Dermpath Diagnosis

The best diagnosis is:

a. granular cell tumor
b. intradermal nevus
c. Langerhans cell disease
d. mastocytosis
e. multicentric reticulohistiocytosis

Monomorphic cell infiltrate in the upper dermis (H&E, original magnification ×100).

A closer view reveals cuboidal or spindle cells with basal hyperpigmentation (H&E, original magnification ×200).

Continue to the next page for the diagnosis >>

Mastocytosis

Mastocytosis is a clonal proliferation of mast cells in the skin and various systems of the body including the bone marrow, liver, lymph nodes, and gastrointestinal tract.^1,2 Mast cell proliferation is closely associated with germline and acquired activating KIT mutations.^3-5 Adult-onset mastocytosis is likely to involve several organs, whereas pediatric mastocytosis usually affects only the skin and is self-limiting. Patients with profound mast cell infiltration in the skin or other organs are likely to have attacks of flushing, palpitation, or diarrhea resulting from the degranulation of mast cells and release of histamine.^6,7 In a majority of patients with advanced systemic mastocytosis, mast cells are positive for the Ki-1 antigen (CD30), whereas in most patients with indolent systemic mastocytosis, only a few mast cells are positive for CD30.⁸ Recently, CD30 was reported as a new drug target in patients with CD30⁺ advanced systemic mastocytosis.⁹ Because the skin frequently is involved and easily accessible in comparison with other organs, skin biopsy often is performed to establish a diagnosis of mastocytosis. Cutaneous mastocytosis comprises urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans; approximately 80% of all cases have urticaria pigmentosa.^10-12 In cutaneous mastocytosis, skin biopsy typically shows monomorphous mast cell infiltrate mostly in the upper third of the dermis. The density of mast cells varies according to the clinical variant. For example, a lesion of telangiectasia macularis eruptiva perstans has only a perivascular mast cell infiltrate, whereas a solitary mastocytoma has sheets of mast cells in the dermis, sometimes extending into the subcutis. A skin biopsy of the brown macule on the waist showed a number of cuboidal or spindle mast cells in the upper dermis with occasional eosinophils. These mast cells are monomorphous, and no mitotic figures, necrotic cells, or atypical cells are seen. Mast cells have metachromatic granules in the cytoplasm, which can be seen with toluidine blue or Giemsa stain. CD117 (c-kit) also is positive. Mast cells in urticaria pigmentosa easily may be mistaken for nevus cells. Hyperpigmentation of the basal layer, a characteristic feature seen in urticaria pigmentosa, also may erroneously suggest a diagnosis of a melanocytic nevus.

Granular cell tumors predominantly affect the oral cavity, but the skin also can be involved. It comprises a fascicular infiltrate of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (Figure 1).¹³ Cell membranes are not always distinct. Although the nuclei usually are small and centrally located, irregular and plump nuclei with distinct nucleoli also may be seen. The overlying epidermis tends to be hyperplastic. Granular cell tumor is considered a group of lesions of varying histogenesis. Cases in which tumors originated from a neural crest–derived peripheral nerve–related cell as well as a Schwann cell have been reported.^14,15 The origin of granular cell tumors is controversial.

Figure 1. Granular cell tumor showing fascicles of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (H&E, original magnification ×200).

Figure 2. Intradermal nevus showing nests with melanin in the uppermost area of the lesion and neurotized nevus cells in the lower part (H&E, original magnification ×100). Pseudovascular spaces are seen on the right side.

Intradermal nevus usually has nests and cords of nevus cells in the upper dermis. The uppermost melanocytes often contain a moderate amount of melanin, whereas nevus cells in the mid and lower dermis usually do not contain melanin (Figure 2). Shrinkage during tissue processing maycause clefts between nevus cells, resulting in pseudovascular spaces.¹⁶ The deeper dermis may have a neuroid appearance with spindle-shaped cells and Meissner corpuscle–like structures.¹⁷

Although Langerhans cell disease was formerly known as Langerhans cell histiocytosis and subdivided into several clinical subtypes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma, these clinical subtypes commonly overlapped. Langerhans cell disease is now used as a terminology that encompasses all subtypes.^18,19 Langerhans cell disease is characterized by a proliferation of Langerhans cells with a variable mixture of other inflammatory cells. The constituent cells are large and ovoid with a distinct folded or lobulated, often kidney-shaped nucleus.²⁰ Langerhans cells usually infiltrate the upper dermis and occasionally the epidermis (Figure 3). CD1a, HLA-DR, S-100 protein, and langerin are positive in Langerhans cells.²¹

Figure 3. Langerhans cell disease showing an infiltrate of large and ovoid Langerhans cells with a distinct folded or lobulated, often kidney-shaped nucleus in the upper dermis and epidermis (H&E, original magnification ×200).

Figure 4. Multicentric reticulohistiocytosis showing a mixture of mononuclear and multinucleate histiocytes with abundant eosinophilic and finely granular cytoplasm (H&E, original magnification ×200).

Multicentric reticulohistiocytosis is characterized by a combination of papulonodular cutaneous lesions and severe arthropathy.²² An irregular mixture of mononuclear and multinucleate histiocytes showing abundant eosinophilic and finely granular cytoplasm, often with a ground-glass appearance, is seen along with lymphocytic infiltration (Figure 4).²³ A few giant cells may be seen in early lesions; older lesions more commonly have giant cells and fibrosis.

The best diagnosis is:

a. granular cell tumor
b. intradermal nevus
c. Langerhans cell disease
d. mastocytosis
e. multicentric reticulohistiocytosis

Monomorphic cell infiltrate in the upper dermis (H&E, original magnification ×100).

A closer view reveals cuboidal or spindle cells with basal hyperpigmentation (H&E, original magnification ×200).

Continue to the next page for the diagnosis >>

Mastocytosis

Mastocytosis is a clonal proliferation of mast cells in the skin and various systems of the body including the bone marrow, liver, lymph nodes, and gastrointestinal tract.^1,2 Mast cell proliferation is closely associated with germline and acquired activating KIT mutations.^3-5 Adult-onset mastocytosis is likely to involve several organs, whereas pediatric mastocytosis usually affects only the skin and is self-limiting. Patients with profound mast cell infiltration in the skin or other organs are likely to have attacks of flushing, palpitation, or diarrhea resulting from the degranulation of mast cells and release of histamine.^6,7 In a majority of patients with advanced systemic mastocytosis, mast cells are positive for the Ki-1 antigen (CD30), whereas in most patients with indolent systemic mastocytosis, only a few mast cells are positive for CD30.⁸ Recently, CD30 was reported as a new drug target in patients with CD30⁺ advanced systemic mastocytosis.⁹ Because the skin frequently is involved and easily accessible in comparison with other organs, skin biopsy often is performed to establish a diagnosis of mastocytosis. Cutaneous mastocytosis comprises urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans; approximately 80% of all cases have urticaria pigmentosa.^10-12 In cutaneous mastocytosis, skin biopsy typically shows monomorphous mast cell infiltrate mostly in the upper third of the dermis. The density of mast cells varies according to the clinical variant. For example, a lesion of telangiectasia macularis eruptiva perstans has only a perivascular mast cell infiltrate, whereas a solitary mastocytoma has sheets of mast cells in the dermis, sometimes extending into the subcutis. A skin biopsy of the brown macule on the waist showed a number of cuboidal or spindle mast cells in the upper dermis with occasional eosinophils. These mast cells are monomorphous, and no mitotic figures, necrotic cells, or atypical cells are seen. Mast cells have metachromatic granules in the cytoplasm, which can be seen with toluidine blue or Giemsa stain. CD117 (c-kit) also is positive. Mast cells in urticaria pigmentosa easily may be mistaken for nevus cells. Hyperpigmentation of the basal layer, a characteristic feature seen in urticaria pigmentosa, also may erroneously suggest a diagnosis of a melanocytic nevus.

Granular cell tumors predominantly affect the oral cavity, but the skin also can be involved. It comprises a fascicular infiltrate of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (Figure 1).¹³ Cell membranes are not always distinct. Although the nuclei usually are small and centrally located, irregular and plump nuclei with distinct nucleoli also may be seen. The overlying epidermis tends to be hyperplastic. Granular cell tumor is considered a group of lesions of varying histogenesis. Cases in which tumors originated from a neural crest–derived peripheral nerve–related cell as well as a Schwann cell have been reported.^14,15 The origin of granular cell tumors is controversial.

Figure 1. Granular cell tumor showing fascicles of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (H&E, original magnification ×200).

Figure 2. Intradermal nevus showing nests with melanin in the uppermost area of the lesion and neurotized nevus cells in the lower part (H&E, original magnification ×100). Pseudovascular spaces are seen on the right side.

Intradermal nevus usually has nests and cords of nevus cells in the upper dermis. The uppermost melanocytes often contain a moderate amount of melanin, whereas nevus cells in the mid and lower dermis usually do not contain melanin (Figure 2). Shrinkage during tissue processing maycause clefts between nevus cells, resulting in pseudovascular spaces.¹⁶ The deeper dermis may have a neuroid appearance with spindle-shaped cells and Meissner corpuscle–like structures.¹⁷

Although Langerhans cell disease was formerly known as Langerhans cell histiocytosis and subdivided into several clinical subtypes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma, these clinical subtypes commonly overlapped. Langerhans cell disease is now used as a terminology that encompasses all subtypes.^18,19 Langerhans cell disease is characterized by a proliferation of Langerhans cells with a variable mixture of other inflammatory cells. The constituent cells are large and ovoid with a distinct folded or lobulated, often kidney-shaped nucleus.²⁰ Langerhans cells usually infiltrate the upper dermis and occasionally the epidermis (Figure 3). CD1a, HLA-DR, S-100 protein, and langerin are positive in Langerhans cells.²¹

Figure 3. Langerhans cell disease showing an infiltrate of large and ovoid Langerhans cells with a distinct folded or lobulated, often kidney-shaped nucleus in the upper dermis and epidermis (H&E, original magnification ×200).

Figure 4. Multicentric reticulohistiocytosis showing a mixture of mononuclear and multinucleate histiocytes with abundant eosinophilic and finely granular cytoplasm (H&E, original magnification ×200).

Multicentric reticulohistiocytosis is characterized by a combination of papulonodular cutaneous lesions and severe arthropathy.²² An irregular mixture of mononuclear and multinucleate histiocytes showing abundant eosinophilic and finely granular cytoplasm, often with a ground-glass appearance, is seen along with lymphocytic infiltration (Figure 4).²³ A few giant cells may be seen in early lesions; older lesions more commonly have giant cells and fibrosis.

The best diagnosis is:

a. granular cell tumor
b. intradermal nevus
c. Langerhans cell disease
d. mastocytosis
e. multicentric reticulohistiocytosis

Monomorphic cell infiltrate in the upper dermis (H&E, original magnification ×100).

A closer view reveals cuboidal or spindle cells with basal hyperpigmentation (H&E, original magnification ×200).

Continue to the next page for the diagnosis >>

Mastocytosis

Mastocytosis is a clonal proliferation of mast cells in the skin and various systems of the body including the bone marrow, liver, lymph nodes, and gastrointestinal tract.^1,2 Mast cell proliferation is closely associated with germline and acquired activating KIT mutations.^3-5 Adult-onset mastocytosis is likely to involve several organs, whereas pediatric mastocytosis usually affects only the skin and is self-limiting. Patients with profound mast cell infiltration in the skin or other organs are likely to have attacks of flushing, palpitation, or diarrhea resulting from the degranulation of mast cells and release of histamine.^6,7 In a majority of patients with advanced systemic mastocytosis, mast cells are positive for the Ki-1 antigen (CD30), whereas in most patients with indolent systemic mastocytosis, only a few mast cells are positive for CD30.⁸ Recently, CD30 was reported as a new drug target in patients with CD30⁺ advanced systemic mastocytosis.⁹ Because the skin frequently is involved and easily accessible in comparison with other organs, skin biopsy often is performed to establish a diagnosis of mastocytosis. Cutaneous mastocytosis comprises urticaria pigmentosa, solitary mastocytoma, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans; approximately 80% of all cases have urticaria pigmentosa.^10-12 In cutaneous mastocytosis, skin biopsy typically shows monomorphous mast cell infiltrate mostly in the upper third of the dermis. The density of mast cells varies according to the clinical variant. For example, a lesion of telangiectasia macularis eruptiva perstans has only a perivascular mast cell infiltrate, whereas a solitary mastocytoma has sheets of mast cells in the dermis, sometimes extending into the subcutis. A skin biopsy of the brown macule on the waist showed a number of cuboidal or spindle mast cells in the upper dermis with occasional eosinophils. These mast cells are monomorphous, and no mitotic figures, necrotic cells, or atypical cells are seen. Mast cells have metachromatic granules in the cytoplasm, which can be seen with toluidine blue or Giemsa stain. CD117 (c-kit) also is positive. Mast cells in urticaria pigmentosa easily may be mistaken for nevus cells. Hyperpigmentation of the basal layer, a characteristic feature seen in urticaria pigmentosa, also may erroneously suggest a diagnosis of a melanocytic nevus.

Granular cell tumors predominantly affect the oral cavity, but the skin also can be involved. It comprises a fascicular infiltrate of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (Figure 1).¹³ Cell membranes are not always distinct. Although the nuclei usually are small and centrally located, irregular and plump nuclei with distinct nucleoli also may be seen. The overlying epidermis tends to be hyperplastic. Granular cell tumor is considered a group of lesions of varying histogenesis. Cases in which tumors originated from a neural crest–derived peripheral nerve–related cell as well as a Schwann cell have been reported.^14,15 The origin of granular cell tumors is controversial.

Figure 1. Granular cell tumor showing fascicles of large and polygonal cells with characteristic eosinophilic granular cytoplasm in the dermis (H&E, original magnification ×200).

Figure 2. Intradermal nevus showing nests with melanin in the uppermost area of the lesion and neurotized nevus cells in the lower part (H&E, original magnification ×100). Pseudovascular spaces are seen on the right side.

Intradermal nevus usually has nests and cords of nevus cells in the upper dermis. The uppermost melanocytes often contain a moderate amount of melanin, whereas nevus cells in the mid and lower dermis usually do not contain melanin (Figure 2). Shrinkage during tissue processing maycause clefts between nevus cells, resulting in pseudovascular spaces.¹⁶ The deeper dermis may have a neuroid appearance with spindle-shaped cells and Meissner corpuscle–like structures.¹⁷

Although Langerhans cell disease was formerly known as Langerhans cell histiocytosis and subdivided into several clinical subtypes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, and eosinophilic granuloma, these clinical subtypes commonly overlapped. Langerhans cell disease is now used as a terminology that encompasses all subtypes.^18,19 Langerhans cell disease is characterized by a proliferation of Langerhans cells with a variable mixture of other inflammatory cells. The constituent cells are large and ovoid with a distinct folded or lobulated, often kidney-shaped nucleus.²⁰ Langerhans cells usually infiltrate the upper dermis and occasionally the epidermis (Figure 3). CD1a, HLA-DR, S-100 protein, and langerin are positive in Langerhans cells.²¹

Figure 3. Langerhans cell disease showing an infiltrate of large and ovoid Langerhans cells with a distinct folded or lobulated, often kidney-shaped nucleus in the upper dermis and epidermis (H&E, original magnification ×200).

Figure 4. Multicentric reticulohistiocytosis showing a mixture of mononuclear and multinucleate histiocytes with abundant eosinophilic and finely granular cytoplasm (H&E, original magnification ×200).

Multicentric reticulohistiocytosis is characterized by a combination of papulonodular cutaneous lesions and severe arthropathy.²² An irregular mixture of mononuclear and multinucleate histiocytes showing abundant eosinophilic and finely granular cytoplasm, often with a ground-glass appearance, is seen along with lymphocytic infiltration (Figure 4).²³ A few giant cells may be seen in early lesions; older lesions more commonly have giant cells and fibrosis.

Lichen striatus (LS) is a benign, uncommon, self-limited, linear inflammatory skin disorder that primarily affects children up to 15 years of age, most commonly around 2 to 3 years of age, and is seen more frequently in girls.¹ It presents with a sudden eruption of asymptomatic small, flat-topped, lichenoid, scaly papules in a linear array on a single extremity. The lesions may be erythematous, flesh colored, or hypopigmented.^1,2 Multiple lesions appear over days to weeks and coalesce into linear plaques in a continuous or interrupted pattern along the lines of Blaschko, indicating possible somatic mosaicism.¹ Although typically asymptomatic, it may be pruritic. Most cases spontaneously resolve within 1 year.³ Recurrences are unusual. Digital involvement may result in onycholysis, longitudinal ridging, splitting, and nail loss.¹ The underlying cause of LS may be an abnormal immunologic reaction or genetic predisposition that is precipitated by some trigger such as a viral infection, trauma, hypersensitivity reaction, vaccine, seasonal variation, medication, or pregnancy.^1,2 An association with atopy has been described. Treatment is not necessary but options include topical steroids, topical retinoids, and topical calcineurin inhibitors.²

Histologically, findings in LS are somewhat variable but typically show a combination of spongiotic and lichenoid interface dermatitis with a perivascular and periadnexal lymphocytic infiltrate (Figure 1). Epidermal changes include intercellular and intracellular edema, focal spongiosis, lymphocytic exocytosis, parakeratosis, patchy hyperkeratosis, and keratinocyte necrosis (Figure 2A).^1,3 The epidermis is normal or slightly acanthotic, and dyskeratotic keratinocytes can be found in the granular and horny layers or at the dermoepidermal junction.² The lymphohistiocytic infiltrate in the superficial and deep dermis surrounds vascular plexuses and cutaneous adnexa such as eccrine glands and hair follicles.¹ Perivascular lymphoid aggregates and eccrine coil involvement are particularly distinctive of LS (Figure 2B).⁴ Pigment incontinence also may be seen.

Another condition that distributes linearly along the lines of Blaschko is linear epidermolytic hyperkeratosis (EHK). Similar to LS, histology shows hyperkeratosis, focal parakeratosis, and acanthosis of the epidermis.⁵ However, EHK shows epidermolysis, acantholysis, and perinuclear vacuolization in spinous and granular layers (Figure 3).⁵ The lack of perivascular and periadnexal inflammation also can help differentiate EHK from LS.

Linear lichen planus (LLP), similar to LS, histologically shows a lichenoid lymphocytic bandlike infiltrate obscuring the dermoepidermal junction, vacuolization of the basal cell layer, and pigment incontinence.^1,2 Although LS and LLP can have histologic overlap, the absence of adnexal or perieccrine lymphocytic inflammation can help distinguish the two.³ The histopathologic changes of intercellular edema or mild spongiosis, exocytosis, and parakeratosis present in LS also are typically absent in LLP. Linear lichen planus characteristically consists of wedge-shaped hypergranulosis and irregular acanthosis with saw-toothed rete ridges (Figure 4).² In addition, lobular eosinophilic deposits known as cytoid or Civatte bodies representing degenerated keratinocytes can be visualized at the dermoepidermal junction in LLP.² Immunofluorescence will highlight Civatte bodies with IgM, IgG, and C3, also helping to differentiate these 2 conditions.¹

Linear porokeratosis can be mistaken for the linear lesion of LS. Both entities may reveal perivascular lymphocytes in the dermis, and porokeratosis can be lichenoid in the central portion of the lesion.⁶ However, porokeratosis is unique in that it contains a cornoid lamella, characterized by a thin column of tightly packed parakeratotic cells extending from an invagination of the epidermis through the adjacent stratum corneum (Figure 5).⁶ Beneath the cornoid lamella, the granular layer is either absent or markedly attenuated, and pyknotic keratinocytes with perinuclear edema are present in the spinous layer.⁶ The epidermis in the central portion of the porokeratotic lesion may be normal, hyperplastic, or atrophic with effacement of rete ridges.

Similar to LS, linear psoriasis follows lines of Blaschko clinically. However, it is distinguished by its characteristic psoriatic epidermal changes as well as its lack of lichenoid or perieccrine inflammation.³ Typical findings in linear psoriasis include hyperkeratosis, confluent parakeratosis with entrapped neutrophilic microabscesses, acanthosis with regular elongation of rete ridges, intraepidermal neutrophils, thinned suprapapillary plates, dilated capillaries in the tips of the dermal papillae, and a chronic dermal inflammatory infiltrate (Figure 6).⁴

Lichen striatus (LS) is a benign, uncommon, self-limited, linear inflammatory skin disorder that primarily affects children up to 15 years of age, most commonly around 2 to 3 years of age, and is seen more frequently in girls.¹ It presents with a sudden eruption of asymptomatic small, flat-topped, lichenoid, scaly papules in a linear array on a single extremity. The lesions may be erythematous, flesh colored, or hypopigmented.^1,2 Multiple lesions appear over days to weeks and coalesce into linear plaques in a continuous or interrupted pattern along the lines of Blaschko, indicating possible somatic mosaicism.¹ Although typically asymptomatic, it may be pruritic. Most cases spontaneously resolve within 1 year.³ Recurrences are unusual. Digital involvement may result in onycholysis, longitudinal ridging, splitting, and nail loss.¹ The underlying cause of LS may be an abnormal immunologic reaction or genetic predisposition that is precipitated by some trigger such as a viral infection, trauma, hypersensitivity reaction, vaccine, seasonal variation, medication, or pregnancy.^1,2 An association with atopy has been described. Treatment is not necessary but options include topical steroids, topical retinoids, and topical calcineurin inhibitors.²

Histologically, findings in LS are somewhat variable but typically show a combination of spongiotic and lichenoid interface dermatitis with a perivascular and periadnexal lymphocytic infiltrate (Figure 1). Epidermal changes include intercellular and intracellular edema, focal spongiosis, lymphocytic exocytosis, parakeratosis, patchy hyperkeratosis, and keratinocyte necrosis (Figure 2A).^1,3 The epidermis is normal or slightly acanthotic, and dyskeratotic keratinocytes can be found in the granular and horny layers or at the dermoepidermal junction.² The lymphohistiocytic infiltrate in the superficial and deep dermis surrounds vascular plexuses and cutaneous adnexa such as eccrine glands and hair follicles.¹ Perivascular lymphoid aggregates and eccrine coil involvement are particularly distinctive of LS (Figure 2B).⁴ Pigment incontinence also may be seen.

Another condition that distributes linearly along the lines of Blaschko is linear epidermolytic hyperkeratosis (EHK). Similar to LS, histology shows hyperkeratosis, focal parakeratosis, and acanthosis of the epidermis.⁵ However, EHK shows epidermolysis, acantholysis, and perinuclear vacuolization in spinous and granular layers (Figure 3).⁵ The lack of perivascular and periadnexal inflammation also can help differentiate EHK from LS.

Linear lichen planus (LLP), similar to LS, histologically shows a lichenoid lymphocytic bandlike infiltrate obscuring the dermoepidermal junction, vacuolization of the basal cell layer, and pigment incontinence.^1,2 Although LS and LLP can have histologic overlap, the absence of adnexal or perieccrine lymphocytic inflammation can help distinguish the two.³ The histopathologic changes of intercellular edema or mild spongiosis, exocytosis, and parakeratosis present in LS also are typically absent in LLP. Linear lichen planus characteristically consists of wedge-shaped hypergranulosis and irregular acanthosis with saw-toothed rete ridges (Figure 4).² In addition, lobular eosinophilic deposits known as cytoid or Civatte bodies representing degenerated keratinocytes can be visualized at the dermoepidermal junction in LLP.² Immunofluorescence will highlight Civatte bodies with IgM, IgG, and C3, also helping to differentiate these 2 conditions.¹

Linear porokeratosis can be mistaken for the linear lesion of LS. Both entities may reveal perivascular lymphocytes in the dermis, and porokeratosis can be lichenoid in the central portion of the lesion.⁶ However, porokeratosis is unique in that it contains a cornoid lamella, characterized by a thin column of tightly packed parakeratotic cells extending from an invagination of the epidermis through the adjacent stratum corneum (Figure 5).⁶ Beneath the cornoid lamella, the granular layer is either absent or markedly attenuated, and pyknotic keratinocytes with perinuclear edema are present in the spinous layer.⁶ The epidermis in the central portion of the porokeratotic lesion may be normal, hyperplastic, or atrophic with effacement of rete ridges.

Similar to LS, linear psoriasis follows lines of Blaschko clinically. However, it is distinguished by its characteristic psoriatic epidermal changes as well as its lack of lichenoid or perieccrine inflammation.³ Typical findings in linear psoriasis include hyperkeratosis, confluent parakeratosis with entrapped neutrophilic microabscesses, acanthosis with regular elongation of rete ridges, intraepidermal neutrophils, thinned suprapapillary plates, dilated capillaries in the tips of the dermal papillae, and a chronic dermal inflammatory infiltrate (Figure 6).⁴

Lichen striatus (LS) is a benign, uncommon, self-limited, linear inflammatory skin disorder that primarily affects children up to 15 years of age, most commonly around 2 to 3 years of age, and is seen more frequently in girls.¹ It presents with a sudden eruption of asymptomatic small, flat-topped, lichenoid, scaly papules in a linear array on a single extremity. The lesions may be erythematous, flesh colored, or hypopigmented.^1,2 Multiple lesions appear over days to weeks and coalesce into linear plaques in a continuous or interrupted pattern along the lines of Blaschko, indicating possible somatic mosaicism.¹ Although typically asymptomatic, it may be pruritic. Most cases spontaneously resolve within 1 year.³ Recurrences are unusual. Digital involvement may result in onycholysis, longitudinal ridging, splitting, and nail loss.¹ The underlying cause of LS may be an abnormal immunologic reaction or genetic predisposition that is precipitated by some trigger such as a viral infection, trauma, hypersensitivity reaction, vaccine, seasonal variation, medication, or pregnancy.^1,2 An association with atopy has been described. Treatment is not necessary but options include topical steroids, topical retinoids, and topical calcineurin inhibitors.²

Histologically, findings in LS are somewhat variable but typically show a combination of spongiotic and lichenoid interface dermatitis with a perivascular and periadnexal lymphocytic infiltrate (Figure 1). Epidermal changes include intercellular and intracellular edema, focal spongiosis, lymphocytic exocytosis, parakeratosis, patchy hyperkeratosis, and keratinocyte necrosis (Figure 2A).^1,3 The epidermis is normal or slightly acanthotic, and dyskeratotic keratinocytes can be found in the granular and horny layers or at the dermoepidermal junction.² The lymphohistiocytic infiltrate in the superficial and deep dermis surrounds vascular plexuses and cutaneous adnexa such as eccrine glands and hair follicles.¹ Perivascular lymphoid aggregates and eccrine coil involvement are particularly distinctive of LS (Figure 2B).⁴ Pigment incontinence also may be seen.

Another condition that distributes linearly along the lines of Blaschko is linear epidermolytic hyperkeratosis (EHK). Similar to LS, histology shows hyperkeratosis, focal parakeratosis, and acanthosis of the epidermis.⁵ However, EHK shows epidermolysis, acantholysis, and perinuclear vacuolization in spinous and granular layers (Figure 3).⁵ The lack of perivascular and periadnexal inflammation also can help differentiate EHK from LS.

Linear lichen planus (LLP), similar to LS, histologically shows a lichenoid lymphocytic bandlike infiltrate obscuring the dermoepidermal junction, vacuolization of the basal cell layer, and pigment incontinence.^1,2 Although LS and LLP can have histologic overlap, the absence of adnexal or perieccrine lymphocytic inflammation can help distinguish the two.³ The histopathologic changes of intercellular edema or mild spongiosis, exocytosis, and parakeratosis present in LS also are typically absent in LLP. Linear lichen planus characteristically consists of wedge-shaped hypergranulosis and irregular acanthosis with saw-toothed rete ridges (Figure 4).² In addition, lobular eosinophilic deposits known as cytoid or Civatte bodies representing degenerated keratinocytes can be visualized at the dermoepidermal junction in LLP.² Immunofluorescence will highlight Civatte bodies with IgM, IgG, and C3, also helping to differentiate these 2 conditions.¹

Linear porokeratosis can be mistaken for the linear lesion of LS. Both entities may reveal perivascular lymphocytes in the dermis, and porokeratosis can be lichenoid in the central portion of the lesion.⁶ However, porokeratosis is unique in that it contains a cornoid lamella, characterized by a thin column of tightly packed parakeratotic cells extending from an invagination of the epidermis through the adjacent stratum corneum (Figure 5).⁶ Beneath the cornoid lamella, the granular layer is either absent or markedly attenuated, and pyknotic keratinocytes with perinuclear edema are present in the spinous layer.⁶ The epidermis in the central portion of the porokeratotic lesion may be normal, hyperplastic, or atrophic with effacement of rete ridges.

Similar to LS, linear psoriasis follows lines of Blaschko clinically. However, it is distinguished by its characteristic psoriatic epidermal changes as well as its lack of lichenoid or perieccrine inflammation.³ Typical findings in linear psoriasis include hyperkeratosis, confluent parakeratosis with entrapped neutrophilic microabscesses, acanthosis with regular elongation of rete ridges, intraepidermal neutrophils, thinned suprapapillary plates, dilated capillaries in the tips of the dermal papillae, and a chronic dermal inflammatory infiltrate (Figure 6).⁴

Syphilis often is referred to as the “great imitator” due to the protean presentations of secondary-stage disease, the most common of which are skin manifestations.¹ Secondary syphilis typically begins 3 to 10 weeks after initial exposure due to systemic dissemination of Treponema pallidum, and although presentations can vary widely, the classic presentation includes nonspecific generalized symptoms (eg, fever, malaise, lymphadenopathy), variable skin findings (eg, nonpruritic papulosquamous eruption), and mucosal ulcerations or plaques.¹ Early and accurate diagnosis of syphilis is critical to avoid the morbidity associated with advanced disease.

The classic histopathologic appearance of secondary syphilis is characterized by psoriasiform epidermal changes; a dermal inflammatory infiltrate of lymphocytes, histiocytes, and plasma cells in a lichenoid and/or superficial and deep perivascular distribution (Figure 1); and endothelial swelling of dermal blood vessels.¹ The presence of plasma cells in the infiltrate (Figure 2) is particularly useful for differentiating secondary syphilis from other clinicopathological mimickers, but this finding is not always present. Silver-based histochemical stains (eg, Warthin-Starry silver stain) can be used to high-light T pallidum organisms; however, histochemical staining is plagued by low diagnostic sensitivity for identifying the causative organism, making immunohistochemical and/or serologic testing the preferred method for confirming the diagnosis.¹

Arthropod assault is characterized by a superficial and deep perivascular lymphocytic inflammatory infiltrate with a variable number of polymorphonuclear cells.² Overlying spongiosis or focal epidermal necrosis and increased eosinophils are typical of arthropod assault (Figure 3).² The infiltrate seen following insect bites is classically described as wedge-shaped, although recent literature has disputed the sensitivity of this finding, identifying adnexal structure involvement as an alternative sensitive marker for identifying insect bites.²

Chronic cutaneous lupus erythematosus demonstrates a spectrum of histopathologic changes depending on the age of the lesion biopsied; however, characteristic histopathologic features typically include variable epidermal atrophy or acanthosis with basal layer vacuolar degeneration, basement membrane thickening, follicular plugging, superficial and deep perivascular and periappendageal lymphocytic inflammation, and dermal mucin deposition (Figure 4).⁴

Fixed drug eruption histopathologically presents as an interface tissue reaction–associated single-cell necrosis to broader areas of epidermal necrosis, as well as superficial to mid-dermal lymphocytic infiltrate. Unlike secondary syphilis, a fixed drug eruption is characterized by prominent melanin pigment incontinence and eosinophils (Figure 5).⁵

Similar to secondary syphilis, pityriasis lichenoides et varioliformis acuta (PLEVA) demonstrates variable psoriasiform epidermal hyperplasia with a lichenoid and perivascular lymphocytic infiltrate. Other findings in PLEVA include parakeratosis, variable epidermal necrosis, and prominent exocytosis of lymphocytes. Unlike typical secondary syphilis, PLEVA often is associated with lymphocytic vasculitis, consisting of the invasion of vessel walls by lymphocytes with extravasation of erythrocytes and an absence of conspicuous plasma cells (Figure 6).⁶

Syphilis often is referred to as the “great imitator” due to the protean presentations of secondary-stage disease, the most common of which are skin manifestations.¹ Secondary syphilis typically begins 3 to 10 weeks after initial exposure due to systemic dissemination of Treponema pallidum, and although presentations can vary widely, the classic presentation includes nonspecific generalized symptoms (eg, fever, malaise, lymphadenopathy), variable skin findings (eg, nonpruritic papulosquamous eruption), and mucosal ulcerations or plaques.¹ Early and accurate diagnosis of syphilis is critical to avoid the morbidity associated with advanced disease.

The classic histopathologic appearance of secondary syphilis is characterized by psoriasiform epidermal changes; a dermal inflammatory infiltrate of lymphocytes, histiocytes, and plasma cells in a lichenoid and/or superficial and deep perivascular distribution (Figure 1); and endothelial swelling of dermal blood vessels.¹ The presence of plasma cells in the infiltrate (Figure 2) is particularly useful for differentiating secondary syphilis from other clinicopathological mimickers, but this finding is not always present. Silver-based histochemical stains (eg, Warthin-Starry silver stain) can be used to high-light T pallidum organisms; however, histochemical staining is plagued by low diagnostic sensitivity for identifying the causative organism, making immunohistochemical and/or serologic testing the preferred method for confirming the diagnosis.¹

Arthropod assault is characterized by a superficial and deep perivascular lymphocytic inflammatory infiltrate with a variable number of polymorphonuclear cells.² Overlying spongiosis or focal epidermal necrosis and increased eosinophils are typical of arthropod assault (Figure 3).² The infiltrate seen following insect bites is classically described as wedge-shaped, although recent literature has disputed the sensitivity of this finding, identifying adnexal structure involvement as an alternative sensitive marker for identifying insect bites.²

Chronic cutaneous lupus erythematosus demonstrates a spectrum of histopathologic changes depending on the age of the lesion biopsied; however, characteristic histopathologic features typically include variable epidermal atrophy or acanthosis with basal layer vacuolar degeneration, basement membrane thickening, follicular plugging, superficial and deep perivascular and periappendageal lymphocytic inflammation, and dermal mucin deposition (Figure 4).⁴

Fixed drug eruption histopathologically presents as an interface tissue reaction–associated single-cell necrosis to broader areas of epidermal necrosis, as well as superficial to mid-dermal lymphocytic infiltrate. Unlike secondary syphilis, a fixed drug eruption is characterized by prominent melanin pigment incontinence and eosinophils (Figure 5).⁵

Similar to secondary syphilis, pityriasis lichenoides et varioliformis acuta (PLEVA) demonstrates variable psoriasiform epidermal hyperplasia with a lichenoid and perivascular lymphocytic infiltrate. Other findings in PLEVA include parakeratosis, variable epidermal necrosis, and prominent exocytosis of lymphocytes. Unlike typical secondary syphilis, PLEVA often is associated with lymphocytic vasculitis, consisting of the invasion of vessel walls by lymphocytes with extravasation of erythrocytes and an absence of conspicuous plasma cells (Figure 6).⁶

Syphilis often is referred to as the “great imitator” due to the protean presentations of secondary-stage disease, the most common of which are skin manifestations.¹ Secondary syphilis typically begins 3 to 10 weeks after initial exposure due to systemic dissemination of Treponema pallidum, and although presentations can vary widely, the classic presentation includes nonspecific generalized symptoms (eg, fever, malaise, lymphadenopathy), variable skin findings (eg, nonpruritic papulosquamous eruption), and mucosal ulcerations or plaques.¹ Early and accurate diagnosis of syphilis is critical to avoid the morbidity associated with advanced disease.

The classic histopathologic appearance of secondary syphilis is characterized by psoriasiform epidermal changes; a dermal inflammatory infiltrate of lymphocytes, histiocytes, and plasma cells in a lichenoid and/or superficial and deep perivascular distribution (Figure 1); and endothelial swelling of dermal blood vessels.¹ The presence of plasma cells in the infiltrate (Figure 2) is particularly useful for differentiating secondary syphilis from other clinicopathological mimickers, but this finding is not always present. Silver-based histochemical stains (eg, Warthin-Starry silver stain) can be used to high-light T pallidum organisms; however, histochemical staining is plagued by low diagnostic sensitivity for identifying the causative organism, making immunohistochemical and/or serologic testing the preferred method for confirming the diagnosis.¹

Arthropod assault is characterized by a superficial and deep perivascular lymphocytic inflammatory infiltrate with a variable number of polymorphonuclear cells.² Overlying spongiosis or focal epidermal necrosis and increased eosinophils are typical of arthropod assault (Figure 3).² The infiltrate seen following insect bites is classically described as wedge-shaped, although recent literature has disputed the sensitivity of this finding, identifying adnexal structure involvement as an alternative sensitive marker for identifying insect bites.²

Chronic cutaneous lupus erythematosus demonstrates a spectrum of histopathologic changes depending on the age of the lesion biopsied; however, characteristic histopathologic features typically include variable epidermal atrophy or acanthosis with basal layer vacuolar degeneration, basement membrane thickening, follicular plugging, superficial and deep perivascular and periappendageal lymphocytic inflammation, and dermal mucin deposition (Figure 4).⁴

Fixed drug eruption histopathologically presents as an interface tissue reaction–associated single-cell necrosis to broader areas of epidermal necrosis, as well as superficial to mid-dermal lymphocytic infiltrate. Unlike secondary syphilis, a fixed drug eruption is characterized by prominent melanin pigment incontinence and eosinophils (Figure 5).⁵

Similar to secondary syphilis, pityriasis lichenoides et varioliformis acuta (PLEVA) demonstrates variable psoriasiform epidermal hyperplasia with a lichenoid and perivascular lymphocytic infiltrate. Other findings in PLEVA include parakeratosis, variable epidermal necrosis, and prominent exocytosis of lymphocytes. Unlike typical secondary syphilis, PLEVA often is associated with lymphocytic vasculitis, consisting of the invasion of vessel walls by lymphocytes with extravasation of erythrocytes and an absence of conspicuous plasma cells (Figure 6).⁶

Cutaneous leishmaniasis is a parasitic infection caused by intracellular organisms found in tropical climates. Old World leishmaniasis is endemic to Asia, Africa, and parts of Europe, while New World leishmaniasis is native to Central and South Americas.¹ Depending upon a host’s immune status and the specific Leishmania species, clinical presentations vary in appearance and severity, ranging from self-limited, localized cutaneous disease to potentially fatal visceral and mucocutaneous involvement. Most cutaneous manifestations of leishmaniasis begin as distinct, painless papules that may progress to nodules or become ulcerated over time.¹ Histologically, leishmaniasis is diagnosed by the identification of intracellular organisms that characteristically align along the peripheral rim inside the vacuole of a histiocyte.² This unique finding is called the “marquee sign” due to its resemblance to light bulbs arranged around a dressing room mirror (Figure 1).²Leishmania amastigotes (also known as Leishman-Donovan bodies) have kinetoplasts that are helpful in diagnosis but also may be difficult to detect.² Along with the Leishmania parasites, there typically is a mixed inflammatory infiltrate of plasma cells, lymphocytes, histiocytes, and neutrophils (Figure 2).^1,2 There also may be varying degrees of pseudoepitheliomatous hyperplasia and overlying epidermal ulceration.¹

Cutaneous botryomycosis can present clinically as a number of various primary lesions, including papules, nodules, or ulcers that may resemble leishmaniasis.³ Botryomycosis represents a specific histologic collection of bacterial granules, most commonly caused by Staphylococcus aureus.³ The dermal granulomatous infiltrate seen in botryomycosis often is similar to that seen in chronic leishmaniasis; however, one histologic feature unique to botryomycosis is the presence of characteristic basophilic staphylococcal grains that are arranged in clusters resembling bunches of grapes (the term botryo means “bunch of grapes” in Greek).³ A thin, eosinophilic rim consisting of antibodies, bacterial debris, and complement proteins and glycoproteins may encircle the basophilic grains but does not need to be present for diagnosis (Figure 3).³

Lepromatous leprosy presents as a symmetric, widespread eruption of macules, patches, plaques, or papules that are most prominent in acral areas.⁴ Perivascular infiltration of lymphocytes and histiocytes is characteristic of lepromatous leprosy.² Mycobacteria bacilli also are seen within histiocytic vacuoles, similarly to leishmaniasis; however, collections of these bacilli congregate within the center of a foamy histiocyte to form a distinctive histologic finding known as a globus. These individual histiocytes containing central globi are called Virchow cells (Figure 4).² However, lepromatous leprosy can be distinguished from leishmaniasis histologically by carefully observing the intracellular location of the infectious organism. Mycobacteria bacilli are located in the center of a histiocyte vacuole whereas Leishmania parasites demonstrate a peripheral alignment along a histiocyte vacuole. If any uncertainty remains between a diagnosis of leishmaniasis and lepromatous leprosy, positive Fite staining for mycobacteria easily differentiates between the 2 conditions.^2,4

Cutaneous lobomycosis, a rare fungal infection transmitted by dolphins, manifests clinically as an asymptomatic nodule that is similar in appearance to a keloid. Histologic similarities to leishmaniasis include pseudoepitheliomatous hyperplasia and dermal granulomatous inflammation.⁴ The most distinguishing characteristic of lobomycosis is the presence of round, thick-walled, white organisms connected in a “string of beads” or chainlike configuration (Figure 5).² Unlike leishmaniasis, lobomycosis fungal organisms would stain positive on periodic acid–Schiff staining.⁴

Cutaneous protothecosis is a rare clinical entity that presents as an isolated nodule or plaque or bursitis.⁴ It occurs following minor trauma and inoculation with Prototheca organisms, a genus of algae found in contaminated water.^2,4 In its morula form, Prototheca adopts a characteristic arrangement within histiocytes that strikingly resembles a soccer ball (Figure 6).² Conversely, nonmorulating forms of protothecosis can also be seen; these exhibit a central basophilic, dotlike structure within the histiocytes surrounded by a white halo.² Definitive diagnosis of protothecosis can only be made upon successful culture of the algae.⁵

Cutaneous leishmaniasis is a parasitic infection caused by intracellular organisms found in tropical climates. Old World leishmaniasis is endemic to Asia, Africa, and parts of Europe, while New World leishmaniasis is native to Central and South Americas.¹ Depending upon a host’s immune status and the specific Leishmania species, clinical presentations vary in appearance and severity, ranging from self-limited, localized cutaneous disease to potentially fatal visceral and mucocutaneous involvement. Most cutaneous manifestations of leishmaniasis begin as distinct, painless papules that may progress to nodules or become ulcerated over time.¹ Histologically, leishmaniasis is diagnosed by the identification of intracellular organisms that characteristically align along the peripheral rim inside the vacuole of a histiocyte.² This unique finding is called the “marquee sign” due to its resemblance to light bulbs arranged around a dressing room mirror (Figure 1).²Leishmania amastigotes (also known as Leishman-Donovan bodies) have kinetoplasts that are helpful in diagnosis but also may be difficult to detect.² Along with the Leishmania parasites, there typically is a mixed inflammatory infiltrate of plasma cells, lymphocytes, histiocytes, and neutrophils (Figure 2).^1,2 There also may be varying degrees of pseudoepitheliomatous hyperplasia and overlying epidermal ulceration.¹

Cutaneous botryomycosis can present clinically as a number of various primary lesions, including papules, nodules, or ulcers that may resemble leishmaniasis.³ Botryomycosis represents a specific histologic collection of bacterial granules, most commonly caused by Staphylococcus aureus.³ The dermal granulomatous infiltrate seen in botryomycosis often is similar to that seen in chronic leishmaniasis; however, one histologic feature unique to botryomycosis is the presence of characteristic basophilic staphylococcal grains that are arranged in clusters resembling bunches of grapes (the term botryo means “bunch of grapes” in Greek).³ A thin, eosinophilic rim consisting of antibodies, bacterial debris, and complement proteins and glycoproteins may encircle the basophilic grains but does not need to be present for diagnosis (Figure 3).³

Lepromatous leprosy presents as a symmetric, widespread eruption of macules, patches, plaques, or papules that are most prominent in acral areas.⁴ Perivascular infiltration of lymphocytes and histiocytes is characteristic of lepromatous leprosy.² Mycobacteria bacilli also are seen within histiocytic vacuoles, similarly to leishmaniasis; however, collections of these bacilli congregate within the center of a foamy histiocyte to form a distinctive histologic finding known as a globus. These individual histiocytes containing central globi are called Virchow cells (Figure 4).² However, lepromatous leprosy can be distinguished from leishmaniasis histologically by carefully observing the intracellular location of the infectious organism. Mycobacteria bacilli are located in the center of a histiocyte vacuole whereas Leishmania parasites demonstrate a peripheral alignment along a histiocyte vacuole. If any uncertainty remains between a diagnosis of leishmaniasis and lepromatous leprosy, positive Fite staining for mycobacteria easily differentiates between the 2 conditions.^2,4

Cutaneous lobomycosis, a rare fungal infection transmitted by dolphins, manifests clinically as an asymptomatic nodule that is similar in appearance to a keloid. Histologic similarities to leishmaniasis include pseudoepitheliomatous hyperplasia and dermal granulomatous inflammation.⁴ The most distinguishing characteristic of lobomycosis is the presence of round, thick-walled, white organisms connected in a “string of beads” or chainlike configuration (Figure 5).² Unlike leishmaniasis, lobomycosis fungal organisms would stain positive on periodic acid–Schiff staining.⁴

Cutaneous protothecosis is a rare clinical entity that presents as an isolated nodule or plaque or bursitis.⁴ It occurs following minor trauma and inoculation with Prototheca organisms, a genus of algae found in contaminated water.^2,4 In its morula form, Prototheca adopts a characteristic arrangement within histiocytes that strikingly resembles a soccer ball (Figure 6).² Conversely, nonmorulating forms of protothecosis can also be seen; these exhibit a central basophilic, dotlike structure within the histiocytes surrounded by a white halo.² Definitive diagnosis of protothecosis can only be made upon successful culture of the algae.⁵

Cutaneous leishmaniasis is a parasitic infection caused by intracellular organisms found in tropical climates. Old World leishmaniasis is endemic to Asia, Africa, and parts of Europe, while New World leishmaniasis is native to Central and South Americas.¹ Depending upon a host’s immune status and the specific Leishmania species, clinical presentations vary in appearance and severity, ranging from self-limited, localized cutaneous disease to potentially fatal visceral and mucocutaneous involvement. Most cutaneous manifestations of leishmaniasis begin as distinct, painless papules that may progress to nodules or become ulcerated over time.¹ Histologically, leishmaniasis is diagnosed by the identification of intracellular organisms that characteristically align along the peripheral rim inside the vacuole of a histiocyte.² This unique finding is called the “marquee sign” due to its resemblance to light bulbs arranged around a dressing room mirror (Figure 1).²Leishmania amastigotes (also known as Leishman-Donovan bodies) have kinetoplasts that are helpful in diagnosis but also may be difficult to detect.² Along with the Leishmania parasites, there typically is a mixed inflammatory infiltrate of plasma cells, lymphocytes, histiocytes, and neutrophils (Figure 2).^1,2 There also may be varying degrees of pseudoepitheliomatous hyperplasia and overlying epidermal ulceration.¹

Cutaneous botryomycosis can present clinically as a number of various primary lesions, including papules, nodules, or ulcers that may resemble leishmaniasis.³ Botryomycosis represents a specific histologic collection of bacterial granules, most commonly caused by Staphylococcus aureus.³ The dermal granulomatous infiltrate seen in botryomycosis often is similar to that seen in chronic leishmaniasis; however, one histologic feature unique to botryomycosis is the presence of characteristic basophilic staphylococcal grains that are arranged in clusters resembling bunches of grapes (the term botryo means “bunch of grapes” in Greek).³ A thin, eosinophilic rim consisting of antibodies, bacterial debris, and complement proteins and glycoproteins may encircle the basophilic grains but does not need to be present for diagnosis (Figure 3).³

Lepromatous leprosy presents as a symmetric, widespread eruption of macules, patches, plaques, or papules that are most prominent in acral areas.⁴ Perivascular infiltration of lymphocytes and histiocytes is characteristic of lepromatous leprosy.² Mycobacteria bacilli also are seen within histiocytic vacuoles, similarly to leishmaniasis; however, collections of these bacilli congregate within the center of a foamy histiocyte to form a distinctive histologic finding known as a globus. These individual histiocytes containing central globi are called Virchow cells (Figure 4).² However, lepromatous leprosy can be distinguished from leishmaniasis histologically by carefully observing the intracellular location of the infectious organism. Mycobacteria bacilli are located in the center of a histiocyte vacuole whereas Leishmania parasites demonstrate a peripheral alignment along a histiocyte vacuole. If any uncertainty remains between a diagnosis of leishmaniasis and lepromatous leprosy, positive Fite staining for mycobacteria easily differentiates between the 2 conditions.^2,4

Cutaneous lobomycosis, a rare fungal infection transmitted by dolphins, manifests clinically as an asymptomatic nodule that is similar in appearance to a keloid. Histologic similarities to leishmaniasis include pseudoepitheliomatous hyperplasia and dermal granulomatous inflammation.⁴ The most distinguishing characteristic of lobomycosis is the presence of round, thick-walled, white organisms connected in a “string of beads” or chainlike configuration (Figure 5).² Unlike leishmaniasis, lobomycosis fungal organisms would stain positive on periodic acid–Schiff staining.⁴

Cutaneous protothecosis is a rare clinical entity that presents as an isolated nodule or plaque or bursitis.⁴ It occurs following minor trauma and inoculation with Prototheca organisms, a genus of algae found in contaminated water.^2,4 In its morula form, Prototheca adopts a characteristic arrangement within histiocytes that strikingly resembles a soccer ball (Figure 6).² Conversely, nonmorulating forms of protothecosis can also be seen; these exhibit a central basophilic, dotlike structure within the histiocytes surrounded by a white halo.² Definitive diagnosis of protothecosis can only be made upon successful culture of the algae.⁵

Desmoplastic melanoma, an uncommon variant of melanoma, poses a diagnostic challenge to the clinician because the tumors frequently appear as nonspecific flesh-colored or amelanotic plaques or nodules. They are more common in men than in women and are frequently found on the head and neck.^1,2 Their innocuous appearance may lead to a delay in diagnosis and may explain why desmoplastic melanomas often are deeply infiltrative at the time of biopsy. Desmoplastic melanoma arises de novo in approximately one-third of cases.¹ In the remainder of cases, it is seen in conjunction with overlying melanoma in situ, most commonly lentigo maligna melanoma.¹ Histologically, desmoplastic melanomas are characterized by malignant spindle cells within a densely fibrotic stroma (Figure 1). Adjacent lymphoid aggregates and perineural involvement are common features,² while pigment and atypical mitoses can be infrequent. Desmoplastic melanoma can be classified as mixed or pure based on the degree of desmoplasia and cellularity. Within mixed desmoplastic melanomas, there are areas that have histologic features of conventional melanomas while others demonstrate more typical desmoplastic characteristics. Pure desmoplastic melanoma has a higher degree of desmoplasia and fewer tumor cells than the mixed type.¹ The pure subtype tends to be less aggressive and is less likely to metastasize to the lymph nodes.¹ In the absence of an in situ component (Figure 2), desmoplastic melanoma may be indistinguishable from other spindle cell tumors on routine hematoxylin and eosin staining; thus, immunohistochemical staining generally is required. The most reliable stains in confirming a diagnosis of desmoplastic melanoma are S100 and SOX10 (SRY-related HMG-box 10)(Figure 3)(eTable).³

Atypical fibroxathoma typically presents as a nodule in the head and neck region or other sun-exposed areas in elderly individuals and is more commonly seen in men than in women.⁴ Histologically, atypical fibroxanthomas are composed of pleomorphic spindle, epithelioid, and multinucleated giant cells with numerous and atypical mitoses (Figure 4).⁵ Atypical fibroxanthoma is considered a diagnosis of exclusion; therefore, other dermal spindle cell tumors need to be ruled out before diagnosis can be made. Atypical fibroxanthomas generally stain negative for cytokeratin, S100, SOX10, and desmin, but in some cases there is positive focal staining for smooth muscle actin.⁴ Multiple immunohistochemical markers, including CD10, have shown reactivity in atypical fibroxanthomas,⁴ but none of these markers has a high specificity for this tumor; thus, it remains a diagnosis of exclusion.

Cutaneous angiosarcomas are aggressive tumors associated with a high mortality rate despite appropriate treatment with surgical resection and postoperative radiation treatment. They typically present as ecchymotic macules or nodules on the face or scalp of elderly patients.^6,7 Ionizing radiation and chronic lymphedema are risk factors for cutaneous angiosarcoma.⁶ Histologically, well-differentiated cutaneous angiosarcomas are composed of irregular, anastomosing vascular channels that dissect through the dermis (Figure 5).^6,7 Less well-differentiated tumors may contain spindle cells and lack obvious vascular structures; thus immunohistochemistry is essential for making the correct diagnosis in these cases. Cutaneous angiosarcomas typically stain positive for ERG (ETS-related gene) protein, CD31, CD34, and factor VIII.^6,8 Unfortunately these tumors may also occasionally stain with cytokeratin, which may lead to the erroneous diagnosis of a carcinoma.⁶

Figure 4. Pleomorphic spindle, epithelioid, and multinucleate giant cells with atypical mitoses filling the dermis in atypical fibroxanthoma (H&E, original magnification ×200).		Figure 5. Anastamosing vascular channels dissecting through collagen bundles and consuming the epidermis in cutaneous angiosarcoma (H&E, original magnification ×100).

Cutaneous leiomyosarcoma is a smooth muscle neoplasm that arises from arrector pili muscles, genital smooth muscles, or vascular smooth muscles. It typically presents as a single plaque or nodule on the arms and legs of individuals older than 50 years of age.⁹ Cutaneous leiomyosarcomas can be classified as either dermal, in which at least 90% of the tumor is confined to the dermis, or subcutaneous; this distinction is important because the latter type has a higher rate of metastasis and a poorer prognosis.⁹ Because of this tumor’s smooth muscle derivation, well-differentiated tumors may retain features of typical smooth muscle cells, including cigar-shaped nuclei with adjacent glycogen vacuoles (Figure 6). If fascicle formation is observed, this may be an additional clue to the diagnosis. In poorly differentiated tumors, immunohistochemistry is invaluable. Leiomyosarcoma often stains positive for smooth muscle actin, muscle specific actin, h-caldesmon, desmin, and calponin.^9-11

Spindle cell squamous cell carcinomas often present as ulcerated nodules on sun-exposed skin or on sites of prior ionizing radiation.^2,12 Like desmoplastic melanoma, spindle cell squamous cell carcinomas are characterized by spindle cells in the dermis. Helpful diagnostic clues may include evidence of squamous differentiation, including keratin pearls or overlying actinic keratosis (Figure 7). However, actinic keratosis is common on sun-damaged skin and cannot be used to definitively confirm this diagnosis. There also may be areas of the tumor with more typical epithelioid cells that are easily identified as squamous cell carcinoma.² Spindle cell squamous cell carcinoma stains positive for high–molecular weight cytokeratin antibodies and p63,² which can help to differentiate it from the other spindle cell tumors in the differential.

Figure 6. Spindle cells of leiomyosarcoma with cigar-shaped nuclei and adjacent glycogen vacuoles (H&E, original magnification ×600).		Figure 7. Spindle cell squamous cell carcinoma with overlying epidermal atypia that blends with the underlying dermal spindle cells (H&E, original magnification ×100).

Desmoplastic melanoma, an uncommon variant of melanoma, poses a diagnostic challenge to the clinician because the tumors frequently appear as nonspecific flesh-colored or amelanotic plaques or nodules. They are more common in men than in women and are frequently found on the head and neck.^1,2 Their innocuous appearance may lead to a delay in diagnosis and may explain why desmoplastic melanomas often are deeply infiltrative at the time of biopsy. Desmoplastic melanoma arises de novo in approximately one-third of cases.¹ In the remainder of cases, it is seen in conjunction with overlying melanoma in situ, most commonly lentigo maligna melanoma.¹ Histologically, desmoplastic melanomas are characterized by malignant spindle cells within a densely fibrotic stroma (Figure 1). Adjacent lymphoid aggregates and perineural involvement are common features,² while pigment and atypical mitoses can be infrequent. Desmoplastic melanoma can be classified as mixed or pure based on the degree of desmoplasia and cellularity. Within mixed desmoplastic melanomas, there are areas that have histologic features of conventional melanomas while others demonstrate more typical desmoplastic characteristics. Pure desmoplastic melanoma has a higher degree of desmoplasia and fewer tumor cells than the mixed type.¹ The pure subtype tends to be less aggressive and is less likely to metastasize to the lymph nodes.¹ In the absence of an in situ component (Figure 2), desmoplastic melanoma may be indistinguishable from other spindle cell tumors on routine hematoxylin and eosin staining; thus, immunohistochemical staining generally is required. The most reliable stains in confirming a diagnosis of desmoplastic melanoma are S100 and SOX10 (SRY-related HMG-box 10)(Figure 3)(eTable).³

Atypical fibroxathoma typically presents as a nodule in the head and neck region or other sun-exposed areas in elderly individuals and is more commonly seen in men than in women.⁴ Histologically, atypical fibroxanthomas are composed of pleomorphic spindle, epithelioid, and multinucleated giant cells with numerous and atypical mitoses (Figure 4).⁵ Atypical fibroxanthoma is considered a diagnosis of exclusion; therefore, other dermal spindle cell tumors need to be ruled out before diagnosis can be made. Atypical fibroxanthomas generally stain negative for cytokeratin, S100, SOX10, and desmin, but in some cases there is positive focal staining for smooth muscle actin.⁴ Multiple immunohistochemical markers, including CD10, have shown reactivity in atypical fibroxanthomas,⁴ but none of these markers has a high specificity for this tumor; thus, it remains a diagnosis of exclusion.

Cutaneous angiosarcomas are aggressive tumors associated with a high mortality rate despite appropriate treatment with surgical resection and postoperative radiation treatment. They typically present as ecchymotic macules or nodules on the face or scalp of elderly patients.^6,7 Ionizing radiation and chronic lymphedema are risk factors for cutaneous angiosarcoma.⁶ Histologically, well-differentiated cutaneous angiosarcomas are composed of irregular, anastomosing vascular channels that dissect through the dermis (Figure 5).^6,7 Less well-differentiated tumors may contain spindle cells and lack obvious vascular structures; thus immunohistochemistry is essential for making the correct diagnosis in these cases. Cutaneous angiosarcomas typically stain positive for ERG (ETS-related gene) protein, CD31, CD34, and factor VIII.^6,8 Unfortunately these tumors may also occasionally stain with cytokeratin, which may lead to the erroneous diagnosis of a carcinoma.⁶

Figure 4. Pleomorphic spindle, epithelioid, and multinucleate giant cells with atypical mitoses filling the dermis in atypical fibroxanthoma (H&E, original magnification ×200).		Figure 5. Anastamosing vascular channels dissecting through collagen bundles and consuming the epidermis in cutaneous angiosarcoma (H&E, original magnification ×100).

Cutaneous leiomyosarcoma is a smooth muscle neoplasm that arises from arrector pili muscles, genital smooth muscles, or vascular smooth muscles. It typically presents as a single plaque or nodule on the arms and legs of individuals older than 50 years of age.⁹ Cutaneous leiomyosarcomas can be classified as either dermal, in which at least 90% of the tumor is confined to the dermis, or subcutaneous; this distinction is important because the latter type has a higher rate of metastasis and a poorer prognosis.⁹ Because of this tumor’s smooth muscle derivation, well-differentiated tumors may retain features of typical smooth muscle cells, including cigar-shaped nuclei with adjacent glycogen vacuoles (Figure 6). If fascicle formation is observed, this may be an additional clue to the diagnosis. In poorly differentiated tumors, immunohistochemistry is invaluable. Leiomyosarcoma often stains positive for smooth muscle actin, muscle specific actin, h-caldesmon, desmin, and calponin.^9-11

Spindle cell squamous cell carcinomas often present as ulcerated nodules on sun-exposed skin or on sites of prior ionizing radiation.^2,12 Like desmoplastic melanoma, spindle cell squamous cell carcinomas are characterized by spindle cells in the dermis. Helpful diagnostic clues may include evidence of squamous differentiation, including keratin pearls or overlying actinic keratosis (Figure 7). However, actinic keratosis is common on sun-damaged skin and cannot be used to definitively confirm this diagnosis. There also may be areas of the tumor with more typical epithelioid cells that are easily identified as squamous cell carcinoma.² Spindle cell squamous cell carcinoma stains positive for high–molecular weight cytokeratin antibodies and p63,² which can help to differentiate it from the other spindle cell tumors in the differential.

Figure 6. Spindle cells of leiomyosarcoma with cigar-shaped nuclei and adjacent glycogen vacuoles (H&E, original magnification ×600).		Figure 7. Spindle cell squamous cell carcinoma with overlying epidermal atypia that blends with the underlying dermal spindle cells (H&E, original magnification ×100).

Desmoplastic melanoma, an uncommon variant of melanoma, poses a diagnostic challenge to the clinician because the tumors frequently appear as nonspecific flesh-colored or amelanotic plaques or nodules. They are more common in men than in women and are frequently found on the head and neck.^1,2 Their innocuous appearance may lead to a delay in diagnosis and may explain why desmoplastic melanomas often are deeply infiltrative at the time of biopsy. Desmoplastic melanoma arises de novo in approximately one-third of cases.¹ In the remainder of cases, it is seen in conjunction with overlying melanoma in situ, most commonly lentigo maligna melanoma.¹ Histologically, desmoplastic melanomas are characterized by malignant spindle cells within a densely fibrotic stroma (Figure 1). Adjacent lymphoid aggregates and perineural involvement are common features,² while pigment and atypical mitoses can be infrequent. Desmoplastic melanoma can be classified as mixed or pure based on the degree of desmoplasia and cellularity. Within mixed desmoplastic melanomas, there are areas that have histologic features of conventional melanomas while others demonstrate more typical desmoplastic characteristics. Pure desmoplastic melanoma has a higher degree of desmoplasia and fewer tumor cells than the mixed type.¹ The pure subtype tends to be less aggressive and is less likely to metastasize to the lymph nodes.¹ In the absence of an in situ component (Figure 2), desmoplastic melanoma may be indistinguishable from other spindle cell tumors on routine hematoxylin and eosin staining; thus, immunohistochemical staining generally is required. The most reliable stains in confirming a diagnosis of desmoplastic melanoma are S100 and SOX10 (SRY-related HMG-box 10)(Figure 3)(eTable).³

Atypical fibroxathoma typically presents as a nodule in the head and neck region or other sun-exposed areas in elderly individuals and is more commonly seen in men than in women.⁴ Histologically, atypical fibroxanthomas are composed of pleomorphic spindle, epithelioid, and multinucleated giant cells with numerous and atypical mitoses (Figure 4).⁵ Atypical fibroxanthoma is considered a diagnosis of exclusion; therefore, other dermal spindle cell tumors need to be ruled out before diagnosis can be made. Atypical fibroxanthomas generally stain negative for cytokeratin, S100, SOX10, and desmin, but in some cases there is positive focal staining for smooth muscle actin.⁴ Multiple immunohistochemical markers, including CD10, have shown reactivity in atypical fibroxanthomas,⁴ but none of these markers has a high specificity for this tumor; thus, it remains a diagnosis of exclusion.

Cutaneous angiosarcomas are aggressive tumors associated with a high mortality rate despite appropriate treatment with surgical resection and postoperative radiation treatment. They typically present as ecchymotic macules or nodules on the face or scalp of elderly patients.^6,7 Ionizing radiation and chronic lymphedema are risk factors for cutaneous angiosarcoma.⁶ Histologically, well-differentiated cutaneous angiosarcomas are composed of irregular, anastomosing vascular channels that dissect through the dermis (Figure 5).^6,7 Less well-differentiated tumors may contain spindle cells and lack obvious vascular structures; thus immunohistochemistry is essential for making the correct diagnosis in these cases. Cutaneous angiosarcomas typically stain positive for ERG (ETS-related gene) protein, CD31, CD34, and factor VIII.^6,8 Unfortunately these tumors may also occasionally stain with cytokeratin, which may lead to the erroneous diagnosis of a carcinoma.⁶

Figure 4. Pleomorphic spindle, epithelioid, and multinucleate giant cells with atypical mitoses filling the dermis in atypical fibroxanthoma (H&E, original magnification ×200).		Figure 5. Anastamosing vascular channels dissecting through collagen bundles and consuming the epidermis in cutaneous angiosarcoma (H&E, original magnification ×100).

Cutaneous leiomyosarcoma is a smooth muscle neoplasm that arises from arrector pili muscles, genital smooth muscles, or vascular smooth muscles. It typically presents as a single plaque or nodule on the arms and legs of individuals older than 50 years of age.⁹ Cutaneous leiomyosarcomas can be classified as either dermal, in which at least 90% of the tumor is confined to the dermis, or subcutaneous; this distinction is important because the latter type has a higher rate of metastasis and a poorer prognosis.⁹ Because of this tumor’s smooth muscle derivation, well-differentiated tumors may retain features of typical smooth muscle cells, including cigar-shaped nuclei with adjacent glycogen vacuoles (Figure 6). If fascicle formation is observed, this may be an additional clue to the diagnosis. In poorly differentiated tumors, immunohistochemistry is invaluable. Leiomyosarcoma often stains positive for smooth muscle actin, muscle specific actin, h-caldesmon, desmin, and calponin.^9-11

Spindle cell squamous cell carcinomas often present as ulcerated nodules on sun-exposed skin or on sites of prior ionizing radiation.^2,12 Like desmoplastic melanoma, spindle cell squamous cell carcinomas are characterized by spindle cells in the dermis. Helpful diagnostic clues may include evidence of squamous differentiation, including keratin pearls or overlying actinic keratosis (Figure 7). However, actinic keratosis is common on sun-damaged skin and cannot be used to definitively confirm this diagnosis. There also may be areas of the tumor with more typical epithelioid cells that are easily identified as squamous cell carcinoma.² Spindle cell squamous cell carcinoma stains positive for high–molecular weight cytokeratin antibodies and p63,² which can help to differentiate it from the other spindle cell tumors in the differential.

Figure 6. Spindle cells of leiomyosarcoma with cigar-shaped nuclei and adjacent glycogen vacuoles (H&E, original magnification ×600).		Figure 7. Spindle cell squamous cell carcinoma with overlying epidermal atypia that blends with the underlying dermal spindle cells (H&E, original magnification ×100).

Chromoblastomycosis is a chronic fungal infection of the skin and subcutaneous tissues that demonstrates characteristic Medlar or sclerotic bodies that resemble copper pennies on histopathology.¹ Cutaneous infection often results from direct inoculation, such as from a wood splinter. Clinically, the lesion typically is a pink papule that progresses to a verrucous plaque on the legs of farmers or rural workers in the tropics or subtropics. There usually are no associated constitutional symptoms. Several dematiaceous (darkly pigmented) fungi cause chromoblastomycosis, including Fonsecaea compacta, Cladophialophora carrionii, Rhinocladiella aquaspersa, Phialophora verrucosa, and Fonsecaea pedrosoi. Cellular division occurs by internal septation rather than budding. Skin biopsy can confirm the diagnosis.¹ Chromoblastomycosis is histopathologically characterized by pseudoepitheli-
omatous hyperplasia (Figure 1) with histiocytes and neutrophils surrounding distinct copper-colored 
Medlar bodies (6–12 μm)(Figure 2), which are fungal spores.^1-3 Several conditions demonstrate pseudoepitheliomatous hyperplasia with intraepidermal pustules and can be remembered by the mnemonic “here come big green leafy vegetables”: halogenoderma, chromoblastomycosis, blastomycosis, granuloma inguinale, leishmaniasis, and pemphigus vegetans.² Treatment of chromoblastomycosis can be challenging, as no standard treatment has been established and therapy can be complicated by low cure rates and high relapse rates, especially in chronic and extensive disease. Treatment can include cryotherapy or surgical excision for small lesions in combination with systemic antifungals.⁴ Itraconazole (200–400 mg daily) for at least 
6 months has been reported to have up to a 
90% cure rate with mild to moderate disease and 44% with severe disease.⁵ Combination oral antifungal treatment with itraconazole and terbinafine has been recommended.⁶ There are reports of progression of chromoblastomycosis to squamous cell carcinoma, which is rare and occurred after 
long-standing, inadequately treated lesions.⁷

Blastomycosis also presents with pseudoepitheliomatous hyperplasia, as seen in chromoblastomycosis, but organisms typically are few in number 
and demonstrate a thick, asymmetrical, refractile wall and a dark nucleus. Although chromoblastomycosis and blastomycosis are similar in 
size (8–15 μm), the broad-based budding of blastomycosis (Figure 3) is a key feature and the yeast 
are not pigmented.^1-3 Blastomycosis is caused by Blastomyces dermatitidis and is endemic to the Mississippi and Ohio River valleys, Great Lakes region, and Southeastern United States. Cutaneous infection typically occurs from inhalation of the dimorphic fungi into the lungs and occasional dissemination involving the skin, causing papulopustules and 
thick, crusted, warty plaques with central ulceration. 
Rarely, primary cutaneous blastomycosis can occur from direct inoculation, typically in a laboratory. Treatment of disseminated blastomycosis includes systemic antifungals.¹

Coccidioidomycosis is characterized by large spherules (10–80 μm) with refractile walls and granular gray cytoplasm.^2,3 Coccidioidomycosis spherules occasionally contain endospores² and often are noticeably larger than surrounding histiocyte nuclei (Figure 4), whereas chromoblastomycosis, blastomycosis, cryptococcosis, and lobomycosis are more similar in size to histiocyte nuclei. Coccidioidomycosis is caused by Coccidioides immitis, a highly virulent dimorphic fungus found in the Southwestern United States, northern Mexico, and Central and South America. Pulmonary infection occurs by inhalation of arthroconidia, often from soil, and is asymptomatic in most patients; however, immunocompromised patients are predisposed to disseminated cutaneous infection. Facial lesions are most common and can present as papules, pustules, plaques, abscesses, sinus tracts, and/or ulcerations. Treatment of disseminated infection requires systemic antifungals; amphotericin B has proven most effective.¹

Cryptococcosis is characterized by vacuoles 
with small (2–20 μm), central, pleomorphic 
yeast (Figure 5). The vacuole is due to a gelati-
nous capsule that stains red with mucicarmine 
 and blue with Alcian blue.^2,3 Cryptococcosis is caused by Cryptococcus neoformans and is associated with pigeon droppings. Disseminated infection in patients with human immunodefi-
ciency virus often presents as umbilicated 
molluscumlike lesions and portends a poor prognosis with a mortality rate of up to 80%.⁸ Disseminated 
infection necessitates aggressive treatment with systemic antifungals.¹

Lobomycosis demonstrates thick-walled, refractile spherules with surrounding histiocytes and multinucleated giant cells. The yeast of lobomycosis (6–12 μm) is of similar size to chromoblastomycosis and blastomycosis, but linear chains resembling 
a child’s pop beads are characteristic of this 
condition (Figure 6).^2,3 Lobomycosis is caused by Lacazia loboi and is acquired most frequently through contact with dolphins in Central 
and South America. Clinically, lesions present as slow-growing, keloidlike nodules, often on the 
face, ears, and distal extremities. Surgical treatment may be required given that oral antifungals typically are ineffective.¹

Chromoblastomycosis is a chronic fungal infection of the skin and subcutaneous tissues that demonstrates characteristic Medlar or sclerotic bodies that resemble copper pennies on histopathology.¹ Cutaneous infection often results from direct inoculation, such as from a wood splinter. Clinically, the lesion typically is a pink papule that progresses to a verrucous plaque on the legs of farmers or rural workers in the tropics or subtropics. There usually are no associated constitutional symptoms. Several dematiaceous (darkly pigmented) fungi cause chromoblastomycosis, including Fonsecaea compacta, Cladophialophora carrionii, Rhinocladiella aquaspersa, Phialophora verrucosa, and Fonsecaea pedrosoi. Cellular division occurs by internal septation rather than budding. Skin biopsy can confirm the diagnosis.¹ Chromoblastomycosis is histopathologically characterized by pseudoepitheli-
omatous hyperplasia (Figure 1) with histiocytes and neutrophils surrounding distinct copper-colored 
Medlar bodies (6–12 μm)(Figure 2), which are fungal spores.^1-3 Several conditions demonstrate pseudoepitheliomatous hyperplasia with intraepidermal pustules and can be remembered by the mnemonic “here come big green leafy vegetables”: halogenoderma, chromoblastomycosis, blastomycosis, granuloma inguinale, leishmaniasis, and pemphigus vegetans.² Treatment of chromoblastomycosis can be challenging, as no standard treatment has been established and therapy can be complicated by low cure rates and high relapse rates, especially in chronic and extensive disease. Treatment can include cryotherapy or surgical excision for small lesions in combination with systemic antifungals.⁴ Itraconazole (200–400 mg daily) for at least 
6 months has been reported to have up to a 
90% cure rate with mild to moderate disease and 44% with severe disease.⁵ Combination oral antifungal treatment with itraconazole and terbinafine has been recommended.⁶ There are reports of progression of chromoblastomycosis to squamous cell carcinoma, which is rare and occurred after 
long-standing, inadequately treated lesions.⁷

Blastomycosis also presents with pseudoepitheliomatous hyperplasia, as seen in chromoblastomycosis, but organisms typically are few in number 
and demonstrate a thick, asymmetrical, refractile wall and a dark nucleus. Although chromoblastomycosis and blastomycosis are similar in 
size (8–15 μm), the broad-based budding of blastomycosis (Figure 3) is a key feature and the yeast 
are not pigmented.^1-3 Blastomycosis is caused by Blastomyces dermatitidis and is endemic to the Mississippi and Ohio River valleys, Great Lakes region, and Southeastern United States. Cutaneous infection typically occurs from inhalation of the dimorphic fungi into the lungs and occasional dissemination involving the skin, causing papulopustules and 
thick, crusted, warty plaques with central ulceration. 
Rarely, primary cutaneous blastomycosis can occur from direct inoculation, typically in a laboratory. Treatment of disseminated blastomycosis includes systemic antifungals.¹

Coccidioidomycosis is characterized by large spherules (10–80 μm) with refractile walls and granular gray cytoplasm.^2,3 Coccidioidomycosis spherules occasionally contain endospores² and often are noticeably larger than surrounding histiocyte nuclei (Figure 4), whereas chromoblastomycosis, blastomycosis, cryptococcosis, and lobomycosis are more similar in size to histiocyte nuclei. Coccidioidomycosis is caused by Coccidioides immitis, a highly virulent dimorphic fungus found in the Southwestern United States, northern Mexico, and Central and South America. Pulmonary infection occurs by inhalation of arthroconidia, often from soil, and is asymptomatic in most patients; however, immunocompromised patients are predisposed to disseminated cutaneous infection. Facial lesions are most common and can present as papules, pustules, plaques, abscesses, sinus tracts, and/or ulcerations. Treatment of disseminated infection requires systemic antifungals; amphotericin B has proven most effective.¹

Cryptococcosis is characterized by vacuoles 
with small (2–20 μm), central, pleomorphic 
yeast (Figure 5). The vacuole is due to a gelati-
nous capsule that stains red with mucicarmine 
 and blue with Alcian blue.^2,3 Cryptococcosis is caused by Cryptococcus neoformans and is associated with pigeon droppings. Disseminated infection in patients with human immunodefi-
ciency virus often presents as umbilicated 
molluscumlike lesions and portends a poor prognosis with a mortality rate of up to 80%.⁸ Disseminated 
infection necessitates aggressive treatment with systemic antifungals.¹

Lobomycosis demonstrates thick-walled, refractile spherules with surrounding histiocytes and multinucleated giant cells. The yeast of lobomycosis (6–12 μm) is of similar size to chromoblastomycosis and blastomycosis, but linear chains resembling 
a child’s pop beads are characteristic of this 
condition (Figure 6).^2,3 Lobomycosis is caused by Lacazia loboi and is acquired most frequently through contact with dolphins in Central 
and South America. Clinically, lesions present as slow-growing, keloidlike nodules, often on the 
face, ears, and distal extremities. Surgical treatment may be required given that oral antifungals typically are ineffective.¹

Chromoblastomycosis is a chronic fungal infection of the skin and subcutaneous tissues that demonstrates characteristic Medlar or sclerotic bodies that resemble copper pennies on histopathology.¹ Cutaneous infection often results from direct inoculation, such as from a wood splinter. Clinically, the lesion typically is a pink papule that progresses to a verrucous plaque on the legs of farmers or rural workers in the tropics or subtropics. There usually are no associated constitutional symptoms. Several dematiaceous (darkly pigmented) fungi cause chromoblastomycosis, including Fonsecaea compacta, Cladophialophora carrionii, Rhinocladiella aquaspersa, Phialophora verrucosa, and Fonsecaea pedrosoi. Cellular division occurs by internal septation rather than budding. Skin biopsy can confirm the diagnosis.¹ Chromoblastomycosis is histopathologically characterized by pseudoepitheli-
omatous hyperplasia (Figure 1) with histiocytes and neutrophils surrounding distinct copper-colored 
Medlar bodies (6–12 μm)(Figure 2), which are fungal spores.^1-3 Several conditions demonstrate pseudoepitheliomatous hyperplasia with intraepidermal pustules and can be remembered by the mnemonic “here come big green leafy vegetables”: halogenoderma, chromoblastomycosis, blastomycosis, granuloma inguinale, leishmaniasis, and pemphigus vegetans.² Treatment of chromoblastomycosis can be challenging, as no standard treatment has been established and therapy can be complicated by low cure rates and high relapse rates, especially in chronic and extensive disease. Treatment can include cryotherapy or surgical excision for small lesions in combination with systemic antifungals.⁴ Itraconazole (200–400 mg daily) for at least 
6 months has been reported to have up to a 
90% cure rate with mild to moderate disease and 44% with severe disease.⁵ Combination oral antifungal treatment with itraconazole and terbinafine has been recommended.⁶ There are reports of progression of chromoblastomycosis to squamous cell carcinoma, which is rare and occurred after 
long-standing, inadequately treated lesions.⁷

Blastomycosis also presents with pseudoepitheliomatous hyperplasia, as seen in chromoblastomycosis, but organisms typically are few in number 
and demonstrate a thick, asymmetrical, refractile wall and a dark nucleus. Although chromoblastomycosis and blastomycosis are similar in 
size (8–15 μm), the broad-based budding of blastomycosis (Figure 3) is a key feature and the yeast 
are not pigmented.^1-3 Blastomycosis is caused by Blastomyces dermatitidis and is endemic to the Mississippi and Ohio River valleys, Great Lakes region, and Southeastern United States. Cutaneous infection typically occurs from inhalation of the dimorphic fungi into the lungs and occasional dissemination involving the skin, causing papulopustules and 
thick, crusted, warty plaques with central ulceration. 
Rarely, primary cutaneous blastomycosis can occur from direct inoculation, typically in a laboratory. Treatment of disseminated blastomycosis includes systemic antifungals.¹

Coccidioidomycosis is characterized by large spherules (10–80 μm) with refractile walls and granular gray cytoplasm.^2,3 Coccidioidomycosis spherules occasionally contain endospores² and often are noticeably larger than surrounding histiocyte nuclei (Figure 4), whereas chromoblastomycosis, blastomycosis, cryptococcosis, and lobomycosis are more similar in size to histiocyte nuclei. Coccidioidomycosis is caused by Coccidioides immitis, a highly virulent dimorphic fungus found in the Southwestern United States, northern Mexico, and Central and South America. Pulmonary infection occurs by inhalation of arthroconidia, often from soil, and is asymptomatic in most patients; however, immunocompromised patients are predisposed to disseminated cutaneous infection. Facial lesions are most common and can present as papules, pustules, plaques, abscesses, sinus tracts, and/or ulcerations. Treatment of disseminated infection requires systemic antifungals; amphotericin B has proven most effective.¹

Cryptococcosis is characterized by vacuoles 
with small (2–20 μm), central, pleomorphic 
yeast (Figure 5). The vacuole is due to a gelati-
nous capsule that stains red with mucicarmine 
 and blue with Alcian blue.^2,3 Cryptococcosis is caused by Cryptococcus neoformans and is associated with pigeon droppings. Disseminated infection in patients with human immunodefi-
ciency virus often presents as umbilicated 
molluscumlike lesions and portends a poor prognosis with a mortality rate of up to 80%.⁸ Disseminated 
infection necessitates aggressive treatment with systemic antifungals.¹

Lobomycosis demonstrates thick-walled, refractile spherules with surrounding histiocytes and multinucleated giant cells. The yeast of lobomycosis (6–12 μm) is of similar size to chromoblastomycosis and blastomycosis, but linear chains resembling 
a child’s pop beads are characteristic of this 
condition (Figure 6).^2,3 Lobomycosis is caused by Lacazia loboi and is acquired most frequently through contact with dolphins in Central 
and South America. Clinically, lesions present as slow-growing, keloidlike nodules, often on the 
face, ears, and distal extremities. Surgical treatment may be required given that oral antifungals typically are ineffective.¹

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Trichilemmomas are benign follicular neoplasms that exhibit differentiation toward the outer root sheath of the pilosebaceous follicular epithelium.¹ Trichilemmomas clinically present as individual or multiple, slowly growing, verrucous papules appearing most commonly on the face or neck. The lesions may coalesce to form small plaques. Although trichilemmomas typically are isolated, patients with multiple trichilemmomas require a cancer screening workup due to their association with Cowden disease, which results from a mutation in the phosphatase and tensin homolog tumor suppressor gene, PTEN.² An easy way to remember the association between trichilemmomas and Cowden disease is to alter the spelling to “trichile-moo-moo,” using the “moo moo” sound of an animal cow as a clue linking the tumor to Cowden disease.

Histologically, trichilemmomas exhibit a lobular epidermal downgrowth into the dermis (Figure 1). The surface of the lesion may be hyperkeratotic and somewhat papillomatous. Cells toward the center of the lobule are pale staining, periodic acid–Schiff positive, and diastase labile due to high levels of intracellular glycogen (Figure 2). Cells toward the periphery of the lobule usually appear basophilic with a palisading arrangement of the peripheral cells. The entire lobule is enclosed within an eosinophilic basement membrane that stains positively with periodic acid–Schiff (Figure 2).¹ Consistent with the tumor’s differentiation toward the outer root sheath of the hair follicle, trichilemmomas have been reported to express CD34 focally or diffusely.³

Figure 1. A lobular trichilemmoma composed of aggregates of epithelial cells extending from the epidermis into the dermis. The cells of the tumor are composed of squamoid cells showing variable glycogen vacuolation (pale-staining cytoplasm) and there is a surrounding prominent basement membrane (arrow)(H&E, original magnification ×40).

Figure 2. High-power magnification showing the pale-staining cells comprising a trichilemmoma (asterisk) as well as peripheral palisading of the cells at the periphery of the lesion and a thickened surrounding membrane (arrow)(H&E, original magnification ×200).

Similar to trichilemmoma, inverted follicular keratosis (IFK) commonly presents as a solitary asymptomatic papule on the face. Inverted follicular keratosis is a somewhat controversial entity, with some authorities arguing IFK is a variant of verruca vulgaris or seborrheic keratosis. Histologically, IFKs can be differentiated by the presence of squamous eddies (concentric layers of squamous cells in a whorled pattern), which are diagnostic, and central longitudinal crypts that contain keratin and are lined by squamous epithelium.⁴ Basaloid cells can be seen at the periphery of the tumors; however, IFKs lack an eosinophilic basement membrane surrounding the tumor (Figure 3).

Figure 3. Sections of a biopsy from an inverted follicular keratosis show an endophytic lesion with acanthosis consisting of fairly uniform squamous cells with eosinophilic cytoplasm. Numerous squamous eddies can be seen (H&E, original magnification ×100).

Squamous cell carcinoma in situ classically appears as an erythematous hyperkeratotic papule or plaque on sun-exposed sites that can become crusted or ulcerated. Microscopically, squamous cell carcinoma in situ displays full-thickness disorderly maturation of keratinocytes. The keratinocytes exhibit nuclear pleomorphism. Atypical mitotic figures and dyskeratotic keratinocytes also can be seen throughout the full thickness of the epidermis (Figure 4).⁵

Figure 4. The epidermis is acanthotic and shows full-thickness disorderly maturation of keratinocytes, mitoses at different levels, and dyskeratotic cells in a squamous cell carcinoma in situ. Overlying parakeratosis also can be noted (H&E, original magnification ×100).

Verruca vulgaris (Figure 5) histologically demonstrates hyperkeratosis with tiers of parakeratosis, digitated epidermal hyperplasia, and dilated tortuous capillaries within the dermal papillae. At the edges of the lesion there often is inward turning of elongated rete ridges,^6,7 which can be thought of as the rete reaching out for a hug of sorts to spread the human papillomavirus infection. Although the surface of a trichilemmoma can bear resemblance to a verruca vulgaris, the remainder of the histologic features can be used to help differentiate these tumors. Additionally, there has been no evidence suggestive of a viral etiology for trichilemmomas.⁸

Figure 5. Compact hyperorthokeratosis with tiers of parakeratosis (arrow), digitated epidermal hyperplasia, hypergranulosis, vacuolated granular layer cells, and small blood vessels extending into the tips of the dermal papillae (asterisk) in the setting of a verruca vulgaris (H&E, original magnification ×100).

Warty dyskeratoma features an umbilicated papule, usually on the face, head, or neck, that is associated with a follicular unit. The papule shows a cup-shaped, keratin-filled invagination; suprabasilar clefting; and acantholytic dyskeratotic cells, which are features that are not seen in trichilemmomas (Figure 6).⁹

Figure 6. A cup-shaped invagination filled with cornified material and surrounded by slight epidermal hyperplasia in association with acantholytic dyskeratosis in a warty dyskeratoma (H&E, original magnifi-cation ×100).

Acknowledgment—The authors would like to thank Brandon Litzner, MD, St Louis, Missouri, for proofreading the manuscript.

Trichilemmomas are benign follicular neoplasms that exhibit differentiation toward the outer root sheath of the pilosebaceous follicular epithelium.¹ Trichilemmomas clinically present as individual or multiple, slowly growing, verrucous papules appearing most commonly on the face or neck. The lesions may coalesce to form small plaques. Although trichilemmomas typically are isolated, patients with multiple trichilemmomas require a cancer screening workup due to their association with Cowden disease, which results from a mutation in the phosphatase and tensin homolog tumor suppressor gene, PTEN.² An easy way to remember the association between trichilemmomas and Cowden disease is to alter the spelling to “trichile-moo-moo,” using the “moo moo” sound of an animal cow as a clue linking the tumor to Cowden disease.

Histologically, trichilemmomas exhibit a lobular epidermal downgrowth into the dermis (Figure 1). The surface of the lesion may be hyperkeratotic and somewhat papillomatous. Cells toward the center of the lobule are pale staining, periodic acid–Schiff positive, and diastase labile due to high levels of intracellular glycogen (Figure 2). Cells toward the periphery of the lobule usually appear basophilic with a palisading arrangement of the peripheral cells. The entire lobule is enclosed within an eosinophilic basement membrane that stains positively with periodic acid–Schiff (Figure 2).¹ Consistent with the tumor’s differentiation toward the outer root sheath of the hair follicle, trichilemmomas have been reported to express CD34 focally or diffusely.³

Figure 1. A lobular trichilemmoma composed of aggregates of epithelial cells extending from the epidermis into the dermis. The cells of the tumor are composed of squamoid cells showing variable glycogen vacuolation (pale-staining cytoplasm) and there is a surrounding prominent basement membrane (arrow)(H&E, original magnification ×40).

Figure 2. High-power magnification showing the pale-staining cells comprising a trichilemmoma (asterisk) as well as peripheral palisading of the cells at the periphery of the lesion and a thickened surrounding membrane (arrow)(H&E, original magnification ×200).

Similar to trichilemmoma, inverted follicular keratosis (IFK) commonly presents as a solitary asymptomatic papule on the face. Inverted follicular keratosis is a somewhat controversial entity, with some authorities arguing IFK is a variant of verruca vulgaris or seborrheic keratosis. Histologically, IFKs can be differentiated by the presence of squamous eddies (concentric layers of squamous cells in a whorled pattern), which are diagnostic, and central longitudinal crypts that contain keratin and are lined by squamous epithelium.⁴ Basaloid cells can be seen at the periphery of the tumors; however, IFKs lack an eosinophilic basement membrane surrounding the tumor (Figure 3).

Figure 3. Sections of a biopsy from an inverted follicular keratosis show an endophytic lesion with acanthosis consisting of fairly uniform squamous cells with eosinophilic cytoplasm. Numerous squamous eddies can be seen (H&E, original magnification ×100).

Squamous cell carcinoma in situ classically appears as an erythematous hyperkeratotic papule or plaque on sun-exposed sites that can become crusted or ulcerated. Microscopically, squamous cell carcinoma in situ displays full-thickness disorderly maturation of keratinocytes. The keratinocytes exhibit nuclear pleomorphism. Atypical mitotic figures and dyskeratotic keratinocytes also can be seen throughout the full thickness of the epidermis (Figure 4).⁵

Figure 4. The epidermis is acanthotic and shows full-thickness disorderly maturation of keratinocytes, mitoses at different levels, and dyskeratotic cells in a squamous cell carcinoma in situ. Overlying parakeratosis also can be noted (H&E, original magnification ×100).

Verruca vulgaris (Figure 5) histologically demonstrates hyperkeratosis with tiers of parakeratosis, digitated epidermal hyperplasia, and dilated tortuous capillaries within the dermal papillae. At the edges of the lesion there often is inward turning of elongated rete ridges,^6,7 which can be thought of as the rete reaching out for a hug of sorts to spread the human papillomavirus infection. Although the surface of a trichilemmoma can bear resemblance to a verruca vulgaris, the remainder of the histologic features can be used to help differentiate these tumors. Additionally, there has been no evidence suggestive of a viral etiology for trichilemmomas.⁸

Figure 5. Compact hyperorthokeratosis with tiers of parakeratosis (arrow), digitated epidermal hyperplasia, hypergranulosis, vacuolated granular layer cells, and small blood vessels extending into the tips of the dermal papillae (asterisk) in the setting of a verruca vulgaris (H&E, original magnification ×100).

Warty dyskeratoma features an umbilicated papule, usually on the face, head, or neck, that is associated with a follicular unit. The papule shows a cup-shaped, keratin-filled invagination; suprabasilar clefting; and acantholytic dyskeratotic cells, which are features that are not seen in trichilemmomas (Figure 6).⁹

Figure 6. A cup-shaped invagination filled with cornified material and surrounded by slight epidermal hyperplasia in association with acantholytic dyskeratosis in a warty dyskeratoma (H&E, original magnifi-cation ×100).

Acknowledgment—The authors would like to thank Brandon Litzner, MD, St Louis, Missouri, for proofreading the manuscript.

Trichilemmomas are benign follicular neoplasms that exhibit differentiation toward the outer root sheath of the pilosebaceous follicular epithelium.¹ Trichilemmomas clinically present as individual or multiple, slowly growing, verrucous papules appearing most commonly on the face or neck. The lesions may coalesce to form small plaques. Although trichilemmomas typically are isolated, patients with multiple trichilemmomas require a cancer screening workup due to their association with Cowden disease, which results from a mutation in the phosphatase and tensin homolog tumor suppressor gene, PTEN.² An easy way to remember the association between trichilemmomas and Cowden disease is to alter the spelling to “trichile-moo-moo,” using the “moo moo” sound of an animal cow as a clue linking the tumor to Cowden disease.

Histologically, trichilemmomas exhibit a lobular epidermal downgrowth into the dermis (Figure 1). The surface of the lesion may be hyperkeratotic and somewhat papillomatous. Cells toward the center of the lobule are pale staining, periodic acid–Schiff positive, and diastase labile due to high levels of intracellular glycogen (Figure 2). Cells toward the periphery of the lobule usually appear basophilic with a palisading arrangement of the peripheral cells. The entire lobule is enclosed within an eosinophilic basement membrane that stains positively with periodic acid–Schiff (Figure 2).¹ Consistent with the tumor’s differentiation toward the outer root sheath of the hair follicle, trichilemmomas have been reported to express CD34 focally or diffusely.³

Figure 1. A lobular trichilemmoma composed of aggregates of epithelial cells extending from the epidermis into the dermis. The cells of the tumor are composed of squamoid cells showing variable glycogen vacuolation (pale-staining cytoplasm) and there is a surrounding prominent basement membrane (arrow)(H&E, original magnification ×40).

Figure 2. High-power magnification showing the pale-staining cells comprising a trichilemmoma (asterisk) as well as peripheral palisading of the cells at the periphery of the lesion and a thickened surrounding membrane (arrow)(H&E, original magnification ×200).

Similar to trichilemmoma, inverted follicular keratosis (IFK) commonly presents as a solitary asymptomatic papule on the face. Inverted follicular keratosis is a somewhat controversial entity, with some authorities arguing IFK is a variant of verruca vulgaris or seborrheic keratosis. Histologically, IFKs can be differentiated by the presence of squamous eddies (concentric layers of squamous cells in a whorled pattern), which are diagnostic, and central longitudinal crypts that contain keratin and are lined by squamous epithelium.⁴ Basaloid cells can be seen at the periphery of the tumors; however, IFKs lack an eosinophilic basement membrane surrounding the tumor (Figure 3).

Figure 3. Sections of a biopsy from an inverted follicular keratosis show an endophytic lesion with acanthosis consisting of fairly uniform squamous cells with eosinophilic cytoplasm. Numerous squamous eddies can be seen (H&E, original magnification ×100).

Squamous cell carcinoma in situ classically appears as an erythematous hyperkeratotic papule or plaque on sun-exposed sites that can become crusted or ulcerated. Microscopically, squamous cell carcinoma in situ displays full-thickness disorderly maturation of keratinocytes. The keratinocytes exhibit nuclear pleomorphism. Atypical mitotic figures and dyskeratotic keratinocytes also can be seen throughout the full thickness of the epidermis (Figure 4).⁵

Figure 4. The epidermis is acanthotic and shows full-thickness disorderly maturation of keratinocytes, mitoses at different levels, and dyskeratotic cells in a squamous cell carcinoma in situ. Overlying parakeratosis also can be noted (H&E, original magnification ×100).

Verruca vulgaris (Figure 5) histologically demonstrates hyperkeratosis with tiers of parakeratosis, digitated epidermal hyperplasia, and dilated tortuous capillaries within the dermal papillae. At the edges of the lesion there often is inward turning of elongated rete ridges,^6,7 which can be thought of as the rete reaching out for a hug of sorts to spread the human papillomavirus infection. Although the surface of a trichilemmoma can bear resemblance to a verruca vulgaris, the remainder of the histologic features can be used to help differentiate these tumors. Additionally, there has been no evidence suggestive of a viral etiology for trichilemmomas.⁸

Figure 5. Compact hyperorthokeratosis with tiers of parakeratosis (arrow), digitated epidermal hyperplasia, hypergranulosis, vacuolated granular layer cells, and small blood vessels extending into the tips of the dermal papillae (asterisk) in the setting of a verruca vulgaris (H&E, original magnification ×100).

Warty dyskeratoma features an umbilicated papule, usually on the face, head, or neck, that is associated with a follicular unit. The papule shows a cup-shaped, keratin-filled invagination; suprabasilar clefting; and acantholytic dyskeratotic cells, which are features that are not seen in trichilemmomas (Figure 6).⁹

Figure 6. A cup-shaped invagination filled with cornified material and surrounded by slight epidermal hyperplasia in association with acantholytic dyskeratosis in a warty dyskeratoma (H&E, original magnifi-cation ×100).

Acknowledgment—The authors would like to thank Brandon Litzner, MD, St Louis, Missouri, for proofreading the manuscript.

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).