiocytosis typically is S-100 positive, CD1a positive, and langerin positive. Reticulohistiocytoma features histiocytes that have a characteristic dusty rose or ground glass cytoplasm with two-toned darker and lighter areas (Figure 6). Reticulohistiocytoma cells stain positively for CD68 but typically stain negatively for both CD1a and S-100.

Figure 3. Lipid-laden macrophages with foamy cytoplasm and extracellular lipid seen in eruptive xanthoma (H&E, original magnification ×400).			Figure 4. Touton giant cell (wreath of nuclei surrounded by foamy cytoplasm) featured in juvenile xanthogranuloma (H&E, original magnification ×600).
Figure 5. Dermal infiltrate of ovoid Langerhans cells with reniform nuclei in Langerhans cell histiocytosis (H&E, original magnification ×600).			Figure 6. Histiocytes with dusty rose–colored cytoplasm and admixed lymphocytes in a reticulohistiocytoma (H&E, original magnification ×400).

Extramammary Paget disease (EMPD) is an uncommon condition that usually presents in apocrine sweat gland–rich areas, most commonly the vulva followed by the perianal region. Lesions clinically present as erythematous, well-demarcated plaques that may become ulcerated, erosive, scaly, or eczematous. Extramammary Paget disease has a female predominance and usually occurs in the sixth to eighth decades of life.¹ Histologically, EMPD displays intraepidermal spread of large cells with plentiful amphophilic cytoplasm and large nuclei (Figure 1). These atypical cells may be seen “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells (Figure 2). Frequently, the cytoplasm of these tumor cells is positive on mucicarmine staining, which indicates the presence of mucin, giving the cytoplasm a bluish gray color on hematoxylin and eosin–stained sections. Typically, EMPD cells can be found alone or in nests throughout the epithelium. The basal layer of the epithelium will appear crushed but not infiltrated by these atypical cells in some areas.² Extramammary Paget disease is epithelial membrane antigen and cytokeratin 7 positive, unlike other conditions in the differential diagnosis such as benign acral nevus, Bowen disease, mycosis fungoides, and superficial spreading melanoma in situ, with the rare exception of cytokeratin 7 positivity in Bowen disease.³

Figure 1. Intraepidermal spread of large cells with plentiful amphophilic cytoplasm in extramammary Paget disease (H&E, original magnification ×10).

Figure 2. Atypical cells of extramammary Paget disease “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells (H&E, original magnification ×20).

Benign acral nevi, similar to melanoma in situ, can have melanocytes scattered above the basal layer, but they usually appear in the lower half of the epidermis without cytologic atypia.⁴ When present, these pagetoid cells are most often limited to the center of a well-delineated lesion. The compact thick stratum corneum characteristic of acral skin also is helpful in distinguishing a benign acral nevus from EMPD, which does not involve acral sites (Figure 3).²

Figure 3. Cytologically normal melanocytes in the lower half of the epidermis in a benign acral nevus with a thick stratum corneum that is indicative of acral skin (H&E, original magnification ×20).

Bowen disease (squamous cell carcinoma in situ) may have pagetoid spread (or buckshot scatter) through the epidermis similar to EMPD and melanoma in situ. However, in Bowen disease the malignant cells are keratinocytes that keratinize and become incorporated into the stratum corneum as parakeratotic nuclei rather than intact “spit out” cells, as seen in melanoma in situ and EMPD. Usually the pagetoid spread is only focal in Bowen disease with other areas of more characteristic full-thickness keratinocyte atypia (Figure 4).²

Figure 4. Parakeratosis and pagetoid spread of cells adjacent to areas of full-thickness epidermal keratinocyte atypia in Bowen disease (H&E, original magnification ×10).

Mycosis fungoides displays atypical lymphocytes with large dark nuclei and minimal to no cytoplasm scattered throughout the epidermis. The atypical cells have irregular nuclear contours and often a clear perinuclear space (Figure 5). These cells tend to line up along the dermoepidermal junction and form intraepidermal clusters known as Pautrier microabscesses. Papillary dermal fibroplasia also is usually present in mycosis fungoides.²

Figure 5. Atypical lymphocytes in the epidermis of mycosis fungoides display nuclei that are large, dark, and have irregular nuclear contours with perinuclear clearing (H&E, original magnification ×20).

Similar to EMPD, superficial spreading melanoma in situ shows single or nested atypical cells scattered throughout all levels of the epithelium and may be “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells. However, in melanoma, nests of atypical melanocytes predominate and involve the basal layer (Figure 6), whereas clusters of cells in EMPD typically are located superficial to the basal layer. The cells of melanoma also lack the amphophilic mucinous cytoplasm of EMPD.¹

Figure 6. Nests of atypical melanocytes predominately involving the basal layer in superficial spreading melanoma in situ (H&E, original magnification ×20).

Extramammary Paget disease (EMPD) is an uncommon condition that usually presents in apocrine sweat gland–rich areas, most commonly the vulva followed by the perianal region. Lesions clinically present as erythematous, well-demarcated plaques that may become ulcerated, erosive, scaly, or eczematous. Extramammary Paget disease has a female predominance and usually occurs in the sixth to eighth decades of life.¹ Histologically, EMPD displays intraepidermal spread of large cells with plentiful amphophilic cytoplasm and large nuclei (Figure 1). These atypical cells may be seen “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells (Figure 2). Frequently, the cytoplasm of these tumor cells is positive on mucicarmine staining, which indicates the presence of mucin, giving the cytoplasm a bluish gray color on hematoxylin and eosin–stained sections. Typically, EMPD cells can be found alone or in nests throughout the epithelium. The basal layer of the epithelium will appear crushed but not infiltrated by these atypical cells in some areas.² Extramammary Paget disease is epithelial membrane antigen and cytokeratin 7 positive, unlike other conditions in the differential diagnosis such as benign acral nevus, Bowen disease, mycosis fungoides, and superficial spreading melanoma in situ, with the rare exception of cytokeratin 7 positivity in Bowen disease.³

Figure 1. Intraepidermal spread of large cells with plentiful amphophilic cytoplasm in extramammary Paget disease (H&E, original magnification ×10).

Figure 2. Atypical cells of extramammary Paget disease “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells (H&E, original magnification ×20).

Benign acral nevi, similar to melanoma in situ, can have melanocytes scattered above the basal layer, but they usually appear in the lower half of the epidermis without cytologic atypia.⁴ When present, these pagetoid cells are most often limited to the center of a well-delineated lesion. The compact thick stratum corneum characteristic of acral skin also is helpful in distinguishing a benign acral nevus from EMPD, which does not involve acral sites (Figure 3).²

Figure 3. Cytologically normal melanocytes in the lower half of the epidermis in a benign acral nevus with a thick stratum corneum that is indicative of acral skin (H&E, original magnification ×20).

Bowen disease (squamous cell carcinoma in situ) may have pagetoid spread (or buckshot scatter) through the epidermis similar to EMPD and melanoma in situ. However, in Bowen disease the malignant cells are keratinocytes that keratinize and become incorporated into the stratum corneum as parakeratotic nuclei rather than intact “spit out” cells, as seen in melanoma in situ and EMPD. Usually the pagetoid spread is only focal in Bowen disease with other areas of more characteristic full-thickness keratinocyte atypia (Figure 4).²

Figure 4. Parakeratosis and pagetoid spread of cells adjacent to areas of full-thickness epidermal keratinocyte atypia in Bowen disease (H&E, original magnification ×10).

Mycosis fungoides displays atypical lymphocytes with large dark nuclei and minimal to no cytoplasm scattered throughout the epidermis. The atypical cells have irregular nuclear contours and often a clear perinuclear space (Figure 5). These cells tend to line up along the dermoepidermal junction and form intraepidermal clusters known as Pautrier microabscesses. Papillary dermal fibroplasia also is usually present in mycosis fungoides.²

Figure 5. Atypical lymphocytes in the epidermis of mycosis fungoides display nuclei that are large, dark, and have irregular nuclear contours with perinuclear clearing (H&E, original magnification ×20).

Similar to EMPD, superficial spreading melanoma in situ shows single or nested atypical cells scattered throughout all levels of the epithelium and may be “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells. However, in melanoma, nests of atypical melanocytes predominate and involve the basal layer (Figure 6), whereas clusters of cells in EMPD typically are located superficial to the basal layer. The cells of melanoma also lack the amphophilic mucinous cytoplasm of EMPD.¹

Figure 6. Nests of atypical melanocytes predominately involving the basal layer in superficial spreading melanoma in situ (H&E, original magnification ×20).

Extramammary Paget disease (EMPD) is an uncommon condition that usually presents in apocrine sweat gland–rich areas, most commonly the vulva followed by the perianal region. Lesions clinically present as erythematous, well-demarcated plaques that may become ulcerated, erosive, scaly, or eczematous. Extramammary Paget disease has a female predominance and usually occurs in the sixth to eighth decades of life.¹ Histologically, EMPD displays intraepidermal spread of large cells with plentiful amphophilic cytoplasm and large nuclei (Figure 1). These atypical cells may be seen “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells (Figure 2). Frequently, the cytoplasm of these tumor cells is positive on mucicarmine staining, which indicates the presence of mucin, giving the cytoplasm a bluish gray color on hematoxylin and eosin–stained sections. Typically, EMPD cells can be found alone or in nests throughout the epithelium. The basal layer of the epithelium will appear crushed but not infiltrated by these atypical cells in some areas.² Extramammary Paget disease is epithelial membrane antigen and cytokeratin 7 positive, unlike other conditions in the differential diagnosis such as benign acral nevus, Bowen disease, mycosis fungoides, and superficial spreading melanoma in situ, with the rare exception of cytokeratin 7 positivity in Bowen disease.³

Figure 1. Intraepidermal spread of large cells with plentiful amphophilic cytoplasm in extramammary Paget disease (H&E, original magnification ×10).

Figure 2. Atypical cells of extramammary Paget disease “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells (H&E, original magnification ×20).

Benign acral nevi, similar to melanoma in situ, can have melanocytes scattered above the basal layer, but they usually appear in the lower half of the epidermis without cytologic atypia.⁴ When present, these pagetoid cells are most often limited to the center of a well-delineated lesion. The compact thick stratum corneum characteristic of acral skin also is helpful in distinguishing a benign acral nevus from EMPD, which does not involve acral sites (Figure 3).²

Figure 3. Cytologically normal melanocytes in the lower half of the epidermis in a benign acral nevus with a thick stratum corneum that is indicative of acral skin (H&E, original magnification ×20).

Bowen disease (squamous cell carcinoma in situ) may have pagetoid spread (or buckshot scatter) through the epidermis similar to EMPD and melanoma in situ. However, in Bowen disease the malignant cells are keratinocytes that keratinize and become incorporated into the stratum corneum as parakeratotic nuclei rather than intact “spit out” cells, as seen in melanoma in situ and EMPD. Usually the pagetoid spread is only focal in Bowen disease with other areas of more characteristic full-thickness keratinocyte atypia (Figure 4).²

Figure 4. Parakeratosis and pagetoid spread of cells adjacent to areas of full-thickness epidermal keratinocyte atypia in Bowen disease (H&E, original magnification ×10).

Mycosis fungoides displays atypical lymphocytes with large dark nuclei and minimal to no cytoplasm scattered throughout the epidermis. The atypical cells have irregular nuclear contours and often a clear perinuclear space (Figure 5). These cells tend to line up along the dermoepidermal junction and form intraepidermal clusters known as Pautrier microabscesses. Papillary dermal fibroplasia also is usually present in mycosis fungoides.²

Figure 5. Atypical lymphocytes in the epidermis of mycosis fungoides display nuclei that are large, dark, and have irregular nuclear contours with perinuclear clearing (H&E, original magnification ×20).

Similar to EMPD, superficial spreading melanoma in situ shows single or nested atypical cells scattered throughout all levels of the epithelium and may be “spit out” whole into the stratum corneum rather than keratinizing into parakeratotic cells. However, in melanoma, nests of atypical melanocytes predominate and involve the basal layer (Figure 6), whereas clusters of cells in EMPD typically are located superficial to the basal layer. The cells of melanoma also lack the amphophilic mucinous cytoplasm of EMPD.¹

Figure 6. Nests of atypical melanocytes predominately involving the basal layer in superficial spreading melanoma in situ (H&E, original magnification ×20).

Necrobiosis lipoidica diabeticorum (NLD) is a rare granulomatous skin manifestation that is strongly associated with diabetes mellitus. Necrobiosis lipoidica diabeticorum is more common among females and occurs primarily in the pretibial area.¹ Necrobiosis lipoidica diabeticorum may clinically manifest as single or multiple lesions that begin as small red papules and progress into patches or plaques. Lesions ultimately develop into areas of yellowish brown atrophic tissue with central depression and telangiectasia. The etiology of NLD is not completely understood, but it is thought to be a presentation of diabetic microangiopathy.¹ Histologically, NLD demonstrates broad horizontal zones of necrobiosis with a surrounding inflammatory infiltrate that is principally composed of histiocytes but also may contain multinucleated giant cells, lymphocytes, and plasma cells (Figures 1 and 2). Occasionally, sarcoidal granulomas are seen in NLD. There also may be thickening of vessel walls and edema of the endothelial cells.¹

Figure 1. Broad horizontal arrangement of necrobiotic collagen with a surrounding inflammatory infiltrate of histiocytes and lymphocytes seen in necrobiosis lipoidica diabeticorum (H&E, original magnification ×20).

Figure 2. High-power view demonstrating lymphocytes and plasma cells at the inferior border of the necrobiotic collagen seen in necrobiosis lipoidica diabeticorum (H&E, original magnification ×200).

Cutaneous Rosai-Dorfman disease (RDD) is characterized by the presence of diffuse, large, pale histiocytes (commonly known as Rosai-Dorfman cells) with an admixed infiltrate of lymphocytes and plasma cells (Figure 3).² Additionally, Rosai-Dorfman cells display emperipolesis. They stain positively for S-100 protein and CD68 and negatively for CD1a.² Clinically, cutaneous RDD has a myriad of manifestations but most commonly presents as cutaneous nodules that can be tender or pruritic. It also may be associated with systemic symptoms. Patients with cutaneous RDD often have an elevated erythrocyte sedimentation rate and concomitant anemia.²

Figure 3. Sea of pale histiocytes with a patchy infiltrate of lymphocytes and plasma cells seen in cutaneous Rosai-Dorfman disease. Lymphocytes are seen within the cytoplasm of the histiocytes (emperipolesis)(H&E, original magnification ×200).

Granuloma annulare demonstrates necrobiosis and palisaded granulomatous dermatitis similar to NLD; however, the necrobiotic foci in granuloma annulare usually are more focal than in NLD and typically are surrounded by well-formed palisaded granulomas. There also is an increase in dermal mucin (Figure 4), which can be highlighted on colloidal iron or Alcian blue staining.¹ Granuloma annulare also typically has scattered eosinophils rather than plasma cells as seen in NLD. Granuloma annulare also may present in an interstitial pattern, with scattered histiocytes, mucin, and eosinophils between collagen bundles. Granuloma annulare clinically presents as variably colored papules arranged in an annular pattern on the distal extremities but also can present as widespread papules or plaques.

Figure 4. Necrobiotic collagen with abundant mucin surrounded by palisaded histiocytes, often with eosinophils characteristic of granuloma annulare (H&E, original magnification ×100).

Juvenile xanthogranuloma (JXG) is a benign condition typically seen in children that is characterized by the presence of 1 or more pink or yellow nodules, most commonly presenting on the head and neck. Histologically, JXG demonstrates a dermal collection of histiocytes, lymphocytes, eosinophils, and characteristic Touton giant cells, which contain nuclei that are arranged in a wreathlike pattern and exhibit peripheral xanthomatization (Figure 5).³ The histiocytes in JXG typically stain positive for CD68 and negative for S-100 protein, though occasional S-100–positive cases are reported.³

Figure 5. Touton giant cells and occasional eosinophils in a sea of histiocytes and lymphocytes characterize juvenile xanthogranuloma (H&E, original magnification ×200).

Necrobiotic xanthogranuloma presents as yellowish to brown plaques and nodules most commonly in the periorbital area. Necrobiotic xanthogranuloma is strongly associated with monoclonal gammopathy, typically IgGk monoclonal gammopathy. Necrobiotic xanthogranuloma is histologically similar to NLD but is distinguished by a nodular pattern of inflammation and the frequent presence of cholesterol clefts (Figure 6).⁴

Necrobiosis lipoidica diabeticorum (NLD) is a rare granulomatous skin manifestation that is strongly associated with diabetes mellitus. Necrobiosis lipoidica diabeticorum is more common among females and occurs primarily in the pretibial area.¹ Necrobiosis lipoidica diabeticorum may clinically manifest as single or multiple lesions that begin as small red papules and progress into patches or plaques. Lesions ultimately develop into areas of yellowish brown atrophic tissue with central depression and telangiectasia. The etiology of NLD is not completely understood, but it is thought to be a presentation of diabetic microangiopathy.¹ Histologically, NLD demonstrates broad horizontal zones of necrobiosis with a surrounding inflammatory infiltrate that is principally composed of histiocytes but also may contain multinucleated giant cells, lymphocytes, and plasma cells (Figures 1 and 2). Occasionally, sarcoidal granulomas are seen in NLD. There also may be thickening of vessel walls and edema of the endothelial cells.¹

Figure 1. Broad horizontal arrangement of necrobiotic collagen with a surrounding inflammatory infiltrate of histiocytes and lymphocytes seen in necrobiosis lipoidica diabeticorum (H&E, original magnification ×20).

Figure 2. High-power view demonstrating lymphocytes and plasma cells at the inferior border of the necrobiotic collagen seen in necrobiosis lipoidica diabeticorum (H&E, original magnification ×200).

Cutaneous Rosai-Dorfman disease (RDD) is characterized by the presence of diffuse, large, pale histiocytes (commonly known as Rosai-Dorfman cells) with an admixed infiltrate of lymphocytes and plasma cells (Figure 3).² Additionally, Rosai-Dorfman cells display emperipolesis. They stain positively for S-100 protein and CD68 and negatively for CD1a.² Clinically, cutaneous RDD has a myriad of manifestations but most commonly presents as cutaneous nodules that can be tender or pruritic. It also may be associated with systemic symptoms. Patients with cutaneous RDD often have an elevated erythrocyte sedimentation rate and concomitant anemia.²

Figure 3. Sea of pale histiocytes with a patchy infiltrate of lymphocytes and plasma cells seen in cutaneous Rosai-Dorfman disease. Lymphocytes are seen within the cytoplasm of the histiocytes (emperipolesis)(H&E, original magnification ×200).

Granuloma annulare demonstrates necrobiosis and palisaded granulomatous dermatitis similar to NLD; however, the necrobiotic foci in granuloma annulare usually are more focal than in NLD and typically are surrounded by well-formed palisaded granulomas. There also is an increase in dermal mucin (Figure 4), which can be highlighted on colloidal iron or Alcian blue staining.¹ Granuloma annulare also typically has scattered eosinophils rather than plasma cells as seen in NLD. Granuloma annulare also may present in an interstitial pattern, with scattered histiocytes, mucin, and eosinophils between collagen bundles. Granuloma annulare clinically presents as variably colored papules arranged in an annular pattern on the distal extremities but also can present as widespread papules or plaques.

Figure 4. Necrobiotic collagen with abundant mucin surrounded by palisaded histiocytes, often with eosinophils characteristic of granuloma annulare (H&E, original magnification ×100).

Juvenile xanthogranuloma (JXG) is a benign condition typically seen in children that is characterized by the presence of 1 or more pink or yellow nodules, most commonly presenting on the head and neck. Histologically, JXG demonstrates a dermal collection of histiocytes, lymphocytes, eosinophils, and characteristic Touton giant cells, which contain nuclei that are arranged in a wreathlike pattern and exhibit peripheral xanthomatization (Figure 5).³ The histiocytes in JXG typically stain positive for CD68 and negative for S-100 protein, though occasional S-100–positive cases are reported.³

Figure 5. Touton giant cells and occasional eosinophils in a sea of histiocytes and lymphocytes characterize juvenile xanthogranuloma (H&E, original magnification ×200).

Necrobiotic xanthogranuloma presents as yellowish to brown plaques and nodules most commonly in the periorbital area. Necrobiotic xanthogranuloma is strongly associated with monoclonal gammopathy, typically IgGk monoclonal gammopathy. Necrobiotic xanthogranuloma is histologically similar to NLD but is distinguished by a nodular pattern of inflammation and the frequent presence of cholesterol clefts (Figure 6).⁴

Necrobiosis lipoidica diabeticorum (NLD) is a rare granulomatous skin manifestation that is strongly associated with diabetes mellitus. Necrobiosis lipoidica diabeticorum is more common among females and occurs primarily in the pretibial area.¹ Necrobiosis lipoidica diabeticorum may clinically manifest as single or multiple lesions that begin as small red papules and progress into patches or plaques. Lesions ultimately develop into areas of yellowish brown atrophic tissue with central depression and telangiectasia. The etiology of NLD is not completely understood, but it is thought to be a presentation of diabetic microangiopathy.¹ Histologically, NLD demonstrates broad horizontal zones of necrobiosis with a surrounding inflammatory infiltrate that is principally composed of histiocytes but also may contain multinucleated giant cells, lymphocytes, and plasma cells (Figures 1 and 2). Occasionally, sarcoidal granulomas are seen in NLD. There also may be thickening of vessel walls and edema of the endothelial cells.¹

Figure 1. Broad horizontal arrangement of necrobiotic collagen with a surrounding inflammatory infiltrate of histiocytes and lymphocytes seen in necrobiosis lipoidica diabeticorum (H&E, original magnification ×20).

Figure 2. High-power view demonstrating lymphocytes and plasma cells at the inferior border of the necrobiotic collagen seen in necrobiosis lipoidica diabeticorum (H&E, original magnification ×200).

Cutaneous Rosai-Dorfman disease (RDD) is characterized by the presence of diffuse, large, pale histiocytes (commonly known as Rosai-Dorfman cells) with an admixed infiltrate of lymphocytes and plasma cells (Figure 3).² Additionally, Rosai-Dorfman cells display emperipolesis. They stain positively for S-100 protein and CD68 and negatively for CD1a.² Clinically, cutaneous RDD has a myriad of manifestations but most commonly presents as cutaneous nodules that can be tender or pruritic. It also may be associated with systemic symptoms. Patients with cutaneous RDD often have an elevated erythrocyte sedimentation rate and concomitant anemia.²

Figure 3. Sea of pale histiocytes with a patchy infiltrate of lymphocytes and plasma cells seen in cutaneous Rosai-Dorfman disease. Lymphocytes are seen within the cytoplasm of the histiocytes (emperipolesis)(H&E, original magnification ×200).

Granuloma annulare demonstrates necrobiosis and palisaded granulomatous dermatitis similar to NLD; however, the necrobiotic foci in granuloma annulare usually are more focal than in NLD and typically are surrounded by well-formed palisaded granulomas. There also is an increase in dermal mucin (Figure 4), which can be highlighted on colloidal iron or Alcian blue staining.¹ Granuloma annulare also typically has scattered eosinophils rather than plasma cells as seen in NLD. Granuloma annulare also may present in an interstitial pattern, with scattered histiocytes, mucin, and eosinophils between collagen bundles. Granuloma annulare clinically presents as variably colored papules arranged in an annular pattern on the distal extremities but also can present as widespread papules or plaques.

Figure 4. Necrobiotic collagen with abundant mucin surrounded by palisaded histiocytes, often with eosinophils characteristic of granuloma annulare (H&E, original magnification ×100).

Juvenile xanthogranuloma (JXG) is a benign condition typically seen in children that is characterized by the presence of 1 or more pink or yellow nodules, most commonly presenting on the head and neck. Histologically, JXG demonstrates a dermal collection of histiocytes, lymphocytes, eosinophils, and characteristic Touton giant cells, which contain nuclei that are arranged in a wreathlike pattern and exhibit peripheral xanthomatization (Figure 5).³ The histiocytes in JXG typically stain positive for CD68 and negative for S-100 protein, though occasional S-100–positive cases are reported.³

Figure 5. Touton giant cells and occasional eosinophils in a sea of histiocytes and lymphocytes characterize juvenile xanthogranuloma (H&E, original magnification ×200).

Necrobiotic xanthogranuloma presents as yellowish to brown plaques and nodules most commonly in the periorbital area. Necrobiotic xanthogranuloma is strongly associated with monoclonal gammopathy, typically IgGk monoclonal gammopathy. Necrobiotic xanthogranuloma is histologically similar to NLD but is distinguished by a nodular pattern of inflammation and the frequent presence of cholesterol clefts (Figure 6).⁴

The coexistence of more than one cutaneous adnexal neoplasm in a single biopsy specimen is unusual and is most frequently recognized in the context of a nevus sebaceous or Brooke-Spiegler syndrome, an autosomal-dominant inherited disease characterized by cutaneous adnexal neoplasms, most commonly cylindromas and trichoepitheliomas.^1-3 Brooke-Spiegler syndrome is caused by germline mutations in the cylindromatosis gene, CYLD, located on band 16q12; it functions as a tumor suppressor gene and has regulatory roles in development, immunity, and inflammation.¹ Weyers et al³ first recognized the tendency for adnexal collision tumors to present in patients with Brooke-Spiegler syndrome; they reported a patient with Brooke-Spiegler syndrome with spiradenomas found in the immediate vicinity of trichoepitheliomas and in continuity with hair follicles.

Spiradenomas are composed of large, sharply demarcated, rounded nodules of basaloid cells with little cytoplasm (Figure 1).⁴ The basaloid nodules may demonstrate a trabecular architecture, and on close inspection 2 cell types—paler cells with more cytoplasm and darker cells with less cytoplasm—are distinguishable (Figure 2A). Lymphocytes often are scattered within the tumor nodules and/or stroma. In Brooke-Spiegler syndrome, collision tumors containing a spiradenomatous component in collision with trichoepithelioma are not uncommon.¹ Spiradenomas in Brooke-Spiegler syndrome have been reported to contain sebaceous differentiation or foci with an adenoid cystic carcinoma (ACC)–like pattern and are known to occur as hybrid lesions of spiradenoma and cylindroma or trichoepithelioma (as in this case).

Figure 1. Two distinct neoplasms are apparent, side by side, with an intervening hair follicle. The spirade-noma (right) is a large, sharply demarcated, rounded nodule of basaloid cells containing little cytoplasm. The trichoepithelioma (left) is composed of lobules of basaloid cells with a cribriform architecture, surrounded by a fibroblast-rich stroma. Mucin is apparent within the cystic spaces (H&E, original magnification ×2).

In this case, 2 distinct neoplasms (spiradenoma and trichoepithelioma) are apparent, side by side, with an intervening hair follicle (Figure 1). Trichoepitheliomas, also known as cribriform trichoblastomas,⁵ are characterized by lobules of basaloid cells resembling basal cell carcinoma surrounded by a fibroblast-rich stroma. They often contain fingerlike projections and adopt a cribriform morphology within the tumor lobules (Figure 2B).⁴ Numerous horn cysts may be present, but their absence does not preclude the diagnosis. Mucin may be present within the cribriform tumor islands (Figure 2B) but not in the stroma. Characteristically, trichoepitheliomas are distinctly negative for CK7 (Figure 3), and unlike spiradenomas, they lack a myoepithelial component.⁶ This staining pattern in combination with the tumor’s proximity to an adjacent hair follicle makes a diagnosis of trichoepithelioma and spiradenoma collision tumor most likely and supports a clinical suspicion for Brooke-Spiegler syndrome.

Figure 2. Spiradenomas may demonstrate a trabecular architecture, and on close inspection 2 cell types—paler cells with more cytoplasm and darker cells with less cytoplasm—are distinguishable. Lymphocytes are scattered within the tumor nodules and/or stroma (A)(H&E, original magnification ×100).The individual lobules within a trichoepithelioma can adopt a cribriform morphology, and mucin may be present within the cystic spaces (B)(H&E, original magnification ×90).

Although spiradenomas sometimes contain cystic cavities (microcystic change), they typically are filled with finely granular eosinophilic material, not mucin, that is diastase resistant and periodic acid–Schiff positive (Figure 4).⁷ Spiradenomas classically stain positive with CK7 (Figure 3), epithelial membrane antigen, and carcinoembryonic antigen, and have a substantial myoepithelial component, as evidenced by the myoepithelial component staining with p63, S-100, and smooth muscle actin (SMA).^7-9 The distinct lack of staining with CK7 and SMA in the tumor on the left in Figure 3 confirms that these tumors are of different lineage, rather than representing cystic change within a spiradenoma.

Figure 3. Positive staining with CK7 can be noted in the spiradenoma (right) and negative staining is noted in the trichoepithelioma (left)(original magnification ×3).

Figure 4. Cystic cavities within a spiradenoma are filled with finely granular eosinophilic material, not mucin, that is diastase resistant and periodic acid–Schiff positive (H&E, original magnification ×30).

Adenoid cystic carcinoma is a rare neoplasm that may occur in a primary cutaneous form, as a direct extension from an underlying salivary gland neoplasm, or rarely as a focal pattern within spiradenomas occurring both sporadically or in the context of Brooke-Spiegler syndrome.^2,7 The tumor is composed of variably sized cribriform islands of basaloid to pink cells concentrically arranged around glandlike spaces filled with mucin (Figure 5A). In contrast to trichoepithelioma, ACC occurs in the mid to deep dermis, often extending into subcutaneous fat with an infiltrative border, and is not often found in close proximity to hair follicles.⁷ Characteristically, hyaline basement membrane–like material that is periodic acid–Schiff positive is found between the tumor cells and also surrounding the individual lobules. Immunohistochemically, ACC has a myoepithelial component that stains positive with SMA, S-100, and p63; additionally, the tumor cells express low- and high-molecular-weight keratin and demonstrate variable epithelial membrane antigen positivity.¹⁰ In the current case, the superficial location, close association with a hair follicle, and lack of staining with both CK7 (Figure 3) and SMA (not shown) make ACC arising within a spiradenoma a less likely diagnosis.

Cylindromas are composed of basaloid islands interconnected in a jigsaw puzzle configuration (Figure 5B).⁴ Similar to spiradenomas, they also are composed of 2 cell populations. Characteristically, the tumor islands are outlined by a hyalinized eosinophilic basement membrane. Hyalinized droplets of basement membrane zone material also may be noted in the islands. Unlike spiradenomas, they lack both intratumoral lymphocytes and a trabecular growth pattern. Although spiradenocylindromas (cylindroma and spiradenoma collision tumors) are perhaps the most common collision tumor associated with Brooke-Spiegler syndrome, there is no evidence suggesting the presence of a cylindroma in the current case.

Figure 5. Adenoid cystic carcinoma is composed of variably sized cribriform islands of basaloid to pink cells concentrically arranged around glandlike spaces filled with mucin (A)(H&E, original magnification ×20). Cylindromas are composed of basaloid islands interconnected in a jigsaw puzzle configuration. Characteristically, the tumor islands are outlined by a hyalinized eosinophilic basement membrane (B) (H&E, original magnification ×100).

Primary cutaneous mucinous carcinoma is a rare neoplasm with a predilection for the eyelids; lesions occurring outside of this facial distribution, particularly of the breast, warrant a workup for metastatic disease.⁷ It typically occurs in the deeper dermis with involvement of the subcutaneous fat and is characterized by delicate fibrous septa enveloping large lakes of mucin, which contain islands of tumor cells (Figure 6). It has not been reported in association with spiradenomas. In addition, the tumor cells typically are CK7 positive.

Figure 6. Mucinous carcinoma is characterized by delicate fibrous septa enclosing large lakes of mucin containing islands of tumor cells (H&E, original magnification ×20).

The coexistence of more than one cutaneous adnexal neoplasm in a single biopsy specimen is unusual and is most frequently recognized in the context of a nevus sebaceous or Brooke-Spiegler syndrome, an autosomal-dominant inherited disease characterized by cutaneous adnexal neoplasms, most commonly cylindromas and trichoepitheliomas.^1-3 Brooke-Spiegler syndrome is caused by germline mutations in the cylindromatosis gene, CYLD, located on band 16q12; it functions as a tumor suppressor gene and has regulatory roles in development, immunity, and inflammation.¹ Weyers et al³ first recognized the tendency for adnexal collision tumors to present in patients with Brooke-Spiegler syndrome; they reported a patient with Brooke-Spiegler syndrome with spiradenomas found in the immediate vicinity of trichoepitheliomas and in continuity with hair follicles.

Spiradenomas are composed of large, sharply demarcated, rounded nodules of basaloid cells with little cytoplasm (Figure 1).⁴ The basaloid nodules may demonstrate a trabecular architecture, and on close inspection 2 cell types—paler cells with more cytoplasm and darker cells with less cytoplasm—are distinguishable (Figure 2A). Lymphocytes often are scattered within the tumor nodules and/or stroma. In Brooke-Spiegler syndrome, collision tumors containing a spiradenomatous component in collision with trichoepithelioma are not uncommon.¹ Spiradenomas in Brooke-Spiegler syndrome have been reported to contain sebaceous differentiation or foci with an adenoid cystic carcinoma (ACC)–like pattern and are known to occur as hybrid lesions of spiradenoma and cylindroma or trichoepithelioma (as in this case).

Figure 1. Two distinct neoplasms are apparent, side by side, with an intervening hair follicle. The spirade-noma (right) is a large, sharply demarcated, rounded nodule of basaloid cells containing little cytoplasm. The trichoepithelioma (left) is composed of lobules of basaloid cells with a cribriform architecture, surrounded by a fibroblast-rich stroma. Mucin is apparent within the cystic spaces (H&E, original magnification ×2).

In this case, 2 distinct neoplasms (spiradenoma and trichoepithelioma) are apparent, side by side, with an intervening hair follicle (Figure 1). Trichoepitheliomas, also known as cribriform trichoblastomas,⁵ are characterized by lobules of basaloid cells resembling basal cell carcinoma surrounded by a fibroblast-rich stroma. They often contain fingerlike projections and adopt a cribriform morphology within the tumor lobules (Figure 2B).⁴ Numerous horn cysts may be present, but their absence does not preclude the diagnosis. Mucin may be present within the cribriform tumor islands (Figure 2B) but not in the stroma. Characteristically, trichoepitheliomas are distinctly negative for CK7 (Figure 3), and unlike spiradenomas, they lack a myoepithelial component.⁶ This staining pattern in combination with the tumor’s proximity to an adjacent hair follicle makes a diagnosis of trichoepithelioma and spiradenoma collision tumor most likely and supports a clinical suspicion for Brooke-Spiegler syndrome.

Figure 2. Spiradenomas may demonstrate a trabecular architecture, and on close inspection 2 cell types—paler cells with more cytoplasm and darker cells with less cytoplasm—are distinguishable. Lymphocytes are scattered within the tumor nodules and/or stroma (A)(H&E, original magnification ×100).The individual lobules within a trichoepithelioma can adopt a cribriform morphology, and mucin may be present within the cystic spaces (B)(H&E, original magnification ×90).

Although spiradenomas sometimes contain cystic cavities (microcystic change), they typically are filled with finely granular eosinophilic material, not mucin, that is diastase resistant and periodic acid–Schiff positive (Figure 4).⁷ Spiradenomas classically stain positive with CK7 (Figure 3), epithelial membrane antigen, and carcinoembryonic antigen, and have a substantial myoepithelial component, as evidenced by the myoepithelial component staining with p63, S-100, and smooth muscle actin (SMA).^7-9 The distinct lack of staining with CK7 and SMA in the tumor on the left in Figure 3 confirms that these tumors are of different lineage, rather than representing cystic change within a spiradenoma.

Figure 3. Positive staining with CK7 can be noted in the spiradenoma (right) and negative staining is noted in the trichoepithelioma (left)(original magnification ×3).

Figure 4. Cystic cavities within a spiradenoma are filled with finely granular eosinophilic material, not mucin, that is diastase resistant and periodic acid–Schiff positive (H&E, original magnification ×30).

Adenoid cystic carcinoma is a rare neoplasm that may occur in a primary cutaneous form, as a direct extension from an underlying salivary gland neoplasm, or rarely as a focal pattern within spiradenomas occurring both sporadically or in the context of Brooke-Spiegler syndrome.^2,7 The tumor is composed of variably sized cribriform islands of basaloid to pink cells concentrically arranged around glandlike spaces filled with mucin (Figure 5A). In contrast to trichoepithelioma, ACC occurs in the mid to deep dermis, often extending into subcutaneous fat with an infiltrative border, and is not often found in close proximity to hair follicles.⁷ Characteristically, hyaline basement membrane–like material that is periodic acid–Schiff positive is found between the tumor cells and also surrounding the individual lobules. Immunohistochemically, ACC has a myoepithelial component that stains positive with SMA, S-100, and p63; additionally, the tumor cells express low- and high-molecular-weight keratin and demonstrate variable epithelial membrane antigen positivity.¹⁰ In the current case, the superficial location, close association with a hair follicle, and lack of staining with both CK7 (Figure 3) and SMA (not shown) make ACC arising within a spiradenoma a less likely diagnosis.

Cylindromas are composed of basaloid islands interconnected in a jigsaw puzzle configuration (Figure 5B).⁴ Similar to spiradenomas, they also are composed of 2 cell populations. Characteristically, the tumor islands are outlined by a hyalinized eosinophilic basement membrane. Hyalinized droplets of basement membrane zone material also may be noted in the islands. Unlike spiradenomas, they lack both intratumoral lymphocytes and a trabecular growth pattern. Although spiradenocylindromas (cylindroma and spiradenoma collision tumors) are perhaps the most common collision tumor associated with Brooke-Spiegler syndrome, there is no evidence suggesting the presence of a cylindroma in the current case.

Figure 5. Adenoid cystic carcinoma is composed of variably sized cribriform islands of basaloid to pink cells concentrically arranged around glandlike spaces filled with mucin (A)(H&E, original magnification ×20). Cylindromas are composed of basaloid islands interconnected in a jigsaw puzzle configuration. Characteristically, the tumor islands are outlined by a hyalinized eosinophilic basement membrane (B) (H&E, original magnification ×100).

Primary cutaneous mucinous carcinoma is a rare neoplasm with a predilection for the eyelids; lesions occurring outside of this facial distribution, particularly of the breast, warrant a workup for metastatic disease.⁷ It typically occurs in the deeper dermis with involvement of the subcutaneous fat and is characterized by delicate fibrous septa enveloping large lakes of mucin, which contain islands of tumor cells (Figure 6). It has not been reported in association with spiradenomas. In addition, the tumor cells typically are CK7 positive.

Figure 6. Mucinous carcinoma is characterized by delicate fibrous septa enclosing large lakes of mucin containing islands of tumor cells (H&E, original magnification ×20).

The coexistence of more than one cutaneous adnexal neoplasm in a single biopsy specimen is unusual and is most frequently recognized in the context of a nevus sebaceous or Brooke-Spiegler syndrome, an autosomal-dominant inherited disease characterized by cutaneous adnexal neoplasms, most commonly cylindromas and trichoepitheliomas.^1-3 Brooke-Spiegler syndrome is caused by germline mutations in the cylindromatosis gene, CYLD, located on band 16q12; it functions as a tumor suppressor gene and has regulatory roles in development, immunity, and inflammation.¹ Weyers et al³ first recognized the tendency for adnexal collision tumors to present in patients with Brooke-Spiegler syndrome; they reported a patient with Brooke-Spiegler syndrome with spiradenomas found in the immediate vicinity of trichoepitheliomas and in continuity with hair follicles.

Spiradenomas are composed of large, sharply demarcated, rounded nodules of basaloid cells with little cytoplasm (Figure 1).⁴ The basaloid nodules may demonstrate a trabecular architecture, and on close inspection 2 cell types—paler cells with more cytoplasm and darker cells with less cytoplasm—are distinguishable (Figure 2A). Lymphocytes often are scattered within the tumor nodules and/or stroma. In Brooke-Spiegler syndrome, collision tumors containing a spiradenomatous component in collision with trichoepithelioma are not uncommon.¹ Spiradenomas in Brooke-Spiegler syndrome have been reported to contain sebaceous differentiation or foci with an adenoid cystic carcinoma (ACC)–like pattern and are known to occur as hybrid lesions of spiradenoma and cylindroma or trichoepithelioma (as in this case).

Figure 1. Two distinct neoplasms are apparent, side by side, with an intervening hair follicle. The spirade-noma (right) is a large, sharply demarcated, rounded nodule of basaloid cells containing little cytoplasm. The trichoepithelioma (left) is composed of lobules of basaloid cells with a cribriform architecture, surrounded by a fibroblast-rich stroma. Mucin is apparent within the cystic spaces (H&E, original magnification ×2).

In this case, 2 distinct neoplasms (spiradenoma and trichoepithelioma) are apparent, side by side, with an intervening hair follicle (Figure 1). Trichoepitheliomas, also known as cribriform trichoblastomas,⁵ are characterized by lobules of basaloid cells resembling basal cell carcinoma surrounded by a fibroblast-rich stroma. They often contain fingerlike projections and adopt a cribriform morphology within the tumor lobules (Figure 2B).⁴ Numerous horn cysts may be present, but their absence does not preclude the diagnosis. Mucin may be present within the cribriform tumor islands (Figure 2B) but not in the stroma. Characteristically, trichoepitheliomas are distinctly negative for CK7 (Figure 3), and unlike spiradenomas, they lack a myoepithelial component.⁶ This staining pattern in combination with the tumor’s proximity to an adjacent hair follicle makes a diagnosis of trichoepithelioma and spiradenoma collision tumor most likely and supports a clinical suspicion for Brooke-Spiegler syndrome.

Figure 2. Spiradenomas may demonstrate a trabecular architecture, and on close inspection 2 cell types—paler cells with more cytoplasm and darker cells with less cytoplasm—are distinguishable. Lymphocytes are scattered within the tumor nodules and/or stroma (A)(H&E, original magnification ×100).The individual lobules within a trichoepithelioma can adopt a cribriform morphology, and mucin may be present within the cystic spaces (B)(H&E, original magnification ×90).

Although spiradenomas sometimes contain cystic cavities (microcystic change), they typically are filled with finely granular eosinophilic material, not mucin, that is diastase resistant and periodic acid–Schiff positive (Figure 4).⁷ Spiradenomas classically stain positive with CK7 (Figure 3), epithelial membrane antigen, and carcinoembryonic antigen, and have a substantial myoepithelial component, as evidenced by the myoepithelial component staining with p63, S-100, and smooth muscle actin (SMA).^7-9 The distinct lack of staining with CK7 and SMA in the tumor on the left in Figure 3 confirms that these tumors are of different lineage, rather than representing cystic change within a spiradenoma.

Figure 3. Positive staining with CK7 can be noted in the spiradenoma (right) and negative staining is noted in the trichoepithelioma (left)(original magnification ×3).

Figure 4. Cystic cavities within a spiradenoma are filled with finely granular eosinophilic material, not mucin, that is diastase resistant and periodic acid–Schiff positive (H&E, original magnification ×30).

Adenoid cystic carcinoma is a rare neoplasm that may occur in a primary cutaneous form, as a direct extension from an underlying salivary gland neoplasm, or rarely as a focal pattern within spiradenomas occurring both sporadically or in the context of Brooke-Spiegler syndrome.^2,7 The tumor is composed of variably sized cribriform islands of basaloid to pink cells concentrically arranged around glandlike spaces filled with mucin (Figure 5A). In contrast to trichoepithelioma, ACC occurs in the mid to deep dermis, often extending into subcutaneous fat with an infiltrative border, and is not often found in close proximity to hair follicles.⁷ Characteristically, hyaline basement membrane–like material that is periodic acid–Schiff positive is found between the tumor cells and also surrounding the individual lobules. Immunohistochemically, ACC has a myoepithelial component that stains positive with SMA, S-100, and p63; additionally, the tumor cells express low- and high-molecular-weight keratin and demonstrate variable epithelial membrane antigen positivity.¹⁰ In the current case, the superficial location, close association with a hair follicle, and lack of staining with both CK7 (Figure 3) and SMA (not shown) make ACC arising within a spiradenoma a less likely diagnosis.

Cylindromas are composed of basaloid islands interconnected in a jigsaw puzzle configuration (Figure 5B).⁴ Similar to spiradenomas, they also are composed of 2 cell populations. Characteristically, the tumor islands are outlined by a hyalinized eosinophilic basement membrane. Hyalinized droplets of basement membrane zone material also may be noted in the islands. Unlike spiradenomas, they lack both intratumoral lymphocytes and a trabecular growth pattern. Although spiradenocylindromas (cylindroma and spiradenoma collision tumors) are perhaps the most common collision tumor associated with Brooke-Spiegler syndrome, there is no evidence suggesting the presence of a cylindroma in the current case.

Figure 5. Adenoid cystic carcinoma is composed of variably sized cribriform islands of basaloid to pink cells concentrically arranged around glandlike spaces filled with mucin (A)(H&E, original magnification ×20). Cylindromas are composed of basaloid islands interconnected in a jigsaw puzzle configuration. Characteristically, the tumor islands are outlined by a hyalinized eosinophilic basement membrane (B) (H&E, original magnification ×100).

Primary cutaneous mucinous carcinoma is a rare neoplasm with a predilection for the eyelids; lesions occurring outside of this facial distribution, particularly of the breast, warrant a workup for metastatic disease.⁷ It typically occurs in the deeper dermis with involvement of the subcutaneous fat and is characterized by delicate fibrous septa enveloping large lakes of mucin, which contain islands of tumor cells (Figure 6). It has not been reported in association with spiradenomas. In addition, the tumor cells typically are CK7 positive.

Figure 6. Mucinous carcinoma is characterized by delicate fibrous septa enclosing large lakes of mucin containing islands of tumor cells (H&E, original magnification ×20).

The larvae of Onchocerca volvulus, a nematode that is most commonly found in tropical Africa, Yemen, Central America, and South America, are transmitted by flies of the genus Simulium that breed near fast-flowing rivers.¹ The flies bite the host and transmit the larvae, and the larvae then mature into adults within the skin and subcutis, forming nodules that typically are not painful. The worms may reside within the skin for years and produce microfilariae, which can migrate and cause visual impairment, blindness, or a pruritic papular rash.¹

The nematode produces a nodule within the dermis or subcutis with surrounding fibrous tissue and a mixed inflammatory infiltrate with eosinophils (Figure 1). In some cases, microfilariae can be seen within the lymphatics or within the uteri of the worms.¹ Male and female worms typically are present and have a corrugated cuticle with a thin underlying layer of striated muscle. The females have paired uteri, which usually contain microfilariae² (Figure 2).

Figure 1. Cross-section of a nematode with surrounding inflammatory reaction, characteristic of onchocerciasis (H&E, original magnification ×20).

Figure 2. Onchocerca volvulus with a cuticle, underlying thin layer of muscle, and paired uteri containing microfilariae (H&E, original magnification ×100).

Dirofilaria repens also is a nematode that produces a subcutaneous nodule with an inflammatory reaction. This worm typically has a thick cuticle with longitudinal ridges, long thick muscle, and lateral cords.³ Additionally, because humans are not the usual host, Dirofilaria species do not complete their lifecycle and typically are not gravid, unlike Onchocerca species.

Myiasis is the presence of fly larvae within the skin. The larvae demonstrate a thick hyaline cuticle with pigmented brown-yellow spikes (Figure 3). There is a thick muscular layer under the cuticle and a tubular tracheal system containing vertical striations. The digestive system has an epithelial lining with prominent vessels. Adipose tissue with granulated cytoplasm, prominent nuclei, and coarse chromatin also are present.⁴

Figure 3. A fly larva demonstrates a thick hyaline cuticle with yellow spikes, characteristic of myiasis (H&E, original magnification ×40).

Scabies mites (Figure 4), ova, and scybala are present within the stratum corneum. A mixed inflammatory infiltrate also can be present.¹ Tungiasis is caused by burrowing fleas and typically occurs on acral skin; therefore, it is more frequently found in the superficial portion of the skin. Erythrocytes usually are present in the gastrointestinal tract, and the females usually are gravid.² A surrounding mixed inflammatory infiltrate is present, and necrosis also can occur (Figure 5).¹

Figure 4. Scabies mites within the stratum corneum (H&E, original magnification ×100).

Figure 5. Tunga penetrans at the surface of acral skin. Erythrocytes can be noted within the gastrointestinal tract (H&E, original magnification ×40).

The larvae of Onchocerca volvulus, a nematode that is most commonly found in tropical Africa, Yemen, Central America, and South America, are transmitted by flies of the genus Simulium that breed near fast-flowing rivers.¹ The flies bite the host and transmit the larvae, and the larvae then mature into adults within the skin and subcutis, forming nodules that typically are not painful. The worms may reside within the skin for years and produce microfilariae, which can migrate and cause visual impairment, blindness, or a pruritic papular rash.¹

The nematode produces a nodule within the dermis or subcutis with surrounding fibrous tissue and a mixed inflammatory infiltrate with eosinophils (Figure 1). In some cases, microfilariae can be seen within the lymphatics or within the uteri of the worms.¹ Male and female worms typically are present and have a corrugated cuticle with a thin underlying layer of striated muscle. The females have paired uteri, which usually contain microfilariae² (Figure 2).

Figure 1. Cross-section of a nematode with surrounding inflammatory reaction, characteristic of onchocerciasis (H&E, original magnification ×20).

Figure 2. Onchocerca volvulus with a cuticle, underlying thin layer of muscle, and paired uteri containing microfilariae (H&E, original magnification ×100).

Dirofilaria repens also is a nematode that produces a subcutaneous nodule with an inflammatory reaction. This worm typically has a thick cuticle with longitudinal ridges, long thick muscle, and lateral cords.³ Additionally, because humans are not the usual host, Dirofilaria species do not complete their lifecycle and typically are not gravid, unlike Onchocerca species.

Myiasis is the presence of fly larvae within the skin. The larvae demonstrate a thick hyaline cuticle with pigmented brown-yellow spikes (Figure 3). There is a thick muscular layer under the cuticle and a tubular tracheal system containing vertical striations. The digestive system has an epithelial lining with prominent vessels. Adipose tissue with granulated cytoplasm, prominent nuclei, and coarse chromatin also are present.⁴

Figure 3. A fly larva demonstrates a thick hyaline cuticle with yellow spikes, characteristic of myiasis (H&E, original magnification ×40).

Scabies mites (Figure 4), ova, and scybala are present within the stratum corneum. A mixed inflammatory infiltrate also can be present.¹ Tungiasis is caused by burrowing fleas and typically occurs on acral skin; therefore, it is more frequently found in the superficial portion of the skin. Erythrocytes usually are present in the gastrointestinal tract, and the females usually are gravid.² A surrounding mixed inflammatory infiltrate is present, and necrosis also can occur (Figure 5).¹

Figure 4. Scabies mites within the stratum corneum (H&E, original magnification ×100).

Figure 5. Tunga penetrans at the surface of acral skin. Erythrocytes can be noted within the gastrointestinal tract (H&E, original magnification ×40).

The larvae of Onchocerca volvulus, a nematode that is most commonly found in tropical Africa, Yemen, Central America, and South America, are transmitted by flies of the genus Simulium that breed near fast-flowing rivers.¹ The flies bite the host and transmit the larvae, and the larvae then mature into adults within the skin and subcutis, forming nodules that typically are not painful. The worms may reside within the skin for years and produce microfilariae, which can migrate and cause visual impairment, blindness, or a pruritic papular rash.¹

The nematode produces a nodule within the dermis or subcutis with surrounding fibrous tissue and a mixed inflammatory infiltrate with eosinophils (Figure 1). In some cases, microfilariae can be seen within the lymphatics or within the uteri of the worms.¹ Male and female worms typically are present and have a corrugated cuticle with a thin underlying layer of striated muscle. The females have paired uteri, which usually contain microfilariae² (Figure 2).

Figure 1. Cross-section of a nematode with surrounding inflammatory reaction, characteristic of onchocerciasis (H&E, original magnification ×20).

Figure 2. Onchocerca volvulus with a cuticle, underlying thin layer of muscle, and paired uteri containing microfilariae (H&E, original magnification ×100).

Dirofilaria repens also is a nematode that produces a subcutaneous nodule with an inflammatory reaction. This worm typically has a thick cuticle with longitudinal ridges, long thick muscle, and lateral cords.³ Additionally, because humans are not the usual host, Dirofilaria species do not complete their lifecycle and typically are not gravid, unlike Onchocerca species.

Myiasis is the presence of fly larvae within the skin. The larvae demonstrate a thick hyaline cuticle with pigmented brown-yellow spikes (Figure 3). There is a thick muscular layer under the cuticle and a tubular tracheal system containing vertical striations. The digestive system has an epithelial lining with prominent vessels. Adipose tissue with granulated cytoplasm, prominent nuclei, and coarse chromatin also are present.⁴

Figure 3. A fly larva demonstrates a thick hyaline cuticle with yellow spikes, characteristic of myiasis (H&E, original magnification ×40).

Scabies mites (Figure 4), ova, and scybala are present within the stratum corneum. A mixed inflammatory infiltrate also can be present.¹ Tungiasis is caused by burrowing fleas and typically occurs on acral skin; therefore, it is more frequently found in the superficial portion of the skin. Erythrocytes usually are present in the gastrointestinal tract, and the females usually are gravid.² A surrounding mixed inflammatory infiltrate is present, and necrosis also can occur (Figure 5).¹

Figure 4. Scabies mites within the stratum corneum (H&E, original magnification ×100).

Figure 5. Tunga penetrans at the surface of acral skin. Erythrocytes can be noted within the gastrointestinal tract (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).

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).

Localized cutaneous argyria often presents as asymptomatic black or blue-gray pigmented macules in areas of the skin exposed to silver-containing compounds.¹ Silver may enter the skin by traumatic implantation or absorption via eccrine sweat glands.² Our patient witnessed a gun fight several years ago while on a mission trip and sustained multiple shrapnel wounds.

As in our patient, hyperpigmentation may appear years following initial exposure. Over time, incident light reduces colorless silver salts and compounds to black elemental silver.³ It also has been suggested that metallic silver granules stimulate tyrosine kinase activity, leading to locally increased melanin production.⁴ Together, these processes result in the clinical appearance of a blue-black macule. Despite its long-standing association with silver, this appearance also has been noted with deposition of other metals.⁵ Histologically, metal deposits can be seen as black granules surrounding eccrine glands, blood vessels, and elastic fibers on higher magnification.⁶ Granules also may be found in sebaceous glands and arrector pili muscle fibers. These findings do not distinguish from generalized argyria due to increased serum silver levels; however, some cases of localized cutaneous argyria have demonstrated spheroid black globules with surrounding collagen necrosis,¹ which have not been reported with generalized disease. Localized cutaneous argyria also may be associated with ocher pigmentation of thickened collagen fibers, resembling changes typically found in alkaptonuria, an inherited deficiency of homogentisic acid oxidase (an enzyme involved in tyrosine metabolism).⁷ The resulting buildup of metabolic intermediates leads to ochronosis, a deposition of ocher-pigmented intermediates in connective tissue throughout the body. In the skin, ocher pigmentation occurs in elastic fibers of the reticular dermis.¹ Grossly, these changes result in a blue-gray discoloration of the skin due to a light-scattering phenomenon known as the Tyndall effect. Exogenous ochronosis also can occur, most commonly from the topical application of hydroquinone or other skin-lightening compounds.^1,5 Ocher  pigmentation occurring in the setting of localized cutaneous argyria is referred to as pseudo-ochronosis, a finding first described by Robinson-Bostom et al.¹ The etiology of this condition is poorly understood, but Robinson-Bostom et al¹ noted the appearance of dark metal granules surrounding collagen bundles and hypothesized that metal aggregates surrounding collagen bundles in pseudo-ochronosis cause a homogenized appearance under light microscopy. Yellow-brown, swollen, homogenized collagen bundles can be visualized in the reticular dermis with surrounding deposition of metal granules (Figures 1 and 2).¹ Typical patterns of granule deposition in localized argyria also are present.

A blue nevus is a collection of proliferating dermal melanocytes. Many histologic subtypes exist and there may be extensive variability in the extent of sclerosis, cellular architecture, and tissue cellularity between each variant.⁸ Blue nevi commonly present as blue-black hyperpigmentation in the dermis and subcutaneous tissue.⁹ Histologically, they are characterized by slender, bipolar, dendritic melanocytes in a sclerotic stroma (Figure 3).⁸ Melanocytes are highly pigmented and contain small monomorphic nuclei. Lesions are relatively homogenous and typically are restricted to the dermis with epidermal sparing.⁹ Dark granules and ocher fibers are absent.

Long-term use of hydroxychloroquine or other antimalarials may cause a macular pattern of blue-gray hyperpigmentation.¹⁰ Biopsy specimens typically reveal coarse, yellow-brown pigment granules primarily affecting the superficial dermis (Figure 4). Granules are found both extracellularly and within macrophages. Fontana-Masson silver staining may identify melanin, as hydroxychloroquine-melanin binding may contribute to patterns of hyperpigmentation.¹⁰ Hemosiderin often is present in cases of hydroxychloroquine pigmentation. Preceding ecchymosis appears to favor the deposition of hydroxychloroquine in the skin.¹¹ The absence of dark metal granules helps distinguish hydroxychloroquine pigmentation from argyria.

Regressed melanomas may appear clinically as gray macules. These lesions arise in cases of malignant melanoma that spontaneously regress without treatment. Spontaneous regression occurs in 10% to 35% of cases depending on tumor subtype.¹² Lesions can have a variable appearance based on the degree of regression. Partial regression is demonstrated by mixed melanosis and fibrosis in the dermis (Figure 5).^13,14 Melanin is housed within melanophages present in a variably expanded papillary dermis. Tumors in early stages of regression can be surrounded by an inflammatory infiltrate, which becomes diminished at later stages. However, a few exceptional cases have been noted with extensive inflammatory infiltrate and no residual tumor.¹⁴ Completely regressed lesions typically appear as a band of dermal melanophages in the absence of inflammation or melanocytic atypia.¹⁵ The finding of regressed melanoma should prompt further investigation including sentinel lymph node biopsy, as it may be associated with metastasis.

Tattooing occurs following traumatic penetration of the skin with impregnation of pigmented foreign material into deep dermal layers.¹⁶ Histologic examination usually reveals clumps of fine particulate material in the dermis (Figure 6). The color of the pigment depends on the agent used. For example, graphite appears as black particles that may be confused with localized cutaneous argyria. Distinction can be made using elemental identification techniques such as energy-dispersive X-ray spectroscopy.¹ The intensity of the pigment in granules found in tattoos or localized cutaneous argyria will fail to diminish with the application of melanin bleach.⁶

Localized cutaneous argyria often presents as asymptomatic black or blue-gray pigmented macules in areas of the skin exposed to silver-containing compounds.¹ Silver may enter the skin by traumatic implantation or absorption via eccrine sweat glands.² Our patient witnessed a gun fight several years ago while on a mission trip and sustained multiple shrapnel wounds.

As in our patient, hyperpigmentation may appear years following initial exposure. Over time, incident light reduces colorless silver salts and compounds to black elemental silver.³ It also has been suggested that metallic silver granules stimulate tyrosine kinase activity, leading to locally increased melanin production.⁴ Together, these processes result in the clinical appearance of a blue-black macule. Despite its long-standing association with silver, this appearance also has been noted with deposition of other metals.⁵ Histologically, metal deposits can be seen as black granules surrounding eccrine glands, blood vessels, and elastic fibers on higher magnification.⁶ Granules also may be found in sebaceous glands and arrector pili muscle fibers. These findings do not distinguish from generalized argyria due to increased serum silver levels; however, some cases of localized cutaneous argyria have demonstrated spheroid black globules with surrounding collagen necrosis,¹ which have not been reported with generalized disease. Localized cutaneous argyria also may be associated with ocher pigmentation of thickened collagen fibers, resembling changes typically found in alkaptonuria, an inherited deficiency of homogentisic acid oxidase (an enzyme involved in tyrosine metabolism).⁷ The resulting buildup of metabolic intermediates leads to ochronosis, a deposition of ocher-pigmented intermediates in connective tissue throughout the body. In the skin, ocher pigmentation occurs in elastic fibers of the reticular dermis.¹ Grossly, these changes result in a blue-gray discoloration of the skin due to a light-scattering phenomenon known as the Tyndall effect. Exogenous ochronosis also can occur, most commonly from the topical application of hydroquinone or other skin-lightening compounds.^1,5 Ocher  pigmentation occurring in the setting of localized cutaneous argyria is referred to as pseudo-ochronosis, a finding first described by Robinson-Bostom et al.¹ The etiology of this condition is poorly understood, but Robinson-Bostom et al¹ noted the appearance of dark metal granules surrounding collagen bundles and hypothesized that metal aggregates surrounding collagen bundles in pseudo-ochronosis cause a homogenized appearance under light microscopy. Yellow-brown, swollen, homogenized collagen bundles can be visualized in the reticular dermis with surrounding deposition of metal granules (Figures 1 and 2).¹ Typical patterns of granule deposition in localized argyria also are present.

A blue nevus is a collection of proliferating dermal melanocytes. Many histologic subtypes exist and there may be extensive variability in the extent of sclerosis, cellular architecture, and tissue cellularity between each variant.⁸ Blue nevi commonly present as blue-black hyperpigmentation in the dermis and subcutaneous tissue.⁹ Histologically, they are characterized by slender, bipolar, dendritic melanocytes in a sclerotic stroma (Figure 3).⁸ Melanocytes are highly pigmented and contain small monomorphic nuclei. Lesions are relatively homogenous and typically are restricted to the dermis with epidermal sparing.⁹ Dark granules and ocher fibers are absent.

Long-term use of hydroxychloroquine or other antimalarials may cause a macular pattern of blue-gray hyperpigmentation.¹⁰ Biopsy specimens typically reveal coarse, yellow-brown pigment granules primarily affecting the superficial dermis (Figure 4). Granules are found both extracellularly and within macrophages. Fontana-Masson silver staining may identify melanin, as hydroxychloroquine-melanin binding may contribute to patterns of hyperpigmentation.¹⁰ Hemosiderin often is present in cases of hydroxychloroquine pigmentation. Preceding ecchymosis appears to favor the deposition of hydroxychloroquine in the skin.¹¹ The absence of dark metal granules helps distinguish hydroxychloroquine pigmentation from argyria.

Regressed melanomas may appear clinically as gray macules. These lesions arise in cases of malignant melanoma that spontaneously regress without treatment. Spontaneous regression occurs in 10% to 35% of cases depending on tumor subtype.¹² Lesions can have a variable appearance based on the degree of regression. Partial regression is demonstrated by mixed melanosis and fibrosis in the dermis (Figure 5).^13,14 Melanin is housed within melanophages present in a variably expanded papillary dermis. Tumors in early stages of regression can be surrounded by an inflammatory infiltrate, which becomes diminished at later stages. However, a few exceptional cases have been noted with extensive inflammatory infiltrate and no residual tumor.¹⁴ Completely regressed lesions typically appear as a band of dermal melanophages in the absence of inflammation or melanocytic atypia.¹⁵ The finding of regressed melanoma should prompt further investigation including sentinel lymph node biopsy, as it may be associated with metastasis.

Tattooing occurs following traumatic penetration of the skin with impregnation of pigmented foreign material into deep dermal layers.¹⁶ Histologic examination usually reveals clumps of fine particulate material in the dermis (Figure 6). The color of the pigment depends on the agent used. For example, graphite appears as black particles that may be confused with localized cutaneous argyria. Distinction can be made using elemental identification techniques such as energy-dispersive X-ray spectroscopy.¹ The intensity of the pigment in granules found in tattoos or localized cutaneous argyria will fail to diminish with the application of melanin bleach.⁶

Localized cutaneous argyria often presents as asymptomatic black or blue-gray pigmented macules in areas of the skin exposed to silver-containing compounds.¹ Silver may enter the skin by traumatic implantation or absorption via eccrine sweat glands.² Our patient witnessed a gun fight several years ago while on a mission trip and sustained multiple shrapnel wounds.

As in our patient, hyperpigmentation may appear years following initial exposure. Over time, incident light reduces colorless silver salts and compounds to black elemental silver.³ It also has been suggested that metallic silver granules stimulate tyrosine kinase activity, leading to locally increased melanin production.⁴ Together, these processes result in the clinical appearance of a blue-black macule. Despite its long-standing association with silver, this appearance also has been noted with deposition of other metals.⁵ Histologically, metal deposits can be seen as black granules surrounding eccrine glands, blood vessels, and elastic fibers on higher magnification.⁶ Granules also may be found in sebaceous glands and arrector pili muscle fibers. These findings do not distinguish from generalized argyria due to increased serum silver levels; however, some cases of localized cutaneous argyria have demonstrated spheroid black globules with surrounding collagen necrosis,¹ which have not been reported with generalized disease. Localized cutaneous argyria also may be associated with ocher pigmentation of thickened collagen fibers, resembling changes typically found in alkaptonuria, an inherited deficiency of homogentisic acid oxidase (an enzyme involved in tyrosine metabolism).⁷ The resulting buildup of metabolic intermediates leads to ochronosis, a deposition of ocher-pigmented intermediates in connective tissue throughout the body. In the skin, ocher pigmentation occurs in elastic fibers of the reticular dermis.¹ Grossly, these changes result in a blue-gray discoloration of the skin due to a light-scattering phenomenon known as the Tyndall effect. Exogenous ochronosis also can occur, most commonly from the topical application of hydroquinone or other skin-lightening compounds.^1,5 Ocher  pigmentation occurring in the setting of localized cutaneous argyria is referred to as pseudo-ochronosis, a finding first described by Robinson-Bostom et al.¹ The etiology of this condition is poorly understood, but Robinson-Bostom et al¹ noted the appearance of dark metal granules surrounding collagen bundles and hypothesized that metal aggregates surrounding collagen bundles in pseudo-ochronosis cause a homogenized appearance under light microscopy. Yellow-brown, swollen, homogenized collagen bundles can be visualized in the reticular dermis with surrounding deposition of metal granules (Figures 1 and 2).¹ Typical patterns of granule deposition in localized argyria also are present.

A blue nevus is a collection of proliferating dermal melanocytes. Many histologic subtypes exist and there may be extensive variability in the extent of sclerosis, cellular architecture, and tissue cellularity between each variant.⁸ Blue nevi commonly present as blue-black hyperpigmentation in the dermis and subcutaneous tissue.⁹ Histologically, they are characterized by slender, bipolar, dendritic melanocytes in a sclerotic stroma (Figure 3).⁸ Melanocytes are highly pigmented and contain small monomorphic nuclei. Lesions are relatively homogenous and typically are restricted to the dermis with epidermal sparing.⁹ Dark granules and ocher fibers are absent.

Long-term use of hydroxychloroquine or other antimalarials may cause a macular pattern of blue-gray hyperpigmentation.¹⁰ Biopsy specimens typically reveal coarse, yellow-brown pigment granules primarily affecting the superficial dermis (Figure 4). Granules are found both extracellularly and within macrophages. Fontana-Masson silver staining may identify melanin, as hydroxychloroquine-melanin binding may contribute to patterns of hyperpigmentation.¹⁰ Hemosiderin often is present in cases of hydroxychloroquine pigmentation. Preceding ecchymosis appears to favor the deposition of hydroxychloroquine in the skin.¹¹ The absence of dark metal granules helps distinguish hydroxychloroquine pigmentation from argyria.

Regressed melanomas may appear clinically as gray macules. These lesions arise in cases of malignant melanoma that spontaneously regress without treatment. Spontaneous regression occurs in 10% to 35% of cases depending on tumor subtype.¹² Lesions can have a variable appearance based on the degree of regression. Partial regression is demonstrated by mixed melanosis and fibrosis in the dermis (Figure 5).^13,14 Melanin is housed within melanophages present in a variably expanded papillary dermis. Tumors in early stages of regression can be surrounded by an inflammatory infiltrate, which becomes diminished at later stages. However, a few exceptional cases have been noted with extensive inflammatory infiltrate and no residual tumor.¹⁴ Completely regressed lesions typically appear as a band of dermal melanophages in the absence of inflammation or melanocytic atypia.¹⁵ The finding of regressed melanoma should prompt further investigation including sentinel lymph node biopsy, as it may be associated with metastasis.

Tattooing occurs following traumatic penetration of the skin with impregnation of pigmented foreign material into deep dermal layers.¹⁶ Histologic examination usually reveals clumps of fine particulate material in the dermis (Figure 6). The color of the pigment depends on the agent used. For example, graphite appears as black particles that may be confused with localized cutaneous argyria. Distinction can be made using elemental identification techniques such as energy-dispersive X-ray spectroscopy.¹ The intensity of the pigment in granules found in tattoos or localized cutaneous argyria will fail to diminish with the application of melanin bleach.⁶

Granular cell tumors (GCTs) tend to present as solitary nodules, not uncommonly affecting the dorsum of the tongue but also involving the skin, breasts, and internal organs.¹ Cutaneous GCTs typically present as 0.5- to 3-cm firm nodules with a verrucous or eroded surface.² They most commonly present in dark-skinned, middle-aged women but have been reported in all age groups and in both sexes.³ Multiple GCTs are reported in up to 25% of cases, rarely in association with LEOPARD syndrome (consisting of lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness).⁴ Granular cell tumors generally are benign with a metastatic rate of approximately 3%.²

Granular cell tumors are histopathologically characterized by sheets of large polygonal cells with small, round, central nuclei; cytoplasm that is eosinophilic, coarse, and granular, as well as periodic acid–Schiff positive and diastase resistant; and distinct cytoplasmic membranes (Figure 1). Pustulo-ovoid bodies of Milian often generally appear as larger eosinophilic granules surrounded by a clear halo (Figure 2).⁵ Increased mitotic activity, a high nuclear-cytoplasmic ratio, pleomorphism, and necrosis suggest malignancy.⁶

Figure 1. Pseudoepitheliomatous hyperplasia and sheets of polygonal cells with light pink cytoplasm of a granular cell tumor (H&E, original magnification ×40).

Figure 2. Sheets of large polygonal cells with central nuclei; coarse, eosinophilic, granular cytoplasm; and large eosinophilic cytoplasmic pustulo-ovoid bodies of Milian characterize a granular cell tumor (H&E, original magnification ×600).

Lepromatous leprosy is characterized by sheets of histiocytes with vacuolated cytoplasm, some with clumped amphophilic bacilli known as globi (Figure 3). Mastocytoma can be distinguished from GCTs by the “fried egg” appearance of the mast cells (Figure 4). Although mast cells have a pale granular cytoplasm, they are smaller and lack pustulo-ovoid bodies and the polygonal shape of GCT cells. Reticulohistiocytoma, on the other hand, has two-toned dusty rose ground glass histiocytes (Figure 5), and xanthelasma can be distinguished histologically from GCT by the presence of a foamy rather than granular cytoplasm (Figure 6).

Figure 3. Lymphohistiocytic infiltrate with amphophilic collections of mycobacteria (globi) in lepromatous leprosy (H&E, original magnification ×600).

Figure 4. Small “fried egg” mast cells with pale granular cytoplasm and admixed eosinophils in a mastocytoma (H&E, original magnification ×600).

Figure 5. Sea of histiocytes containing dusty rose or ground glass cytoplasm with two-toned darker and lighter areas in a reticulohistiocytoma (H&E, original magnification ×600).

Figure 6. Aggregates of histiocytes with foamy cytoplasm in xanthelasma (H&E, original magnifi-cation ×600).

Granular cell tumors (GCTs) tend to present as solitary nodules, not uncommonly affecting the dorsum of the tongue but also involving the skin, breasts, and internal organs.¹ Cutaneous GCTs typically present as 0.5- to 3-cm firm nodules with a verrucous or eroded surface.² They most commonly present in dark-skinned, middle-aged women but have been reported in all age groups and in both sexes.³ Multiple GCTs are reported in up to 25% of cases, rarely in association with LEOPARD syndrome (consisting of lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness).⁴ Granular cell tumors generally are benign with a metastatic rate of approximately 3%.²

Granular cell tumors are histopathologically characterized by sheets of large polygonal cells with small, round, central nuclei; cytoplasm that is eosinophilic, coarse, and granular, as well as periodic acid–Schiff positive and diastase resistant; and distinct cytoplasmic membranes (Figure 1). Pustulo-ovoid bodies of Milian often generally appear as larger eosinophilic granules surrounded by a clear halo (Figure 2).⁵ Increased mitotic activity, a high nuclear-cytoplasmic ratio, pleomorphism, and necrosis suggest malignancy.⁶

Figure 1. Pseudoepitheliomatous hyperplasia and sheets of polygonal cells with light pink cytoplasm of a granular cell tumor (H&E, original magnification ×40).

Figure 2. Sheets of large polygonal cells with central nuclei; coarse, eosinophilic, granular cytoplasm; and large eosinophilic cytoplasmic pustulo-ovoid bodies of Milian characterize a granular cell tumor (H&E, original magnification ×600).

Lepromatous leprosy is characterized by sheets of histiocytes with vacuolated cytoplasm, some with clumped amphophilic bacilli known as globi (Figure 3). Mastocytoma can be distinguished from GCTs by the “fried egg” appearance of the mast cells (Figure 4). Although mast cells have a pale granular cytoplasm, they are smaller and lack pustulo-ovoid bodies and the polygonal shape of GCT cells. Reticulohistiocytoma, on the other hand, has two-toned dusty rose ground glass histiocytes (Figure 5), and xanthelasma can be distinguished histologically from GCT by the presence of a foamy rather than granular cytoplasm (Figure 6).

Figure 3. Lymphohistiocytic infiltrate with amphophilic collections of mycobacteria (globi) in lepromatous leprosy (H&E, original magnification ×600).

Figure 4. Small “fried egg” mast cells with pale granular cytoplasm and admixed eosinophils in a mastocytoma (H&E, original magnification ×600).

Figure 5. Sea of histiocytes containing dusty rose or ground glass cytoplasm with two-toned darker and lighter areas in a reticulohistiocytoma (H&E, original magnification ×600).

Figure 6. Aggregates of histiocytes with foamy cytoplasm in xanthelasma (H&E, original magnifi-cation ×600).

Granular cell tumors (GCTs) tend to present as solitary nodules, not uncommonly affecting the dorsum of the tongue but also involving the skin, breasts, and internal organs.¹ Cutaneous GCTs typically present as 0.5- to 3-cm firm nodules with a verrucous or eroded surface.² They most commonly present in dark-skinned, middle-aged women but have been reported in all age groups and in both sexes.³ Multiple GCTs are reported in up to 25% of cases, rarely in association with LEOPARD syndrome (consisting of lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness).⁴ Granular cell tumors generally are benign with a metastatic rate of approximately 3%.²

Granular cell tumors are histopathologically characterized by sheets of large polygonal cells with small, round, central nuclei; cytoplasm that is eosinophilic, coarse, and granular, as well as periodic acid–Schiff positive and diastase resistant; and distinct cytoplasmic membranes (Figure 1). Pustulo-ovoid bodies of Milian often generally appear as larger eosinophilic granules surrounded by a clear halo (Figure 2).⁵ Increased mitotic activity, a high nuclear-cytoplasmic ratio, pleomorphism, and necrosis suggest malignancy.⁶

Figure 1. Pseudoepitheliomatous hyperplasia and sheets of polygonal cells with light pink cytoplasm of a granular cell tumor (H&E, original magnification ×40).

Figure 2. Sheets of large polygonal cells with central nuclei; coarse, eosinophilic, granular cytoplasm; and large eosinophilic cytoplasmic pustulo-ovoid bodies of Milian characterize a granular cell tumor (H&E, original magnification ×600).

Lepromatous leprosy is characterized by sheets of histiocytes with vacuolated cytoplasm, some with clumped amphophilic bacilli known as globi (Figure 3). Mastocytoma can be distinguished from GCTs by the “fried egg” appearance of the mast cells (Figure 4). Although mast cells have a pale granular cytoplasm, they are smaller and lack pustulo-ovoid bodies and the polygonal shape of GCT cells. Reticulohistiocytoma, on the other hand, has two-toned dusty rose ground glass histiocytes (Figure 5), and xanthelasma can be distinguished histologically from GCT by the presence of a foamy rather than granular cytoplasm (Figure 6).

Figure 3. Lymphohistiocytic infiltrate with amphophilic collections of mycobacteria (globi) in lepromatous leprosy (H&E, original magnification ×600).

Figure 4. Small “fried egg” mast cells with pale granular cytoplasm and admixed eosinophils in a mastocytoma (H&E, original magnification ×600).

Figure 5. Sea of histiocytes containing dusty rose or ground glass cytoplasm with two-toned darker and lighter areas in a reticulohistiocytoma (H&E, original magnification ×600).

Figure 6. Aggregates of histiocytes with foamy cytoplasm in xanthelasma (H&E, original magnifi-cation ×600).

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.

Lipidized dermatofibromas most commonly are found on the ankles, which has led some authors to refer to these lesions as ankle-type fibrous histiocytomas.¹ Compared to ordinary dermatofibromas, patients with lipidized dermatofibromas tend to be older, most commonly presenting in the fifth or sixth decades of life, and are predominantly male. Lipidized dermatofibromas typically present as well-circumscribed solitary nodules in the dermis. Characteristic features include numerous xanthomatous cells dissected by distinctive hyalinized wiry collagen fibers (Figures 1 and 2).¹ Xanthomatous cells can be round, polygonal, or stellate in shape. These characteristic features in combination with others of dermatofibromas (eg, epidermal acanthosis [Figure 1]) fulfill the criteria for diagnosis of a lipidized dermatofibroma. Additionally, lipidized dermatofibromas tend to be larger than ordinary dermatofibromas, which typically are less than 2 cm in diameter.¹

Figure 1. Lipidized dermatofibromas are characterized by classic epidermal features of dermatofibromas, such as acanthosis, along with numerous foam cells and extensive stromal hyalinization (H&E, original magnification ×1.5).

Figure 2. Higher-power view of a lipidized dermatofibroma shows the characteristic irregular dissection of hyalinized wiry collagen fibers between the xanthomatous cells (H&E, original magnification ×20).

Eruptive xanthomas are characterized by a lacelike infiltrate of extravascular lipid deposits between collagen bundles (Figure 3).² Granular cell tumors are composed of sheets and/or nests of large cells with abundant eosinophilic cytoplasm and may be confused with lipidized dermatofibromas, as they also may induce overlying pseudoepitheliomatous hyperplasia³; however, on closer examination of the cells, the cytoplasm is found to be granular (Figure 4), which contrasts the finely vacuolated cytoplasm of xanthomatous cells found in lipidized dermatofibromas. Giant lysosomal granules (eg, pustulo-ovoid bodies of Milian) are present in some cases.² Of note, an unusual variant of dermatofibroma exists that features prominent granular cells.⁴

Figure 3. Lacelike deposition of extravascular lipid deposits is seen infiltrating between collagen bundles in an eruptive xanthoma (H&E, original magnification ×20).

Figure 4. An abundant eosinophilic, finely granular cytoplasm is characteristic of granular cell tumor (H&E, original magnification ×40).

Tuberous xanthomas most commonly occur around the pressure areas, such as the knees, elbows, and buttocks. Foam cells are a main feature of tuberous xanthomas and are arranged in large aggregates throughout the dermis.² Tuberous xanthomas lack Touton giant cells or inflammatory cells. Older lesions tend to develop substantial fibrosis (Figure 5). Although foam cells can be present in older lesions, they are never as conspicuous as those found in other xanthomas.

Xanthogranulomas commonly occur on the head and neck. Findings noted on low magnification include a well-circumscribed exophytic nodule and an epidermal collarette, which help to easily distinguish xanthogranulomas from lipidized dermatofibromas. Additionally, the presence of a more prominent inflammatory infiltrate, which often includes eosinophils, as well as multinucleated Touton giant cells (Figure 6) and histiocytes with more eosinophilic and less xanthomatous cytoplasm can help distinguish between the lesions.^1,5 Notably, Touton giant cells also can be seen in lipidized dermatofibromas,¹ but the presence of unique features such as distinctive stromal hyalinization are clues to the correct diagnosis of a lipidized dermatofibroma.

Lipidized dermatofibromas most commonly are found on the ankles, which has led some authors to refer to these lesions as ankle-type fibrous histiocytomas.¹ Compared to ordinary dermatofibromas, patients with lipidized dermatofibromas tend to be older, most commonly presenting in the fifth or sixth decades of life, and are predominantly male. Lipidized dermatofibromas typically present as well-circumscribed solitary nodules in the dermis. Characteristic features include numerous xanthomatous cells dissected by distinctive hyalinized wiry collagen fibers (Figures 1 and 2).¹ Xanthomatous cells can be round, polygonal, or stellate in shape. These characteristic features in combination with others of dermatofibromas (eg, epidermal acanthosis [Figure 1]) fulfill the criteria for diagnosis of a lipidized dermatofibroma. Additionally, lipidized dermatofibromas tend to be larger than ordinary dermatofibromas, which typically are less than 2 cm in diameter.¹

Figure 1. Lipidized dermatofibromas are characterized by classic epidermal features of dermatofibromas, such as acanthosis, along with numerous foam cells and extensive stromal hyalinization (H&E, original magnification ×1.5).

Figure 2. Higher-power view of a lipidized dermatofibroma shows the characteristic irregular dissection of hyalinized wiry collagen fibers between the xanthomatous cells (H&E, original magnification ×20).

Eruptive xanthomas are characterized by a lacelike infiltrate of extravascular lipid deposits between collagen bundles (Figure 3).² Granular cell tumors are composed of sheets and/or nests of large cells with abundant eosinophilic cytoplasm and may be confused with lipidized dermatofibromas, as they also may induce overlying pseudoepitheliomatous hyperplasia³; however, on closer examination of the cells, the cytoplasm is found to be granular (Figure 4), which contrasts the finely vacuolated cytoplasm of xanthomatous cells found in lipidized dermatofibromas. Giant lysosomal granules (eg, pustulo-ovoid bodies of Milian) are present in some cases.² Of note, an unusual variant of dermatofibroma exists that features prominent granular cells.⁴

Figure 3. Lacelike deposition of extravascular lipid deposits is seen infiltrating between collagen bundles in an eruptive xanthoma (H&E, original magnification ×20).

Figure 4. An abundant eosinophilic, finely granular cytoplasm is characteristic of granular cell tumor (H&E, original magnification ×40).

Tuberous xanthomas most commonly occur around the pressure areas, such as the knees, elbows, and buttocks. Foam cells are a main feature of tuberous xanthomas and are arranged in large aggregates throughout the dermis.² Tuberous xanthomas lack Touton giant cells or inflammatory cells. Older lesions tend to develop substantial fibrosis (Figure 5). Although foam cells can be present in older lesions, they are never as conspicuous as those found in other xanthomas.

Xanthogranulomas commonly occur on the head and neck. Findings noted on low magnification include a well-circumscribed exophytic nodule and an epidermal collarette, which help to easily distinguish xanthogranulomas from lipidized dermatofibromas. Additionally, the presence of a more prominent inflammatory infiltrate, which often includes eosinophils, as well as multinucleated Touton giant cells (Figure 6) and histiocytes with more eosinophilic and less xanthomatous cytoplasm can help distinguish between the lesions.^1,5 Notably, Touton giant cells also can be seen in lipidized dermatofibromas,¹ but the presence of unique features such as distinctive stromal hyalinization are clues to the correct diagnosis of a lipidized dermatofibroma.

Lipidized dermatofibromas most commonly are found on the ankles, which has led some authors to refer to these lesions as ankle-type fibrous histiocytomas.¹ Compared to ordinary dermatofibromas, patients with lipidized dermatofibromas tend to be older, most commonly presenting in the fifth or sixth decades of life, and are predominantly male. Lipidized dermatofibromas typically present as well-circumscribed solitary nodules in the dermis. Characteristic features include numerous xanthomatous cells dissected by distinctive hyalinized wiry collagen fibers (Figures 1 and 2).¹ Xanthomatous cells can be round, polygonal, or stellate in shape. These characteristic features in combination with others of dermatofibromas (eg, epidermal acanthosis [Figure 1]) fulfill the criteria for diagnosis of a lipidized dermatofibroma. Additionally, lipidized dermatofibromas tend to be larger than ordinary dermatofibromas, which typically are less than 2 cm in diameter.¹

Figure 1. Lipidized dermatofibromas are characterized by classic epidermal features of dermatofibromas, such as acanthosis, along with numerous foam cells and extensive stromal hyalinization (H&E, original magnification ×1.5).

Figure 2. Higher-power view of a lipidized dermatofibroma shows the characteristic irregular dissection of hyalinized wiry collagen fibers between the xanthomatous cells (H&E, original magnification ×20).

Eruptive xanthomas are characterized by a lacelike infiltrate of extravascular lipid deposits between collagen bundles (Figure 3).² Granular cell tumors are composed of sheets and/or nests of large cells with abundant eosinophilic cytoplasm and may be confused with lipidized dermatofibromas, as they also may induce overlying pseudoepitheliomatous hyperplasia³; however, on closer examination of the cells, the cytoplasm is found to be granular (Figure 4), which contrasts the finely vacuolated cytoplasm of xanthomatous cells found in lipidized dermatofibromas. Giant lysosomal granules (eg, pustulo-ovoid bodies of Milian) are present in some cases.² Of note, an unusual variant of dermatofibroma exists that features prominent granular cells.⁴

Figure 3. Lacelike deposition of extravascular lipid deposits is seen infiltrating between collagen bundles in an eruptive xanthoma (H&E, original magnification ×20).

Figure 4. An abundant eosinophilic, finely granular cytoplasm is characteristic of granular cell tumor (H&E, original magnification ×40).

Tuberous xanthomas most commonly occur around the pressure areas, such as the knees, elbows, and buttocks. Foam cells are a main feature of tuberous xanthomas and are arranged in large aggregates throughout the dermis.² Tuberous xanthomas lack Touton giant cells or inflammatory cells. Older lesions tend to develop substantial fibrosis (Figure 5). Although foam cells can be present in older lesions, they are never as conspicuous as those found in other xanthomas.

Xanthogranulomas commonly occur on the head and neck. Findings noted on low magnification include a well-circumscribed exophytic nodule and an epidermal collarette, which help to easily distinguish xanthogranulomas from lipidized dermatofibromas. Additionally, the presence of a more prominent inflammatory infiltrate, which often includes eosinophils, as well as multinucleated Touton giant cells (Figure 6) and histiocytes with more eosinophilic and less xanthomatous cytoplasm can help distinguish between the lesions.^1,5 Notably, Touton giant cells also can be seen in lipidized dermatofibromas,¹ but the presence of unique features such as distinctive stromal hyalinization are clues to the correct diagnosis of a lipidized dermatofibroma.