Dermpath Diagnosis

The Diagnosis: Cutaneous Metastases

Cutaneous metastases (CMs) can present in an otherwise asymptomatic patient as the only sign of an underlying disease process. In women, the most common cause of CM is breast carcinoma.^1-3 Cutaneous metastases are found in approximately 25% of all patients with breast carcinoma,¹ and breast carcinomas represent approximately 69% of all CMs found in women (Table 1).² Cutaneous metastatic breast carcinoma (CMBC) is associated with a poor prognosis with a mean survival of approximately 6 months at the time of diagnosis.^1,3 It commonly presents as a collection of flesh-colored, firm, asymptomatic, and rapidly appearing papules and nodules that can resemble cysts or fibrous tumors.^1,3,4 They typically are located on the chest wall or abdomen near the site of the underlying malignancy.^1-3 The histologic features of CMBC can include hyperchromatic tumor cells infiltrating between the collagen fibers in a characteristic single file manner,^3,5 giving the appearance of a busy dermis, a nonspecific term to describe a focally hypercellular dermis at low-power magnification (Table 2).^5,6 Cords and clusters of atypical cells with intracytoplasmic vacuoles or well-developed ducts also can be seen (quiz image [inset]). The carcinoma en cuirasse subtype of CMBC is characterized by a fibrotic scarlike plaque on the chest wall.^1,3 If a punch biopsy is obtained, the specimen typically appears rectangular rather than tapered because of the sclerotic dermal collagen.⁶ In contrast, inflammatory carcinoma (carcinoma erysipelatoides) presents as an erythematous plaque resembling cellulitis due to the lymphatics being congested by tumor cells.³ Immunohistochemistry is a valuable tool in diagnosis. Positive staining is seen with cytokeratin 7, gross cystic disease fluid protein-15, mammaglobin, and GATA-3.^1,3,6

Kaposi sarcoma (KS) is a low-grade endothelial malignancy associated with human herpesvirus 8.^3,4 Kaposi sarcoma can be divided into 4 main subtypes: classic KS, African KS, AIDS-related KS, and immunosuppression-associated KS that occurs in patients with diseases such as human immunodeficiency virus. The cutaneous lesions are similar between subtypes and present as dark reddish purple macules that may enlarge or become nodular lesions.^3,4 Histologically, 3 distinct stages of progression are described: patch, plaque, and tumor. The plaque stage has the appearance of a busy dermis due to the rapid proliferation of vascular structures within the dermis.^3,6 A useful histologic feature known as the promontory sign can be seen as the proliferating tumor causes preexisting structures to project into vascular spaces (Figure 1).⁶ Immunohistochemistry for the endothelial and lymphatic markers CD31 and D2-40, respectively, are positive and may aid in the diagnosis.³ Staining for the latent nuclear antigen-1 of human herpesvirus 8 is a highly specific marker used to diagnose KS and can further distinguish it from the other busy dermis lesions.³ 

Granuloma annulare (GA) is characterized by rings of small, firm, pink to flesh-colored papules with a variable disease duration.⁴ Histologically, the interstitial variant of GA is characterized by a scattered inflammatory infiltrate consisting of histiocytes and lymphocytes located between altered collagen fibers in the superficial to mid dermis (Figure 2).^3,6 Occasional eosinophils and increased dermal mucin are useful features to distinguish interstitial GA from other entities in the busy dermis differential.⁷

Scleromyxedema, also known as generalized lichen myxedematosus, is a rare mucinosis.^3,8 Although its pathogenesis is unknown, it has been suggested that paraproteins related to the underlying gammopathy act to stimulate fibroblast proliferation and mucin overproduction.⁸ Clinically, characteristic widespread firm, waxy, dome-shaped papules are present over the head, upper trunk, and extremities.^3,8 Histologically, scleromyxedema is characterized by increased dermal fibroblasts, mucin, and fibrosis, leading to the appearance of a busy dermis (Figure 3).^3,6

Neurofibromas are common benign peripheral nerve sheath tumors that can occur sporadically or in the setting of neurofibromatosis.^3-5 They present as soft, flesh-colored papules or nodules most commonly located on the trunk and limbs.⁴ Histologically, neurofibromas are nonencapsulated tumors composed of abundant spindle cells with comma-shaped nuclei diffusely arranged in a pale myxoid stroma (Figure 4). Scattered mast cells can be visualized at higher magnification.^3,6

The Diagnosis: Cutaneous Metastases

Cutaneous metastases (CMs) can present in an otherwise asymptomatic patient as the only sign of an underlying disease process. In women, the most common cause of CM is breast carcinoma.^1-3 Cutaneous metastases are found in approximately 25% of all patients with breast carcinoma,¹ and breast carcinomas represent approximately 69% of all CMs found in women (Table 1).² Cutaneous metastatic breast carcinoma (CMBC) is associated with a poor prognosis with a mean survival of approximately 6 months at the time of diagnosis.^1,3 It commonly presents as a collection of flesh-colored, firm, asymptomatic, and rapidly appearing papules and nodules that can resemble cysts or fibrous tumors.^1,3,4 They typically are located on the chest wall or abdomen near the site of the underlying malignancy.^1-3 The histologic features of CMBC can include hyperchromatic tumor cells infiltrating between the collagen fibers in a characteristic single file manner,^3,5 giving the appearance of a busy dermis, a nonspecific term to describe a focally hypercellular dermis at low-power magnification (Table 2).^5,6 Cords and clusters of atypical cells with intracytoplasmic vacuoles or well-developed ducts also can be seen (quiz image [inset]). The carcinoma en cuirasse subtype of CMBC is characterized by a fibrotic scarlike plaque on the chest wall.^1,3 If a punch biopsy is obtained, the specimen typically appears rectangular rather than tapered because of the sclerotic dermal collagen.⁶ In contrast, inflammatory carcinoma (carcinoma erysipelatoides) presents as an erythematous plaque resembling cellulitis due to the lymphatics being congested by tumor cells.³ Immunohistochemistry is a valuable tool in diagnosis. Positive staining is seen with cytokeratin 7, gross cystic disease fluid protein-15, mammaglobin, and GATA-3.^1,3,6

Kaposi sarcoma (KS) is a low-grade endothelial malignancy associated with human herpesvirus 8.^3,4 Kaposi sarcoma can be divided into 4 main subtypes: classic KS, African KS, AIDS-related KS, and immunosuppression-associated KS that occurs in patients with diseases such as human immunodeficiency virus. The cutaneous lesions are similar between subtypes and present as dark reddish purple macules that may enlarge or become nodular lesions.^3,4 Histologically, 3 distinct stages of progression are described: patch, plaque, and tumor. The plaque stage has the appearance of a busy dermis due to the rapid proliferation of vascular structures within the dermis.^3,6 A useful histologic feature known as the promontory sign can be seen as the proliferating tumor causes preexisting structures to project into vascular spaces (Figure 1).⁶ Immunohistochemistry for the endothelial and lymphatic markers CD31 and D2-40, respectively, are positive and may aid in the diagnosis.³ Staining for the latent nuclear antigen-1 of human herpesvirus 8 is a highly specific marker used to diagnose KS and can further distinguish it from the other busy dermis lesions.³ 

Granuloma annulare (GA) is characterized by rings of small, firm, pink to flesh-colored papules with a variable disease duration.⁴ Histologically, the interstitial variant of GA is characterized by a scattered inflammatory infiltrate consisting of histiocytes and lymphocytes located between altered collagen fibers in the superficial to mid dermis (Figure 2).^3,6 Occasional eosinophils and increased dermal mucin are useful features to distinguish interstitial GA from other entities in the busy dermis differential.⁷

Scleromyxedema, also known as generalized lichen myxedematosus, is a rare mucinosis.^3,8 Although its pathogenesis is unknown, it has been suggested that paraproteins related to the underlying gammopathy act to stimulate fibroblast proliferation and mucin overproduction.⁸ Clinically, characteristic widespread firm, waxy, dome-shaped papules are present over the head, upper trunk, and extremities.^3,8 Histologically, scleromyxedema is characterized by increased dermal fibroblasts, mucin, and fibrosis, leading to the appearance of a busy dermis (Figure 3).^3,6

Neurofibromas are common benign peripheral nerve sheath tumors that can occur sporadically or in the setting of neurofibromatosis.^3-5 They present as soft, flesh-colored papules or nodules most commonly located on the trunk and limbs.⁴ Histologically, neurofibromas are nonencapsulated tumors composed of abundant spindle cells with comma-shaped nuclei diffusely arranged in a pale myxoid stroma (Figure 4). Scattered mast cells can be visualized at higher magnification.^3,6

The Diagnosis: Cutaneous Metastases

Cutaneous metastases (CMs) can present in an otherwise asymptomatic patient as the only sign of an underlying disease process. In women, the most common cause of CM is breast carcinoma.^1-3 Cutaneous metastases are found in approximately 25% of all patients with breast carcinoma,¹ and breast carcinomas represent approximately 69% of all CMs found in women (Table 1).² Cutaneous metastatic breast carcinoma (CMBC) is associated with a poor prognosis with a mean survival of approximately 6 months at the time of diagnosis.^1,3 It commonly presents as a collection of flesh-colored, firm, asymptomatic, and rapidly appearing papules and nodules that can resemble cysts or fibrous tumors.^1,3,4 They typically are located on the chest wall or abdomen near the site of the underlying malignancy.^1-3 The histologic features of CMBC can include hyperchromatic tumor cells infiltrating between the collagen fibers in a characteristic single file manner,^3,5 giving the appearance of a busy dermis, a nonspecific term to describe a focally hypercellular dermis at low-power magnification (Table 2).^5,6 Cords and clusters of atypical cells with intracytoplasmic vacuoles or well-developed ducts also can be seen (quiz image [inset]). The carcinoma en cuirasse subtype of CMBC is characterized by a fibrotic scarlike plaque on the chest wall.^1,3 If a punch biopsy is obtained, the specimen typically appears rectangular rather than tapered because of the sclerotic dermal collagen.⁶ In contrast, inflammatory carcinoma (carcinoma erysipelatoides) presents as an erythematous plaque resembling cellulitis due to the lymphatics being congested by tumor cells.³ Immunohistochemistry is a valuable tool in diagnosis. Positive staining is seen with cytokeratin 7, gross cystic disease fluid protein-15, mammaglobin, and GATA-3.^1,3,6

Kaposi sarcoma (KS) is a low-grade endothelial malignancy associated with human herpesvirus 8.^3,4 Kaposi sarcoma can be divided into 4 main subtypes: classic KS, African KS, AIDS-related KS, and immunosuppression-associated KS that occurs in patients with diseases such as human immunodeficiency virus. The cutaneous lesions are similar between subtypes and present as dark reddish purple macules that may enlarge or become nodular lesions.^3,4 Histologically, 3 distinct stages of progression are described: patch, plaque, and tumor. The plaque stage has the appearance of a busy dermis due to the rapid proliferation of vascular structures within the dermis.^3,6 A useful histologic feature known as the promontory sign can be seen as the proliferating tumor causes preexisting structures to project into vascular spaces (Figure 1).⁶ Immunohistochemistry for the endothelial and lymphatic markers CD31 and D2-40, respectively, are positive and may aid in the diagnosis.³ Staining for the latent nuclear antigen-1 of human herpesvirus 8 is a highly specific marker used to diagnose KS and can further distinguish it from the other busy dermis lesions.³ 

Granuloma annulare (GA) is characterized by rings of small, firm, pink to flesh-colored papules with a variable disease duration.⁴ Histologically, the interstitial variant of GA is characterized by a scattered inflammatory infiltrate consisting of histiocytes and lymphocytes located between altered collagen fibers in the superficial to mid dermis (Figure 2).^3,6 Occasional eosinophils and increased dermal mucin are useful features to distinguish interstitial GA from other entities in the busy dermis differential.⁷

Scleromyxedema, also known as generalized lichen myxedematosus, is a rare mucinosis.^3,8 Although its pathogenesis is unknown, it has been suggested that paraproteins related to the underlying gammopathy act to stimulate fibroblast proliferation and mucin overproduction.⁸ Clinically, characteristic widespread firm, waxy, dome-shaped papules are present over the head, upper trunk, and extremities.^3,8 Histologically, scleromyxedema is characterized by increased dermal fibroblasts, mucin, and fibrosis, leading to the appearance of a busy dermis (Figure 3).^3,6

Neurofibromas are common benign peripheral nerve sheath tumors that can occur sporadically or in the setting of neurofibromatosis.^3-5 They present as soft, flesh-colored papules or nodules most commonly located on the trunk and limbs.⁴ Histologically, neurofibromas are nonencapsulated tumors composed of abundant spindle cells with comma-shaped nuclei diffusely arranged in a pale myxoid stroma (Figure 4). Scattered mast cells can be visualized at higher magnification.^3,6

The Diagnosis: Bacterial Infection

The tetrad arrangement of organisms seen in this case was classic for Micrococcus and Sarcina species. Both are gram-positive cocci that occur in tetrads, but Micrococcus is aerobic and catalase positive, whereas Sarcina species are anaerobic, catalase negative, acidophilic, and form spores in alkaline pH.¹ Although difficult to definitively differentiate on light microscopy, micrococci are smaller in size, ranging from 0.5 to 2.0 μm, and occur in tight clusters, as seen in this case (quiz images), in contrast to Sarcina species, which are relatively larger (1.8-3.0 μm).² Sarcinae typically are found in soil and air, are considered pathogenic, and are associated with gastric symptoms (Sarcina ventriculi).¹Sarcina species also are reported to colonize the skin of patients with diabetes mellitus, but no pathogenic activity is known in the skin.³Micrococcus species, with the majority being Micrococcus luteus, are part of the normal flora of the human skin as well as the oral and nasal cavities. Occasional reports of pneumonia, endocarditis, meningitis, arthritis, endophthalmitis, and sepsis have been reported in immunocompromised individuals.⁴ In the skin, Micrococcus is a commensal organism; however, Micrococcus sedentarius has been associated with pitted keratolysis, and reports of Micrococcus folliculitis in human immunodeficiency virus patients also are described in the literature.^5,6 Micrococci are considered opportunistic bacteria and may worsen and prolong a localized cutaneous infection caused by other organisms under favorable conditions.⁷Micrococcus luteus is one of the most common bacteria cultured from skin and soft tissue infections caused by fungal organisms.⁸ Depending on the immune status of an individual, use of broad-spectrum antibiotic and/or elimination of favorable milieu (ie, primary pathogen, breaks in skin) usually treats the infection.

Because of the rarity of infections caused and being part of the normal flora, the clinical implications of subtyping and sensitivity studies via culture or molecular studies may not be important; however, incidental presence of these organisms with unfamiliar morphology may cause confusion for the dermatopathologist. An extremely small size (0.5-2.0 μm) compared to red blood cells (7-8 μm) and white blood cells (10-12 μm) in a tight tetrad arrangement should raise the suspicion for Micrococcus.1 The refractive nature of these organisms from a thick extracellular layer can mimic fungus or plant matter; a negative Grocott-Gomori methenamine-silver stain in this case helped in not only differentiating but also ruling out secondary fungal infection. Finally, a Gram stain with violet staining of these organisms reaffirmed the diagnosis of gram-positive bacterial organisms, most consistent with Micrococcus species (Figure 1). Culture studies were not performed because of contamination of the tissue specimen and resolution of the patient's symptoms.

The presence of foreign material in the skin may be traumatic, occupational, cosmetic, iatrogenic, or self-inflicted, including a wide variety of substances that appear in different morphological forms on hematoxylin and eosin (H&E)-stained sections, depending on their structure and physiochemical properties.⁹ Although not all foreign bodies may polarize, examining the sample under polarized light is considered an important step to narrow down the differential diagnosis. The tissue reaction is primarily dependent on the nature of the substance and duration, consisting of histiocytes, macrophages, plasma cells, lymphocytes, and fibrosis.⁹ Activated histiocytes, multinucleated giant cells, and granulomas are classic findings that generally are seen surrounding and engulfing the foreign material (Figure 2). In addition to foreign material, substances such as calcium salts, urate crystals, extruded keratin, ruptured cysts, and hair follicles may act as foreign materials and can incite a tissue response.⁹ Absence of histiocytic response, granuloma formation, and fibrosis in a lesion of 1 month's duration made the tetrad bodies unlikely to be foreign material.

Demodex mites are superficial inhabitants of human skin that are acquired shortly after birth, live in or near pilosebaceous units, and obtain nourishment from skin cells and sebum.^10,11 The mites can be recovered on 10% of skin biopsies, most commonly on the face due to high sebum production.¹⁰ Adult mites range from 0.1 to 0.4 mm in length and are round to oval in shape. Females lay eggs inside the hair follicle or sebaceous glands.¹¹ They usually are asymptomatic, but their infestation may become pathogenic, especially in immunocompromised individuals.¹⁰ The clinical picture may resemble bacterial folliculitis, rosacea, and perioral dermatitis, while histology typically is characterized by spongiosis, lymphohistiocytic inflammation around infested follicles, and mite(s) in follicular infundibula (Figure 3). Sometimes the protrusion of mites and keratin from the follicles is seen as follicular spines on histology and referred to as pityriasis folliculorum.

Deposits of urate crystals in skin occur from the elevated serum uric acid levels in gout. The cutaneous deposits are mainly in the dermis and subcutaneous tissue and are extremely painful.¹² Urate crystals get dissolved during formalin fixation and leave needlelike clefts in a homogenous, lightly basophilic material on H&E slide (Figure 4). For the same reason, polarized microscopy also is not helpful despite the birefringent nature of urate crystals.¹²

Fungal yeast forms appear round to oval under light microscopy, ranging from 2 to 100 μm in size.¹³ The common superficial forms involving the epidermis or hair follicles similar to the current case of bacterial infection include Malassezia and dermatophyte infections. Malassezia is part of the normal flora of sebum-rich areas of skin and is associated with superficial infections such as folliculitis, atopic dermatitis, psoriasis, seborrheic dermatitis, and dandruff.¹⁴Malassezia appear as clusters of yeast cells that are pleomorphic and round to oval in shape, ranging from 2 to 6 μm in size. It forms hyphae in its pathogenic form and gives rise to the classic spaghetti and meatball-like appearance that can be highlighted by periodic acid-Schiff (Figure 5) and Grocott-Gomori methenamine-silver special stains. Dermatophytes include 3 genera--Trichophyton, Microsporum, and Epidermophyton--with at least 40 species that causes skin infections in humans.¹⁴ Fungal spores and hyphae forms are restricted to the stratum corneum. The hyphae forms may not be apparent on H&E stain, and periodic acid-Schiff staining is helpful in visualizing the fungal elements. The presence of neutrophils in the corneal layer, basket weave hyperkeratosis, and presence of fungal hyphae within the corneal layer fissures (sandwich sign) are clues to the dermatophyte infection.¹⁵ Other smaller fungi such as Histoplasma capsulatum (2-4 μm), Candida (3-5 μm), and Pneumocystis (2-5 μm) species can be found in skin in disseminated infections, usually affecting immunocompromised individuals.¹³Histoplasma is a basophilic yeast that exhibits narrow-based budding and appears clustered within or outside of macrophages. Candida species generally are dimorphic, and yeasts are found intermingled with filamentous forms. Pneumocystis infection in skin is extremely rare, and the fungi appear as spherical or crescent-shaped bodies in a foamy amorphous material.¹⁶

The Diagnosis: Bacterial Infection

The tetrad arrangement of organisms seen in this case was classic for Micrococcus and Sarcina species. Both are gram-positive cocci that occur in tetrads, but Micrococcus is aerobic and catalase positive, whereas Sarcina species are anaerobic, catalase negative, acidophilic, and form spores in alkaline pH.¹ Although difficult to definitively differentiate on light microscopy, micrococci are smaller in size, ranging from 0.5 to 2.0 μm, and occur in tight clusters, as seen in this case (quiz images), in contrast to Sarcina species, which are relatively larger (1.8-3.0 μm).² Sarcinae typically are found in soil and air, are considered pathogenic, and are associated with gastric symptoms (Sarcina ventriculi).¹Sarcina species also are reported to colonize the skin of patients with diabetes mellitus, but no pathogenic activity is known in the skin.³Micrococcus species, with the majority being Micrococcus luteus, are part of the normal flora of the human skin as well as the oral and nasal cavities. Occasional reports of pneumonia, endocarditis, meningitis, arthritis, endophthalmitis, and sepsis have been reported in immunocompromised individuals.⁴ In the skin, Micrococcus is a commensal organism; however, Micrococcus sedentarius has been associated with pitted keratolysis, and reports of Micrococcus folliculitis in human immunodeficiency virus patients also are described in the literature.^5,6 Micrococci are considered opportunistic bacteria and may worsen and prolong a localized cutaneous infection caused by other organisms under favorable conditions.⁷Micrococcus luteus is one of the most common bacteria cultured from skin and soft tissue infections caused by fungal organisms.⁸ Depending on the immune status of an individual, use of broad-spectrum antibiotic and/or elimination of favorable milieu (ie, primary pathogen, breaks in skin) usually treats the infection.

Because of the rarity of infections caused and being part of the normal flora, the clinical implications of subtyping and sensitivity studies via culture or molecular studies may not be important; however, incidental presence of these organisms with unfamiliar morphology may cause confusion for the dermatopathologist. An extremely small size (0.5-2.0 μm) compared to red blood cells (7-8 μm) and white blood cells (10-12 μm) in a tight tetrad arrangement should raise the suspicion for Micrococcus.1 The refractive nature of these organisms from a thick extracellular layer can mimic fungus or plant matter; a negative Grocott-Gomori methenamine-silver stain in this case helped in not only differentiating but also ruling out secondary fungal infection. Finally, a Gram stain with violet staining of these organisms reaffirmed the diagnosis of gram-positive bacterial organisms, most consistent with Micrococcus species (Figure 1). Culture studies were not performed because of contamination of the tissue specimen and resolution of the patient's symptoms.

The presence of foreign material in the skin may be traumatic, occupational, cosmetic, iatrogenic, or self-inflicted, including a wide variety of substances that appear in different morphological forms on hematoxylin and eosin (H&E)-stained sections, depending on their structure and physiochemical properties.⁹ Although not all foreign bodies may polarize, examining the sample under polarized light is considered an important step to narrow down the differential diagnosis. The tissue reaction is primarily dependent on the nature of the substance and duration, consisting of histiocytes, macrophages, plasma cells, lymphocytes, and fibrosis.⁹ Activated histiocytes, multinucleated giant cells, and granulomas are classic findings that generally are seen surrounding and engulfing the foreign material (Figure 2). In addition to foreign material, substances such as calcium salts, urate crystals, extruded keratin, ruptured cysts, and hair follicles may act as foreign materials and can incite a tissue response.⁹ Absence of histiocytic response, granuloma formation, and fibrosis in a lesion of 1 month's duration made the tetrad bodies unlikely to be foreign material.

Demodex mites are superficial inhabitants of human skin that are acquired shortly after birth, live in or near pilosebaceous units, and obtain nourishment from skin cells and sebum.^10,11 The mites can be recovered on 10% of skin biopsies, most commonly on the face due to high sebum production.¹⁰ Adult mites range from 0.1 to 0.4 mm in length and are round to oval in shape. Females lay eggs inside the hair follicle or sebaceous glands.¹¹ They usually are asymptomatic, but their infestation may become pathogenic, especially in immunocompromised individuals.¹⁰ The clinical picture may resemble bacterial folliculitis, rosacea, and perioral dermatitis, while histology typically is characterized by spongiosis, lymphohistiocytic inflammation around infested follicles, and mite(s) in follicular infundibula (Figure 3). Sometimes the protrusion of mites and keratin from the follicles is seen as follicular spines on histology and referred to as pityriasis folliculorum.

Deposits of urate crystals in skin occur from the elevated serum uric acid levels in gout. The cutaneous deposits are mainly in the dermis and subcutaneous tissue and are extremely painful.¹² Urate crystals get dissolved during formalin fixation and leave needlelike clefts in a homogenous, lightly basophilic material on H&E slide (Figure 4). For the same reason, polarized microscopy also is not helpful despite the birefringent nature of urate crystals.¹²

Fungal yeast forms appear round to oval under light microscopy, ranging from 2 to 100 μm in size.¹³ The common superficial forms involving the epidermis or hair follicles similar to the current case of bacterial infection include Malassezia and dermatophyte infections. Malassezia is part of the normal flora of sebum-rich areas of skin and is associated with superficial infections such as folliculitis, atopic dermatitis, psoriasis, seborrheic dermatitis, and dandruff.¹⁴Malassezia appear as clusters of yeast cells that are pleomorphic and round to oval in shape, ranging from 2 to 6 μm in size. It forms hyphae in its pathogenic form and gives rise to the classic spaghetti and meatball-like appearance that can be highlighted by periodic acid-Schiff (Figure 5) and Grocott-Gomori methenamine-silver special stains. Dermatophytes include 3 genera--Trichophyton, Microsporum, and Epidermophyton--with at least 40 species that causes skin infections in humans.¹⁴ Fungal spores and hyphae forms are restricted to the stratum corneum. The hyphae forms may not be apparent on H&E stain, and periodic acid-Schiff staining is helpful in visualizing the fungal elements. The presence of neutrophils in the corneal layer, basket weave hyperkeratosis, and presence of fungal hyphae within the corneal layer fissures (sandwich sign) are clues to the dermatophyte infection.¹⁵ Other smaller fungi such as Histoplasma capsulatum (2-4 μm), Candida (3-5 μm), and Pneumocystis (2-5 μm) species can be found in skin in disseminated infections, usually affecting immunocompromised individuals.¹³Histoplasma is a basophilic yeast that exhibits narrow-based budding and appears clustered within or outside of macrophages. Candida species generally are dimorphic, and yeasts are found intermingled with filamentous forms. Pneumocystis infection in skin is extremely rare, and the fungi appear as spherical or crescent-shaped bodies in a foamy amorphous material.¹⁶

The Diagnosis: Bacterial Infection

The tetrad arrangement of organisms seen in this case was classic for Micrococcus and Sarcina species. Both are gram-positive cocci that occur in tetrads, but Micrococcus is aerobic and catalase positive, whereas Sarcina species are anaerobic, catalase negative, acidophilic, and form spores in alkaline pH.¹ Although difficult to definitively differentiate on light microscopy, micrococci are smaller in size, ranging from 0.5 to 2.0 μm, and occur in tight clusters, as seen in this case (quiz images), in contrast to Sarcina species, which are relatively larger (1.8-3.0 μm).² Sarcinae typically are found in soil and air, are considered pathogenic, and are associated with gastric symptoms (Sarcina ventriculi).¹Sarcina species also are reported to colonize the skin of patients with diabetes mellitus, but no pathogenic activity is known in the skin.³Micrococcus species, with the majority being Micrococcus luteus, are part of the normal flora of the human skin as well as the oral and nasal cavities. Occasional reports of pneumonia, endocarditis, meningitis, arthritis, endophthalmitis, and sepsis have been reported in immunocompromised individuals.⁴ In the skin, Micrococcus is a commensal organism; however, Micrococcus sedentarius has been associated with pitted keratolysis, and reports of Micrococcus folliculitis in human immunodeficiency virus patients also are described in the literature.^5,6 Micrococci are considered opportunistic bacteria and may worsen and prolong a localized cutaneous infection caused by other organisms under favorable conditions.⁷Micrococcus luteus is one of the most common bacteria cultured from skin and soft tissue infections caused by fungal organisms.⁸ Depending on the immune status of an individual, use of broad-spectrum antibiotic and/or elimination of favorable milieu (ie, primary pathogen, breaks in skin) usually treats the infection.

Because of the rarity of infections caused and being part of the normal flora, the clinical implications of subtyping and sensitivity studies via culture or molecular studies may not be important; however, incidental presence of these organisms with unfamiliar morphology may cause confusion for the dermatopathologist. An extremely small size (0.5-2.0 μm) compared to red blood cells (7-8 μm) and white blood cells (10-12 μm) in a tight tetrad arrangement should raise the suspicion for Micrococcus.1 The refractive nature of these organisms from a thick extracellular layer can mimic fungus or plant matter; a negative Grocott-Gomori methenamine-silver stain in this case helped in not only differentiating but also ruling out secondary fungal infection. Finally, a Gram stain with violet staining of these organisms reaffirmed the diagnosis of gram-positive bacterial organisms, most consistent with Micrococcus species (Figure 1). Culture studies were not performed because of contamination of the tissue specimen and resolution of the patient's symptoms.

The presence of foreign material in the skin may be traumatic, occupational, cosmetic, iatrogenic, or self-inflicted, including a wide variety of substances that appear in different morphological forms on hematoxylin and eosin (H&E)-stained sections, depending on their structure and physiochemical properties.⁹ Although not all foreign bodies may polarize, examining the sample under polarized light is considered an important step to narrow down the differential diagnosis. The tissue reaction is primarily dependent on the nature of the substance and duration, consisting of histiocytes, macrophages, plasma cells, lymphocytes, and fibrosis.⁹ Activated histiocytes, multinucleated giant cells, and granulomas are classic findings that generally are seen surrounding and engulfing the foreign material (Figure 2). In addition to foreign material, substances such as calcium salts, urate crystals, extruded keratin, ruptured cysts, and hair follicles may act as foreign materials and can incite a tissue response.⁹ Absence of histiocytic response, granuloma formation, and fibrosis in a lesion of 1 month's duration made the tetrad bodies unlikely to be foreign material.

Demodex mites are superficial inhabitants of human skin that are acquired shortly after birth, live in or near pilosebaceous units, and obtain nourishment from skin cells and sebum.^10,11 The mites can be recovered on 10% of skin biopsies, most commonly on the face due to high sebum production.¹⁰ Adult mites range from 0.1 to 0.4 mm in length and are round to oval in shape. Females lay eggs inside the hair follicle or sebaceous glands.¹¹ They usually are asymptomatic, but their infestation may become pathogenic, especially in immunocompromised individuals.¹⁰ The clinical picture may resemble bacterial folliculitis, rosacea, and perioral dermatitis, while histology typically is characterized by spongiosis, lymphohistiocytic inflammation around infested follicles, and mite(s) in follicular infundibula (Figure 3). Sometimes the protrusion of mites and keratin from the follicles is seen as follicular spines on histology and referred to as pityriasis folliculorum.

Deposits of urate crystals in skin occur from the elevated serum uric acid levels in gout. The cutaneous deposits are mainly in the dermis and subcutaneous tissue and are extremely painful.¹² Urate crystals get dissolved during formalin fixation and leave needlelike clefts in a homogenous, lightly basophilic material on H&E slide (Figure 4). For the same reason, polarized microscopy also is not helpful despite the birefringent nature of urate crystals.¹²

Fungal yeast forms appear round to oval under light microscopy, ranging from 2 to 100 μm in size.¹³ The common superficial forms involving the epidermis or hair follicles similar to the current case of bacterial infection include Malassezia and dermatophyte infections. Malassezia is part of the normal flora of sebum-rich areas of skin and is associated with superficial infections such as folliculitis, atopic dermatitis, psoriasis, seborrheic dermatitis, and dandruff.¹⁴Malassezia appear as clusters of yeast cells that are pleomorphic and round to oval in shape, ranging from 2 to 6 μm in size. It forms hyphae in its pathogenic form and gives rise to the classic spaghetti and meatball-like appearance that can be highlighted by periodic acid-Schiff (Figure 5) and Grocott-Gomori methenamine-silver special stains. Dermatophytes include 3 genera--Trichophyton, Microsporum, and Epidermophyton--with at least 40 species that causes skin infections in humans.¹⁴ Fungal spores and hyphae forms are restricted to the stratum corneum. The hyphae forms may not be apparent on H&E stain, and periodic acid-Schiff staining is helpful in visualizing the fungal elements. The presence of neutrophils in the corneal layer, basket weave hyperkeratosis, and presence of fungal hyphae within the corneal layer fissures (sandwich sign) are clues to the dermatophyte infection.¹⁵ Other smaller fungi such as Histoplasma capsulatum (2-4 μm), Candida (3-5 μm), and Pneumocystis (2-5 μm) species can be found in skin in disseminated infections, usually affecting immunocompromised individuals.¹³Histoplasma is a basophilic yeast that exhibits narrow-based budding and appears clustered within or outside of macrophages. Candida species generally are dimorphic, and yeasts are found intermingled with filamentous forms. Pneumocystis infection in skin is extremely rare, and the fungi appear as spherical or crescent-shaped bodies in a foamy amorphous material.¹⁶

The Diagnosis: Monsel Solution Reaction

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

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

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

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

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

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

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

The Diagnosis: Monsel Solution Reaction

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

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

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

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

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

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

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

The Diagnosis: Monsel Solution Reaction

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

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

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

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

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

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

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

The Diagnosis: Nodular Fasciitis

The diagnosis of spindle cell tumors can be challenging; however, by using a variety of immunoperoxidase stains and fluorescent in situ hybridization (FISH) testing in conjunction with histology, it often is possible to arrive at a definitive diagnosis. For this case, the histologic features in conjunction with the immunoperoxidase stains and FISH were consistent with a diagnosis of nodular fasciitis.

Nodular fasciitis is a benign, self-limiting, myofibroblastic, soft-tissue proliferation typically found in the subcutaneous tissue.¹ It can be found anywhere on the body but most commonly on the upper arms and trunk. It most often is seen in young adults, and many cases have been reported in association with a history of trauma to the area.^1,2 It typically measures less than 2 cm in diameter.³ The diagnosis of nodular fasciitis is particularly challenging because it mimics sarcoma, both in presentation and in histologic findings with rapid growth, high mitotic activity, and increased cellularity.^1,4-7 In contrast to malignancy, nodular fasciitis has no atypical mitoses and little cytologic atypia.^8,9 Rather, it contains plump myofibroblasts loosely arranged in a myxoid or fibrous stroma that also may contain lymphocytes, extravasated erythrocytes, and osteoclastlike giant cells distributed throughout.^5,10,11 In this case, lymphocytes, extravasated red blood cells, and myxoid change are present, suggesting the diagnosis of nodular fasciitis. In other cases, however, these features may be much more limited, making the diagnosis more challenging. The spindle cells are arranged in poorly defined short fascicles. The tumor cells do not infiltrate between individual adipocytes. There is no notable cytologic atypia.

Because of the difficulty in making the diagnosis, overtreatment of this benign condition can be a problem, causing increased morbidity.¹ Erickson-Johnson et al¹² identified the role of an ubiquitin-specific peptidase 6, USP6, gene rearrangement on chromosome 17p13 in 92% (44/48) of cases of nodular fasciitis. The USP6 gene most often is rearranged with the myosin heavy chain 9 gene, MYH9, on chromosome 22q12.3. With this rearrangement, the MYH9 promoter leads to the overexpression of USP6, causing tumor formation.^2,13 The use of multiple immunoperoxidase stains can be important in the identification of nodular fasciitis. Nodular fasciitis stains negative for S-100, epithelial membrane antigen, CD34, β-catenin, and cytokeratin, but typically stains positive for smooth muscle actin.⁹

Although dermatofibrosarcoma protuberans (DFSP) was in the differential diagnosis, these tumors tend to have greater cellularity than nodular fasciitis. In addition, the spindle cells of DFSP typically are arranged in a storiform pattern. Another characteristic feature of DFSP is that the tumor cells will infiltrate between adipose cells creating a lacelike or honeycomblike appearance within the subcutaneous tissue (Figure 1). Immunohistochemistry staining and FISH testing may be useful in making a diagnosis of DFSP. These tumors typically are positive for CD34 by immunoperoxidase staining and demonstrate a translocation t(17;22)(q21;q13) between platelet-derived growth factor subunit B gene, PDGFB, and collagen type I alpha 1 chain gene, COL1A1, by FISH.

The distinction between the fibrous phase of nodular fasciitis and fibromatosis can be challenging. The size of the lesion may be helpful, with most lesions of nodular fasciitis being less than 3 cm, while lesions of fibromatosis have a mean diameter of 7 cm.^5,14 Microscopically, both tumors demonstrate a fascicular growth pattern; however, the fascicles in nodular fasciitis tend to be short and irregular compared to the longer fascicles seen in fibromatosis (Figure 2). Immunohistochemistry staining has limited utility with only 56% (14/25) of superficial fibromatoses having positive nuclear staining for β-catenin.¹⁵

Low-grade fibromyxoid sarcoma (LGFMS) would be unusual in this clinical scenario. Only 13% to 19% of cases present in patients younger than 18 years (mean age, 33 years).¹⁶ In LGFMS there are cytologically bland spindle cells that are typically arranged in a patternless or whorled pattern (Figure 3), though fascicular architecture may be seen. There are alternating areas of fibrous and myxoid stroma. A curvilinear vasculature network and lack of lymphocytes and extravasated red blood cells are histologic features favoring LGFMS over nodular fasciitis. Immunohistochemistry staining and FISH testing can be useful in making the diagnosis of LGFMS. These tumors are characterized by a translocation t(7;16)(q34;p11) involving the fusion in sarcoma, FUS, and cAMP responsive element binding protein 3 like 2, CREB3L2, genes.¹⁶ Positive immunohistochemistry staining for MUC4 can be seen in up to 100% of LGFMS and is absent in many other spindle cell tumors.¹⁶

Plexiform fibrohistiocytic tumor (PFT) is least likely to be confused with nodular fasciitis. Histologically these tumors are characterized by multiple small nodules arranged in a plexiform pattern (Figure 4). Within the nodules, 3 cell types may be noted: spindle fibroblast-like cells, mononuclear histiocyte-like cells, and osteoclastlike cells.¹⁷ Either the spindle cells or the mononuclear cells may predominate in cases of PFT. Immunohistochemistry staining of PFT is nonspecific and there are no molecular/FISH studies that can be used to help confirm the diagnosis.

The Diagnosis: Nodular Fasciitis

The diagnosis of spindle cell tumors can be challenging; however, by using a variety of immunoperoxidase stains and fluorescent in situ hybridization (FISH) testing in conjunction with histology, it often is possible to arrive at a definitive diagnosis. For this case, the histologic features in conjunction with the immunoperoxidase stains and FISH were consistent with a diagnosis of nodular fasciitis.

Nodular fasciitis is a benign, self-limiting, myofibroblastic, soft-tissue proliferation typically found in the subcutaneous tissue.¹ It can be found anywhere on the body but most commonly on the upper arms and trunk. It most often is seen in young adults, and many cases have been reported in association with a history of trauma to the area.^1,2 It typically measures less than 2 cm in diameter.³ The diagnosis of nodular fasciitis is particularly challenging because it mimics sarcoma, both in presentation and in histologic findings with rapid growth, high mitotic activity, and increased cellularity.^1,4-7 In contrast to malignancy, nodular fasciitis has no atypical mitoses and little cytologic atypia.^8,9 Rather, it contains plump myofibroblasts loosely arranged in a myxoid or fibrous stroma that also may contain lymphocytes, extravasated erythrocytes, and osteoclastlike giant cells distributed throughout.^5,10,11 In this case, lymphocytes, extravasated red blood cells, and myxoid change are present, suggesting the diagnosis of nodular fasciitis. In other cases, however, these features may be much more limited, making the diagnosis more challenging. The spindle cells are arranged in poorly defined short fascicles. The tumor cells do not infiltrate between individual adipocytes. There is no notable cytologic atypia.

Because of the difficulty in making the diagnosis, overtreatment of this benign condition can be a problem, causing increased morbidity.¹ Erickson-Johnson et al¹² identified the role of an ubiquitin-specific peptidase 6, USP6, gene rearrangement on chromosome 17p13 in 92% (44/48) of cases of nodular fasciitis. The USP6 gene most often is rearranged with the myosin heavy chain 9 gene, MYH9, on chromosome 22q12.3. With this rearrangement, the MYH9 promoter leads to the overexpression of USP6, causing tumor formation.^2,13 The use of multiple immunoperoxidase stains can be important in the identification of nodular fasciitis. Nodular fasciitis stains negative for S-100, epithelial membrane antigen, CD34, β-catenin, and cytokeratin, but typically stains positive for smooth muscle actin.⁹

Although dermatofibrosarcoma protuberans (DFSP) was in the differential diagnosis, these tumors tend to have greater cellularity than nodular fasciitis. In addition, the spindle cells of DFSP typically are arranged in a storiform pattern. Another characteristic feature of DFSP is that the tumor cells will infiltrate between adipose cells creating a lacelike or honeycomblike appearance within the subcutaneous tissue (Figure 1). Immunohistochemistry staining and FISH testing may be useful in making a diagnosis of DFSP. These tumors typically are positive for CD34 by immunoperoxidase staining and demonstrate a translocation t(17;22)(q21;q13) between platelet-derived growth factor subunit B gene, PDGFB, and collagen type I alpha 1 chain gene, COL1A1, by FISH.

The distinction between the fibrous phase of nodular fasciitis and fibromatosis can be challenging. The size of the lesion may be helpful, with most lesions of nodular fasciitis being less than 3 cm, while lesions of fibromatosis have a mean diameter of 7 cm.^5,14 Microscopically, both tumors demonstrate a fascicular growth pattern; however, the fascicles in nodular fasciitis tend to be short and irregular compared to the longer fascicles seen in fibromatosis (Figure 2). Immunohistochemistry staining has limited utility with only 56% (14/25) of superficial fibromatoses having positive nuclear staining for β-catenin.¹⁵

Low-grade fibromyxoid sarcoma (LGFMS) would be unusual in this clinical scenario. Only 13% to 19% of cases present in patients younger than 18 years (mean age, 33 years).¹⁶ In LGFMS there are cytologically bland spindle cells that are typically arranged in a patternless or whorled pattern (Figure 3), though fascicular architecture may be seen. There are alternating areas of fibrous and myxoid stroma. A curvilinear vasculature network and lack of lymphocytes and extravasated red blood cells are histologic features favoring LGFMS over nodular fasciitis. Immunohistochemistry staining and FISH testing can be useful in making the diagnosis of LGFMS. These tumors are characterized by a translocation t(7;16)(q34;p11) involving the fusion in sarcoma, FUS, and cAMP responsive element binding protein 3 like 2, CREB3L2, genes.¹⁶ Positive immunohistochemistry staining for MUC4 can be seen in up to 100% of LGFMS and is absent in many other spindle cell tumors.¹⁶

Plexiform fibrohistiocytic tumor (PFT) is least likely to be confused with nodular fasciitis. Histologically these tumors are characterized by multiple small nodules arranged in a plexiform pattern (Figure 4). Within the nodules, 3 cell types may be noted: spindle fibroblast-like cells, mononuclear histiocyte-like cells, and osteoclastlike cells.¹⁷ Either the spindle cells or the mononuclear cells may predominate in cases of PFT. Immunohistochemistry staining of PFT is nonspecific and there are no molecular/FISH studies that can be used to help confirm the diagnosis.

The Diagnosis: Nodular Fasciitis

The diagnosis of spindle cell tumors can be challenging; however, by using a variety of immunoperoxidase stains and fluorescent in situ hybridization (FISH) testing in conjunction with histology, it often is possible to arrive at a definitive diagnosis. For this case, the histologic features in conjunction with the immunoperoxidase stains and FISH were consistent with a diagnosis of nodular fasciitis.

Nodular fasciitis is a benign, self-limiting, myofibroblastic, soft-tissue proliferation typically found in the subcutaneous tissue.¹ It can be found anywhere on the body but most commonly on the upper arms and trunk. It most often is seen in young adults, and many cases have been reported in association with a history of trauma to the area.^1,2 It typically measures less than 2 cm in diameter.³ The diagnosis of nodular fasciitis is particularly challenging because it mimics sarcoma, both in presentation and in histologic findings with rapid growth, high mitotic activity, and increased cellularity.^1,4-7 In contrast to malignancy, nodular fasciitis has no atypical mitoses and little cytologic atypia.^8,9 Rather, it contains plump myofibroblasts loosely arranged in a myxoid or fibrous stroma that also may contain lymphocytes, extravasated erythrocytes, and osteoclastlike giant cells distributed throughout.^5,10,11 In this case, lymphocytes, extravasated red blood cells, and myxoid change are present, suggesting the diagnosis of nodular fasciitis. In other cases, however, these features may be much more limited, making the diagnosis more challenging. The spindle cells are arranged in poorly defined short fascicles. The tumor cells do not infiltrate between individual adipocytes. There is no notable cytologic atypia.

Because of the difficulty in making the diagnosis, overtreatment of this benign condition can be a problem, causing increased morbidity.¹ Erickson-Johnson et al¹² identified the role of an ubiquitin-specific peptidase 6, USP6, gene rearrangement on chromosome 17p13 in 92% (44/48) of cases of nodular fasciitis. The USP6 gene most often is rearranged with the myosin heavy chain 9 gene, MYH9, on chromosome 22q12.3. With this rearrangement, the MYH9 promoter leads to the overexpression of USP6, causing tumor formation.^2,13 The use of multiple immunoperoxidase stains can be important in the identification of nodular fasciitis. Nodular fasciitis stains negative for S-100, epithelial membrane antigen, CD34, β-catenin, and cytokeratin, but typically stains positive for smooth muscle actin.⁹

Although dermatofibrosarcoma protuberans (DFSP) was in the differential diagnosis, these tumors tend to have greater cellularity than nodular fasciitis. In addition, the spindle cells of DFSP typically are arranged in a storiform pattern. Another characteristic feature of DFSP is that the tumor cells will infiltrate between adipose cells creating a lacelike or honeycomblike appearance within the subcutaneous tissue (Figure 1). Immunohistochemistry staining and FISH testing may be useful in making a diagnosis of DFSP. These tumors typically are positive for CD34 by immunoperoxidase staining and demonstrate a translocation t(17;22)(q21;q13) between platelet-derived growth factor subunit B gene, PDGFB, and collagen type I alpha 1 chain gene, COL1A1, by FISH.

The distinction between the fibrous phase of nodular fasciitis and fibromatosis can be challenging. The size of the lesion may be helpful, with most lesions of nodular fasciitis being less than 3 cm, while lesions of fibromatosis have a mean diameter of 7 cm.^5,14 Microscopically, both tumors demonstrate a fascicular growth pattern; however, the fascicles in nodular fasciitis tend to be short and irregular compared to the longer fascicles seen in fibromatosis (Figure 2). Immunohistochemistry staining has limited utility with only 56% (14/25) of superficial fibromatoses having positive nuclear staining for β-catenin.¹⁵

Low-grade fibromyxoid sarcoma (LGFMS) would be unusual in this clinical scenario. Only 13% to 19% of cases present in patients younger than 18 years (mean age, 33 years).¹⁶ In LGFMS there are cytologically bland spindle cells that are typically arranged in a patternless or whorled pattern (Figure 3), though fascicular architecture may be seen. There are alternating areas of fibrous and myxoid stroma. A curvilinear vasculature network and lack of lymphocytes and extravasated red blood cells are histologic features favoring LGFMS over nodular fasciitis. Immunohistochemistry staining and FISH testing can be useful in making the diagnosis of LGFMS. These tumors are characterized by a translocation t(7;16)(q34;p11) involving the fusion in sarcoma, FUS, and cAMP responsive element binding protein 3 like 2, CREB3L2, genes.¹⁶ Positive immunohistochemistry staining for MUC4 can be seen in up to 100% of LGFMS and is absent in many other spindle cell tumors.¹⁶

Plexiform fibrohistiocytic tumor (PFT) is least likely to be confused with nodular fasciitis. Histologically these tumors are characterized by multiple small nodules arranged in a plexiform pattern (Figure 4). Within the nodules, 3 cell types may be noted: spindle fibroblast-like cells, mononuclear histiocyte-like cells, and osteoclastlike cells.¹⁷ Either the spindle cells or the mononuclear cells may predominate in cases of PFT. Immunohistochemistry staining of PFT is nonspecific and there are no molecular/FISH studies that can be used to help confirm the diagnosis.

The Diagnosis: Erythrasma

Erythrasma usually involves intertriginous areas (eg, axillae, groin, inframammary area). Patients present with well-demarcated, minimally scaly, red-brown patches. The interdigital web space of the toes also can be involved with macerated white plaques, often with coexistent dermatophyte infection. Corynebacterium minutissimum, the bacteria responsible for erythrasma, produces coproporphyrin type III, which emits coral red fluorescence under Wood lamp examination.¹ Bathing may result in removal of the porphyrin and result in a false-negative finding. Potassium hydroxide preparation of skin scrapings can show chains of bacilli. Biopsy appears relatively normal at low power but reveals compact orthokeratosis with coccobacilli and filamentous organisms in the superficial stratum corneum (quiz image). When not obvious on hematoxylin and eosin-stained sections, the organisms are Gram-positive and also are seen with periodic acid-Schiff (PAS) and methenamine silver stains. Unlike fungal hyphae, these organisms are thinner and nonrefractile. Inflammation typically is minimal. Due to the subtle histologic findings at low power, erythrasma is considered one of the invisible dermatoses.² The differential diagnosis of these inconspicuous dermatoses that appear normal at first glance can be approached in a stepwise fashion starting in the stratum corneum, followed by the granular layer, basal layer, dermal papillae, dermal inflammatory cells, dermal connective tissue, and eccrine glands, and should consider each of the following diagnoses: candidiasis, dermatophytosis, ichthyosis vulgaris, vitiligo, macular amyloid, urticaria, telangiectasia macularis eruptiva perstans, connective tissue nevus, and argyria.² 

Candidiasis, most commonly caused by Candida albicans, usually involves the oral cavity (eg, thrush, median rhomboid glossitis, angular cheilitis), intertriginous zones, nail fold (paronychia), genital areas (eg, vulvovaginitis, balanitis), and diaper area.³ The web space between the third and fourth fingers (erosio interdigitalis blastomycetica) can be involved in patients whose hands are frequently in water. Intertriginous candidiasis presents with bright red, sometimes erosive patches with satellite lesions. Spores and mycelia (filamentous forms) are noted on potassium hydroxide preparation of skin scrapings. Histologically, the epidermis often is acanthotic, mildly spongiotic, and contains groups of neutrophils in the superficial layers. The mnemonic device for diseases with clusters of neutrophils in the stratum corneum is PTICSS (psoriasis, tinea, impetigo, candida, seborrheic dermatitis, syphilis).² Yeast, pseudohyphae, and even true hyphae can be seen in the stratum corneum with hematoxylin and eosin-stained sections and PAS. The filamentous forms tend to be vertically oriented in relation to the skin surface (Figure 1) compared to dermatophyte hyphae that tend to be parallel to the surface.²

Pitted keratolysis is a superficial bacterial infection involving the soles of the feet. The classic clinical findings are shallow 1- to 2-mm pits in clusters that can coalesce on pressure-bearing areas. Hyperhidrosis, malodor, and maceration commonly are associated. Microscopic examination reveals clusters of small cocci and filamentous bacteria located in the dell or pit of a thick compact orthokeratotic stratum corneum of acral skin with no notable inflammatory infiltrate (Figure 2).² Special stains such as Gram, methenamine silver, or PAS can assist in visualization of the organisms. Pitted keratolysis is caused by Dermatophilus congolensis and Kytococcus sedentarius (formerly Micrococcus sedentarius), which produce keratinolytic enzymes causing the defect in the stratum corneum.³

Tinea cruris, also known as jock itch and ringworm of the groin, presents with advancing pruritic, circinate, erythematous, scaling patches with central clearing on the inner thighs and crural folds. Similar to tinea pedis, Trichophyton rubrum is the most common dermatophyte to cause tinea cruris.⁴ Potassium hydroxide preparation of skin scrapings from the advancing border show fungal hyphae that cross the keratin cell borders. The histopathology of dermatophyte infections can be subtle and resemble normal skin before close inspection of the stratum corneum, which can show compact orthokeratosis, neutrophils, or "sandwich sign" where hyphae are sandwiched between an upper basket weave layer and a lower compact cornified layer (orthokeratotic or parakeratotic)(Figure 3).¹ The presence of these patterns in the stratum corneum should result in performance of PAS to highlight obscure hyphae.

Tinea versicolor, also called pityriasis versicolor, usually presents with hypopigmented or less commonly hyperpigmented circular patches that coalesce on the upper trunk and shoulders. There is a fine fluffy scale that is most notable after scraping the skin for a potassium hydroxide preparation, which shows "spaghetti and meatballs" (hyphae and spores). Tinea versicolor typically is caused by the mycelial phase of the lipophilic yeast Malassezia globosae.³ Histologically, there are yeast and short septate hyphae scattered in a loose basket weave hyperkeratotic stratum corneum with minimal or no inflammation (Figure 4). On occasion, PAS is required for identification.

The Diagnosis: Erythrasma

Erythrasma usually involves intertriginous areas (eg, axillae, groin, inframammary area). Patients present with well-demarcated, minimally scaly, red-brown patches. The interdigital web space of the toes also can be involved with macerated white plaques, often with coexistent dermatophyte infection. Corynebacterium minutissimum, the bacteria responsible for erythrasma, produces coproporphyrin type III, which emits coral red fluorescence under Wood lamp examination.¹ Bathing may result in removal of the porphyrin and result in a false-negative finding. Potassium hydroxide preparation of skin scrapings can show chains of bacilli. Biopsy appears relatively normal at low power but reveals compact orthokeratosis with coccobacilli and filamentous organisms in the superficial stratum corneum (quiz image). When not obvious on hematoxylin and eosin-stained sections, the organisms are Gram-positive and also are seen with periodic acid-Schiff (PAS) and methenamine silver stains. Unlike fungal hyphae, these organisms are thinner and nonrefractile. Inflammation typically is minimal. Due to the subtle histologic findings at low power, erythrasma is considered one of the invisible dermatoses.² The differential diagnosis of these inconspicuous dermatoses that appear normal at first glance can be approached in a stepwise fashion starting in the stratum corneum, followed by the granular layer, basal layer, dermal papillae, dermal inflammatory cells, dermal connective tissue, and eccrine glands, and should consider each of the following diagnoses: candidiasis, dermatophytosis, ichthyosis vulgaris, vitiligo, macular amyloid, urticaria, telangiectasia macularis eruptiva perstans, connective tissue nevus, and argyria.² 

Candidiasis, most commonly caused by Candida albicans, usually involves the oral cavity (eg, thrush, median rhomboid glossitis, angular cheilitis), intertriginous zones, nail fold (paronychia), genital areas (eg, vulvovaginitis, balanitis), and diaper area.³ The web space between the third and fourth fingers (erosio interdigitalis blastomycetica) can be involved in patients whose hands are frequently in water. Intertriginous candidiasis presents with bright red, sometimes erosive patches with satellite lesions. Spores and mycelia (filamentous forms) are noted on potassium hydroxide preparation of skin scrapings. Histologically, the epidermis often is acanthotic, mildly spongiotic, and contains groups of neutrophils in the superficial layers. The mnemonic device for diseases with clusters of neutrophils in the stratum corneum is PTICSS (psoriasis, tinea, impetigo, candida, seborrheic dermatitis, syphilis).² Yeast, pseudohyphae, and even true hyphae can be seen in the stratum corneum with hematoxylin and eosin-stained sections and PAS. The filamentous forms tend to be vertically oriented in relation to the skin surface (Figure 1) compared to dermatophyte hyphae that tend to be parallel to the surface.²

Pitted keratolysis is a superficial bacterial infection involving the soles of the feet. The classic clinical findings are shallow 1- to 2-mm pits in clusters that can coalesce on pressure-bearing areas. Hyperhidrosis, malodor, and maceration commonly are associated. Microscopic examination reveals clusters of small cocci and filamentous bacteria located in the dell or pit of a thick compact orthokeratotic stratum corneum of acral skin with no notable inflammatory infiltrate (Figure 2).² Special stains such as Gram, methenamine silver, or PAS can assist in visualization of the organisms. Pitted keratolysis is caused by Dermatophilus congolensis and Kytococcus sedentarius (formerly Micrococcus sedentarius), which produce keratinolytic enzymes causing the defect in the stratum corneum.³

Tinea cruris, also known as jock itch and ringworm of the groin, presents with advancing pruritic, circinate, erythematous, scaling patches with central clearing on the inner thighs and crural folds. Similar to tinea pedis, Trichophyton rubrum is the most common dermatophyte to cause tinea cruris.⁴ Potassium hydroxide preparation of skin scrapings from the advancing border show fungal hyphae that cross the keratin cell borders. The histopathology of dermatophyte infections can be subtle and resemble normal skin before close inspection of the stratum corneum, which can show compact orthokeratosis, neutrophils, or "sandwich sign" where hyphae are sandwiched between an upper basket weave layer and a lower compact cornified layer (orthokeratotic or parakeratotic)(Figure 3).¹ The presence of these patterns in the stratum corneum should result in performance of PAS to highlight obscure hyphae.

Tinea versicolor, also called pityriasis versicolor, usually presents with hypopigmented or less commonly hyperpigmented circular patches that coalesce on the upper trunk and shoulders. There is a fine fluffy scale that is most notable after scraping the skin for a potassium hydroxide preparation, which shows "spaghetti and meatballs" (hyphae and spores). Tinea versicolor typically is caused by the mycelial phase of the lipophilic yeast Malassezia globosae.³ Histologically, there are yeast and short septate hyphae scattered in a loose basket weave hyperkeratotic stratum corneum with minimal or no inflammation (Figure 4). On occasion, PAS is required for identification.

The Diagnosis: Erythrasma

Erythrasma usually involves intertriginous areas (eg, axillae, groin, inframammary area). Patients present with well-demarcated, minimally scaly, red-brown patches. The interdigital web space of the toes also can be involved with macerated white plaques, often with coexistent dermatophyte infection. Corynebacterium minutissimum, the bacteria responsible for erythrasma, produces coproporphyrin type III, which emits coral red fluorescence under Wood lamp examination.¹ Bathing may result in removal of the porphyrin and result in a false-negative finding. Potassium hydroxide preparation of skin scrapings can show chains of bacilli. Biopsy appears relatively normal at low power but reveals compact orthokeratosis with coccobacilli and filamentous organisms in the superficial stratum corneum (quiz image). When not obvious on hematoxylin and eosin-stained sections, the organisms are Gram-positive and also are seen with periodic acid-Schiff (PAS) and methenamine silver stains. Unlike fungal hyphae, these organisms are thinner and nonrefractile. Inflammation typically is minimal. Due to the subtle histologic findings at low power, erythrasma is considered one of the invisible dermatoses.² The differential diagnosis of these inconspicuous dermatoses that appear normal at first glance can be approached in a stepwise fashion starting in the stratum corneum, followed by the granular layer, basal layer, dermal papillae, dermal inflammatory cells, dermal connective tissue, and eccrine glands, and should consider each of the following diagnoses: candidiasis, dermatophytosis, ichthyosis vulgaris, vitiligo, macular amyloid, urticaria, telangiectasia macularis eruptiva perstans, connective tissue nevus, and argyria.² 

Candidiasis, most commonly caused by Candida albicans, usually involves the oral cavity (eg, thrush, median rhomboid glossitis, angular cheilitis), intertriginous zones, nail fold (paronychia), genital areas (eg, vulvovaginitis, balanitis), and diaper area.³ The web space between the third and fourth fingers (erosio interdigitalis blastomycetica) can be involved in patients whose hands are frequently in water. Intertriginous candidiasis presents with bright red, sometimes erosive patches with satellite lesions. Spores and mycelia (filamentous forms) are noted on potassium hydroxide preparation of skin scrapings. Histologically, the epidermis often is acanthotic, mildly spongiotic, and contains groups of neutrophils in the superficial layers. The mnemonic device for diseases with clusters of neutrophils in the stratum corneum is PTICSS (psoriasis, tinea, impetigo, candida, seborrheic dermatitis, syphilis).² Yeast, pseudohyphae, and even true hyphae can be seen in the stratum corneum with hematoxylin and eosin-stained sections and PAS. The filamentous forms tend to be vertically oriented in relation to the skin surface (Figure 1) compared to dermatophyte hyphae that tend to be parallel to the surface.²

Pitted keratolysis is a superficial bacterial infection involving the soles of the feet. The classic clinical findings are shallow 1- to 2-mm pits in clusters that can coalesce on pressure-bearing areas. Hyperhidrosis, malodor, and maceration commonly are associated. Microscopic examination reveals clusters of small cocci and filamentous bacteria located in the dell or pit of a thick compact orthokeratotic stratum corneum of acral skin with no notable inflammatory infiltrate (Figure 2).² Special stains such as Gram, methenamine silver, or PAS can assist in visualization of the organisms. Pitted keratolysis is caused by Dermatophilus congolensis and Kytococcus sedentarius (formerly Micrococcus sedentarius), which produce keratinolytic enzymes causing the defect in the stratum corneum.³

Tinea cruris, also known as jock itch and ringworm of the groin, presents with advancing pruritic, circinate, erythematous, scaling patches with central clearing on the inner thighs and crural folds. Similar to tinea pedis, Trichophyton rubrum is the most common dermatophyte to cause tinea cruris.⁴ Potassium hydroxide preparation of skin scrapings from the advancing border show fungal hyphae that cross the keratin cell borders. The histopathology of dermatophyte infections can be subtle and resemble normal skin before close inspection of the stratum corneum, which can show compact orthokeratosis, neutrophils, or "sandwich sign" where hyphae are sandwiched between an upper basket weave layer and a lower compact cornified layer (orthokeratotic or parakeratotic)(Figure 3).¹ The presence of these patterns in the stratum corneum should result in performance of PAS to highlight obscure hyphae.

Tinea versicolor, also called pityriasis versicolor, usually presents with hypopigmented or less commonly hyperpigmented circular patches that coalesce on the upper trunk and shoulders. There is a fine fluffy scale that is most notable after scraping the skin for a potassium hydroxide preparation, which shows "spaghetti and meatballs" (hyphae and spores). Tinea versicolor typically is caused by the mycelial phase of the lipophilic yeast Malassezia globosae.³ Histologically, there are yeast and short septate hyphae scattered in a loose basket weave hyperkeratotic stratum corneum with minimal or no inflammation (Figure 4). On occasion, PAS is required for identification.

The Diagnosis: Paraneoplastic Pemphigus

A workup for infectious organisms and vasculitis was negative. The patient reported unintentional weight loss despite taking oral steroids prescribed by her pulmonologist for severe obstructive lung disease that appeared to develop around the same time as the mouth ulcers.

Computed tomography of the abdomen revealed an 8.1-cm pelvic mass that a subsequent biopsy revealed to be a follicular dendritic cell sarcoma. Biopsies of the mouth ulcers showed a mildly hyperplastic mucosa with acantholysis and interface change with dyskeratosis. Direct immunofluorescence of the perilesional mucosa showed IgG and complement C3 in an intercellular distribution (Figure 1). The pathologic findings were consistent with a diagnosis of paraneoplastic pemphigus (PNP). Serologic testing via enzyme-linked immunosorbent assay, immunoblotting, and indirect immunofluorescence were not performed. The patient died within a few months after the initial presentation from bronchiolitis obliterans, a potentially fatal complication of PNP.

Paraneoplastic pemphigus is an autoimmune blistering disease associated with neoplasia, particularly lymphoproliferative disorders and thymoma.¹ Oral mucosal erosions and crusting along the lips commonly is seen along with cutaneous involvement. The main histologic features are interface changes with dyskeratosis and a lichenoid infiltrate and variable acantholysis.²

Direct immunofluorescence of perilesional skin classically shows IgG and complement C3 in an intercellular distribution, usually in a granular or linear distribution along the basement membrane. This same pattern of direct immunofluorescence is seen in pemphigus erythematosus; however, pemphigus erythematosus is clinically distinct from PNP, lacking mucosal involvement and affecting the face and/or seborrheic areas with an appearance more similar to seborrheic dermatitis or lupus erythematosus, depending on the patient.³ Indirect immunofluorescence with rat bladder epithelium typically is positive in PNP and can be a helpful feature in distinguishing PNP from other autoimmune blistering diseases (eg, pemphigus erythematosus, pemphigus vulgaris, pemphigus foliaceus).²

Immunoblotting assays via serology often detect numerous antigens in patients with PNP, including but not limited to plectin, desmoplakin, bullous pemphigoid antigens, envoplakin, desmoplakin II, and desmogleins 1 and 3.⁴ Some of these autoantibodies have been identified in tumors associated with paraneoplastic pemphigus, particularly Castleman disease and follicular dendritic cell sarcoma.

Acute graft-versus-host disease (GVHD) can have a similar histologic appearance to PNP with prominent dyskeratosis and characteristically shows satellite cell necrosis consisting of dyskeratosis with surrounding lymphocytes (Figure 2). Unlike PNP, acantholysis is not a feature of GVHD. Direct immunofluorescence typically is negative; however, nonspecific IgM and complement C3 deposition at the dermoepidermal junction and around the superficial vasculature has been reported in 39% of cases.⁵ Early chronic GVHD often shows retained lichenoid interface change, but late chronic GVHD has a sclerodermoid morphology that is easily distinguished histologically from PNP. Patients also have a history of either a bone marrow or solid organ transplant.⁶

Lichen planus also shows interface change with dyskeratosis and a lichenoid infiltrate; however, acantholysis typically is not seen and, there often is prominent hypergranulosis (Figure 3). Mucosal lesions often show more subtle features with decreased hyperkeratosis, more subtle hypergranulosis, and decreased interface change with plasma cells in the inflammatory infiltrate.⁶ Additionally, direct immunofluorescence is either negative or shows IgM-positive colloid bodies and/or an irregular band of fibrinogen at the dermoepidermal junction. The characteristic intercellular and granular/linear IgG positivity at the dermoepidermal junction of PNP is not seen.

Lupus erythematosus is an interface dermatitis with histologic features that can overlap with PNP, in addition to positive direct immunofluorescence, which has been seen in 50% to 94% of cases and can vary depending on previous steroid treatment and timing of the biopsy in the disease process.⁷ Unlike PNP, lupus erythematosus has a full-house pattern on direct immunofluorescence with IgG, IgM, IgA, and complement C3 deposition in a granular pattern at the dermoepidermal junction. While PNP also typically shows granular deposition of IgG and complement C3 at the dermoepidermal junction, there also is intercellular positivity without a full-house pattern. While both conditions show interface change, histologic features that distinguish lupus erythematosus from PNP are a superficial and deep perivascular lymphocytic infiltrate, basement membrane thickening, follicular plugging, and increased dermal mucin (Figure 4). Subacute lupus erythematosus and discoid lupus erythematosus can have similar histologic features, and definitive distinction on biopsy is not always possible; however, subacute lupus erythematosus shows milder follicular plugging and milder to absent basement membrane thickening, and the inflammatory infiltrate typically is sparser than in discoid lupus erythematosus.⁷ Subacute lupus erythematosus also can show anti-Ro/Sjögren syndrome antigen A antibodies, which typically are not seen in discoid lupus eythematosus.⁸

Stevens-Johnson syndrome (SJS) is on a spectrum with toxic epidermal necrolysis, with SJS involving less than 10% and toxic epidermal necrolysis involving 30% or more of the body surface area.⁵ Erythema multiforme also is on the histologic spectrum of SJS and toxic epidermal necrolysis; however, erythema multiforme typically is more inflammatory than SJS and toxic epidermal necrolysis. Stevens-Johnson syndrome typically affects older adults and shows both cutaneous and mucosal involvement; however, isolated mucosal involvement can be seen in children.⁵ Drugs, particularly sulfonamide antibiotics, usually are implicated as causative agents, but infections from Mycoplasma and other pathogens also may be the cause. There is notable clinical (with a combination of mucosal and cutaneous lesions) as well as histologic overlap between SJS and PNP. The density of the lichenoid infiltrate is variable, with dyskeratosis, basal cell hydropic degeneration, and occasional formation of subepidermal clefts (Figure 5). Unlike PNP, acantholysis is not a characteristic feature of SJS, and direct immunofluorescence generally is negative.

The Diagnosis: Paraneoplastic Pemphigus

A workup for infectious organisms and vasculitis was negative. The patient reported unintentional weight loss despite taking oral steroids prescribed by her pulmonologist for severe obstructive lung disease that appeared to develop around the same time as the mouth ulcers.

Computed tomography of the abdomen revealed an 8.1-cm pelvic mass that a subsequent biopsy revealed to be a follicular dendritic cell sarcoma. Biopsies of the mouth ulcers showed a mildly hyperplastic mucosa with acantholysis and interface change with dyskeratosis. Direct immunofluorescence of the perilesional mucosa showed IgG and complement C3 in an intercellular distribution (Figure 1). The pathologic findings were consistent with a diagnosis of paraneoplastic pemphigus (PNP). Serologic testing via enzyme-linked immunosorbent assay, immunoblotting, and indirect immunofluorescence were not performed. The patient died within a few months after the initial presentation from bronchiolitis obliterans, a potentially fatal complication of PNP.

Paraneoplastic pemphigus is an autoimmune blistering disease associated with neoplasia, particularly lymphoproliferative disorders and thymoma.¹ Oral mucosal erosions and crusting along the lips commonly is seen along with cutaneous involvement. The main histologic features are interface changes with dyskeratosis and a lichenoid infiltrate and variable acantholysis.²

Direct immunofluorescence of perilesional skin classically shows IgG and complement C3 in an intercellular distribution, usually in a granular or linear distribution along the basement membrane. This same pattern of direct immunofluorescence is seen in pemphigus erythematosus; however, pemphigus erythematosus is clinically distinct from PNP, lacking mucosal involvement and affecting the face and/or seborrheic areas with an appearance more similar to seborrheic dermatitis or lupus erythematosus, depending on the patient.³ Indirect immunofluorescence with rat bladder epithelium typically is positive in PNP and can be a helpful feature in distinguishing PNP from other autoimmune blistering diseases (eg, pemphigus erythematosus, pemphigus vulgaris, pemphigus foliaceus).²

Immunoblotting assays via serology often detect numerous antigens in patients with PNP, including but not limited to plectin, desmoplakin, bullous pemphigoid antigens, envoplakin, desmoplakin II, and desmogleins 1 and 3.⁴ Some of these autoantibodies have been identified in tumors associated with paraneoplastic pemphigus, particularly Castleman disease and follicular dendritic cell sarcoma.

Acute graft-versus-host disease (GVHD) can have a similar histologic appearance to PNP with prominent dyskeratosis and characteristically shows satellite cell necrosis consisting of dyskeratosis with surrounding lymphocytes (Figure 2). Unlike PNP, acantholysis is not a feature of GVHD. Direct immunofluorescence typically is negative; however, nonspecific IgM and complement C3 deposition at the dermoepidermal junction and around the superficial vasculature has been reported in 39% of cases.⁵ Early chronic GVHD often shows retained lichenoid interface change, but late chronic GVHD has a sclerodermoid morphology that is easily distinguished histologically from PNP. Patients also have a history of either a bone marrow or solid organ transplant.⁶

Lichen planus also shows interface change with dyskeratosis and a lichenoid infiltrate; however, acantholysis typically is not seen and, there often is prominent hypergranulosis (Figure 3). Mucosal lesions often show more subtle features with decreased hyperkeratosis, more subtle hypergranulosis, and decreased interface change with plasma cells in the inflammatory infiltrate.⁶ Additionally, direct immunofluorescence is either negative or shows IgM-positive colloid bodies and/or an irregular band of fibrinogen at the dermoepidermal junction. The characteristic intercellular and granular/linear IgG positivity at the dermoepidermal junction of PNP is not seen.

Lupus erythematosus is an interface dermatitis with histologic features that can overlap with PNP, in addition to positive direct immunofluorescence, which has been seen in 50% to 94% of cases and can vary depending on previous steroid treatment and timing of the biopsy in the disease process.⁷ Unlike PNP, lupus erythematosus has a full-house pattern on direct immunofluorescence with IgG, IgM, IgA, and complement C3 deposition in a granular pattern at the dermoepidermal junction. While PNP also typically shows granular deposition of IgG and complement C3 at the dermoepidermal junction, there also is intercellular positivity without a full-house pattern. While both conditions show interface change, histologic features that distinguish lupus erythematosus from PNP are a superficial and deep perivascular lymphocytic infiltrate, basement membrane thickening, follicular plugging, and increased dermal mucin (Figure 4). Subacute lupus erythematosus and discoid lupus erythematosus can have similar histologic features, and definitive distinction on biopsy is not always possible; however, subacute lupus erythematosus shows milder follicular plugging and milder to absent basement membrane thickening, and the inflammatory infiltrate typically is sparser than in discoid lupus erythematosus.⁷ Subacute lupus erythematosus also can show anti-Ro/Sjögren syndrome antigen A antibodies, which typically are not seen in discoid lupus eythematosus.⁸

Stevens-Johnson syndrome (SJS) is on a spectrum with toxic epidermal necrolysis, with SJS involving less than 10% and toxic epidermal necrolysis involving 30% or more of the body surface area.⁵ Erythema multiforme also is on the histologic spectrum of SJS and toxic epidermal necrolysis; however, erythema multiforme typically is more inflammatory than SJS and toxic epidermal necrolysis. Stevens-Johnson syndrome typically affects older adults and shows both cutaneous and mucosal involvement; however, isolated mucosal involvement can be seen in children.⁵ Drugs, particularly sulfonamide antibiotics, usually are implicated as causative agents, but infections from Mycoplasma and other pathogens also may be the cause. There is notable clinical (with a combination of mucosal and cutaneous lesions) as well as histologic overlap between SJS and PNP. The density of the lichenoid infiltrate is variable, with dyskeratosis, basal cell hydropic degeneration, and occasional formation of subepidermal clefts (Figure 5). Unlike PNP, acantholysis is not a characteristic feature of SJS, and direct immunofluorescence generally is negative.

The Diagnosis: Paraneoplastic Pemphigus

A workup for infectious organisms and vasculitis was negative. The patient reported unintentional weight loss despite taking oral steroids prescribed by her pulmonologist for severe obstructive lung disease that appeared to develop around the same time as the mouth ulcers.

Computed tomography of the abdomen revealed an 8.1-cm pelvic mass that a subsequent biopsy revealed to be a follicular dendritic cell sarcoma. Biopsies of the mouth ulcers showed a mildly hyperplastic mucosa with acantholysis and interface change with dyskeratosis. Direct immunofluorescence of the perilesional mucosa showed IgG and complement C3 in an intercellular distribution (Figure 1). The pathologic findings were consistent with a diagnosis of paraneoplastic pemphigus (PNP). Serologic testing via enzyme-linked immunosorbent assay, immunoblotting, and indirect immunofluorescence were not performed. The patient died within a few months after the initial presentation from bronchiolitis obliterans, a potentially fatal complication of PNP.

Paraneoplastic pemphigus is an autoimmune blistering disease associated with neoplasia, particularly lymphoproliferative disorders and thymoma.¹ Oral mucosal erosions and crusting along the lips commonly is seen along with cutaneous involvement. The main histologic features are interface changes with dyskeratosis and a lichenoid infiltrate and variable acantholysis.²

Direct immunofluorescence of perilesional skin classically shows IgG and complement C3 in an intercellular distribution, usually in a granular or linear distribution along the basement membrane. This same pattern of direct immunofluorescence is seen in pemphigus erythematosus; however, pemphigus erythematosus is clinically distinct from PNP, lacking mucosal involvement and affecting the face and/or seborrheic areas with an appearance more similar to seborrheic dermatitis or lupus erythematosus, depending on the patient.³ Indirect immunofluorescence with rat bladder epithelium typically is positive in PNP and can be a helpful feature in distinguishing PNP from other autoimmune blistering diseases (eg, pemphigus erythematosus, pemphigus vulgaris, pemphigus foliaceus).²

Immunoblotting assays via serology often detect numerous antigens in patients with PNP, including but not limited to plectin, desmoplakin, bullous pemphigoid antigens, envoplakin, desmoplakin II, and desmogleins 1 and 3.⁴ Some of these autoantibodies have been identified in tumors associated with paraneoplastic pemphigus, particularly Castleman disease and follicular dendritic cell sarcoma.

Acute graft-versus-host disease (GVHD) can have a similar histologic appearance to PNP with prominent dyskeratosis and characteristically shows satellite cell necrosis consisting of dyskeratosis with surrounding lymphocytes (Figure 2). Unlike PNP, acantholysis is not a feature of GVHD. Direct immunofluorescence typically is negative; however, nonspecific IgM and complement C3 deposition at the dermoepidermal junction and around the superficial vasculature has been reported in 39% of cases.⁵ Early chronic GVHD often shows retained lichenoid interface change, but late chronic GVHD has a sclerodermoid morphology that is easily distinguished histologically from PNP. Patients also have a history of either a bone marrow or solid organ transplant.⁶

Lichen planus also shows interface change with dyskeratosis and a lichenoid infiltrate; however, acantholysis typically is not seen and, there often is prominent hypergranulosis (Figure 3). Mucosal lesions often show more subtle features with decreased hyperkeratosis, more subtle hypergranulosis, and decreased interface change with plasma cells in the inflammatory infiltrate.⁶ Additionally, direct immunofluorescence is either negative or shows IgM-positive colloid bodies and/or an irregular band of fibrinogen at the dermoepidermal junction. The characteristic intercellular and granular/linear IgG positivity at the dermoepidermal junction of PNP is not seen.

Lupus erythematosus is an interface dermatitis with histologic features that can overlap with PNP, in addition to positive direct immunofluorescence, which has been seen in 50% to 94% of cases and can vary depending on previous steroid treatment and timing of the biopsy in the disease process.⁷ Unlike PNP, lupus erythematosus has a full-house pattern on direct immunofluorescence with IgG, IgM, IgA, and complement C3 deposition in a granular pattern at the dermoepidermal junction. While PNP also typically shows granular deposition of IgG and complement C3 at the dermoepidermal junction, there also is intercellular positivity without a full-house pattern. While both conditions show interface change, histologic features that distinguish lupus erythematosus from PNP are a superficial and deep perivascular lymphocytic infiltrate, basement membrane thickening, follicular plugging, and increased dermal mucin (Figure 4). Subacute lupus erythematosus and discoid lupus erythematosus can have similar histologic features, and definitive distinction on biopsy is not always possible; however, subacute lupus erythematosus shows milder follicular plugging and milder to absent basement membrane thickening, and the inflammatory infiltrate typically is sparser than in discoid lupus erythematosus.⁷ Subacute lupus erythematosus also can show anti-Ro/Sjögren syndrome antigen A antibodies, which typically are not seen in discoid lupus eythematosus.⁸

Stevens-Johnson syndrome (SJS) is on a spectrum with toxic epidermal necrolysis, with SJS involving less than 10% and toxic epidermal necrolysis involving 30% or more of the body surface area.⁵ Erythema multiforme also is on the histologic spectrum of SJS and toxic epidermal necrolysis; however, erythema multiforme typically is more inflammatory than SJS and toxic epidermal necrolysis. Stevens-Johnson syndrome typically affects older adults and shows both cutaneous and mucosal involvement; however, isolated mucosal involvement can be seen in children.⁵ Drugs, particularly sulfonamide antibiotics, usually are implicated as causative agents, but infections from Mycoplasma and other pathogens also may be the cause. There is notable clinical (with a combination of mucosal and cutaneous lesions) as well as histologic overlap between SJS and PNP. The density of the lichenoid infiltrate is variable, with dyskeratosis, basal cell hydropic degeneration, and occasional formation of subepidermal clefts (Figure 5). Unlike PNP, acantholysis is not a characteristic feature of SJS, and direct immunofluorescence generally is negative.

The Diagnosis: Metastatic Crohn Disease

Crohn disease (CD), a chronic inflammatory granulomatous disease of the gastrointestinal tract, has a wide spectrum of presentations.¹ The condition may affect the vulva, perineum, or perianal skin by direct extension from the gastrointestinal tract or may appear as a separate and distinct cutaneous focus of disease referred to as metastatic Crohn disease (MCD).²

Cutaneous lesions of MCD include ulcers, fissures, sinus tracts, abscesses, and vegetative plaques, which typically extend in continuity with sites of intra-abdominal disease to the perineum, buttocks, or abdominal wall, as well as ostomy sites or incisional scars. Erythema nodosum and pyoderma gangrenosum are the most common nonspecific cutaneous manifestations. Other cutaneous lesions described in CD include polyarteritis nodosa, psoriasis, erythema multiforme, erythema elevatum diutinum, epidermolysis bullosa acquisita, acne fulminans, pyoderma faciale, neutrophilic lobular panniculitis, granulomatous vasculitis, and porokeratosis.³

Perianal skin is the most common site of cutaneous involvement in individuals with CD. It is a marker of more severe disease and is associated with multiple surgical interventions and frequent relapses and has been reported in 22% of patients with CD.⁴ Most already had an existing diagnosis of gastrointestinal CD, which was active in one-third of individuals; however, 20% presented with disease at nongastrointestinal sites 2 months to 4 years prior to developing the gastrointestinal CD manifestations.⁵ Our patient presented with lesions on the perianal skin of 2 years' duration and a 6-month history of diarrhea. A colonoscopy demonstrated shallow ulcers involving the ileocecal portion of the gut, colon, and rectum. A biopsy from intestinal mucosal tissue showed acute and chronic inflammation with necrosis mixed with granulomatous inflammation, suggestive of CD.

Microscopically, the dominant histologic features of MCD are similar to those of bowel lesions, including an inflammatory infiltrate commonly consisting of sterile noncaseating sarcoidal granulomas, foreign body and Langhans giant cells, epithelioid histiocytes, and plasma cells surrounded by numerous mononuclear cells within the dermis with occasional extension into the subcutis (quiz image). Less common features include collagen degeneration, an infiltrate rich in eosinophils, dermal edema, and mixed lichenoid and granulomatous dermatitis.⁶

Metastatic CD often is misdiagnosed. A detailed history and physical examination may help narrow the differential; however, biopsy is necessary to establish a diagnosis of MCD. The histologic differential diagnosis of sarcoidal granulomatous inflammation of genital skin includes sarcoidosis, rheumatoid arthritis, leprosy or other mycobacterial and parasitic infection, granulomatosis with polyangiitis (GPA), and granulomatous infiltrate associated with certain exogenous material (eg, silica, zirconium, beryllium, tattoo pigment).

Sarcoidosis is a multiorgan disease that most frequently affects the lungs, skin, and lymph nodes. Its etiopathogenesis has not been clearly elucidated.⁷ Cutaneous lesions are present in 20% to 35% of patients.⁸ Given the wide variability of clinical manifestations, cutaneous sarcoidosis is another one of the great imitators. Cutaneous lesions are classified as specific and nonspecific depending on the presence of noncaseating granulomas on histologic studies and include maculopapules, plaques, nodules, lupus pernio, scar infiltration, alopecia, ulcerative lesions, and hypopigmentation. The most common nonspecific lesion of cutaneous sarcoidosis is erythema nodosum. Other manifestations include calcifications, prurigo, erythema multiforme, nail clubbing, and Sweet syndrome.⁹

Histologic findings in sarcoidosis generally are independent of the respective organ and clinical disease presentation. The epidermis usually remains unchanged, whereas the dermis shows a superficial and deep nodular granulomatous infiltrate. Granulomas consist of epithelioid cells with only few giant cells and no surrounding lymphocytes or a very sparse lymphocytic infiltrate ("naked" granuloma)(Figure 1). Foreign bodies, including silica, are known to be able to induce sarcoid granulomas, especially in patients with sarcoidosis. A sarcoidal reaction in long-standing scar tissue points to a diagnosis of sarcoidosis.¹⁰

Cutaneous tuberculosis primarily is caused by Mycobacterium tuberculosis and less frequently Mycobacterium bovis.^11,12 The manifestations of cutaneous tuberculosis depends on various factors such as the type of infection, mode of dissemination, host immunity, and whether it is a first-time infection or a recurrence. In Europe, the head and neck regions are most frequently affected.¹³ Lesions present as red-brown papules coalescing into a plaque. The tissue, especially in central parts of the lesion, is fragile (probe phenomenon). Diascopy shows the typical apple jelly-like color.

Histologically, cutaneous tuberculosis is characterized by typical tuberculoid granulomas with epithelioid cells and Langhans giant cells at the center surrounded by lymphocytes (Figure 2). Caseous necrosis as well as fibrosis may occur,^14,15 and the granulomas tend to coalesce.

Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a complex, multisystemic disease with varying manifestations. The condition has been defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tracts and necrotizing vasculitis affecting predominantly small- to medium-sized vessels.¹⁶ The etiology of GPA is thought to be linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Antineutrophil cytoplasmic antibodies play an important role in the pathogenesis of this disease. Cutaneous vasculitis secondary to GPA can present as papules, nodules, palpable purpura, ulcers resembling pyoderma gangrenosum, or necrotizing lesions leading to gangrene.¹⁷

The predominant histopathologic pattern in cutaneous lesions of GPA is leukocytoclastic vasculitis, which is present in up to 50% of biopsies.¹⁸ Characteristic findings that aid in establishing the diagnosis include histologic evidence of focal necrosis, fibrinoid degeneration, palisading granuloma surrounding neutrophils (Figure 3), and granulomatous vasculitis involving muscular vessel walls.¹⁹ Nonpalisading foci of necrosis or fibrinoid degeneration may precede the development of the typical palisading granuloma.²⁰

The typical histopathologic pattern of cutaneous amebiasis is ulceration with vascular necrosis (Figure 4).²¹ The organisms have prominent round nuclei and nucleoli and the cytoplasm may have a scalloped border.

The Diagnosis: Metastatic Crohn Disease

Crohn disease (CD), a chronic inflammatory granulomatous disease of the gastrointestinal tract, has a wide spectrum of presentations.¹ The condition may affect the vulva, perineum, or perianal skin by direct extension from the gastrointestinal tract or may appear as a separate and distinct cutaneous focus of disease referred to as metastatic Crohn disease (MCD).²

Cutaneous lesions of MCD include ulcers, fissures, sinus tracts, abscesses, and vegetative plaques, which typically extend in continuity with sites of intra-abdominal disease to the perineum, buttocks, or abdominal wall, as well as ostomy sites or incisional scars. Erythema nodosum and pyoderma gangrenosum are the most common nonspecific cutaneous manifestations. Other cutaneous lesions described in CD include polyarteritis nodosa, psoriasis, erythema multiforme, erythema elevatum diutinum, epidermolysis bullosa acquisita, acne fulminans, pyoderma faciale, neutrophilic lobular panniculitis, granulomatous vasculitis, and porokeratosis.³

Perianal skin is the most common site of cutaneous involvement in individuals with CD. It is a marker of more severe disease and is associated with multiple surgical interventions and frequent relapses and has been reported in 22% of patients with CD.⁴ Most already had an existing diagnosis of gastrointestinal CD, which was active in one-third of individuals; however, 20% presented with disease at nongastrointestinal sites 2 months to 4 years prior to developing the gastrointestinal CD manifestations.⁵ Our patient presented with lesions on the perianal skin of 2 years' duration and a 6-month history of diarrhea. A colonoscopy demonstrated shallow ulcers involving the ileocecal portion of the gut, colon, and rectum. A biopsy from intestinal mucosal tissue showed acute and chronic inflammation with necrosis mixed with granulomatous inflammation, suggestive of CD.

Microscopically, the dominant histologic features of MCD are similar to those of bowel lesions, including an inflammatory infiltrate commonly consisting of sterile noncaseating sarcoidal granulomas, foreign body and Langhans giant cells, epithelioid histiocytes, and plasma cells surrounded by numerous mononuclear cells within the dermis with occasional extension into the subcutis (quiz image). Less common features include collagen degeneration, an infiltrate rich in eosinophils, dermal edema, and mixed lichenoid and granulomatous dermatitis.⁶

Metastatic CD often is misdiagnosed. A detailed history and physical examination may help narrow the differential; however, biopsy is necessary to establish a diagnosis of MCD. The histologic differential diagnosis of sarcoidal granulomatous inflammation of genital skin includes sarcoidosis, rheumatoid arthritis, leprosy or other mycobacterial and parasitic infection, granulomatosis with polyangiitis (GPA), and granulomatous infiltrate associated with certain exogenous material (eg, silica, zirconium, beryllium, tattoo pigment).

Sarcoidosis is a multiorgan disease that most frequently affects the lungs, skin, and lymph nodes. Its etiopathogenesis has not been clearly elucidated.⁷ Cutaneous lesions are present in 20% to 35% of patients.⁸ Given the wide variability of clinical manifestations, cutaneous sarcoidosis is another one of the great imitators. Cutaneous lesions are classified as specific and nonspecific depending on the presence of noncaseating granulomas on histologic studies and include maculopapules, plaques, nodules, lupus pernio, scar infiltration, alopecia, ulcerative lesions, and hypopigmentation. The most common nonspecific lesion of cutaneous sarcoidosis is erythema nodosum. Other manifestations include calcifications, prurigo, erythema multiforme, nail clubbing, and Sweet syndrome.⁹

Histologic findings in sarcoidosis generally are independent of the respective organ and clinical disease presentation. The epidermis usually remains unchanged, whereas the dermis shows a superficial and deep nodular granulomatous infiltrate. Granulomas consist of epithelioid cells with only few giant cells and no surrounding lymphocytes or a very sparse lymphocytic infiltrate ("naked" granuloma)(Figure 1). Foreign bodies, including silica, are known to be able to induce sarcoid granulomas, especially in patients with sarcoidosis. A sarcoidal reaction in long-standing scar tissue points to a diagnosis of sarcoidosis.¹⁰

Cutaneous tuberculosis primarily is caused by Mycobacterium tuberculosis and less frequently Mycobacterium bovis.^11,12 The manifestations of cutaneous tuberculosis depends on various factors such as the type of infection, mode of dissemination, host immunity, and whether it is a first-time infection or a recurrence. In Europe, the head and neck regions are most frequently affected.¹³ Lesions present as red-brown papules coalescing into a plaque. The tissue, especially in central parts of the lesion, is fragile (probe phenomenon). Diascopy shows the typical apple jelly-like color.

Histologically, cutaneous tuberculosis is characterized by typical tuberculoid granulomas with epithelioid cells and Langhans giant cells at the center surrounded by lymphocytes (Figure 2). Caseous necrosis as well as fibrosis may occur,^14,15 and the granulomas tend to coalesce.

Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a complex, multisystemic disease with varying manifestations. The condition has been defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tracts and necrotizing vasculitis affecting predominantly small- to medium-sized vessels.¹⁶ The etiology of GPA is thought to be linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Antineutrophil cytoplasmic antibodies play an important role in the pathogenesis of this disease. Cutaneous vasculitis secondary to GPA can present as papules, nodules, palpable purpura, ulcers resembling pyoderma gangrenosum, or necrotizing lesions leading to gangrene.¹⁷

The predominant histopathologic pattern in cutaneous lesions of GPA is leukocytoclastic vasculitis, which is present in up to 50% of biopsies.¹⁸ Characteristic findings that aid in establishing the diagnosis include histologic evidence of focal necrosis, fibrinoid degeneration, palisading granuloma surrounding neutrophils (Figure 3), and granulomatous vasculitis involving muscular vessel walls.¹⁹ Nonpalisading foci of necrosis or fibrinoid degeneration may precede the development of the typical palisading granuloma.²⁰

The typical histopathologic pattern of cutaneous amebiasis is ulceration with vascular necrosis (Figure 4).²¹ The organisms have prominent round nuclei and nucleoli and the cytoplasm may have a scalloped border.

The Diagnosis: Metastatic Crohn Disease

Crohn disease (CD), a chronic inflammatory granulomatous disease of the gastrointestinal tract, has a wide spectrum of presentations.¹ The condition may affect the vulva, perineum, or perianal skin by direct extension from the gastrointestinal tract or may appear as a separate and distinct cutaneous focus of disease referred to as metastatic Crohn disease (MCD).²

Cutaneous lesions of MCD include ulcers, fissures, sinus tracts, abscesses, and vegetative plaques, which typically extend in continuity with sites of intra-abdominal disease to the perineum, buttocks, or abdominal wall, as well as ostomy sites or incisional scars. Erythema nodosum and pyoderma gangrenosum are the most common nonspecific cutaneous manifestations. Other cutaneous lesions described in CD include polyarteritis nodosa, psoriasis, erythema multiforme, erythema elevatum diutinum, epidermolysis bullosa acquisita, acne fulminans, pyoderma faciale, neutrophilic lobular panniculitis, granulomatous vasculitis, and porokeratosis.³

Perianal skin is the most common site of cutaneous involvement in individuals with CD. It is a marker of more severe disease and is associated with multiple surgical interventions and frequent relapses and has been reported in 22% of patients with CD.⁴ Most already had an existing diagnosis of gastrointestinal CD, which was active in one-third of individuals; however, 20% presented with disease at nongastrointestinal sites 2 months to 4 years prior to developing the gastrointestinal CD manifestations.⁵ Our patient presented with lesions on the perianal skin of 2 years' duration and a 6-month history of diarrhea. A colonoscopy demonstrated shallow ulcers involving the ileocecal portion of the gut, colon, and rectum. A biopsy from intestinal mucosal tissue showed acute and chronic inflammation with necrosis mixed with granulomatous inflammation, suggestive of CD.

Microscopically, the dominant histologic features of MCD are similar to those of bowel lesions, including an inflammatory infiltrate commonly consisting of sterile noncaseating sarcoidal granulomas, foreign body and Langhans giant cells, epithelioid histiocytes, and plasma cells surrounded by numerous mononuclear cells within the dermis with occasional extension into the subcutis (quiz image). Less common features include collagen degeneration, an infiltrate rich in eosinophils, dermal edema, and mixed lichenoid and granulomatous dermatitis.⁶

Metastatic CD often is misdiagnosed. A detailed history and physical examination may help narrow the differential; however, biopsy is necessary to establish a diagnosis of MCD. The histologic differential diagnosis of sarcoidal granulomatous inflammation of genital skin includes sarcoidosis, rheumatoid arthritis, leprosy or other mycobacterial and parasitic infection, granulomatosis with polyangiitis (GPA), and granulomatous infiltrate associated with certain exogenous material (eg, silica, zirconium, beryllium, tattoo pigment).

Sarcoidosis is a multiorgan disease that most frequently affects the lungs, skin, and lymph nodes. Its etiopathogenesis has not been clearly elucidated.⁷ Cutaneous lesions are present in 20% to 35% of patients.⁸ Given the wide variability of clinical manifestations, cutaneous sarcoidosis is another one of the great imitators. Cutaneous lesions are classified as specific and nonspecific depending on the presence of noncaseating granulomas on histologic studies and include maculopapules, plaques, nodules, lupus pernio, scar infiltration, alopecia, ulcerative lesions, and hypopigmentation. The most common nonspecific lesion of cutaneous sarcoidosis is erythema nodosum. Other manifestations include calcifications, prurigo, erythema multiforme, nail clubbing, and Sweet syndrome.⁹

Histologic findings in sarcoidosis generally are independent of the respective organ and clinical disease presentation. The epidermis usually remains unchanged, whereas the dermis shows a superficial and deep nodular granulomatous infiltrate. Granulomas consist of epithelioid cells with only few giant cells and no surrounding lymphocytes or a very sparse lymphocytic infiltrate ("naked" granuloma)(Figure 1). Foreign bodies, including silica, are known to be able to induce sarcoid granulomas, especially in patients with sarcoidosis. A sarcoidal reaction in long-standing scar tissue points to a diagnosis of sarcoidosis.¹⁰

Cutaneous tuberculosis primarily is caused by Mycobacterium tuberculosis and less frequently Mycobacterium bovis.^11,12 The manifestations of cutaneous tuberculosis depends on various factors such as the type of infection, mode of dissemination, host immunity, and whether it is a first-time infection or a recurrence. In Europe, the head and neck regions are most frequently affected.¹³ Lesions present as red-brown papules coalescing into a plaque. The tissue, especially in central parts of the lesion, is fragile (probe phenomenon). Diascopy shows the typical apple jelly-like color.

Histologically, cutaneous tuberculosis is characterized by typical tuberculoid granulomas with epithelioid cells and Langhans giant cells at the center surrounded by lymphocytes (Figure 2). Caseous necrosis as well as fibrosis may occur,^14,15 and the granulomas tend to coalesce.

Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a complex, multisystemic disease with varying manifestations. The condition has been defined as a necrotizing granulomatous inflammation usually involving the upper and lower respiratory tracts and necrotizing vasculitis affecting predominantly small- to medium-sized vessels.¹⁶ The etiology of GPA is thought to be linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Antineutrophil cytoplasmic antibodies play an important role in the pathogenesis of this disease. Cutaneous vasculitis secondary to GPA can present as papules, nodules, palpable purpura, ulcers resembling pyoderma gangrenosum, or necrotizing lesions leading to gangrene.¹⁷

The predominant histopathologic pattern in cutaneous lesions of GPA is leukocytoclastic vasculitis, which is present in up to 50% of biopsies.¹⁸ Characteristic findings that aid in establishing the diagnosis include histologic evidence of focal necrosis, fibrinoid degeneration, palisading granuloma surrounding neutrophils (Figure 3), and granulomatous vasculitis involving muscular vessel walls.¹⁹ Nonpalisading foci of necrosis or fibrinoid degeneration may precede the development of the typical palisading granuloma.²⁰

The typical histopathologic pattern of cutaneous amebiasis is ulceration with vascular necrosis (Figure 4).²¹ The organisms have prominent round nuclei and nucleoli and the cytoplasm may have a scalloped border.

The Diagnosis: Lymphoepitheliomalike Carcinoma of the Skin

The term lymphoepitheliomalike carcinoma of the skin (LELCS) initially was proposed by Swanson et al¹ in 1988 when they described 5 patients with cutaneous neoplasms histologically resembling nasopharyngeal carcinoma, also known as lymphoepithelioma. A PubMed search of articles indexed for MEDLINE using the term lymphoepitheliomalike carcinoma of the skin revealed over 60 cases of LELCS since 1988. However, unlike nasopharyngeal carcinoma, LELCS has not been associated with Epstein-Barr virus, with the exception of 1 known reported case.² The clinical appearance of LELCS is nonspecific but usually presents as a flesh-colored to erythematous nodule, as was seen in the current case. Lesions commonly are found on the head and neck in middle-aged to elderly patients with a slight male predominance.²

On histology, LELCS is characterized by aggregations of large, atypical epithelioid cells surrounded by a dense lymphoplasmocytic infiltrate (right quiz image). The neoplasm tends to reside within the deep dermis and/or subcutis¹ without appreciable epidermal involvement (left quiz image). The atypical epithelioid cells demonstrate positive immunoreactivity for cytokeratins (right quiz image inset), p40/p63, and epithelial membrane antigen,³ and the surrounding lymphocytic infiltrate stains positively for leukocyte common antigen. The tumor histogenesis still is unknown, although an epidermal origin has been suggested given its staining pattern.² Other investigators have postulated on an adnexal origin, citing the tumor's dermal location along with case reports describing possible glandular, sebaceous, or follicular differentiation.^2,4

Treatment for LELCS can include either standard surgical excision or Mohs micrographic surgery, with radiation reserved for lymph node involvement, tumor recurrence, or poor surgical candidates.^2,3,5 With appropriate therapy, prognosis may be considered favorable. Data from 49 LELCS patients presenting from 1988 and 2008 showed that 36 (73.5%) had no evidence of recurrence after treatment with standard surgical excision, 4 (8.2%) had local recurrence, and 6 (12.2%) developed lymph node metastasis, which led to death in 1 (2.0%) patient.²

Given the histologic similarity of LELCS to nasopharyngeal carcinoma, it is important to rule out the possibility of cutaneous metastasis, which can be done by testing for Epstein-Barr virus and performing either computed tomography imaging or comprehensive laryngoscopic examination of the head and neck region. In the current case, the patient was referred for laryngoscopy, at which time no suspicious lesions were identified. He subsequently underwent treatment with Mohs micrographic surgery, and the tumor was cleared after 2 surgical stages. At 5-month follow-up, the patient continued to do well with no signs of clinical recurrence.

Cutaneous lymphadenoma may be included in the differential diagnosis for LELCS on histopathology. This neoplasm is characterized by a well-circumscribed dermal proliferation of basaloid tumor islands within a fibrotic stroma (Figure 1). The basaloid cells may display peripheral palisading, and lymphocytes often are seen infiltrating the tumor lobules and the surrounding stroma (Figure 1 inset). Clinically, cutaneous lymphadenomas are slowly growing nodules that typically occur in young to middle-aged patients,^4,6 unlike LELCS, which is more commonly observed in middle-aged to elderly patients.²

The dense lymphocytic infiltrate seen in LELCS may obscure the neoplastic epithelioid cells and in doing so may mimic a lymphoproliferative disorder, such as lymphomatoid papulosis (LyP). Lymphomatoid papulosis is a chronic CD30⁺ lymphoproliferative disorder consisting of recurrent crops of self-resolving papulonodules occurring on the trunk, arms, and legs. The average age of onset is in the third to fourth decades of life. Histology is dependent on the subtype; type A, the most common subtype, displays a wedge-shaped dermal infiltrate consisting of small lymphocytes (Figure 2) admixed with larger CD30⁺ atypical lymphocytes with prominent nucleoli (Figure 2 inset).⁷ Bizarre, binucleated forms resembling Reed-Sternberg cells also may be observed along with hallmark cells, which contain a horseshoe-shaped nucleus. The presence of admixed neutrophils and eosinophils also are common in type A LyP, a feature that is not characteristic of LELCS. Moreover, the atypical cells in LyP would not stain positively for epithelial markers as they would in LELCS.

Rosai-Dorfman disease is a rare condition that usually presents with painless cervical lymphadenopathy, typically in the first and second decades of life. Skin involvement can be seen in a small subset of extranodal cases, but cutaneous involvement alone is uncommon. On histopathology, cutaneous lesions are characterized by a dense dermal infiltrate of atypical histiocytes with vesicular nuclei and pale cytoplasm admixed with inflammatory cells, including lymphocytes, neutrophils, and plasma cells (Figure 3). Intracytoplasmic inflammatory cells or emperipolesis often is appreciated (Figure 3 inset).^8,9 The atypical histiocytes stain positively for S100 and negatively for CD1a.

Lymphoepitheliomalike carcinoma of the skin sometimes is considered to be a poorly differentiated, inflamed variant of squamous cell carcinoma (SCC).¹⁰ A number of features may allow distinction of a primary cutaneous SCC from LELCS; for instance, SCC is more likely to have an epidermal connection and at least focal signs of squamous differentiation,11 which can include the presence of poorly differentiated epithelial cells with mitoses (Figure 4), keratin pearls, dyskeratotic cells, or intercellular bridges.¹² Moreover, SCCs have a more variable surrounding inflammatory infiltrate compared to LELCS.

The Diagnosis: Lymphoepitheliomalike Carcinoma of the Skin

The term lymphoepitheliomalike carcinoma of the skin (LELCS) initially was proposed by Swanson et al¹ in 1988 when they described 5 patients with cutaneous neoplasms histologically resembling nasopharyngeal carcinoma, also known as lymphoepithelioma. A PubMed search of articles indexed for MEDLINE using the term lymphoepitheliomalike carcinoma of the skin revealed over 60 cases of LELCS since 1988. However, unlike nasopharyngeal carcinoma, LELCS has not been associated with Epstein-Barr virus, with the exception of 1 known reported case.² The clinical appearance of LELCS is nonspecific but usually presents as a flesh-colored to erythematous nodule, as was seen in the current case. Lesions commonly are found on the head and neck in middle-aged to elderly patients with a slight male predominance.²

On histology, LELCS is characterized by aggregations of large, atypical epithelioid cells surrounded by a dense lymphoplasmocytic infiltrate (right quiz image). The neoplasm tends to reside within the deep dermis and/or subcutis¹ without appreciable epidermal involvement (left quiz image). The atypical epithelioid cells demonstrate positive immunoreactivity for cytokeratins (right quiz image inset), p40/p63, and epithelial membrane antigen,³ and the surrounding lymphocytic infiltrate stains positively for leukocyte common antigen. The tumor histogenesis still is unknown, although an epidermal origin has been suggested given its staining pattern.² Other investigators have postulated on an adnexal origin, citing the tumor's dermal location along with case reports describing possible glandular, sebaceous, or follicular differentiation.^2,4

Treatment for LELCS can include either standard surgical excision or Mohs micrographic surgery, with radiation reserved for lymph node involvement, tumor recurrence, or poor surgical candidates.^2,3,5 With appropriate therapy, prognosis may be considered favorable. Data from 49 LELCS patients presenting from 1988 and 2008 showed that 36 (73.5%) had no evidence of recurrence after treatment with standard surgical excision, 4 (8.2%) had local recurrence, and 6 (12.2%) developed lymph node metastasis, which led to death in 1 (2.0%) patient.²

Given the histologic similarity of LELCS to nasopharyngeal carcinoma, it is important to rule out the possibility of cutaneous metastasis, which can be done by testing for Epstein-Barr virus and performing either computed tomography imaging or comprehensive laryngoscopic examination of the head and neck region. In the current case, the patient was referred for laryngoscopy, at which time no suspicious lesions were identified. He subsequently underwent treatment with Mohs micrographic surgery, and the tumor was cleared after 2 surgical stages. At 5-month follow-up, the patient continued to do well with no signs of clinical recurrence.

Cutaneous lymphadenoma may be included in the differential diagnosis for LELCS on histopathology. This neoplasm is characterized by a well-circumscribed dermal proliferation of basaloid tumor islands within a fibrotic stroma (Figure 1). The basaloid cells may display peripheral palisading, and lymphocytes often are seen infiltrating the tumor lobules and the surrounding stroma (Figure 1 inset). Clinically, cutaneous lymphadenomas are slowly growing nodules that typically occur in young to middle-aged patients,^4,6 unlike LELCS, which is more commonly observed in middle-aged to elderly patients.²

The dense lymphocytic infiltrate seen in LELCS may obscure the neoplastic epithelioid cells and in doing so may mimic a lymphoproliferative disorder, such as lymphomatoid papulosis (LyP). Lymphomatoid papulosis is a chronic CD30⁺ lymphoproliferative disorder consisting of recurrent crops of self-resolving papulonodules occurring on the trunk, arms, and legs. The average age of onset is in the third to fourth decades of life. Histology is dependent on the subtype; type A, the most common subtype, displays a wedge-shaped dermal infiltrate consisting of small lymphocytes (Figure 2) admixed with larger CD30⁺ atypical lymphocytes with prominent nucleoli (Figure 2 inset).⁷ Bizarre, binucleated forms resembling Reed-Sternberg cells also may be observed along with hallmark cells, which contain a horseshoe-shaped nucleus. The presence of admixed neutrophils and eosinophils also are common in type A LyP, a feature that is not characteristic of LELCS. Moreover, the atypical cells in LyP would not stain positively for epithelial markers as they would in LELCS.

Rosai-Dorfman disease is a rare condition that usually presents with painless cervical lymphadenopathy, typically in the first and second decades of life. Skin involvement can be seen in a small subset of extranodal cases, but cutaneous involvement alone is uncommon. On histopathology, cutaneous lesions are characterized by a dense dermal infiltrate of atypical histiocytes with vesicular nuclei and pale cytoplasm admixed with inflammatory cells, including lymphocytes, neutrophils, and plasma cells (Figure 3). Intracytoplasmic inflammatory cells or emperipolesis often is appreciated (Figure 3 inset).^8,9 The atypical histiocytes stain positively for S100 and negatively for CD1a.

Lymphoepitheliomalike carcinoma of the skin sometimes is considered to be a poorly differentiated, inflamed variant of squamous cell carcinoma (SCC).¹⁰ A number of features may allow distinction of a primary cutaneous SCC from LELCS; for instance, SCC is more likely to have an epidermal connection and at least focal signs of squamous differentiation,11 which can include the presence of poorly differentiated epithelial cells with mitoses (Figure 4), keratin pearls, dyskeratotic cells, or intercellular bridges.¹² Moreover, SCCs have a more variable surrounding inflammatory infiltrate compared to LELCS.

The Diagnosis: Lymphoepitheliomalike Carcinoma of the Skin

The term lymphoepitheliomalike carcinoma of the skin (LELCS) initially was proposed by Swanson et al¹ in 1988 when they described 5 patients with cutaneous neoplasms histologically resembling nasopharyngeal carcinoma, also known as lymphoepithelioma. A PubMed search of articles indexed for MEDLINE using the term lymphoepitheliomalike carcinoma of the skin revealed over 60 cases of LELCS since 1988. However, unlike nasopharyngeal carcinoma, LELCS has not been associated with Epstein-Barr virus, with the exception of 1 known reported case.² The clinical appearance of LELCS is nonspecific but usually presents as a flesh-colored to erythematous nodule, as was seen in the current case. Lesions commonly are found on the head and neck in middle-aged to elderly patients with a slight male predominance.²

On histology, LELCS is characterized by aggregations of large, atypical epithelioid cells surrounded by a dense lymphoplasmocytic infiltrate (right quiz image). The neoplasm tends to reside within the deep dermis and/or subcutis¹ without appreciable epidermal involvement (left quiz image). The atypical epithelioid cells demonstrate positive immunoreactivity for cytokeratins (right quiz image inset), p40/p63, and epithelial membrane antigen,³ and the surrounding lymphocytic infiltrate stains positively for leukocyte common antigen. The tumor histogenesis still is unknown, although an epidermal origin has been suggested given its staining pattern.² Other investigators have postulated on an adnexal origin, citing the tumor's dermal location along with case reports describing possible glandular, sebaceous, or follicular differentiation.^2,4

Treatment for LELCS can include either standard surgical excision or Mohs micrographic surgery, with radiation reserved for lymph node involvement, tumor recurrence, or poor surgical candidates.^2,3,5 With appropriate therapy, prognosis may be considered favorable. Data from 49 LELCS patients presenting from 1988 and 2008 showed that 36 (73.5%) had no evidence of recurrence after treatment with standard surgical excision, 4 (8.2%) had local recurrence, and 6 (12.2%) developed lymph node metastasis, which led to death in 1 (2.0%) patient.²

Given the histologic similarity of LELCS to nasopharyngeal carcinoma, it is important to rule out the possibility of cutaneous metastasis, which can be done by testing for Epstein-Barr virus and performing either computed tomography imaging or comprehensive laryngoscopic examination of the head and neck region. In the current case, the patient was referred for laryngoscopy, at which time no suspicious lesions were identified. He subsequently underwent treatment with Mohs micrographic surgery, and the tumor was cleared after 2 surgical stages. At 5-month follow-up, the patient continued to do well with no signs of clinical recurrence.

Cutaneous lymphadenoma may be included in the differential diagnosis for LELCS on histopathology. This neoplasm is characterized by a well-circumscribed dermal proliferation of basaloid tumor islands within a fibrotic stroma (Figure 1). The basaloid cells may display peripheral palisading, and lymphocytes often are seen infiltrating the tumor lobules and the surrounding stroma (Figure 1 inset). Clinically, cutaneous lymphadenomas are slowly growing nodules that typically occur in young to middle-aged patients,^4,6 unlike LELCS, which is more commonly observed in middle-aged to elderly patients.²

The dense lymphocytic infiltrate seen in LELCS may obscure the neoplastic epithelioid cells and in doing so may mimic a lymphoproliferative disorder, such as lymphomatoid papulosis (LyP). Lymphomatoid papulosis is a chronic CD30⁺ lymphoproliferative disorder consisting of recurrent crops of self-resolving papulonodules occurring on the trunk, arms, and legs. The average age of onset is in the third to fourth decades of life. Histology is dependent on the subtype; type A, the most common subtype, displays a wedge-shaped dermal infiltrate consisting of small lymphocytes (Figure 2) admixed with larger CD30⁺ atypical lymphocytes with prominent nucleoli (Figure 2 inset).⁷ Bizarre, binucleated forms resembling Reed-Sternberg cells also may be observed along with hallmark cells, which contain a horseshoe-shaped nucleus. The presence of admixed neutrophils and eosinophils also are common in type A LyP, a feature that is not characteristic of LELCS. Moreover, the atypical cells in LyP would not stain positively for epithelial markers as they would in LELCS.

Rosai-Dorfman disease is a rare condition that usually presents with painless cervical lymphadenopathy, typically in the first and second decades of life. Skin involvement can be seen in a small subset of extranodal cases, but cutaneous involvement alone is uncommon. On histopathology, cutaneous lesions are characterized by a dense dermal infiltrate of atypical histiocytes with vesicular nuclei and pale cytoplasm admixed with inflammatory cells, including lymphocytes, neutrophils, and plasma cells (Figure 3). Intracytoplasmic inflammatory cells or emperipolesis often is appreciated (Figure 3 inset).^8,9 The atypical histiocytes stain positively for S100 and negatively for CD1a.

Lymphoepitheliomalike carcinoma of the skin sometimes is considered to be a poorly differentiated, inflamed variant of squamous cell carcinoma (SCC).¹⁰ A number of features may allow distinction of a primary cutaneous SCC from LELCS; for instance, SCC is more likely to have an epidermal connection and at least focal signs of squamous differentiation,11 which can include the presence of poorly differentiated epithelial cells with mitoses (Figure 4), keratin pearls, dyskeratotic cells, or intercellular bridges.¹² Moreover, SCCs have a more variable surrounding inflammatory infiltrate compared to LELCS.

The Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma

Primary cutaneous CD30⁺ lymphoproliferative disorders encompass lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma (PCALCL) as well as borderline cases. Primary cutaneous anaplastic large cell lymphoma is a rare disease that is more common in white patients with slight male predominance and median age at diagnosis of 61 years.1 Prognosis is excellent, with a 90% survival rate at 10 years. Although lesions spontaneously regress in 6% to 22% of cases, complete resolution is rare.2 Clinically, the classic presentation is a solitary, rapidly growing, flesh-colored, erythematous nodule or plaque on the arms and legs or trunk, often with ulceration. Proper diagnosis requires clinical, histopathologic, and immunophenotypic correlation.

Histopathologic examination of PCALCL typically reveals large, atypical, Reed-Sternberg-like cells most commonly with anaplastic cytomorphology, but pleomorphic or immunoblastic morphology is not uncommon. Cells are in sheets or nodules, diffusely occupying the dermis and often the subcutaneous fat, with more than 75% of large cells expressing CD30.³ In addition to CD30 positivity, immunophenotype is classically CD4⁺, cutaneous lymphocyte-associated antigen positive, epithelial membrane antigen negative, and anaplastic lymphoma kinase negative; CD2, CD5, and CD3 expression is variable. Interestingly, in our case, there was a minor population of CD8⁺ cells. CD8 expression is seen in less than 5% of PCALCL cases; this phenotype is associated with an indolent disease with favorable prognosis.³ Of note, anaplastic lymphoma kinase positivity corresponding to a t(2;5) translocation is more suggestive of systemic anaplastic large cell lymphoma with secondary skin involvement and more commonly is seen in children. For reasons possibly related to mediators such as epidermal growth factor or transforming growth factor α from CD30⁺ cells, epidermal hyperplasia can be seen in PCALCL.⁴ The subsequent hyperkeratosis, crusting, and ulceration can be difficult to distinguish from lesions such as pyoderma gangrenosum, squamous cell carcinoma, arthropod bite, leukemia cutis, Merkel cell carcinoma (MCC), and metastatic breast cancer.

Skin involvement with leukemia is rare but most commonly is seen in acute myelogenous leukemia, specifically more mature forms such as acute myelomonocytic leukemia and acute monocytic leukemia. Approximately 10% to 20% of acute myelomonocytic leukemia cases have cutaneous involvement.⁵ Although there is a variety of potential skin lesions, the most common is a red-purple papule or nodule, sometimes with hemorrhage or ulceration, on the head, neck, and trunk. Leukemic infiltrates may arise from sites of prior trauma. Histopathology depends on the type of leukemia; however, general features include a normal epidermis without epidermotropism and perivascular, nodular, or diffuse infiltrate of neoplastic cells in the dermis, often with a Grenz zone (Figure 1). Compared to PCALCL, leukemia cutis shows sparing of the papillary dermis (Grenz zone), and the cells have more cytoplasm and show a different immunophenotype. The cells often are fragile and show crush artifact. Acute myelogenous leukemia often will show cytoplasmic granules; however, immature precursor cells may not have granules. The myeloid cells will stain with myeloperoxidase and chloroacetate. Positivity is seen for CD13, CD33, and CD68. Clinical correlation is important because other diseases with nodular or diffuse infiltrates of small cell infiltrates, such as extramedullary hematopoiesis and lymphoma, appear similar. Acute myelogenous leukemia is associated with neutrophilic dermatoses such as Sweet syndrome and pyoderma gangrenosum. Cutaneous eruption resolves with successful treatment of the leukemia.

Breast cancer is the most common cancer to metastasize to the skin in women, accounting for 73% of cutaneous metastases, followed by melanoma, which is responsible for 11%.⁵ The classic presentation is an erythematous patch with spreading borders or a nodule on the trunk. Many cases of metastatic breast cancer with skin involvement may represent direct extension of the cancer into the skin. General histologic clues to cutaneous metastasis include well-circumscribed dermal or subcutaneous nodules of atypical cells with an increase in mitotic activity without connection to the epidermis. Tumor cells may show diffuse, nodular, or single file pattern and may exhibit areas of necrosis. Ductal carcinoma additionally may show ductal or glandular differentiation with surrounding desmoplasia (Figure 2). Immunohistochemistry typically is positive for cytokeratin (CK) 7, estrogen receptor/progesterone receptor, mammaglobin, and gross cystic disease fluid protein-15, and negative for CK20, CK5/6, and thyroid transcription factor-1.

Papulovesicular and nodular lesions appearing as an arthropod bite have been noted in hematologic malignancies, underscoring the importance of histopathology and clinical correlation. Arthropod bites commonly present as red papules, nodules, vesicles, or pustules at the site of the bite. Pseudolymphomatous nodules occasionally develop. Excoriations and further progression to persistent prurigo also may occur. Histopathology shows variable epidermal features including spongiosis, acanthosis, parakeratosis, dermal edema, and superficial and deep perivascular neutrophils (Figure 3). Additionally, lymphocytes sometimes with CD30 positivity may be seen. The presence of eosinophils in interstitial areas, especially in the deep dermis, is a useful clue.

Lack of staining for epithelial and neuroendocrine markers differentiates PCALCL from MCC; specifically CK20, an epithelial marker positive in more than 90% of MCC cases, excludes lymphoma.⁶ Merkel cell carcinoma presents as a solitary, quickly growing, red and often ulcerated nodule or plaque on the head, neck, or legs of elderly patients. The lesions often are in areas of sun damage. Histopathology classically shows a diffuse dermal infiltrate of monotonous round blue cells with a scant cytoplasmic rim and multiple inconspicuous nucleoli in nests, rosettes, or strands in the dermis. There are frequent mitotic figures. The cells are uniform and 2 to 3 times larger than mature lymphocytes. Single-cell necrosis and crush artifact is common. Epidermotropism or coexisting Bowenoid change also may be observed (Figure 4). The term primary neuroendocrine carcinoma of the skin is preferred over Merkel cell carcinoma because the tumor cells share similar morphology to the specialized touch receptor of the basal layer (Merkel cell), but no direct histogenetic relationship has been established.^7,8

Immunohistochemistry is key to diagnosis because MCC stains for both epithelial and neuroendocrine markers. Positivity is seen for neuron-specific enolase, epithelial membrane antigen, neurofilament, synaptophysin, and chromogranin. Because the histology of MCC may resemble small cell carcinoma of the lung, staining for low-molecular-weight keratin such as CK20 and CK7 help to distinguish MCC. Merkel cell carcinoma typically is CK20⁺ and CK7^-, while small cell carcinoma of the lung is the opposite.⁹ The tumor grows aggressively and metastasis is common, thus surgery is the primary approach, but adjuvant chemotherapy and radiation often are given in addition.

The Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma

Primary cutaneous CD30⁺ lymphoproliferative disorders encompass lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma (PCALCL) as well as borderline cases. Primary cutaneous anaplastic large cell lymphoma is a rare disease that is more common in white patients with slight male predominance and median age at diagnosis of 61 years.1 Prognosis is excellent, with a 90% survival rate at 10 years. Although lesions spontaneously regress in 6% to 22% of cases, complete resolution is rare.2 Clinically, the classic presentation is a solitary, rapidly growing, flesh-colored, erythematous nodule or plaque on the arms and legs or trunk, often with ulceration. Proper diagnosis requires clinical, histopathologic, and immunophenotypic correlation.

Histopathologic examination of PCALCL typically reveals large, atypical, Reed-Sternberg-like cells most commonly with anaplastic cytomorphology, but pleomorphic or immunoblastic morphology is not uncommon. Cells are in sheets or nodules, diffusely occupying the dermis and often the subcutaneous fat, with more than 75% of large cells expressing CD30.³ In addition to CD30 positivity, immunophenotype is classically CD4⁺, cutaneous lymphocyte-associated antigen positive, epithelial membrane antigen negative, and anaplastic lymphoma kinase negative; CD2, CD5, and CD3 expression is variable. Interestingly, in our case, there was a minor population of CD8⁺ cells. CD8 expression is seen in less than 5% of PCALCL cases; this phenotype is associated with an indolent disease with favorable prognosis.³ Of note, anaplastic lymphoma kinase positivity corresponding to a t(2;5) translocation is more suggestive of systemic anaplastic large cell lymphoma with secondary skin involvement and more commonly is seen in children. For reasons possibly related to mediators such as epidermal growth factor or transforming growth factor α from CD30⁺ cells, epidermal hyperplasia can be seen in PCALCL.⁴ The subsequent hyperkeratosis, crusting, and ulceration can be difficult to distinguish from lesions such as pyoderma gangrenosum, squamous cell carcinoma, arthropod bite, leukemia cutis, Merkel cell carcinoma (MCC), and metastatic breast cancer.

Skin involvement with leukemia is rare but most commonly is seen in acute myelogenous leukemia, specifically more mature forms such as acute myelomonocytic leukemia and acute monocytic leukemia. Approximately 10% to 20% of acute myelomonocytic leukemia cases have cutaneous involvement.⁵ Although there is a variety of potential skin lesions, the most common is a red-purple papule or nodule, sometimes with hemorrhage or ulceration, on the head, neck, and trunk. Leukemic infiltrates may arise from sites of prior trauma. Histopathology depends on the type of leukemia; however, general features include a normal epidermis without epidermotropism and perivascular, nodular, or diffuse infiltrate of neoplastic cells in the dermis, often with a Grenz zone (Figure 1). Compared to PCALCL, leukemia cutis shows sparing of the papillary dermis (Grenz zone), and the cells have more cytoplasm and show a different immunophenotype. The cells often are fragile and show crush artifact. Acute myelogenous leukemia often will show cytoplasmic granules; however, immature precursor cells may not have granules. The myeloid cells will stain with myeloperoxidase and chloroacetate. Positivity is seen for CD13, CD33, and CD68. Clinical correlation is important because other diseases with nodular or diffuse infiltrates of small cell infiltrates, such as extramedullary hematopoiesis and lymphoma, appear similar. Acute myelogenous leukemia is associated with neutrophilic dermatoses such as Sweet syndrome and pyoderma gangrenosum. Cutaneous eruption resolves with successful treatment of the leukemia.

Breast cancer is the most common cancer to metastasize to the skin in women, accounting for 73% of cutaneous metastases, followed by melanoma, which is responsible for 11%.⁵ The classic presentation is an erythematous patch with spreading borders or a nodule on the trunk. Many cases of metastatic breast cancer with skin involvement may represent direct extension of the cancer into the skin. General histologic clues to cutaneous metastasis include well-circumscribed dermal or subcutaneous nodules of atypical cells with an increase in mitotic activity without connection to the epidermis. Tumor cells may show diffuse, nodular, or single file pattern and may exhibit areas of necrosis. Ductal carcinoma additionally may show ductal or glandular differentiation with surrounding desmoplasia (Figure 2). Immunohistochemistry typically is positive for cytokeratin (CK) 7, estrogen receptor/progesterone receptor, mammaglobin, and gross cystic disease fluid protein-15, and negative for CK20, CK5/6, and thyroid transcription factor-1.

Papulovesicular and nodular lesions appearing as an arthropod bite have been noted in hematologic malignancies, underscoring the importance of histopathology and clinical correlation. Arthropod bites commonly present as red papules, nodules, vesicles, or pustules at the site of the bite. Pseudolymphomatous nodules occasionally develop. Excoriations and further progression to persistent prurigo also may occur. Histopathology shows variable epidermal features including spongiosis, acanthosis, parakeratosis, dermal edema, and superficial and deep perivascular neutrophils (Figure 3). Additionally, lymphocytes sometimes with CD30 positivity may be seen. The presence of eosinophils in interstitial areas, especially in the deep dermis, is a useful clue.

Lack of staining for epithelial and neuroendocrine markers differentiates PCALCL from MCC; specifically CK20, an epithelial marker positive in more than 90% of MCC cases, excludes lymphoma.⁶ Merkel cell carcinoma presents as a solitary, quickly growing, red and often ulcerated nodule or plaque on the head, neck, or legs of elderly patients. The lesions often are in areas of sun damage. Histopathology classically shows a diffuse dermal infiltrate of monotonous round blue cells with a scant cytoplasmic rim and multiple inconspicuous nucleoli in nests, rosettes, or strands in the dermis. There are frequent mitotic figures. The cells are uniform and 2 to 3 times larger than mature lymphocytes. Single-cell necrosis and crush artifact is common. Epidermotropism or coexisting Bowenoid change also may be observed (Figure 4). The term primary neuroendocrine carcinoma of the skin is preferred over Merkel cell carcinoma because the tumor cells share similar morphology to the specialized touch receptor of the basal layer (Merkel cell), but no direct histogenetic relationship has been established.^7,8

Immunohistochemistry is key to diagnosis because MCC stains for both epithelial and neuroendocrine markers. Positivity is seen for neuron-specific enolase, epithelial membrane antigen, neurofilament, synaptophysin, and chromogranin. Because the histology of MCC may resemble small cell carcinoma of the lung, staining for low-molecular-weight keratin such as CK20 and CK7 help to distinguish MCC. Merkel cell carcinoma typically is CK20⁺ and CK7^-, while small cell carcinoma of the lung is the opposite.⁹ The tumor grows aggressively and metastasis is common, thus surgery is the primary approach, but adjuvant chemotherapy and radiation often are given in addition.

The Diagnosis: Primary Cutaneous Anaplastic Large Cell Lymphoma

Primary cutaneous CD30⁺ lymphoproliferative disorders encompass lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma (PCALCL) as well as borderline cases. Primary cutaneous anaplastic large cell lymphoma is a rare disease that is more common in white patients with slight male predominance and median age at diagnosis of 61 years.1 Prognosis is excellent, with a 90% survival rate at 10 years. Although lesions spontaneously regress in 6% to 22% of cases, complete resolution is rare.2 Clinically, the classic presentation is a solitary, rapidly growing, flesh-colored, erythematous nodule or plaque on the arms and legs or trunk, often with ulceration. Proper diagnosis requires clinical, histopathologic, and immunophenotypic correlation.

Histopathologic examination of PCALCL typically reveals large, atypical, Reed-Sternberg-like cells most commonly with anaplastic cytomorphology, but pleomorphic or immunoblastic morphology is not uncommon. Cells are in sheets or nodules, diffusely occupying the dermis and often the subcutaneous fat, with more than 75% of large cells expressing CD30.³ In addition to CD30 positivity, immunophenotype is classically CD4⁺, cutaneous lymphocyte-associated antigen positive, epithelial membrane antigen negative, and anaplastic lymphoma kinase negative; CD2, CD5, and CD3 expression is variable. Interestingly, in our case, there was a minor population of CD8⁺ cells. CD8 expression is seen in less than 5% of PCALCL cases; this phenotype is associated with an indolent disease with favorable prognosis.³ Of note, anaplastic lymphoma kinase positivity corresponding to a t(2;5) translocation is more suggestive of systemic anaplastic large cell lymphoma with secondary skin involvement and more commonly is seen in children. For reasons possibly related to mediators such as epidermal growth factor or transforming growth factor α from CD30⁺ cells, epidermal hyperplasia can be seen in PCALCL.⁴ The subsequent hyperkeratosis, crusting, and ulceration can be difficult to distinguish from lesions such as pyoderma gangrenosum, squamous cell carcinoma, arthropod bite, leukemia cutis, Merkel cell carcinoma (MCC), and metastatic breast cancer.

Skin involvement with leukemia is rare but most commonly is seen in acute myelogenous leukemia, specifically more mature forms such as acute myelomonocytic leukemia and acute monocytic leukemia. Approximately 10% to 20% of acute myelomonocytic leukemia cases have cutaneous involvement.⁵ Although there is a variety of potential skin lesions, the most common is a red-purple papule or nodule, sometimes with hemorrhage or ulceration, on the head, neck, and trunk. Leukemic infiltrates may arise from sites of prior trauma. Histopathology depends on the type of leukemia; however, general features include a normal epidermis without epidermotropism and perivascular, nodular, or diffuse infiltrate of neoplastic cells in the dermis, often with a Grenz zone (Figure 1). Compared to PCALCL, leukemia cutis shows sparing of the papillary dermis (Grenz zone), and the cells have more cytoplasm and show a different immunophenotype. The cells often are fragile and show crush artifact. Acute myelogenous leukemia often will show cytoplasmic granules; however, immature precursor cells may not have granules. The myeloid cells will stain with myeloperoxidase and chloroacetate. Positivity is seen for CD13, CD33, and CD68. Clinical correlation is important because other diseases with nodular or diffuse infiltrates of small cell infiltrates, such as extramedullary hematopoiesis and lymphoma, appear similar. Acute myelogenous leukemia is associated with neutrophilic dermatoses such as Sweet syndrome and pyoderma gangrenosum. Cutaneous eruption resolves with successful treatment of the leukemia.

Breast cancer is the most common cancer to metastasize to the skin in women, accounting for 73% of cutaneous metastases, followed by melanoma, which is responsible for 11%.⁵ The classic presentation is an erythematous patch with spreading borders or a nodule on the trunk. Many cases of metastatic breast cancer with skin involvement may represent direct extension of the cancer into the skin. General histologic clues to cutaneous metastasis include well-circumscribed dermal or subcutaneous nodules of atypical cells with an increase in mitotic activity without connection to the epidermis. Tumor cells may show diffuse, nodular, or single file pattern and may exhibit areas of necrosis. Ductal carcinoma additionally may show ductal or glandular differentiation with surrounding desmoplasia (Figure 2). Immunohistochemistry typically is positive for cytokeratin (CK) 7, estrogen receptor/progesterone receptor, mammaglobin, and gross cystic disease fluid protein-15, and negative for CK20, CK5/6, and thyroid transcription factor-1.

Papulovesicular and nodular lesions appearing as an arthropod bite have been noted in hematologic malignancies, underscoring the importance of histopathology and clinical correlation. Arthropod bites commonly present as red papules, nodules, vesicles, or pustules at the site of the bite. Pseudolymphomatous nodules occasionally develop. Excoriations and further progression to persistent prurigo also may occur. Histopathology shows variable epidermal features including spongiosis, acanthosis, parakeratosis, dermal edema, and superficial and deep perivascular neutrophils (Figure 3). Additionally, lymphocytes sometimes with CD30 positivity may be seen. The presence of eosinophils in interstitial areas, especially in the deep dermis, is a useful clue.

Lack of staining for epithelial and neuroendocrine markers differentiates PCALCL from MCC; specifically CK20, an epithelial marker positive in more than 90% of MCC cases, excludes lymphoma.⁶ Merkel cell carcinoma presents as a solitary, quickly growing, red and often ulcerated nodule or plaque on the head, neck, or legs of elderly patients. The lesions often are in areas of sun damage. Histopathology classically shows a diffuse dermal infiltrate of monotonous round blue cells with a scant cytoplasmic rim and multiple inconspicuous nucleoli in nests, rosettes, or strands in the dermis. There are frequent mitotic figures. The cells are uniform and 2 to 3 times larger than mature lymphocytes. Single-cell necrosis and crush artifact is common. Epidermotropism or coexisting Bowenoid change also may be observed (Figure 4). The term primary neuroendocrine carcinoma of the skin is preferred over Merkel cell carcinoma because the tumor cells share similar morphology to the specialized touch receptor of the basal layer (Merkel cell), but no direct histogenetic relationship has been established.^7,8

Immunohistochemistry is key to diagnosis because MCC stains for both epithelial and neuroendocrine markers. Positivity is seen for neuron-specific enolase, epithelial membrane antigen, neurofilament, synaptophysin, and chromogranin. Because the histology of MCC may resemble small cell carcinoma of the lung, staining for low-molecular-weight keratin such as CK20 and CK7 help to distinguish MCC. Merkel cell carcinoma typically is CK20⁺ and CK7^-, while small cell carcinoma of the lung is the opposite.⁹ The tumor grows aggressively and metastasis is common, thus surgery is the primary approach, but adjuvant chemotherapy and radiation often are given in addition.

The Diagnosis: Atypical Vascular Lesion

Atypical vascular lesion (AVL)(quiz image), named by Fineberg and Rosen,¹ is a vascular lesion that arises on mammary skin with a history of radiation exposure. Clinically, AVL can present as a papule or erythematous patch that manifests 3 to 7 years after radiation therapy.^2,3 There are 2 histologic subtypes of AVL: lymphatic and vascular.^2,4 Lymphatic-type AVL is comprised of a symmetric distribution of thin, dilated, and anastomosing vessels usually found in the superficial and mid dermis. The vessels are lined by flat or hobnail protuberant endothelial cells that lack nuclear irregularity or pleomorphism; however, hyperchromatism of endothelial cell nuclei is a common finding. Vascular-type AVL is morphologically similar to a capillary hemangioma, and histologic features include irregular growth of capillary-sized vessels that extend to the dermis and subcutis.^2,4 Atypical vascular lesions are benign lesions but may be a precursor to angiosarcoma. Along with vascular markers, D2-40 typically is positive. Surgical excision with clear margins is recommended when the lesion is small.^4,5 Observation is more appropriate for extensive lesions.

Angiosarcoma can arise spontaneously or in association with radiation or chronic lymphedema. Given the shared risk factors and presentation with AVL, it is essential to differentiate angiosarcoma from AVL. Primary cutaneous angiosarcoma usually presents on the head of elderly patients as an ecchymotic patch or plaque with ulceration.⁴ Secondary angiosarcoma may arise following radiation or chronic lymphedema (Stewart-Treves syndrome); however, some authors now prefer to consider lymphangiosarcoma arising in chronic lymphedematous limbs a distinct entity.⁶ Surgical excision with wide margins is the mainstay of therapy, but angiosarcoma has high recurrence rates, and the 5-year survival rate has been reported to be as low as 35%.⁷ Histologic overlap with AVL includes dissecting anastomosing vessels lined by hyperchromatic nuclei; however, angiosarcoma is distinguished by endothelial cell layering, nuclear pleomorphism, and prominent nucleoli (Figure 1).^4,8 Increased positivity for Ki-67 immunostain, which indicates cell proliferation, may be used to distinguish angiosarcoma from an AVL (Figure 1 [inset]).⁹ Further, in contrast to AVL, radiation-induced angiosarcoma is characterized by amplification of C-MYC, a regulator gene, and FLT4 (FMS-related tyrosine kinase 4), a gene encoding vascular endothelial growth factor receptor 3. Gene amplification may be detected through immunohistochemistry or fluorescence in situ hybridization.¹⁰ Ki-67 labeling showed less than 10% staining in endothelial cells in our case (quiz image [inset]), and fluorescence in situ hybridization was negative for C-MYC amplification, supporting the diagnosis of AVL.

Lymphangioma circumscriptum, the most common superficial lymphangioma, is a hamartomatous malformation that usually occurs at the axillary folds, neck, and trunk. It clinically presents as small agminated vesicles with a characteristic frog spawn appearance.¹¹ Dermoscopic features include yellow lacunae that may alternate with a dark red color secondary to extravasation of erythrocytes.¹² These clinical features often lead to a differential diagnosis of verrucae, angiokeratoma, and angiosarcoma. Lymphangioma circumscriptum histologically is characterized by an overgrowth of dilated lymphatic vessels that fill the papillary dermis. The vessels are composed of flat endothelial cells typically filled with acellular proteinaceous debris and occasional erythrocytes (Figure 2). As the lesion traverses deeper into the dermis, the caliber of the lymphatic channel becomes narrower. The presence of deep lymphatic cisterns with surrounding smooth muscle is helpful to differentiate lymphangioma circumscriptum from other lymphatic malformations such as acquired lymphangiectasia. Treatment options include surgical excision, sclerosing agents, and destructive modalities such as cryotherapy.

Hobnail hemangioma, originally termed targetoid hemosiderotic hemangioma by Santa Cruz and Aronberg,¹³ presents as a violaceous papule or nodule surrounded by a characteristic brown halo on the leg. Trauma has been proposed as the inciting factor for the clinical appearance of hobnail hemangioma.¹⁴ Microscopically, the lesion shows vessels in a wedge shape. The superficial component has telangiectatic vessels with focal areas of papillary projections lined by endothelial cells. Although the endothelial nuclei typically project into the lumen, the nuclei are small, bland, and without mitotic activity.¹⁵ Deeper components show slit-shaped vasculature with dermal collagen dissection. Hemosiderin, extravasated red blood cells, and inflammation are found adjacent to the vessels (Figure 3). Given the benign nature, hobnail hemangiomas may be monitored.

Kaposi sarcoma (KS) is a low-grade vascular neoplasm associated with human herpesvirus 8 that arises in multiple clinical settings, especially in immunosuppression secondary to human immunodeficiency virus. There are 3 distinct clinical stages: patch, plaque, and tumor. The patch stage appears as red macules that blend into larger plaques; the tumor stage is defined as larger nodules developing from plaques. Histologic features differ by stage. Similar to angiosarcoma, KS is comprised of anastomosing vessels that dissect collagen bundles; endothelial cell atypia is minimal. A useful feature of KS is its propensity to involve adnexa and display the promontory sign, which involves the tumor growing into normal vasculature (Figure 4).¹⁶ Positive immunohistochemistry for human herpesvirus 8 aids in confirmation of the diagnosis. Treatment options for KS are numerous but include destructive modalities, chemotherapeutic agents such as doxorubicin, or highly active antiretroviral therapy for AIDS-related KS.¹⁷

The Diagnosis: Atypical Vascular Lesion

Atypical vascular lesion (AVL)(quiz image), named by Fineberg and Rosen,¹ is a vascular lesion that arises on mammary skin with a history of radiation exposure. Clinically, AVL can present as a papule or erythematous patch that manifests 3 to 7 years after radiation therapy.^2,3 There are 2 histologic subtypes of AVL: lymphatic and vascular.^2,4 Lymphatic-type AVL is comprised of a symmetric distribution of thin, dilated, and anastomosing vessels usually found in the superficial and mid dermis. The vessels are lined by flat or hobnail protuberant endothelial cells that lack nuclear irregularity or pleomorphism; however, hyperchromatism of endothelial cell nuclei is a common finding. Vascular-type AVL is morphologically similar to a capillary hemangioma, and histologic features include irregular growth of capillary-sized vessels that extend to the dermis and subcutis.^2,4 Atypical vascular lesions are benign lesions but may be a precursor to angiosarcoma. Along with vascular markers, D2-40 typically is positive. Surgical excision with clear margins is recommended when the lesion is small.^4,5 Observation is more appropriate for extensive lesions.

Angiosarcoma can arise spontaneously or in association with radiation or chronic lymphedema. Given the shared risk factors and presentation with AVL, it is essential to differentiate angiosarcoma from AVL. Primary cutaneous angiosarcoma usually presents on the head of elderly patients as an ecchymotic patch or plaque with ulceration.⁴ Secondary angiosarcoma may arise following radiation or chronic lymphedema (Stewart-Treves syndrome); however, some authors now prefer to consider lymphangiosarcoma arising in chronic lymphedematous limbs a distinct entity.⁶ Surgical excision with wide margins is the mainstay of therapy, but angiosarcoma has high recurrence rates, and the 5-year survival rate has been reported to be as low as 35%.⁷ Histologic overlap with AVL includes dissecting anastomosing vessels lined by hyperchromatic nuclei; however, angiosarcoma is distinguished by endothelial cell layering, nuclear pleomorphism, and prominent nucleoli (Figure 1).^4,8 Increased positivity for Ki-67 immunostain, which indicates cell proliferation, may be used to distinguish angiosarcoma from an AVL (Figure 1 [inset]).⁹ Further, in contrast to AVL, radiation-induced angiosarcoma is characterized by amplification of C-MYC, a regulator gene, and FLT4 (FMS-related tyrosine kinase 4), a gene encoding vascular endothelial growth factor receptor 3. Gene amplification may be detected through immunohistochemistry or fluorescence in situ hybridization.¹⁰ Ki-67 labeling showed less than 10% staining in endothelial cells in our case (quiz image [inset]), and fluorescence in situ hybridization was negative for C-MYC amplification, supporting the diagnosis of AVL.

Lymphangioma circumscriptum, the most common superficial lymphangioma, is a hamartomatous malformation that usually occurs at the axillary folds, neck, and trunk. It clinically presents as small agminated vesicles with a characteristic frog spawn appearance.¹¹ Dermoscopic features include yellow lacunae that may alternate with a dark red color secondary to extravasation of erythrocytes.¹² These clinical features often lead to a differential diagnosis of verrucae, angiokeratoma, and angiosarcoma. Lymphangioma circumscriptum histologically is characterized by an overgrowth of dilated lymphatic vessels that fill the papillary dermis. The vessels are composed of flat endothelial cells typically filled with acellular proteinaceous debris and occasional erythrocytes (Figure 2). As the lesion traverses deeper into the dermis, the caliber of the lymphatic channel becomes narrower. The presence of deep lymphatic cisterns with surrounding smooth muscle is helpful to differentiate lymphangioma circumscriptum from other lymphatic malformations such as acquired lymphangiectasia. Treatment options include surgical excision, sclerosing agents, and destructive modalities such as cryotherapy.

Hobnail hemangioma, originally termed targetoid hemosiderotic hemangioma by Santa Cruz and Aronberg,¹³ presents as a violaceous papule or nodule surrounded by a characteristic brown halo on the leg. Trauma has been proposed as the inciting factor for the clinical appearance of hobnail hemangioma.¹⁴ Microscopically, the lesion shows vessels in a wedge shape. The superficial component has telangiectatic vessels with focal areas of papillary projections lined by endothelial cells. Although the endothelial nuclei typically project into the lumen, the nuclei are small, bland, and without mitotic activity.¹⁵ Deeper components show slit-shaped vasculature with dermal collagen dissection. Hemosiderin, extravasated red blood cells, and inflammation are found adjacent to the vessels (Figure 3). Given the benign nature, hobnail hemangiomas may be monitored.

Kaposi sarcoma (KS) is a low-grade vascular neoplasm associated with human herpesvirus 8 that arises in multiple clinical settings, especially in immunosuppression secondary to human immunodeficiency virus. There are 3 distinct clinical stages: patch, plaque, and tumor. The patch stage appears as red macules that blend into larger plaques; the tumor stage is defined as larger nodules developing from plaques. Histologic features differ by stage. Similar to angiosarcoma, KS is comprised of anastomosing vessels that dissect collagen bundles; endothelial cell atypia is minimal. A useful feature of KS is its propensity to involve adnexa and display the promontory sign, which involves the tumor growing into normal vasculature (Figure 4).¹⁶ Positive immunohistochemistry for human herpesvirus 8 aids in confirmation of the diagnosis. Treatment options for KS are numerous but include destructive modalities, chemotherapeutic agents such as doxorubicin, or highly active antiretroviral therapy for AIDS-related KS.¹⁷

The Diagnosis: Atypical Vascular Lesion

Atypical vascular lesion (AVL)(quiz image), named by Fineberg and Rosen,¹ is a vascular lesion that arises on mammary skin with a history of radiation exposure. Clinically, AVL can present as a papule or erythematous patch that manifests 3 to 7 years after radiation therapy.^2,3 There are 2 histologic subtypes of AVL: lymphatic and vascular.^2,4 Lymphatic-type AVL is comprised of a symmetric distribution of thin, dilated, and anastomosing vessels usually found in the superficial and mid dermis. The vessels are lined by flat or hobnail protuberant endothelial cells that lack nuclear irregularity or pleomorphism; however, hyperchromatism of endothelial cell nuclei is a common finding. Vascular-type AVL is morphologically similar to a capillary hemangioma, and histologic features include irregular growth of capillary-sized vessels that extend to the dermis and subcutis.^2,4 Atypical vascular lesions are benign lesions but may be a precursor to angiosarcoma. Along with vascular markers, D2-40 typically is positive. Surgical excision with clear margins is recommended when the lesion is small.^4,5 Observation is more appropriate for extensive lesions.

Angiosarcoma can arise spontaneously or in association with radiation or chronic lymphedema. Given the shared risk factors and presentation with AVL, it is essential to differentiate angiosarcoma from AVL. Primary cutaneous angiosarcoma usually presents on the head of elderly patients as an ecchymotic patch or plaque with ulceration.⁴ Secondary angiosarcoma may arise following radiation or chronic lymphedema (Stewart-Treves syndrome); however, some authors now prefer to consider lymphangiosarcoma arising in chronic lymphedematous limbs a distinct entity.⁶ Surgical excision with wide margins is the mainstay of therapy, but angiosarcoma has high recurrence rates, and the 5-year survival rate has been reported to be as low as 35%.⁷ Histologic overlap with AVL includes dissecting anastomosing vessels lined by hyperchromatic nuclei; however, angiosarcoma is distinguished by endothelial cell layering, nuclear pleomorphism, and prominent nucleoli (Figure 1).^4,8 Increased positivity for Ki-67 immunostain, which indicates cell proliferation, may be used to distinguish angiosarcoma from an AVL (Figure 1 [inset]).⁹ Further, in contrast to AVL, radiation-induced angiosarcoma is characterized by amplification of C-MYC, a regulator gene, and FLT4 (FMS-related tyrosine kinase 4), a gene encoding vascular endothelial growth factor receptor 3. Gene amplification may be detected through immunohistochemistry or fluorescence in situ hybridization.¹⁰ Ki-67 labeling showed less than 10% staining in endothelial cells in our case (quiz image [inset]), and fluorescence in situ hybridization was negative for C-MYC amplification, supporting the diagnosis of AVL.

Lymphangioma circumscriptum, the most common superficial lymphangioma, is a hamartomatous malformation that usually occurs at the axillary folds, neck, and trunk. It clinically presents as small agminated vesicles with a characteristic frog spawn appearance.¹¹ Dermoscopic features include yellow lacunae that may alternate with a dark red color secondary to extravasation of erythrocytes.¹² These clinical features often lead to a differential diagnosis of verrucae, angiokeratoma, and angiosarcoma. Lymphangioma circumscriptum histologically is characterized by an overgrowth of dilated lymphatic vessels that fill the papillary dermis. The vessels are composed of flat endothelial cells typically filled with acellular proteinaceous debris and occasional erythrocytes (Figure 2). As the lesion traverses deeper into the dermis, the caliber of the lymphatic channel becomes narrower. The presence of deep lymphatic cisterns with surrounding smooth muscle is helpful to differentiate lymphangioma circumscriptum from other lymphatic malformations such as acquired lymphangiectasia. Treatment options include surgical excision, sclerosing agents, and destructive modalities such as cryotherapy.

Hobnail hemangioma, originally termed targetoid hemosiderotic hemangioma by Santa Cruz and Aronberg,¹³ presents as a violaceous papule or nodule surrounded by a characteristic brown halo on the leg. Trauma has been proposed as the inciting factor for the clinical appearance of hobnail hemangioma.¹⁴ Microscopically, the lesion shows vessels in a wedge shape. The superficial component has telangiectatic vessels with focal areas of papillary projections lined by endothelial cells. Although the endothelial nuclei typically project into the lumen, the nuclei are small, bland, and without mitotic activity.¹⁵ Deeper components show slit-shaped vasculature with dermal collagen dissection. Hemosiderin, extravasated red blood cells, and inflammation are found adjacent to the vessels (Figure 3). Given the benign nature, hobnail hemangiomas may be monitored.

Kaposi sarcoma (KS) is a low-grade vascular neoplasm associated with human herpesvirus 8 that arises in multiple clinical settings, especially in immunosuppression secondary to human immunodeficiency virus. There are 3 distinct clinical stages: patch, plaque, and tumor. The patch stage appears as red macules that blend into larger plaques; the tumor stage is defined as larger nodules developing from plaques. Histologic features differ by stage. Similar to angiosarcoma, KS is comprised of anastomosing vessels that dissect collagen bundles; endothelial cell atypia is minimal. A useful feature of KS is its propensity to involve adnexa and display the promontory sign, which involves the tumor growing into normal vasculature (Figure 4).¹⁶ Positive immunohistochemistry for human herpesvirus 8 aids in confirmation of the diagnosis. Treatment options for KS are numerous but include destructive modalities, chemotherapeutic agents such as doxorubicin, or highly active antiretroviral therapy for AIDS-related KS.¹⁷