Cutis

To the Editor:

Pseudoepitheliomatous hyperplasia (PEH) is an uncommon type of reactive epidermal proliferation that can occur from a variety of causes, including an underlying infection, inflammation, neoplastic condition, or trauma induced from tattooing.¹ Diagnosis can be challenging and requires clinicopathologic correlation, as PEH can mimic malignancy on histopathology.^2-4 Histologically, PEH shows irregular hyperplasia of the epidermis and adnexal epithelium, elongation of the rete ridges, and extension of the reactive proliferation into the dermis. Absence of cytologic atypia is key to the diagnosis of PEH, helping to distinguish it from squamous cell carcinoma and keratoacanthoma. Clinically, patients typically present with well-demarcated, erythematous, scaly plaques or nodules in reactive areas, which can be symptomatically pruritic.

A 48-year-old woman presented with scaly and crusted verrucous plaques of 2 months’ duration that were isolated to the areas of purple pigment within a tattoo on the right lower leg. The patient reported pruritus in the affected areas that occurred immediately after obtaining the tattoo, which was her first and only tattoo. She denied any pertinent medical history, including an absence of immunosuppression and autoimmune or chronic inflammatory diseases.

Physical examination revealed scaly and crusted plaques isolated to areas of purple tattoo pigment (Figure 1). Areas of red, green, black, and blue pigmentation within the tattoo were uninvolved. With the initial suspicion of allergic contact dermatitis, two 6-mm punch biopsies were taken from adjacent linear plaques on the right leg for histology and tissue culture. Histopathologic evaluation revealed dermal tattoo pigment with overlying PEH and was negative for signs of infection (Figure 2). Infectious stains such as periodic acid–Schiff, Grocott-Gomori methenamine-silver, and Gram stains were performed and found to be negative. In addition, culture for mycobacteria came back negative. Prurigo was on the differential; however, histopathologic changes were more compatible with a PEH reaction to the tattoo.

An increase in the popularity of tattooing has led to more reports of various tattoo skin reactions.^4-6 The differential diagnosis is broad for tattoo reactions and includes granulomatous inflammation, sarcoidosis, psoriasis (Köbner phenomenon), allergic contact dermatitis, lichen planus, morphealike reactions, squamous cell carcinoma, and keratoacanthoma,⁵ which makes clinicopathologic correlation essential for accurate diagnosis. Our case demonstrated the characteristic epithelial hyperplasia in the absence of cytologic atypia. In addition, the presence of mixed dermal inflammation histologically was noted in our patient.

We report an unusual case of PEH occurring secondary to purple tattoo pigment. Our report also demonstrates the clinical and symptomatic improvement of PEH that can be achieved through the use of intralesional corticosteroid therapy. Our patient represents a case of PEH reactive to tattooing with purple ink. Further research to elucidate the precise pathogenesis of PEH tattoo reactions would be helpful in identifying high-risk patients and determining the most efficacious treatments.

To the Editor:

Pseudoepitheliomatous hyperplasia (PEH) is an uncommon type of reactive epidermal proliferation that can occur from a variety of causes, including an underlying infection, inflammation, neoplastic condition, or trauma induced from tattooing.¹ Diagnosis can be challenging and requires clinicopathologic correlation, as PEH can mimic malignancy on histopathology.^2-4 Histologically, PEH shows irregular hyperplasia of the epidermis and adnexal epithelium, elongation of the rete ridges, and extension of the reactive proliferation into the dermis. Absence of cytologic atypia is key to the diagnosis of PEH, helping to distinguish it from squamous cell carcinoma and keratoacanthoma. Clinically, patients typically present with well-demarcated, erythematous, scaly plaques or nodules in reactive areas, which can be symptomatically pruritic.

A 48-year-old woman presented with scaly and crusted verrucous plaques of 2 months’ duration that were isolated to the areas of purple pigment within a tattoo on the right lower leg. The patient reported pruritus in the affected areas that occurred immediately after obtaining the tattoo, which was her first and only tattoo. She denied any pertinent medical history, including an absence of immunosuppression and autoimmune or chronic inflammatory diseases.

Physical examination revealed scaly and crusted plaques isolated to areas of purple tattoo pigment (Figure 1). Areas of red, green, black, and blue pigmentation within the tattoo were uninvolved. With the initial suspicion of allergic contact dermatitis, two 6-mm punch biopsies were taken from adjacent linear plaques on the right leg for histology and tissue culture. Histopathologic evaluation revealed dermal tattoo pigment with overlying PEH and was negative for signs of infection (Figure 2). Infectious stains such as periodic acid–Schiff, Grocott-Gomori methenamine-silver, and Gram stains were performed and found to be negative. In addition, culture for mycobacteria came back negative. Prurigo was on the differential; however, histopathologic changes were more compatible with a PEH reaction to the tattoo.

An increase in the popularity of tattooing has led to more reports of various tattoo skin reactions.^4-6 The differential diagnosis is broad for tattoo reactions and includes granulomatous inflammation, sarcoidosis, psoriasis (Köbner phenomenon), allergic contact dermatitis, lichen planus, morphealike reactions, squamous cell carcinoma, and keratoacanthoma,⁵ which makes clinicopathologic correlation essential for accurate diagnosis. Our case demonstrated the characteristic epithelial hyperplasia in the absence of cytologic atypia. In addition, the presence of mixed dermal inflammation histologically was noted in our patient.

We report an unusual case of PEH occurring secondary to purple tattoo pigment. Our report also demonstrates the clinical and symptomatic improvement of PEH that can be achieved through the use of intralesional corticosteroid therapy. Our patient represents a case of PEH reactive to tattooing with purple ink. Further research to elucidate the precise pathogenesis of PEH tattoo reactions would be helpful in identifying high-risk patients and determining the most efficacious treatments.

To the Editor:

Pseudoepitheliomatous hyperplasia (PEH) is an uncommon type of reactive epidermal proliferation that can occur from a variety of causes, including an underlying infection, inflammation, neoplastic condition, or trauma induced from tattooing.¹ Diagnosis can be challenging and requires clinicopathologic correlation, as PEH can mimic malignancy on histopathology.^2-4 Histologically, PEH shows irregular hyperplasia of the epidermis and adnexal epithelium, elongation of the rete ridges, and extension of the reactive proliferation into the dermis. Absence of cytologic atypia is key to the diagnosis of PEH, helping to distinguish it from squamous cell carcinoma and keratoacanthoma. Clinically, patients typically present with well-demarcated, erythematous, scaly plaques or nodules in reactive areas, which can be symptomatically pruritic.

A 48-year-old woman presented with scaly and crusted verrucous plaques of 2 months’ duration that were isolated to the areas of purple pigment within a tattoo on the right lower leg. The patient reported pruritus in the affected areas that occurred immediately after obtaining the tattoo, which was her first and only tattoo. She denied any pertinent medical history, including an absence of immunosuppression and autoimmune or chronic inflammatory diseases.

Physical examination revealed scaly and crusted plaques isolated to areas of purple tattoo pigment (Figure 1). Areas of red, green, black, and blue pigmentation within the tattoo were uninvolved. With the initial suspicion of allergic contact dermatitis, two 6-mm punch biopsies were taken from adjacent linear plaques on the right leg for histology and tissue culture. Histopathologic evaluation revealed dermal tattoo pigment with overlying PEH and was negative for signs of infection (Figure 2). Infectious stains such as periodic acid–Schiff, Grocott-Gomori methenamine-silver, and Gram stains were performed and found to be negative. In addition, culture for mycobacteria came back negative. Prurigo was on the differential; however, histopathologic changes were more compatible with a PEH reaction to the tattoo.

An increase in the popularity of tattooing has led to more reports of various tattoo skin reactions.^4-6 The differential diagnosis is broad for tattoo reactions and includes granulomatous inflammation, sarcoidosis, psoriasis (Köbner phenomenon), allergic contact dermatitis, lichen planus, morphealike reactions, squamous cell carcinoma, and keratoacanthoma,⁵ which makes clinicopathologic correlation essential for accurate diagnosis. Our case demonstrated the characteristic epithelial hyperplasia in the absence of cytologic atypia. In addition, the presence of mixed dermal inflammation histologically was noted in our patient.

We report an unusual case of PEH occurring secondary to purple tattoo pigment. Our report also demonstrates the clinical and symptomatic improvement of PEH that can be achieved through the use of intralesional corticosteroid therapy. Our patient represents a case of PEH reactive to tattooing with purple ink. Further research to elucidate the precise pathogenesis of PEH tattoo reactions would be helpful in identifying high-risk patients and determining the most efficacious treatments.

To the Editor:

Lymphomatoid papulosis is a rare chronic skin disorder characterized by recurrent, self-healing crops of papulonodular eruptions, often resembling cutaneous T-cell lymphoma.¹ Oral bexarotene, a retinoid X receptor–selective retinoid, can be used to control the disease.^2,3 Lichen planopilaris (LPP) is a type of cicatricial alopecia characterized by irreversible hair loss, perifollicular inflammation, and follicular hyperkeratosis, commonly affecting the scalp vertex in adults.⁴ We report a case of a patient with lymphomatoid papulosis who was treated with bexarotene and subsequently developed LPP. We also discuss a proposed mechanism by which bexarotene may have influenced the onset of LPP.

A 35-year-old woman who was previously healthy initially presented with recurrent pruritic papular eruptions on the flank, axillae, and groin of several months’ duration. The lesions appeared as 2-mm, flat-topped, violaceous papules. The patient had no known drug allergies, no medical or family history of skin disease, and was only taking 3000 mg/d of omega-3 fatty acids (fish oil). Histopathologic examination of a biopsy specimen from the inner thigh showed enlarged, atypical, dermal lymphocytes that were CD30⁺ (Figure 1). These findings were consistent with lymphomatoid papulosis. As she had undergone tubal ligation several years prior, she was prescribed oral bexarotene 300 mg once daily in addition to triamcinolone cream 0.1% twice daily, as needed. Symptoms were well controlled on this regimen.

Although the exact mechanism of LPP is not fully understood, studies have suggested that cellular lipid metabolism may be responsible for the inflammation of the pilosebaceous unit.^4-11 Hyperlipidemia is the most common side effect of oral bexarotene, typically occurring within the first 2 to 4 weeks of treatment.^3,12 Considering the insights into the role of lipid regulation on LPP pathogenesis, it is reasonable to suspect that the dyslipidemia caused by bexarotene may have triggered the onset of LPP in our patient. The patient’s lipid values mostly remained within reference range throughout the course of treatment, though she did have elevation of triglycerides around the onset of LPP. Dyslipidemia has been reported in patients with lichen planus but not in patients with LPP. One case-control study showed no dyslipidemia in patients with LPP, but the triglyceride levels were not tracked over time and patients had varying durations since onset of disease at presentation.^9-11,13 In our case, we were fortunate to have this information, and it may suggest an interaction between lipid dysregulation and the development of LPP. It would be interesting to explore this further in a larger patient population and to evaluate if control of dyslipidemia reduces progression of disease as it appears to have done for our patient.

To the Editor:

Lymphomatoid papulosis is a rare chronic skin disorder characterized by recurrent, self-healing crops of papulonodular eruptions, often resembling cutaneous T-cell lymphoma.¹ Oral bexarotene, a retinoid X receptor–selective retinoid, can be used to control the disease.^2,3 Lichen planopilaris (LPP) is a type of cicatricial alopecia characterized by irreversible hair loss, perifollicular inflammation, and follicular hyperkeratosis, commonly affecting the scalp vertex in adults.⁴ We report a case of a patient with lymphomatoid papulosis who was treated with bexarotene and subsequently developed LPP. We also discuss a proposed mechanism by which bexarotene may have influenced the onset of LPP.

A 35-year-old woman who was previously healthy initially presented with recurrent pruritic papular eruptions on the flank, axillae, and groin of several months’ duration. The lesions appeared as 2-mm, flat-topped, violaceous papules. The patient had no known drug allergies, no medical or family history of skin disease, and was only taking 3000 mg/d of omega-3 fatty acids (fish oil). Histopathologic examination of a biopsy specimen from the inner thigh showed enlarged, atypical, dermal lymphocytes that were CD30⁺ (Figure 1). These findings were consistent with lymphomatoid papulosis. As she had undergone tubal ligation several years prior, she was prescribed oral bexarotene 300 mg once daily in addition to triamcinolone cream 0.1% twice daily, as needed. Symptoms were well controlled on this regimen.

Although the exact mechanism of LPP is not fully understood, studies have suggested that cellular lipid metabolism may be responsible for the inflammation of the pilosebaceous unit.^4-11 Hyperlipidemia is the most common side effect of oral bexarotene, typically occurring within the first 2 to 4 weeks of treatment.^3,12 Considering the insights into the role of lipid regulation on LPP pathogenesis, it is reasonable to suspect that the dyslipidemia caused by bexarotene may have triggered the onset of LPP in our patient. The patient’s lipid values mostly remained within reference range throughout the course of treatment, though she did have elevation of triglycerides around the onset of LPP. Dyslipidemia has been reported in patients with lichen planus but not in patients with LPP. One case-control study showed no dyslipidemia in patients with LPP, but the triglyceride levels were not tracked over time and patients had varying durations since onset of disease at presentation.^9-11,13 In our case, we were fortunate to have this information, and it may suggest an interaction between lipid dysregulation and the development of LPP. It would be interesting to explore this further in a larger patient population and to evaluate if control of dyslipidemia reduces progression of disease as it appears to have done for our patient.

To the Editor:

Lymphomatoid papulosis is a rare chronic skin disorder characterized by recurrent, self-healing crops of papulonodular eruptions, often resembling cutaneous T-cell lymphoma.¹ Oral bexarotene, a retinoid X receptor–selective retinoid, can be used to control the disease.^2,3 Lichen planopilaris (LPP) is a type of cicatricial alopecia characterized by irreversible hair loss, perifollicular inflammation, and follicular hyperkeratosis, commonly affecting the scalp vertex in adults.⁴ We report a case of a patient with lymphomatoid papulosis who was treated with bexarotene and subsequently developed LPP. We also discuss a proposed mechanism by which bexarotene may have influenced the onset of LPP.

A 35-year-old woman who was previously healthy initially presented with recurrent pruritic papular eruptions on the flank, axillae, and groin of several months’ duration. The lesions appeared as 2-mm, flat-topped, violaceous papules. The patient had no known drug allergies, no medical or family history of skin disease, and was only taking 3000 mg/d of omega-3 fatty acids (fish oil). Histopathologic examination of a biopsy specimen from the inner thigh showed enlarged, atypical, dermal lymphocytes that were CD30⁺ (Figure 1). These findings were consistent with lymphomatoid papulosis. As she had undergone tubal ligation several years prior, she was prescribed oral bexarotene 300 mg once daily in addition to triamcinolone cream 0.1% twice daily, as needed. Symptoms were well controlled on this regimen.

Although the exact mechanism of LPP is not fully understood, studies have suggested that cellular lipid metabolism may be responsible for the inflammation of the pilosebaceous unit.^4-11 Hyperlipidemia is the most common side effect of oral bexarotene, typically occurring within the first 2 to 4 weeks of treatment.^3,12 Considering the insights into the role of lipid regulation on LPP pathogenesis, it is reasonable to suspect that the dyslipidemia caused by bexarotene may have triggered the onset of LPP in our patient. The patient’s lipid values mostly remained within reference range throughout the course of treatment, though she did have elevation of triglycerides around the onset of LPP. Dyslipidemia has been reported in patients with lichen planus but not in patients with LPP. One case-control study showed no dyslipidemia in patients with LPP, but the triglyceride levels were not tracked over time and patients had varying durations since onset of disease at presentation.^9-11,13 In our case, we were fortunate to have this information, and it may suggest an interaction between lipid dysregulation and the development of LPP. It would be interesting to explore this further in a larger patient population and to evaluate if control of dyslipidemia reduces progression of disease as it appears to have done for our patient.

The Diagnosis: Eosinophilic Folliculitis 

A  shave biopsy specimen of an intact pustule on the left side of the chest was obtained. Histopathologic examination revealed follicular inflammation with copious eosinophils (Figure, A and B). Based on the histopathology and clinical presentation, a diagnosis of human immunodeficiency virus (HIV)-associated eosinophilic folliculitis (EF) was made. 

The patient was started on triamcinolone ointment 0.1% twice daily to active lesions, oral cetirizine 10 mg in the morning, and oral hydroxyzine 25 mg at bedtime. Laboratory evaluation at the time of diagnosis showed eosinophilia with a peripheral blood eosinophil count of 0.5 K/μL (reference range, 0.03–0.48 K/μL).

Human immunodeficiency virus-associated EF is a pruritic follicular eruption that occurs in HIV-positive individuals with advanced disease. Clinically, it is characterized by intermittent, urticarial, red or flesh-colored, 2- to 5-mm papules with sparse pustules involving the head, neck, arms, and upper trunk.^1,2 The cardinal clinical feature of the disorder is intense pruritus, with overlying crusts and excoriations present on physical examination.³  

Patients usually have a CD4 count of less than 250 cells/mm³.^2,3 Patients with HIV can develop an exacerbation of EF in the first 3 to 6 months after initiating antiretroviral therapy. This clinical pattern is believed to be due to the reconstituted immune system and increased circulation of inflammatory cells.⁴ Peripheral eosinophilia and elevated serum IgE levels are found in 25% to 50% of patients with HIV-associated EF.^2,3  

Clinically, the differential diagnosis of intensely pruritic papules with excoriations should include scabies.³ Other diagnoses to consider include opportunistic infections and papular urticaria.⁵ Acne vulgaris and Demodex folliculitis also may present with lesions similar to HIV-associated EF; however, these lesions tend not to be as intensely pruritic.^1,5 

The etiology of HIV-associated EF is unknown.³ One proposed mechanism involves a hypersensitivity reaction to Pityrosporum or Demodex mite fragments, as evidenced by studies that found fragments of these microorganisms in biopsied lesions of HIV-associated EF.^3,6 In our patient's histopathology, it was noted that the afflicted hair follicle held a single Demodex mite (Figure, C). 

The histopathology is characterized by a perifollicular inflammatory infiltrate of eosinophils and CD8+ lymphocytes with areas of sebaceous lysis.^3,6 Spongiosis of the follicular epithelium is seen in early lesions of HIV-associated EF.⁶ 

The first-line treatment of HIV-associated EF includes antiretroviral therapy with topical steroids and antihistamines. Human immunodeficiency virus-associated EF improves as CD4 helper T-cell counts rise above 250 cells/mm³ with continued antiretroviral therapy, though it initially can cause a flare of the condition.⁴ High-potency steroids and antihistamines are added during this period to treat the severe pruritus.^1,7 In particular, daily cetirizine has been shown to be effective, which may be due to its ability to block eosinophil migration in addition to H1-receptor antagonist properties.^3,7 

Various alternative therapies have been described in case reports and case series; however, there have been no controlled studies comparing therapies. Phototherapy with UVB light 3 times weekly for 3 to 6 weeks has been effective and curative in recalcitrant cases.⁷ Other frequently used treatments include oral metronidazole, oral itraconazole, and permethrin cream 5%. The effectiveness of the latter 2 treatments is believed to be related to the proposed role of Pityrosporum and Demodex in the pathogenesis.³  

Acknowledgment
The authors thank Garth Fraga, MD (Kansas City, Kansas), for his help compiling the histopathological images and their diagnostic descriptions.  
 

The Diagnosis: Eosinophilic Folliculitis 

A  shave biopsy specimen of an intact pustule on the left side of the chest was obtained. Histopathologic examination revealed follicular inflammation with copious eosinophils (Figure, A and B). Based on the histopathology and clinical presentation, a diagnosis of human immunodeficiency virus (HIV)-associated eosinophilic folliculitis (EF) was made. 

The patient was started on triamcinolone ointment 0.1% twice daily to active lesions, oral cetirizine 10 mg in the morning, and oral hydroxyzine 25 mg at bedtime. Laboratory evaluation at the time of diagnosis showed eosinophilia with a peripheral blood eosinophil count of 0.5 K/μL (reference range, 0.03–0.48 K/μL).

Human immunodeficiency virus-associated EF is a pruritic follicular eruption that occurs in HIV-positive individuals with advanced disease. Clinically, it is characterized by intermittent, urticarial, red or flesh-colored, 2- to 5-mm papules with sparse pustules involving the head, neck, arms, and upper trunk.^1,2 The cardinal clinical feature of the disorder is intense pruritus, with overlying crusts and excoriations present on physical examination.³  

Patients usually have a CD4 count of less than 250 cells/mm³.^2,3 Patients with HIV can develop an exacerbation of EF in the first 3 to 6 months after initiating antiretroviral therapy. This clinical pattern is believed to be due to the reconstituted immune system and increased circulation of inflammatory cells.⁴ Peripheral eosinophilia and elevated serum IgE levels are found in 25% to 50% of patients with HIV-associated EF.^2,3  

Clinically, the differential diagnosis of intensely pruritic papules with excoriations should include scabies.³ Other diagnoses to consider include opportunistic infections and papular urticaria.⁵ Acne vulgaris and Demodex folliculitis also may present with lesions similar to HIV-associated EF; however, these lesions tend not to be as intensely pruritic.^1,5 

The etiology of HIV-associated EF is unknown.³ One proposed mechanism involves a hypersensitivity reaction to Pityrosporum or Demodex mite fragments, as evidenced by studies that found fragments of these microorganisms in biopsied lesions of HIV-associated EF.^3,6 In our patient's histopathology, it was noted that the afflicted hair follicle held a single Demodex mite (Figure, C). 

The histopathology is characterized by a perifollicular inflammatory infiltrate of eosinophils and CD8+ lymphocytes with areas of sebaceous lysis.^3,6 Spongiosis of the follicular epithelium is seen in early lesions of HIV-associated EF.⁶ 

The first-line treatment of HIV-associated EF includes antiretroviral therapy with topical steroids and antihistamines. Human immunodeficiency virus-associated EF improves as CD4 helper T-cell counts rise above 250 cells/mm³ with continued antiretroviral therapy, though it initially can cause a flare of the condition.⁴ High-potency steroids and antihistamines are added during this period to treat the severe pruritus.^1,7 In particular, daily cetirizine has been shown to be effective, which may be due to its ability to block eosinophil migration in addition to H1-receptor antagonist properties.^3,7 

Various alternative therapies have been described in case reports and case series; however, there have been no controlled studies comparing therapies. Phototherapy with UVB light 3 times weekly for 3 to 6 weeks has been effective and curative in recalcitrant cases.⁷ Other frequently used treatments include oral metronidazole, oral itraconazole, and permethrin cream 5%. The effectiveness of the latter 2 treatments is believed to be related to the proposed role of Pityrosporum and Demodex in the pathogenesis.³  

Acknowledgment
The authors thank Garth Fraga, MD (Kansas City, Kansas), for his help compiling the histopathological images and their diagnostic descriptions.  
 

The Diagnosis: Eosinophilic Folliculitis 

A  shave biopsy specimen of an intact pustule on the left side of the chest was obtained. Histopathologic examination revealed follicular inflammation with copious eosinophils (Figure, A and B). Based on the histopathology and clinical presentation, a diagnosis of human immunodeficiency virus (HIV)-associated eosinophilic folliculitis (EF) was made. 

The patient was started on triamcinolone ointment 0.1% twice daily to active lesions, oral cetirizine 10 mg in the morning, and oral hydroxyzine 25 mg at bedtime. Laboratory evaluation at the time of diagnosis showed eosinophilia with a peripheral blood eosinophil count of 0.5 K/μL (reference range, 0.03–0.48 K/μL).

Human immunodeficiency virus-associated EF is a pruritic follicular eruption that occurs in HIV-positive individuals with advanced disease. Clinically, it is characterized by intermittent, urticarial, red or flesh-colored, 2- to 5-mm papules with sparse pustules involving the head, neck, arms, and upper trunk.^1,2 The cardinal clinical feature of the disorder is intense pruritus, with overlying crusts and excoriations present on physical examination.³  

Patients usually have a CD4 count of less than 250 cells/mm³.^2,3 Patients with HIV can develop an exacerbation of EF in the first 3 to 6 months after initiating antiretroviral therapy. This clinical pattern is believed to be due to the reconstituted immune system and increased circulation of inflammatory cells.⁴ Peripheral eosinophilia and elevated serum IgE levels are found in 25% to 50% of patients with HIV-associated EF.^2,3  

Clinically, the differential diagnosis of intensely pruritic papules with excoriations should include scabies.³ Other diagnoses to consider include opportunistic infections and papular urticaria.⁵ Acne vulgaris and Demodex folliculitis also may present with lesions similar to HIV-associated EF; however, these lesions tend not to be as intensely pruritic.^1,5 

The etiology of HIV-associated EF is unknown.³ One proposed mechanism involves a hypersensitivity reaction to Pityrosporum or Demodex mite fragments, as evidenced by studies that found fragments of these microorganisms in biopsied lesions of HIV-associated EF.^3,6 In our patient's histopathology, it was noted that the afflicted hair follicle held a single Demodex mite (Figure, C). 

The histopathology is characterized by a perifollicular inflammatory infiltrate of eosinophils and CD8+ lymphocytes with areas of sebaceous lysis.^3,6 Spongiosis of the follicular epithelium is seen in early lesions of HIV-associated EF.⁶ 

The first-line treatment of HIV-associated EF includes antiretroviral therapy with topical steroids and antihistamines. Human immunodeficiency virus-associated EF improves as CD4 helper T-cell counts rise above 250 cells/mm³ with continued antiretroviral therapy, though it initially can cause a flare of the condition.⁴ High-potency steroids and antihistamines are added during this period to treat the severe pruritus.^1,7 In particular, daily cetirizine has been shown to be effective, which may be due to its ability to block eosinophil migration in addition to H1-receptor antagonist properties.^3,7 

Various alternative therapies have been described in case reports and case series; however, there have been no controlled studies comparing therapies. Phototherapy with UVB light 3 times weekly for 3 to 6 weeks has been effective and curative in recalcitrant cases.⁷ Other frequently used treatments include oral metronidazole, oral itraconazole, and permethrin cream 5%. The effectiveness of the latter 2 treatments is believed to be related to the proposed role of Pityrosporum and Demodex in the pathogenesis.³  

Acknowledgment
The authors thank Garth Fraga, MD (Kansas City, Kansas), for his help compiling the histopathological images and their diagnostic descriptions.  
 

The Diagnosis: Majocchi Granuloma 

Majocchi granuloma (MG) is a dermatophytic infection that reveals hyphal elements within the cornified cells of follicles and most commonly is caused by Trichophyton rubrum. However, occasionally other Trichophyton, Trichosporon, and Aspergillus species are involved.¹  

There typically are 2 forms of MG: (1) the small perifollicular papular form that usually is localized to the dermis and occurs in immunocompetent individuals, and (2) a deep form featuring subcutaneous plaques and nodules that generally occur on the hair-bearing surfaces in immunosuppressed hosts.² Majocchi granuloma also commonly occurs from the use of potent topical steroids on unsuspected tinea.³  

Histopathologically, MG generally presents as granulomatous inflammation with perifollicular neutrophilic infiltration. This polymorphonuclear cell infiltrate was visible clinically as a single pustule overlying the nodular plaque, a clue appreciable only on close inspection. Histopathologic examination revealed segmented branching filaments present within cornified elements of a follicle (Figure). Notably, potassium hydroxide (KOH) preparations are unreliable diagnostic aids in MG, as evidenced by the 2 negative KOH preparations in this case. According to Chou and Hsu,⁴ because KOH preparation can only detect fungi located in the stratum corneum, the result may be negative for MG due to deeper invasion of the fungi into the dermal follicular component. In fact, KOH preparations of MG may reveal no hyphae in 23.3% of cases.²  

The initiating factor in MG is not entirely known but is thought to be physical trauma that either directly or indirectly leads to follicle disruption and passive introduction of the organism into the dermis (eg, traumatic implantation via gardening or other recreational activities).² Other proposed mechanisms include the presentation of the membrane-associated ATP-binding cassette transporter on the surface of T rubrum.¹ Dermatophytes evade the host immune system through a variety of mechanisms: (1) cell wall glycoproteins, (2) release of anti-inflammatory cytokines, and (3) generation of immunosuppressive regulatory T cells.¹ 

Collectively, the clinical and histopathologic findings distinguish MG from other cutaneous conditions. Sporotrichosis, a granulomatous infection caused by Sporothrix schenckii, typically is found in tropical regions of the world and often is associated with floriculture.⁵ Sporotrichosis initially presents in a subcutaneous papulonodular form, but unlike MG, it later ulcerates and progresses along adjacent lymphatic chains.⁵ Pathology of sporotrichosis exhibits pseudoepitheliomatous hyperplasia with granulomas, possible foci of suppuration, and yeastlike forms called cigar bodies. Chromoblastomycosis clinically is defined by tumorlike lesions on the skin including verrucous, nodular, or scarlike plaques and typically is associated with traumatic injury and implantation of the microorganism. Histologically, chromoblastomycosis demonstrates pseudoepitheliomatous hyperplasia with granulomas and characteristic darkly pigmented, thick-walled sclerotic cells called Medlar bodies.⁶Mycobacterium marinum is one cause of nontuberculous mycobacterial skin infections in humans. Clinically, M marinum is associated with improper hygiene techniques and contact with fish tanks and other aqueous environments. Mycobacterium marinum can present histopathologically as early neutrophilic infiltration or late dermal granulomatous inflammation.⁷ Acid-fast bacilli typically are scant, leaving the diagnosis best secured via polymerase chain reaction assay. Nodular Kaposi sarcoma (KS) can present as a dusky nodular plaque on an acral surface but typically is seen in patients with underlying human immunodeficiency virus/AIDS or other immunosuppressive conditions. The pathology for KS shows a proliferation of human herpes virus 8-positive spindle cells with slitlike spaces containing red blood cells instead of granulomatous inflammation. 

Treatment regimens with topical corticosteroids can exacerbate the infection due to local suppression of cell-mediated immunity.⁸ In these scenarios, fungal infection is suspected, and systemic antifungals such as ketoconazole; itraconazole; or terbinafine, which has become the mainstay, are prescribed. Resolution of the infection with these medications usually is seen after 4 weeks.² 

A diagnosis of MG can be elusive and often may take multiple visits. Clinicians should note that MG could demonstrate repeated false-negative KOH preparations; therefore, these tests should not be relied on as the sole determination of a diagnosis. Although chromoblastomycosis, sporotrichosis, nodular KS, and infection with M marinum may all present as nodular plaques with granulomatous pathology, a follicular pustule may be a clinical clue to MG, as its mimics typically lack folliculocentric neutrophils.

The Diagnosis: Majocchi Granuloma 

Majocchi granuloma (MG) is a dermatophytic infection that reveals hyphal elements within the cornified cells of follicles and most commonly is caused by Trichophyton rubrum. However, occasionally other Trichophyton, Trichosporon, and Aspergillus species are involved.¹  

There typically are 2 forms of MG: (1) the small perifollicular papular form that usually is localized to the dermis and occurs in immunocompetent individuals, and (2) a deep form featuring subcutaneous plaques and nodules that generally occur on the hair-bearing surfaces in immunosuppressed hosts.² Majocchi granuloma also commonly occurs from the use of potent topical steroids on unsuspected tinea.³  

Histopathologically, MG generally presents as granulomatous inflammation with perifollicular neutrophilic infiltration. This polymorphonuclear cell infiltrate was visible clinically as a single pustule overlying the nodular plaque, a clue appreciable only on close inspection. Histopathologic examination revealed segmented branching filaments present within cornified elements of a follicle (Figure). Notably, potassium hydroxide (KOH) preparations are unreliable diagnostic aids in MG, as evidenced by the 2 negative KOH preparations in this case. According to Chou and Hsu,⁴ because KOH preparation can only detect fungi located in the stratum corneum, the result may be negative for MG due to deeper invasion of the fungi into the dermal follicular component. In fact, KOH preparations of MG may reveal no hyphae in 23.3% of cases.²  

The initiating factor in MG is not entirely known but is thought to be physical trauma that either directly or indirectly leads to follicle disruption and passive introduction of the organism into the dermis (eg, traumatic implantation via gardening or other recreational activities).² Other proposed mechanisms include the presentation of the membrane-associated ATP-binding cassette transporter on the surface of T rubrum.¹ Dermatophytes evade the host immune system through a variety of mechanisms: (1) cell wall glycoproteins, (2) release of anti-inflammatory cytokines, and (3) generation of immunosuppressive regulatory T cells.¹ 

Collectively, the clinical and histopathologic findings distinguish MG from other cutaneous conditions. Sporotrichosis, a granulomatous infection caused by Sporothrix schenckii, typically is found in tropical regions of the world and often is associated with floriculture.⁵ Sporotrichosis initially presents in a subcutaneous papulonodular form, but unlike MG, it later ulcerates and progresses along adjacent lymphatic chains.⁵ Pathology of sporotrichosis exhibits pseudoepitheliomatous hyperplasia with granulomas, possible foci of suppuration, and yeastlike forms called cigar bodies. Chromoblastomycosis clinically is defined by tumorlike lesions on the skin including verrucous, nodular, or scarlike plaques and typically is associated with traumatic injury and implantation of the microorganism. Histologically, chromoblastomycosis demonstrates pseudoepitheliomatous hyperplasia with granulomas and characteristic darkly pigmented, thick-walled sclerotic cells called Medlar bodies.⁶Mycobacterium marinum is one cause of nontuberculous mycobacterial skin infections in humans. Clinically, M marinum is associated with improper hygiene techniques and contact with fish tanks and other aqueous environments. Mycobacterium marinum can present histopathologically as early neutrophilic infiltration or late dermal granulomatous inflammation.⁷ Acid-fast bacilli typically are scant, leaving the diagnosis best secured via polymerase chain reaction assay. Nodular Kaposi sarcoma (KS) can present as a dusky nodular plaque on an acral surface but typically is seen in patients with underlying human immunodeficiency virus/AIDS or other immunosuppressive conditions. The pathology for KS shows a proliferation of human herpes virus 8-positive spindle cells with slitlike spaces containing red blood cells instead of granulomatous inflammation. 

Treatment regimens with topical corticosteroids can exacerbate the infection due to local suppression of cell-mediated immunity.⁸ In these scenarios, fungal infection is suspected, and systemic antifungals such as ketoconazole; itraconazole; or terbinafine, which has become the mainstay, are prescribed. Resolution of the infection with these medications usually is seen after 4 weeks.² 

A diagnosis of MG can be elusive and often may take multiple visits. Clinicians should note that MG could demonstrate repeated false-negative KOH preparations; therefore, these tests should not be relied on as the sole determination of a diagnosis. Although chromoblastomycosis, sporotrichosis, nodular KS, and infection with M marinum may all present as nodular plaques with granulomatous pathology, a follicular pustule may be a clinical clue to MG, as its mimics typically lack folliculocentric neutrophils.

The Diagnosis: Majocchi Granuloma 

Majocchi granuloma (MG) is a dermatophytic infection that reveals hyphal elements within the cornified cells of follicles and most commonly is caused by Trichophyton rubrum. However, occasionally other Trichophyton, Trichosporon, and Aspergillus species are involved.¹  

There typically are 2 forms of MG: (1) the small perifollicular papular form that usually is localized to the dermis and occurs in immunocompetent individuals, and (2) a deep form featuring subcutaneous plaques and nodules that generally occur on the hair-bearing surfaces in immunosuppressed hosts.² Majocchi granuloma also commonly occurs from the use of potent topical steroids on unsuspected tinea.³  

Histopathologically, MG generally presents as granulomatous inflammation with perifollicular neutrophilic infiltration. This polymorphonuclear cell infiltrate was visible clinically as a single pustule overlying the nodular plaque, a clue appreciable only on close inspection. Histopathologic examination revealed segmented branching filaments present within cornified elements of a follicle (Figure). Notably, potassium hydroxide (KOH) preparations are unreliable diagnostic aids in MG, as evidenced by the 2 negative KOH preparations in this case. According to Chou and Hsu,⁴ because KOH preparation can only detect fungi located in the stratum corneum, the result may be negative for MG due to deeper invasion of the fungi into the dermal follicular component. In fact, KOH preparations of MG may reveal no hyphae in 23.3% of cases.²  

The initiating factor in MG is not entirely known but is thought to be physical trauma that either directly or indirectly leads to follicle disruption and passive introduction of the organism into the dermis (eg, traumatic implantation via gardening or other recreational activities).² Other proposed mechanisms include the presentation of the membrane-associated ATP-binding cassette transporter on the surface of T rubrum.¹ Dermatophytes evade the host immune system through a variety of mechanisms: (1) cell wall glycoproteins, (2) release of anti-inflammatory cytokines, and (3) generation of immunosuppressive regulatory T cells.¹ 

Collectively, the clinical and histopathologic findings distinguish MG from other cutaneous conditions. Sporotrichosis, a granulomatous infection caused by Sporothrix schenckii, typically is found in tropical regions of the world and often is associated with floriculture.⁵ Sporotrichosis initially presents in a subcutaneous papulonodular form, but unlike MG, it later ulcerates and progresses along adjacent lymphatic chains.⁵ Pathology of sporotrichosis exhibits pseudoepitheliomatous hyperplasia with granulomas, possible foci of suppuration, and yeastlike forms called cigar bodies. Chromoblastomycosis clinically is defined by tumorlike lesions on the skin including verrucous, nodular, or scarlike plaques and typically is associated with traumatic injury and implantation of the microorganism. Histologically, chromoblastomycosis demonstrates pseudoepitheliomatous hyperplasia with granulomas and characteristic darkly pigmented, thick-walled sclerotic cells called Medlar bodies.⁶Mycobacterium marinum is one cause of nontuberculous mycobacterial skin infections in humans. Clinically, M marinum is associated with improper hygiene techniques and contact with fish tanks and other aqueous environments. Mycobacterium marinum can present histopathologically as early neutrophilic infiltration or late dermal granulomatous inflammation.⁷ Acid-fast bacilli typically are scant, leaving the diagnosis best secured via polymerase chain reaction assay. Nodular Kaposi sarcoma (KS) can present as a dusky nodular plaque on an acral surface but typically is seen in patients with underlying human immunodeficiency virus/AIDS or other immunosuppressive conditions. The pathology for KS shows a proliferation of human herpes virus 8-positive spindle cells with slitlike spaces containing red blood cells instead of granulomatous inflammation. 

Treatment regimens with topical corticosteroids can exacerbate the infection due to local suppression of cell-mediated immunity.⁸ In these scenarios, fungal infection is suspected, and systemic antifungals such as ketoconazole; itraconazole; or terbinafine, which has become the mainstay, are prescribed. Resolution of the infection with these medications usually is seen after 4 weeks.² 

A diagnosis of MG can be elusive and often may take multiple visits. Clinicians should note that MG could demonstrate repeated false-negative KOH preparations; therefore, these tests should not be relied on as the sole determination of a diagnosis. Although chromoblastomycosis, sporotrichosis, nodular KS, and infection with M marinum may all present as nodular plaques with granulomatous pathology, a follicular pustule may be a clinical clue to MG, as its mimics typically lack folliculocentric neutrophils.

It is well known by now that tumor formation is driven by accumulation of numerous genetic and epigenetic mutations. Human cells are equipped with an apparatus called the DNA mismatch repair (MMR) system that corrects errors during replication.¹ If these genes are themselves mutated, cells then start accumulating mutations in other genes, including oncogenes and tumor suppressor genes, which results in the development of sustained proliferative signaling pathways, evasion of growth suppression, resistance to cell death, and the potential for invasion and metastasis.²

Gene mutations in DNA MMR have been detected in several tumors, such as sebaceous tumors,³ colorectal adenocarcinomas,⁴ keratoacanthomas,⁵ and other visceral malignancies.⁶ Sebaceous tumors are rare in the general population; however, they are common in patients with inherited or acquired mutations in MMR genes.⁵ These patients also have been found to have other visceral malignancies such as colorectal adenocarcinomas and breast, lung, and central nervous system (CNS) tumors.⁷ This observation was made in the 1960s, and patients were referred to as having Muir-Torre syndrome (MTS).⁸ This article serves to briefly describe the DNA MMR system and its implication in sebaceous tumors as well as discuss the recent recommendations for screening for MTS in patients presenting with sebaceous tumors.

The DNA MMR System

Mismatch repair proteins are responsible for detecting and repairing errors during cell division, especially in microsatellite regions.⁹ Microsatellites are common and widely distributed DNA motifs consisting of repeated nucleotide sequences that normally account for 3% of the genome.¹⁰ Mutations in MMR result in insertion or deletion of nucleotides in these DNA motifs, making them either abnormally long or short, referred to as microsatellite instability (MSI), which results in downstream cumulative accumulation of mutations in oncogenes and tumor suppressor genes, and thus carcinogenesis.⁹

There are 7 human MMR proteins: MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, and PMS2. These proteins are highly conserved across different living species.¹¹ Loss of MMR proteins can be due to a mutation in the coding sequence of the gene or due to epigenetic hypermethylation of the gene promoter.¹² These alterations can be inherited or acquired and in most cases result in MSI.

When assessing for MSI, tumor genomes can be divided into 3 subtypes: high-level and low-level MSI and stable microsatellites.¹³ Tumors with high-level MSI respond better to treatment and show a better prognosis than those with low-level MSI or stable microsatellites,¹⁴ which is thought to be due to tumor-induced immune activation. Microsatellite instability results in the generation of frameshift peptides that are immunogenic and induce tumor-specific immune responses.¹⁵ Several research laboratories have artificially synthesized frameshift peptides as vaccines and have successfully used them as targets for immune therapy as a way for preventing and treating malignancies.¹⁶

Sebaceous Tumors in MTS

A typical example of tumors that arise from mutations in the DNA MMR system is seen in MTS,a rare inherited genetic syndrome that predisposes patients to sebaceous neoplasms, keratoacanthomas, and visceral malignancies.¹⁷ It was first described as an autosomal-dominant condition in patients who have at least 1 sebaceous tumor and 1 visceral malignancy, with or without keratoacanthomas. It was then later characterized as a skin variant of Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome.¹⁸

Sebaceous tumors are the hallmark of MTS. Although sebaceous hyperplasia is common in the general population, sebaceous tumors are rare outside the context of MTS. There are 3 types of sebaceous tumors with distinct pathologic features: adenoma, epithelioma, and carcinoma.¹⁹ Sebaceous adenomas and epitheliomas are benign growths; however, sebaceous carcinomas can be aggressive and have metastatic potential.²⁰ Because it is difficult to clinically distinguish carcinomas from the benign sebaceous growths, biopsy of a large, changing, or ulcerated lesion is important in these patients to rule out a sebaceous carcinoma. Other aggressive skin tumors can develop in MTS, such as rapidly growing keratoacanthomas and basal cell carcinomas with sebaceous differentiation.²¹

Types of MTS

For most cases, MTS is characterized by germline mutations in DNA MMR genes. The most common mutation involves MSH2 (MutS Homolog 2)—found in approximately 90% of patients—followed by MLH1 (MutL Homolog 1)—found in approximately 10% of patients.²² Other MMR genes such as MSH6 (MutS Homolog 6), PMS2 (PMS1 homolog 2, mismatch repair system component), and MLH3 (MutL Homolog 3) less commonly are reported in MTS. There is a subset of patients who lose MSH2 or MLH1 expression due to promoter hypermethylation rather than a germline mutation. Methylation results in biallelic inactivation of the gene and loss of expression.²³

A new subtype of MTS has been identified that demonstrates an autosomal-recessive pattern of inheritance and is referred to as MTS type 2 (autosomal-recessive colorectal adenomatous polyposis).²⁴ In contrast to the classic MTS type 1, MTS type 2 exhibits microsatellite stability. Recent molecular analyses revealed that type 2 is due to a mutation in a base excision repair gene called MUTYH (mutY DNA glycosylase).²⁵ These patients are likely to develop hundreds of polyps at an early age.

Muir-Torre syndrome also can occur sporadically without inheriting a germline mutation, which has been reported in a transplant patient from de novo somatic mutations or promoter hypermethylation.²⁶ A case report of a renal transplant patient showed that switching from tacrolimus to sirolimus halted the appearance of new sebaceous neoplasms, which suggests that patients with MTS who undergo organ transplantation should potentially avoid tacrolimus and be put on sirolimus instead.²⁷

Visceral Malignancies in MTS

Apart from frequent skin examinations, MTS patients should have frequent and rigorous visceral malignancy screening. Patients most commonly develop colorectal adenocarcinoma, especially in the proximal parts of the colon.²⁸ In addition, they can develop numerous premalignant tumors, especially in MTS type 2. Other common tumors include endometrial, ovarian, genitourinary, hepatobiliary, breast, lung, hematopoietic, and CNS malignancies.²⁹

Studies showed that specific loss of certain MMR proteins predispose patients to different types of visceral malignancies.^30-32 For example, loss of MSH2 predisposes patients to development of extracolonic tumors, while loss of MLH1 more strongly is associated with development of colorectal adenocarcinoma.³⁰ Patients with MSH2 also are at risk for development of CNS tumors, while patients with MLH1 mutations have never been reported to develop CNS tumors.³¹ Patients with loss of PMS2 have the lowest risk for development of any visceral malignancy.³²

Diagnosing MTS

Let us consider a scenario whereby a dermatologist biopsied a solitary lesion and it came back as a sebaceous tumor. What would be the next step to establish a diagnosis of MTS?

Sebaceous tumors are rare outside the context of MTS. Therefore, patients presenting with a solitary sebaceous tumor should be worked up for MTS, as there are implications for further cancer screening. One helpful clue that can affect the pretest probability for MTS diagnosis is location of the tumor. A sebaceous tumor inferior to the neck most likely is associated with MTS. On the other hand, tumors on the head and neck can be spontaneous or associated with MTS.³³ Another helpful tool is the Mayo score, a risk score for MTS in patients with sebaceous tumors.³⁴ The score is established by adding up points, with 1 point given to each of the following: age of onset of a sebaceous tumor less than 60 years, personal history of visceral malignancy, and family history of Lynch syndrome–related visceral malignancy. Two points are given if the patient has 2 or more sebaceous tumors. The score ranges from 0 to 5. A risk score of 2 or more has a sensitivity of 100% and specificity of 81% for predicting a germline mutation in MMR genes.³⁴

These criteria are helpful to determine which patients likely have MTS; however, the ultimate diagnostic test is to look for loss of MMR genes and presence of MSI. It is important to keep in mind that if a patient has a high Mayo risk score, it is suggestive of MTS and molecular testing would be confirmatory rather than diagnostic. However, if the patient has a low Mayo risk score, then it is important to pursue further testing, as it will be crucial for diagnosis or ruling out of MTS.

Testing for loss of MMR proteins is performed using immunohistochemistry (IHC) as well as microsatellite gene analysis on the biopsied tumor. There is no need to perform another biopsy, as these tests can be performed on the paraffin-embedded formalin fixed tissue. Immunohistochemistry testing looks for loss of expression of one of the MMR proteins. Staining usually is performed for MSH2, MSH6, and MLH1, as the combination offers a sensitivity of 81% and a positive predictive value of 100%.^23,35,36

If IHC shows loss of MMR proteins, then MSI gene analysis should be performed as a confirmatory test by using MSI gene locus assays, which utilize 5 markers of mononucleotide and dinucleotide repeats. If the genome is positive for 2 of 5 of these markers, then the patient most likely has MTS.¹³

One caveat for IHC analysis is that there is a subset of patients who develop a solitary sebaceous tumor due to a sporadic loss of MMR protein without having MTS. These tumors also exhibit BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations or loss of p16, features that distinguish these tumors from those developed in MTS.³⁷ As such, in a patient with a low Mayo score who developed a solitary sebaceous tumor that showed loss of MMR protein on IHC without evidence of MSI, it is reasonable to perform IHC for BRAF and p16 to avoid inaccurate diagnosis of MTS.

Another caveat is that standard MSI analysis will not detect MSI in tumors with loss of MSH6 because the markers used in the MSI analysis do not detect MSI caused by MSH6 loss. For these patients, MSI analysis using a panel composed of mononucleotides alone (pentaplex assay) should be performed in lieu of the standard panel.³⁸

It is important to note that these molecular tests are not helpful for patients with MTS type 2, as the sebaceous tumors maintain MMR proteins and have microsatellite stability. As such, if MTS is highly suspected based on the Mayo score (either personal history of malignancy or strong family history) but the IHC and MSI analysis are negative, then referral to a geneticist for identification for MUTYH gene mutation is a reasonable next step. These patients with high Mayo scores should still be managed as MTS patients and should be screened for visceral malignancies despite lack of confirmatory tests.

Final Thoughts

Dermatologists should be highly suspicious of MTS when they diagnose sebaceous tumors. Making a diagnosis of MTS notably affects patients’ primary care. Patients with MTS should have annual skin examinations, neurologic examinations, colonoscopies starting at the age of 18 years, and surveillance for breast and pelvic cancers in women (by annual transvaginal ultrasound and endometrial aspirations) or for prostate and testicular cancers in men.^17,39,40 Other tests to be ordered annually include complete blood cell count with differential and urinalysis.¹⁹

It is well known by now that tumor formation is driven by accumulation of numerous genetic and epigenetic mutations. Human cells are equipped with an apparatus called the DNA mismatch repair (MMR) system that corrects errors during replication.¹ If these genes are themselves mutated, cells then start accumulating mutations in other genes, including oncogenes and tumor suppressor genes, which results in the development of sustained proliferative signaling pathways, evasion of growth suppression, resistance to cell death, and the potential for invasion and metastasis.²

Gene mutations in DNA MMR have been detected in several tumors, such as sebaceous tumors,³ colorectal adenocarcinomas,⁴ keratoacanthomas,⁵ and other visceral malignancies.⁶ Sebaceous tumors are rare in the general population; however, they are common in patients with inherited or acquired mutations in MMR genes.⁵ These patients also have been found to have other visceral malignancies such as colorectal adenocarcinomas and breast, lung, and central nervous system (CNS) tumors.⁷ This observation was made in the 1960s, and patients were referred to as having Muir-Torre syndrome (MTS).⁸ This article serves to briefly describe the DNA MMR system and its implication in sebaceous tumors as well as discuss the recent recommendations for screening for MTS in patients presenting with sebaceous tumors.

The DNA MMR System

Mismatch repair proteins are responsible for detecting and repairing errors during cell division, especially in microsatellite regions.⁹ Microsatellites are common and widely distributed DNA motifs consisting of repeated nucleotide sequences that normally account for 3% of the genome.¹⁰ Mutations in MMR result in insertion or deletion of nucleotides in these DNA motifs, making them either abnormally long or short, referred to as microsatellite instability (MSI), which results in downstream cumulative accumulation of mutations in oncogenes and tumor suppressor genes, and thus carcinogenesis.⁹

There are 7 human MMR proteins: MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, and PMS2. These proteins are highly conserved across different living species.¹¹ Loss of MMR proteins can be due to a mutation in the coding sequence of the gene or due to epigenetic hypermethylation of the gene promoter.¹² These alterations can be inherited or acquired and in most cases result in MSI.

When assessing for MSI, tumor genomes can be divided into 3 subtypes: high-level and low-level MSI and stable microsatellites.¹³ Tumors with high-level MSI respond better to treatment and show a better prognosis than those with low-level MSI or stable microsatellites,¹⁴ which is thought to be due to tumor-induced immune activation. Microsatellite instability results in the generation of frameshift peptides that are immunogenic and induce tumor-specific immune responses.¹⁵ Several research laboratories have artificially synthesized frameshift peptides as vaccines and have successfully used them as targets for immune therapy as a way for preventing and treating malignancies.¹⁶

Sebaceous Tumors in MTS

A typical example of tumors that arise from mutations in the DNA MMR system is seen in MTS,a rare inherited genetic syndrome that predisposes patients to sebaceous neoplasms, keratoacanthomas, and visceral malignancies.¹⁷ It was first described as an autosomal-dominant condition in patients who have at least 1 sebaceous tumor and 1 visceral malignancy, with or without keratoacanthomas. It was then later characterized as a skin variant of Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome.¹⁸

Sebaceous tumors are the hallmark of MTS. Although sebaceous hyperplasia is common in the general population, sebaceous tumors are rare outside the context of MTS. There are 3 types of sebaceous tumors with distinct pathologic features: adenoma, epithelioma, and carcinoma.¹⁹ Sebaceous adenomas and epitheliomas are benign growths; however, sebaceous carcinomas can be aggressive and have metastatic potential.²⁰ Because it is difficult to clinically distinguish carcinomas from the benign sebaceous growths, biopsy of a large, changing, or ulcerated lesion is important in these patients to rule out a sebaceous carcinoma. Other aggressive skin tumors can develop in MTS, such as rapidly growing keratoacanthomas and basal cell carcinomas with sebaceous differentiation.²¹

Types of MTS

For most cases, MTS is characterized by germline mutations in DNA MMR genes. The most common mutation involves MSH2 (MutS Homolog 2)—found in approximately 90% of patients—followed by MLH1 (MutL Homolog 1)—found in approximately 10% of patients.²² Other MMR genes such as MSH6 (MutS Homolog 6), PMS2 (PMS1 homolog 2, mismatch repair system component), and MLH3 (MutL Homolog 3) less commonly are reported in MTS. There is a subset of patients who lose MSH2 or MLH1 expression due to promoter hypermethylation rather than a germline mutation. Methylation results in biallelic inactivation of the gene and loss of expression.²³

A new subtype of MTS has been identified that demonstrates an autosomal-recessive pattern of inheritance and is referred to as MTS type 2 (autosomal-recessive colorectal adenomatous polyposis).²⁴ In contrast to the classic MTS type 1, MTS type 2 exhibits microsatellite stability. Recent molecular analyses revealed that type 2 is due to a mutation in a base excision repair gene called MUTYH (mutY DNA glycosylase).²⁵ These patients are likely to develop hundreds of polyps at an early age.

Muir-Torre syndrome also can occur sporadically without inheriting a germline mutation, which has been reported in a transplant patient from de novo somatic mutations or promoter hypermethylation.²⁶ A case report of a renal transplant patient showed that switching from tacrolimus to sirolimus halted the appearance of new sebaceous neoplasms, which suggests that patients with MTS who undergo organ transplantation should potentially avoid tacrolimus and be put on sirolimus instead.²⁷

Visceral Malignancies in MTS

Apart from frequent skin examinations, MTS patients should have frequent and rigorous visceral malignancy screening. Patients most commonly develop colorectal adenocarcinoma, especially in the proximal parts of the colon.²⁸ In addition, they can develop numerous premalignant tumors, especially in MTS type 2. Other common tumors include endometrial, ovarian, genitourinary, hepatobiliary, breast, lung, hematopoietic, and CNS malignancies.²⁹

Studies showed that specific loss of certain MMR proteins predispose patients to different types of visceral malignancies.^30-32 For example, loss of MSH2 predisposes patients to development of extracolonic tumors, while loss of MLH1 more strongly is associated with development of colorectal adenocarcinoma.³⁰ Patients with MSH2 also are at risk for development of CNS tumors, while patients with MLH1 mutations have never been reported to develop CNS tumors.³¹ Patients with loss of PMS2 have the lowest risk for development of any visceral malignancy.³²

Diagnosing MTS

Let us consider a scenario whereby a dermatologist biopsied a solitary lesion and it came back as a sebaceous tumor. What would be the next step to establish a diagnosis of MTS?

Sebaceous tumors are rare outside the context of MTS. Therefore, patients presenting with a solitary sebaceous tumor should be worked up for MTS, as there are implications for further cancer screening. One helpful clue that can affect the pretest probability for MTS diagnosis is location of the tumor. A sebaceous tumor inferior to the neck most likely is associated with MTS. On the other hand, tumors on the head and neck can be spontaneous or associated with MTS.³³ Another helpful tool is the Mayo score, a risk score for MTS in patients with sebaceous tumors.³⁴ The score is established by adding up points, with 1 point given to each of the following: age of onset of a sebaceous tumor less than 60 years, personal history of visceral malignancy, and family history of Lynch syndrome–related visceral malignancy. Two points are given if the patient has 2 or more sebaceous tumors. The score ranges from 0 to 5. A risk score of 2 or more has a sensitivity of 100% and specificity of 81% for predicting a germline mutation in MMR genes.³⁴

These criteria are helpful to determine which patients likely have MTS; however, the ultimate diagnostic test is to look for loss of MMR genes and presence of MSI. It is important to keep in mind that if a patient has a high Mayo risk score, it is suggestive of MTS and molecular testing would be confirmatory rather than diagnostic. However, if the patient has a low Mayo risk score, then it is important to pursue further testing, as it will be crucial for diagnosis or ruling out of MTS.

Testing for loss of MMR proteins is performed using immunohistochemistry (IHC) as well as microsatellite gene analysis on the biopsied tumor. There is no need to perform another biopsy, as these tests can be performed on the paraffin-embedded formalin fixed tissue. Immunohistochemistry testing looks for loss of expression of one of the MMR proteins. Staining usually is performed for MSH2, MSH6, and MLH1, as the combination offers a sensitivity of 81% and a positive predictive value of 100%.^23,35,36

If IHC shows loss of MMR proteins, then MSI gene analysis should be performed as a confirmatory test by using MSI gene locus assays, which utilize 5 markers of mononucleotide and dinucleotide repeats. If the genome is positive for 2 of 5 of these markers, then the patient most likely has MTS.¹³

One caveat for IHC analysis is that there is a subset of patients who develop a solitary sebaceous tumor due to a sporadic loss of MMR protein without having MTS. These tumors also exhibit BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations or loss of p16, features that distinguish these tumors from those developed in MTS.³⁷ As such, in a patient with a low Mayo score who developed a solitary sebaceous tumor that showed loss of MMR protein on IHC without evidence of MSI, it is reasonable to perform IHC for BRAF and p16 to avoid inaccurate diagnosis of MTS.

Another caveat is that standard MSI analysis will not detect MSI in tumors with loss of MSH6 because the markers used in the MSI analysis do not detect MSI caused by MSH6 loss. For these patients, MSI analysis using a panel composed of mononucleotides alone (pentaplex assay) should be performed in lieu of the standard panel.³⁸

It is important to note that these molecular tests are not helpful for patients with MTS type 2, as the sebaceous tumors maintain MMR proteins and have microsatellite stability. As such, if MTS is highly suspected based on the Mayo score (either personal history of malignancy or strong family history) but the IHC and MSI analysis are negative, then referral to a geneticist for identification for MUTYH gene mutation is a reasonable next step. These patients with high Mayo scores should still be managed as MTS patients and should be screened for visceral malignancies despite lack of confirmatory tests.

Final Thoughts

Dermatologists should be highly suspicious of MTS when they diagnose sebaceous tumors. Making a diagnosis of MTS notably affects patients’ primary care. Patients with MTS should have annual skin examinations, neurologic examinations, colonoscopies starting at the age of 18 years, and surveillance for breast and pelvic cancers in women (by annual transvaginal ultrasound and endometrial aspirations) or for prostate and testicular cancers in men.^17,39,40 Other tests to be ordered annually include complete blood cell count with differential and urinalysis.¹⁹

It is well known by now that tumor formation is driven by accumulation of numerous genetic and epigenetic mutations. Human cells are equipped with an apparatus called the DNA mismatch repair (MMR) system that corrects errors during replication.¹ If these genes are themselves mutated, cells then start accumulating mutations in other genes, including oncogenes and tumor suppressor genes, which results in the development of sustained proliferative signaling pathways, evasion of growth suppression, resistance to cell death, and the potential for invasion and metastasis.²

Gene mutations in DNA MMR have been detected in several tumors, such as sebaceous tumors,³ colorectal adenocarcinomas,⁴ keratoacanthomas,⁵ and other visceral malignancies.⁶ Sebaceous tumors are rare in the general population; however, they are common in patients with inherited or acquired mutations in MMR genes.⁵ These patients also have been found to have other visceral malignancies such as colorectal adenocarcinomas and breast, lung, and central nervous system (CNS) tumors.⁷ This observation was made in the 1960s, and patients were referred to as having Muir-Torre syndrome (MTS).⁸ This article serves to briefly describe the DNA MMR system and its implication in sebaceous tumors as well as discuss the recent recommendations for screening for MTS in patients presenting with sebaceous tumors.

The DNA MMR System

Mismatch repair proteins are responsible for detecting and repairing errors during cell division, especially in microsatellite regions.⁹ Microsatellites are common and widely distributed DNA motifs consisting of repeated nucleotide sequences that normally account for 3% of the genome.¹⁰ Mutations in MMR result in insertion or deletion of nucleotides in these DNA motifs, making them either abnormally long or short, referred to as microsatellite instability (MSI), which results in downstream cumulative accumulation of mutations in oncogenes and tumor suppressor genes, and thus carcinogenesis.⁹

There are 7 human MMR proteins: MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, and PMS2. These proteins are highly conserved across different living species.¹¹ Loss of MMR proteins can be due to a mutation in the coding sequence of the gene or due to epigenetic hypermethylation of the gene promoter.¹² These alterations can be inherited or acquired and in most cases result in MSI.

When assessing for MSI, tumor genomes can be divided into 3 subtypes: high-level and low-level MSI and stable microsatellites.¹³ Tumors with high-level MSI respond better to treatment and show a better prognosis than those with low-level MSI or stable microsatellites,¹⁴ which is thought to be due to tumor-induced immune activation. Microsatellite instability results in the generation of frameshift peptides that are immunogenic and induce tumor-specific immune responses.¹⁵ Several research laboratories have artificially synthesized frameshift peptides as vaccines and have successfully used them as targets for immune therapy as a way for preventing and treating malignancies.¹⁶

Sebaceous Tumors in MTS

A typical example of tumors that arise from mutations in the DNA MMR system is seen in MTS,a rare inherited genetic syndrome that predisposes patients to sebaceous neoplasms, keratoacanthomas, and visceral malignancies.¹⁷ It was first described as an autosomal-dominant condition in patients who have at least 1 sebaceous tumor and 1 visceral malignancy, with or without keratoacanthomas. It was then later characterized as a skin variant of Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer syndrome.¹⁸

Sebaceous tumors are the hallmark of MTS. Although sebaceous hyperplasia is common in the general population, sebaceous tumors are rare outside the context of MTS. There are 3 types of sebaceous tumors with distinct pathologic features: adenoma, epithelioma, and carcinoma.¹⁹ Sebaceous adenomas and epitheliomas are benign growths; however, sebaceous carcinomas can be aggressive and have metastatic potential.²⁰ Because it is difficult to clinically distinguish carcinomas from the benign sebaceous growths, biopsy of a large, changing, or ulcerated lesion is important in these patients to rule out a sebaceous carcinoma. Other aggressive skin tumors can develop in MTS, such as rapidly growing keratoacanthomas and basal cell carcinomas with sebaceous differentiation.²¹

Types of MTS

For most cases, MTS is characterized by germline mutations in DNA MMR genes. The most common mutation involves MSH2 (MutS Homolog 2)—found in approximately 90% of patients—followed by MLH1 (MutL Homolog 1)—found in approximately 10% of patients.²² Other MMR genes such as MSH6 (MutS Homolog 6), PMS2 (PMS1 homolog 2, mismatch repair system component), and MLH3 (MutL Homolog 3) less commonly are reported in MTS. There is a subset of patients who lose MSH2 or MLH1 expression due to promoter hypermethylation rather than a germline mutation. Methylation results in biallelic inactivation of the gene and loss of expression.²³

A new subtype of MTS has been identified that demonstrates an autosomal-recessive pattern of inheritance and is referred to as MTS type 2 (autosomal-recessive colorectal adenomatous polyposis).²⁴ In contrast to the classic MTS type 1, MTS type 2 exhibits microsatellite stability. Recent molecular analyses revealed that type 2 is due to a mutation in a base excision repair gene called MUTYH (mutY DNA glycosylase).²⁵ These patients are likely to develop hundreds of polyps at an early age.

Muir-Torre syndrome also can occur sporadically without inheriting a germline mutation, which has been reported in a transplant patient from de novo somatic mutations or promoter hypermethylation.²⁶ A case report of a renal transplant patient showed that switching from tacrolimus to sirolimus halted the appearance of new sebaceous neoplasms, which suggests that patients with MTS who undergo organ transplantation should potentially avoid tacrolimus and be put on sirolimus instead.²⁷

Visceral Malignancies in MTS

Apart from frequent skin examinations, MTS patients should have frequent and rigorous visceral malignancy screening. Patients most commonly develop colorectal adenocarcinoma, especially in the proximal parts of the colon.²⁸ In addition, they can develop numerous premalignant tumors, especially in MTS type 2. Other common tumors include endometrial, ovarian, genitourinary, hepatobiliary, breast, lung, hematopoietic, and CNS malignancies.²⁹

Studies showed that specific loss of certain MMR proteins predispose patients to different types of visceral malignancies.^30-32 For example, loss of MSH2 predisposes patients to development of extracolonic tumors, while loss of MLH1 more strongly is associated with development of colorectal adenocarcinoma.³⁰ Patients with MSH2 also are at risk for development of CNS tumors, while patients with MLH1 mutations have never been reported to develop CNS tumors.³¹ Patients with loss of PMS2 have the lowest risk for development of any visceral malignancy.³²

Diagnosing MTS

Let us consider a scenario whereby a dermatologist biopsied a solitary lesion and it came back as a sebaceous tumor. What would be the next step to establish a diagnosis of MTS?

Sebaceous tumors are rare outside the context of MTS. Therefore, patients presenting with a solitary sebaceous tumor should be worked up for MTS, as there are implications for further cancer screening. One helpful clue that can affect the pretest probability for MTS diagnosis is location of the tumor. A sebaceous tumor inferior to the neck most likely is associated with MTS. On the other hand, tumors on the head and neck can be spontaneous or associated with MTS.³³ Another helpful tool is the Mayo score, a risk score for MTS in patients with sebaceous tumors.³⁴ The score is established by adding up points, with 1 point given to each of the following: age of onset of a sebaceous tumor less than 60 years, personal history of visceral malignancy, and family history of Lynch syndrome–related visceral malignancy. Two points are given if the patient has 2 or more sebaceous tumors. The score ranges from 0 to 5. A risk score of 2 or more has a sensitivity of 100% and specificity of 81% for predicting a germline mutation in MMR genes.³⁴

These criteria are helpful to determine which patients likely have MTS; however, the ultimate diagnostic test is to look for loss of MMR genes and presence of MSI. It is important to keep in mind that if a patient has a high Mayo risk score, it is suggestive of MTS and molecular testing would be confirmatory rather than diagnostic. However, if the patient has a low Mayo risk score, then it is important to pursue further testing, as it will be crucial for diagnosis or ruling out of MTS.

Testing for loss of MMR proteins is performed using immunohistochemistry (IHC) as well as microsatellite gene analysis on the biopsied tumor. There is no need to perform another biopsy, as these tests can be performed on the paraffin-embedded formalin fixed tissue. Immunohistochemistry testing looks for loss of expression of one of the MMR proteins. Staining usually is performed for MSH2, MSH6, and MLH1, as the combination offers a sensitivity of 81% and a positive predictive value of 100%.^23,35,36

If IHC shows loss of MMR proteins, then MSI gene analysis should be performed as a confirmatory test by using MSI gene locus assays, which utilize 5 markers of mononucleotide and dinucleotide repeats. If the genome is positive for 2 of 5 of these markers, then the patient most likely has MTS.¹³

One caveat for IHC analysis is that there is a subset of patients who develop a solitary sebaceous tumor due to a sporadic loss of MMR protein without having MTS. These tumors also exhibit BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations or loss of p16, features that distinguish these tumors from those developed in MTS.³⁷ As such, in a patient with a low Mayo score who developed a solitary sebaceous tumor that showed loss of MMR protein on IHC without evidence of MSI, it is reasonable to perform IHC for BRAF and p16 to avoid inaccurate diagnosis of MTS.

Another caveat is that standard MSI analysis will not detect MSI in tumors with loss of MSH6 because the markers used in the MSI analysis do not detect MSI caused by MSH6 loss. For these patients, MSI analysis using a panel composed of mononucleotides alone (pentaplex assay) should be performed in lieu of the standard panel.³⁸

It is important to note that these molecular tests are not helpful for patients with MTS type 2, as the sebaceous tumors maintain MMR proteins and have microsatellite stability. As such, if MTS is highly suspected based on the Mayo score (either personal history of malignancy or strong family history) but the IHC and MSI analysis are negative, then referral to a geneticist for identification for MUTYH gene mutation is a reasonable next step. These patients with high Mayo scores should still be managed as MTS patients and should be screened for visceral malignancies despite lack of confirmatory tests.

Final Thoughts

Dermatologists should be highly suspicious of MTS when they diagnose sebaceous tumors. Making a diagnosis of MTS notably affects patients’ primary care. Patients with MTS should have annual skin examinations, neurologic examinations, colonoscopies starting at the age of 18 years, and surveillance for breast and pelvic cancers in women (by annual transvaginal ultrasound and endometrial aspirations) or for prostate and testicular cancers in men.^17,39,40 Other tests to be ordered annually include complete blood cell count with differential and urinalysis.¹⁹

To the Editor:

A 3-year-old boy with a history of tuberous sclerosis presented to our clinic for evaluation of bumps on the second and third fingers of the left hand. Physical examination revealed firm rubbery nodules on the palmar third metacarpophalangeal joint extending to the palm and the lateral aspect of the distal third dorsal finger. There also was asymmetric overgrowth of the left second and third digits consistent with bony segmental overgrowth (Figure).

Tuberous sclerosis and overgrowth syndromes including Proteus syndrome have mutations that share a common pathway, namely the PI3K/AKT/mTOR (phosphoinositide 3-kinase/alpha serine/threonine-protein kinase/mammalian target of rapamycin) pathway.¹ The mutations in tuberous sclerosis involve the loss of TSC1 (TSC complex subunit 1) on chromosome 9 or TSC2 (TSC complex subunit 2) on chromosome 16.² The protein products of these genes, hamartin and tuberin, act together as a tumor suppressor complex.³ The inheritance pattern of tuberous sclerosis is autosomal dominant, though two-thirds of cases are due to de novo germline mutations.⁴ The second copy of the gene must be lost spontaneously in any particular cell for the deleterious effects of the disease to manifest. The mutation in overgrowth syndromes including Proteus syndrome involves the activation of AKT1 (AKT serine/threonine kinase 1) on chromosome 14. This mutation occurs in somatic cells as opposed to germ cells, as in tuberous sclerosis. This difference accounts for the mosaic expression of segmental overgrowth syndromes. This concept has been demonstrated in overgrowth syndromes such as Proteus syndrome, with cells from unaffected areas having different genetic makeup than those from affected tissues.⁵ These mutations, though different, result in the downstream effects of unchecked messenger RNA translation and dysregulated cellular growth.

In our patient, we hypothesized that a small proportion of his postfertilization somatic cells underwent a second de novo mutation in the AKT1 pathway, resulting in the bony overgrowth seen on the left hand. We suspected that this second mutation could be an activation of AKT1, the mutation seen in Proteus syndrome. Sequencing of the tissue may be performed in the future, especially if segmental overgrowth continues and necessitates therapy.

To the Editor:

A 3-year-old boy with a history of tuberous sclerosis presented to our clinic for evaluation of bumps on the second and third fingers of the left hand. Physical examination revealed firm rubbery nodules on the palmar third metacarpophalangeal joint extending to the palm and the lateral aspect of the distal third dorsal finger. There also was asymmetric overgrowth of the left second and third digits consistent with bony segmental overgrowth (Figure).

Tuberous sclerosis and overgrowth syndromes including Proteus syndrome have mutations that share a common pathway, namely the PI3K/AKT/mTOR (phosphoinositide 3-kinase/alpha serine/threonine-protein kinase/mammalian target of rapamycin) pathway.¹ The mutations in tuberous sclerosis involve the loss of TSC1 (TSC complex subunit 1) on chromosome 9 or TSC2 (TSC complex subunit 2) on chromosome 16.² The protein products of these genes, hamartin and tuberin, act together as a tumor suppressor complex.³ The inheritance pattern of tuberous sclerosis is autosomal dominant, though two-thirds of cases are due to de novo germline mutations.⁴ The second copy of the gene must be lost spontaneously in any particular cell for the deleterious effects of the disease to manifest. The mutation in overgrowth syndromes including Proteus syndrome involves the activation of AKT1 (AKT serine/threonine kinase 1) on chromosome 14. This mutation occurs in somatic cells as opposed to germ cells, as in tuberous sclerosis. This difference accounts for the mosaic expression of segmental overgrowth syndromes. This concept has been demonstrated in overgrowth syndromes such as Proteus syndrome, with cells from unaffected areas having different genetic makeup than those from affected tissues.⁵ These mutations, though different, result in the downstream effects of unchecked messenger RNA translation and dysregulated cellular growth.

In our patient, we hypothesized that a small proportion of his postfertilization somatic cells underwent a second de novo mutation in the AKT1 pathway, resulting in the bony overgrowth seen on the left hand. We suspected that this second mutation could be an activation of AKT1, the mutation seen in Proteus syndrome. Sequencing of the tissue may be performed in the future, especially if segmental overgrowth continues and necessitates therapy.

To the Editor:

A 3-year-old boy with a history of tuberous sclerosis presented to our clinic for evaluation of bumps on the second and third fingers of the left hand. Physical examination revealed firm rubbery nodules on the palmar third metacarpophalangeal joint extending to the palm and the lateral aspect of the distal third dorsal finger. There also was asymmetric overgrowth of the left second and third digits consistent with bony segmental overgrowth (Figure).

Tuberous sclerosis and overgrowth syndromes including Proteus syndrome have mutations that share a common pathway, namely the PI3K/AKT/mTOR (phosphoinositide 3-kinase/alpha serine/threonine-protein kinase/mammalian target of rapamycin) pathway.¹ The mutations in tuberous sclerosis involve the loss of TSC1 (TSC complex subunit 1) on chromosome 9 or TSC2 (TSC complex subunit 2) on chromosome 16.² The protein products of these genes, hamartin and tuberin, act together as a tumor suppressor complex.³ The inheritance pattern of tuberous sclerosis is autosomal dominant, though two-thirds of cases are due to de novo germline mutations.⁴ The second copy of the gene must be lost spontaneously in any particular cell for the deleterious effects of the disease to manifest. The mutation in overgrowth syndromes including Proteus syndrome involves the activation of AKT1 (AKT serine/threonine kinase 1) on chromosome 14. This mutation occurs in somatic cells as opposed to germ cells, as in tuberous sclerosis. This difference accounts for the mosaic expression of segmental overgrowth syndromes. This concept has been demonstrated in overgrowth syndromes such as Proteus syndrome, with cells from unaffected areas having different genetic makeup than those from affected tissues.⁵ These mutations, though different, result in the downstream effects of unchecked messenger RNA translation and dysregulated cellular growth.

In our patient, we hypothesized that a small proportion of his postfertilization somatic cells underwent a second de novo mutation in the AKT1 pathway, resulting in the bony overgrowth seen on the left hand. We suspected that this second mutation could be an activation of AKT1, the mutation seen in Proteus syndrome. Sequencing of the tissue may be performed in the future, especially if segmental overgrowth continues and necessitates therapy.

The Diagnosis: Papuloerythroderma of Ofuji 

The patient presented with a characteristic finding of skinfold sparing, known as the "deck-chair sign" (Figure 1).¹ A repeat biopsy at our institution revealed a dermal perivascular and bandlike infiltrate with lymphocytes and occasional eosinophils (Figure 2). The epidermis showed mild spongiosis, lymphocytic exocytosis, and rare necrotic keratinocytes. A T-cell gene rearrangement assay was negative for a monoclonal population of T lymphocytes. Based on the clinical and histologic features, the diagnosis was most consistent with papuloerythroderma of Ofuji (PEO); however, a lymphoproliferative disorder needed to be excluded. Further workup included a peripheral smear, complete blood cell count with differential, comprehensive metabolic panel, IgE level, and hepatitis panel; all were normal, except for an elevated serum IgE level. Human immunodeficiency virus and age-appropriate malignancy screening were negative. The patient was prescribed betamethasone dipropionate cream 0.05% twice daily, which resulted in near-complete resolution of the rash and marked improvement in pruritus.

In 1984, PEO was described as an entity of generalized pruritic erythroderma characterized by flat-topped, red to brown, coalescing papules with sparing of the skinfolds, later coined the deck-chair sign.^1,2 Papuloerythroderma of Ofuji commonly presents in elderly Asian males with a male to female ratio of 4:1.³ Papuloerythroderma of Ofuji is a T cell-mediated skin disease; however, the etiology of the signature rash remains unclear. One explanation includes circulating factors in the skin that elicit an inflammatory response, which does not occur in areas of external pressure.³ The deck-chair sign may occur more frequently in elderly individuals due to increased skin laxity, which creates crease lines that are spared from rubbing and excoriations.⁴  

Although Ofuji et al² initially reported 4 idiopathic cases, subsequent authors described PEO in association with other conditions, including cutaneous T-cell lymphoma (CTCL) and atopic diathesis, and infections, as well as secondary to medications. Some authors have suggested that PEO may be an early variant of mycosis fungoides; therefore, physicians should monitor patients closely.^5-7 Maher et al⁶ commented that multiple causative factors including CTCL underlie the development of papuloerythroderma.  

In a review of PEO, Torchia et al³ proposed diagnostic criteria and an etiologic classification to address whether PEO represents an independent entity or an unusual manifestation of other dermatoses. They established 4 categories of papuloerythroderma--primary, secondary, papuloerythrodermalike CTCL, and pseudopapuloerythroderma--and proposed that primary PEO is a diagnosis of exclusion. If no secondary association is found, they proposed 10 criteria for primary PEO: 5 major criteria include coalescing flat-topped papules, the deck-chair sign, pruritus, histopathologic exclusion of diseases such as CTCL, and a negative workup to exclude other causes.³ In 2018, Maher et al⁶ recommended workup to rule out cutaneous malignancy, including skin biopsy, flow cytometry, Sézary cell count, T-cell rearrangement, lactate dehydrogenase, and human T-cell lymphotropic virus 1. The 5 minor criteria proposed by Torchia et al³ include age older than 55 years, male sex, eosinophilia, elevated IgE level, and lymphopenia. Our patient fulfilled all 5 major criteria and 3 minor criteria; eosinophilia and lymphopenia were absent.  

Clinically, PEO has been associated with the deck-chair sign, a pattern of selective sparing of skinfolds, including axillary, inguinal, submammary, and other flexural areas. Although the deck-chair sign was originally considered pathognomonic for PEO, this clinical pattern also has been observed in other entities, such as angioimmunoblastic lymphoma, cutaneous Waldenström macroglobulinemia, and acanthosis nigricans.^5,8,9  

Specific characteristics of the rash and certain clinical symptoms may help to distinguish the deck-chair sign of PEO from its other causes. Although malignant acanthosis nigricans may spare the skinfolds, lesions have a classic velvety thickening and brownish hyperpigmentation, which is not characteristic of the reddish brown, flat-topped papules of PEO.⁹ Pai et al⁵ described a patient with parthenium dermatitis presenting with the deck-chair sign that developed years after repeated exposure to the allergen. Our patient did not have a history of repeated episodes of allergic contact dermatitis. In addition, areas of sparing may mimic the appearance of pityriasis rubra pilaris. As in our patient, those with PEO generally lack the follicular hyperkeratotic papules, palmoplantar keratoderma, widespread orange-red erythema, and characteristic histopathologic finding of hyperkeratosis with alternating orthokeratosis and parakeratosis, allowing these entities to be easily distinguished in most instances.¹⁰ 

Histopathologically, primary PEO shows a nonspecific spongiotic dermatitis-like pattern characterized by slight epidermal hyperplasia with spongiosis and a predominantly perivascular dermal infiltrate with lymphocytes, histiocytes, and eosinophils.³ These histologic findings may at times show some overlap with CTCL, and therefore T-cell gene rearrangement and flow cytometry may be performed in those instances.⁶  

Treatment includes the management of any underlying condition causing the papuloerythroderma.^3,6 There are no large clinical trials of treatment options for primary PEO due to its rarity. Topical or systemic corticosteroids remain the mainstay of treatment.³ Alternative treatments used with variable success include phototherapy, interferon, etretinate, cyclosporine, and azathioprine.¹¹ Allegue et al¹¹ successfully used methotrexate to treat a patient with primary PEO and postulated that methotrexate may act through an immunosuppressive mechanism on activated T cells due to the involvement of helper T cells T_H2 and T_H22 in its pathogenesis. 

Although the cutaneous manifestations of PEO may respond well to topical steroids, it is important to consider the possible presence of an underlying malignancy and other associated systemic conditions.

The Diagnosis: Papuloerythroderma of Ofuji 

The patient presented with a characteristic finding of skinfold sparing, known as the "deck-chair sign" (Figure 1).¹ A repeat biopsy at our institution revealed a dermal perivascular and bandlike infiltrate with lymphocytes and occasional eosinophils (Figure 2). The epidermis showed mild spongiosis, lymphocytic exocytosis, and rare necrotic keratinocytes. A T-cell gene rearrangement assay was negative for a monoclonal population of T lymphocytes. Based on the clinical and histologic features, the diagnosis was most consistent with papuloerythroderma of Ofuji (PEO); however, a lymphoproliferative disorder needed to be excluded. Further workup included a peripheral smear, complete blood cell count with differential, comprehensive metabolic panel, IgE level, and hepatitis panel; all were normal, except for an elevated serum IgE level. Human immunodeficiency virus and age-appropriate malignancy screening were negative. The patient was prescribed betamethasone dipropionate cream 0.05% twice daily, which resulted in near-complete resolution of the rash and marked improvement in pruritus.

In 1984, PEO was described as an entity of generalized pruritic erythroderma characterized by flat-topped, red to brown, coalescing papules with sparing of the skinfolds, later coined the deck-chair sign.^1,2 Papuloerythroderma of Ofuji commonly presents in elderly Asian males with a male to female ratio of 4:1.³ Papuloerythroderma of Ofuji is a T cell-mediated skin disease; however, the etiology of the signature rash remains unclear. One explanation includes circulating factors in the skin that elicit an inflammatory response, which does not occur in areas of external pressure.³ The deck-chair sign may occur more frequently in elderly individuals due to increased skin laxity, which creates crease lines that are spared from rubbing and excoriations.⁴  

Although Ofuji et al² initially reported 4 idiopathic cases, subsequent authors described PEO in association with other conditions, including cutaneous T-cell lymphoma (CTCL) and atopic diathesis, and infections, as well as secondary to medications. Some authors have suggested that PEO may be an early variant of mycosis fungoides; therefore, physicians should monitor patients closely.^5-7 Maher et al⁶ commented that multiple causative factors including CTCL underlie the development of papuloerythroderma.  

In a review of PEO, Torchia et al³ proposed diagnostic criteria and an etiologic classification to address whether PEO represents an independent entity or an unusual manifestation of other dermatoses. They established 4 categories of papuloerythroderma--primary, secondary, papuloerythrodermalike CTCL, and pseudopapuloerythroderma--and proposed that primary PEO is a diagnosis of exclusion. If no secondary association is found, they proposed 10 criteria for primary PEO: 5 major criteria include coalescing flat-topped papules, the deck-chair sign, pruritus, histopathologic exclusion of diseases such as CTCL, and a negative workup to exclude other causes.³ In 2018, Maher et al⁶ recommended workup to rule out cutaneous malignancy, including skin biopsy, flow cytometry, Sézary cell count, T-cell rearrangement, lactate dehydrogenase, and human T-cell lymphotropic virus 1. The 5 minor criteria proposed by Torchia et al³ include age older than 55 years, male sex, eosinophilia, elevated IgE level, and lymphopenia. Our patient fulfilled all 5 major criteria and 3 minor criteria; eosinophilia and lymphopenia were absent.  

Clinically, PEO has been associated with the deck-chair sign, a pattern of selective sparing of skinfolds, including axillary, inguinal, submammary, and other flexural areas. Although the deck-chair sign was originally considered pathognomonic for PEO, this clinical pattern also has been observed in other entities, such as angioimmunoblastic lymphoma, cutaneous Waldenström macroglobulinemia, and acanthosis nigricans.^5,8,9  

Specific characteristics of the rash and certain clinical symptoms may help to distinguish the deck-chair sign of PEO from its other causes. Although malignant acanthosis nigricans may spare the skinfolds, lesions have a classic velvety thickening and brownish hyperpigmentation, which is not characteristic of the reddish brown, flat-topped papules of PEO.⁹ Pai et al⁵ described a patient with parthenium dermatitis presenting with the deck-chair sign that developed years after repeated exposure to the allergen. Our patient did not have a history of repeated episodes of allergic contact dermatitis. In addition, areas of sparing may mimic the appearance of pityriasis rubra pilaris. As in our patient, those with PEO generally lack the follicular hyperkeratotic papules, palmoplantar keratoderma, widespread orange-red erythema, and characteristic histopathologic finding of hyperkeratosis with alternating orthokeratosis and parakeratosis, allowing these entities to be easily distinguished in most instances.¹⁰ 

Histopathologically, primary PEO shows a nonspecific spongiotic dermatitis-like pattern characterized by slight epidermal hyperplasia with spongiosis and a predominantly perivascular dermal infiltrate with lymphocytes, histiocytes, and eosinophils.³ These histologic findings may at times show some overlap with CTCL, and therefore T-cell gene rearrangement and flow cytometry may be performed in those instances.⁶  

Treatment includes the management of any underlying condition causing the papuloerythroderma.^3,6 There are no large clinical trials of treatment options for primary PEO due to its rarity. Topical or systemic corticosteroids remain the mainstay of treatment.³ Alternative treatments used with variable success include phototherapy, interferon, etretinate, cyclosporine, and azathioprine.¹¹ Allegue et al¹¹ successfully used methotrexate to treat a patient with primary PEO and postulated that methotrexate may act through an immunosuppressive mechanism on activated T cells due to the involvement of helper T cells T_H2 and T_H22 in its pathogenesis. 

Although the cutaneous manifestations of PEO may respond well to topical steroids, it is important to consider the possible presence of an underlying malignancy and other associated systemic conditions.

The Diagnosis: Papuloerythroderma of Ofuji 

The patient presented with a characteristic finding of skinfold sparing, known as the "deck-chair sign" (Figure 1).¹ A repeat biopsy at our institution revealed a dermal perivascular and bandlike infiltrate with lymphocytes and occasional eosinophils (Figure 2). The epidermis showed mild spongiosis, lymphocytic exocytosis, and rare necrotic keratinocytes. A T-cell gene rearrangement assay was negative for a monoclonal population of T lymphocytes. Based on the clinical and histologic features, the diagnosis was most consistent with papuloerythroderma of Ofuji (PEO); however, a lymphoproliferative disorder needed to be excluded. Further workup included a peripheral smear, complete blood cell count with differential, comprehensive metabolic panel, IgE level, and hepatitis panel; all were normal, except for an elevated serum IgE level. Human immunodeficiency virus and age-appropriate malignancy screening were negative. The patient was prescribed betamethasone dipropionate cream 0.05% twice daily, which resulted in near-complete resolution of the rash and marked improvement in pruritus.

In 1984, PEO was described as an entity of generalized pruritic erythroderma characterized by flat-topped, red to brown, coalescing papules with sparing of the skinfolds, later coined the deck-chair sign.^1,2 Papuloerythroderma of Ofuji commonly presents in elderly Asian males with a male to female ratio of 4:1.³ Papuloerythroderma of Ofuji is a T cell-mediated skin disease; however, the etiology of the signature rash remains unclear. One explanation includes circulating factors in the skin that elicit an inflammatory response, which does not occur in areas of external pressure.³ The deck-chair sign may occur more frequently in elderly individuals due to increased skin laxity, which creates crease lines that are spared from rubbing and excoriations.⁴  

Although Ofuji et al² initially reported 4 idiopathic cases, subsequent authors described PEO in association with other conditions, including cutaneous T-cell lymphoma (CTCL) and atopic diathesis, and infections, as well as secondary to medications. Some authors have suggested that PEO may be an early variant of mycosis fungoides; therefore, physicians should monitor patients closely.^5-7 Maher et al⁶ commented that multiple causative factors including CTCL underlie the development of papuloerythroderma.  

In a review of PEO, Torchia et al³ proposed diagnostic criteria and an etiologic classification to address whether PEO represents an independent entity or an unusual manifestation of other dermatoses. They established 4 categories of papuloerythroderma--primary, secondary, papuloerythrodermalike CTCL, and pseudopapuloerythroderma--and proposed that primary PEO is a diagnosis of exclusion. If no secondary association is found, they proposed 10 criteria for primary PEO: 5 major criteria include coalescing flat-topped papules, the deck-chair sign, pruritus, histopathologic exclusion of diseases such as CTCL, and a negative workup to exclude other causes.³ In 2018, Maher et al⁶ recommended workup to rule out cutaneous malignancy, including skin biopsy, flow cytometry, Sézary cell count, T-cell rearrangement, lactate dehydrogenase, and human T-cell lymphotropic virus 1. The 5 minor criteria proposed by Torchia et al³ include age older than 55 years, male sex, eosinophilia, elevated IgE level, and lymphopenia. Our patient fulfilled all 5 major criteria and 3 minor criteria; eosinophilia and lymphopenia were absent.  

Clinically, PEO has been associated with the deck-chair sign, a pattern of selective sparing of skinfolds, including axillary, inguinal, submammary, and other flexural areas. Although the deck-chair sign was originally considered pathognomonic for PEO, this clinical pattern also has been observed in other entities, such as angioimmunoblastic lymphoma, cutaneous Waldenström macroglobulinemia, and acanthosis nigricans.^5,8,9  

Specific characteristics of the rash and certain clinical symptoms may help to distinguish the deck-chair sign of PEO from its other causes. Although malignant acanthosis nigricans may spare the skinfolds, lesions have a classic velvety thickening and brownish hyperpigmentation, which is not characteristic of the reddish brown, flat-topped papules of PEO.⁹ Pai et al⁵ described a patient with parthenium dermatitis presenting with the deck-chair sign that developed years after repeated exposure to the allergen. Our patient did not have a history of repeated episodes of allergic contact dermatitis. In addition, areas of sparing may mimic the appearance of pityriasis rubra pilaris. As in our patient, those with PEO generally lack the follicular hyperkeratotic papules, palmoplantar keratoderma, widespread orange-red erythema, and characteristic histopathologic finding of hyperkeratosis with alternating orthokeratosis and parakeratosis, allowing these entities to be easily distinguished in most instances.¹⁰ 

Histopathologically, primary PEO shows a nonspecific spongiotic dermatitis-like pattern characterized by slight epidermal hyperplasia with spongiosis and a predominantly perivascular dermal infiltrate with lymphocytes, histiocytes, and eosinophils.³ These histologic findings may at times show some overlap with CTCL, and therefore T-cell gene rearrangement and flow cytometry may be performed in those instances.⁶  

Treatment includes the management of any underlying condition causing the papuloerythroderma.^3,6 There are no large clinical trials of treatment options for primary PEO due to its rarity. Topical or systemic corticosteroids remain the mainstay of treatment.³ Alternative treatments used with variable success include phototherapy, interferon, etretinate, cyclosporine, and azathioprine.¹¹ Allegue et al¹¹ successfully used methotrexate to treat a patient with primary PEO and postulated that methotrexate may act through an immunosuppressive mechanism on activated T cells due to the involvement of helper T cells T_H2 and T_H22 in its pathogenesis. 

Although the cutaneous manifestations of PEO may respond well to topical steroids, it is important to consider the possible presence of an underlying malignancy and other associated systemic conditions.

The Diagnosis: Cutaneous Crohn Disease 

Crohn disease (CD) is an inflammatory bowel disease that can involve any region of the gastrointestinal (GI) tract from the mouth to the anus but most commonly presents in the terminal ileum, colon, or small bowel with transmural inflammation, fistula formation, and knife-cut fissures among the frequently described findings. Extraintestinal manifestations may be found in the liver, eyes, and joints, with cutaneous extraintestinal manifestations occurring in up to one-third of patients.¹ 

Crohn disease can be associated with multiple cutaneous findings, including erythema nodosum, pyoderma gangrenosum, aphthous ulcers, pyodermatitis-pyostomatitis vegetans, necrotizing vasculitis, and metastatic Crohn disease (MCD).² Typical histopathologic findings seen in MCD such as noncaseating granulomatous inflammation in the papillary and reticular dermis, possibly extending to the subcutaneous fat, are not specific to MCD. Associated genital edema is thought to be a consequence of granulomatous inflammation of lymphatics. In one study reviewing specimens from 10 cases of CD, a mean of 46% of all granulomas identified on the slides (264 granulomas in total) were located proximal to lymphatic vessels, suggesting a common pathway for development of intestinal disease and genital edema.³ The differential diagnosis for penile and scrotal swelling is broad, and the diagnosis may be missed if attention is not given to the clinical history of the patient in addition to histopathologic findings.² 

Skin changes in CD also can be separated into perianal disease and true metastatic disease--the former recognized when anal lesions appear associated with segmental involvement of the GI tract and the latter as ulceration of the skin separated from the GI tract by normal tissue.¹ The term sarcoidal reaction often is used to describe histopathologic findings in cutaneous CD, as it refers to the noncaseating granulomas found in approximately 60% of all cases.⁴ Ultimately, the location of noncaseating granulomas within the dermis of our patient's biopsy, taken in conjunction with the clinical history and the lack of defining features for other potential etiologies (eg, polarizable material, organisms on special stains), led to the diagnosis of cutaneous CD.  

Cutaneous manifestations of sarcoidosis most commonly occur as papules, plaques, and subcutaneous nodules predominantly on the face, upper back, arms, and legs. Although the histologic features of sarcoidosis are characterized by lymphocyte-poor noncaseating granulomas (Figure 1), these findings also can be seen as a consequence of multiple granulomatous causes.^5,6 In a review of 48 cutaneous specimens from patients with sarcoidosis, the granulomas were found most frequently in the deep dermis (34/48 [70.8%]), with superficial dermis (21/48) and subcutaneous fat granulomas (20/48) each present in less than 50% of biopsies.⁵ Although less typical, cutaneous sarcoidosis also has been noted in the literature to present in the perianal and gluteal region, demonstrating dermal noncaseating granulomas on biopsy.⁷ One distinction in particular to be noted between sarcoid and CD is that sarcoid lesions in the skin rarely ulcerate, while the lesions of cutaneous CD often are ulcerated.^4,6 

Lesions including abscesses in the groin may raise concern for hidradenitis suppurativa (HS), a disease of the apocrine gland-bearing skin. Typical lesions are tender subcutaneous erythematous nodules, cysts, and comedones that develop rapidly and may rupture to drain suppurative bloody discharge, subsequently healing with an atrophic scar.⁸ More persistent inflammation and rupture of nodules into the dermis may lead to formation of dermal tunnels with palpable cords and sinus tracts.⁸ Typical areas of disease involvement are in the axillae, inframammary folds, groin, or perigenital or perineal regions, with the diagnosis made on a combination of lesion morphology, location, and progression/recurrence frequency.⁹ Histologic examination of HS specimens can demonstrate a perifollicular lymphocytic infiltrate, with more advanced disease characterized by increased inflammatory cells, predominantly neutrophils, monocytes, and mast cells (Figure 2). The presence of granulomas in HS most often is of the foreign body type.⁹ Epithelioid granulomas noted in an area separate from inflammation in a patient with HS serve as a clue to be alert for systemic granulomatous disease.¹⁰  

Mycosis fungoides is the most common primary cutaneous lymphoma to show a granulomatous infiltrate; the granuloma generally is sarcoidal, though other forms are described (Figure 3).¹¹ Beyond these granulomatous foci, the key histopathologic feature of granulomatous mycosis fungoides (GMF) is diffuse dermal infiltration by atypical lymphoid cells. Epidermotropism and sparing of dermal nerves is the most critical finding in the diagnosis of GMF, especially in geographic regions where leprosy is endemic and high on the differential, as the conditions have histopathologic similarities.^11,12 At the same time, lack of epidermotropism does not exclude the diagnosis of GMF.¹³ Clinically, GMF presentation is variable, but common findings include erythematous and hyperpigmented patches and plaques. Given the lack of clear clinical criteria, the diagnosis relies primarily on histopathologic features.¹¹ 

Mycobacterial skin and soft tissue infections may be attributed to both tuberculous and nontuberculous strains (atypical species).¹⁴ Clinical features range from small papules to large deformative plaques and ulcers.¹⁵ Histologic features also distinguish cutaneous tuberculosis (TB) from nontuberculous mycobacterial causes. Cutaneous TB shows caseous granulomas in the upper and mid dermis, while nontuberculous mycobacterial infections have more prominent neutrophil infiltration and interstitial granulomas (Figure 4).¹⁶ 

In cutaneous TB specifically, extrapulmonary manifestations may involve the skin in 1% to 1.5% of all TB cases, and although rare, ulcerative skin TB has been noted in one report as a nonhealing perianal ulcer that showed necrotizing granulomas on biopsy.¹⁷ Ultimately, diagnosis of cutaneous mycobacterial infection is confirmed with detection of acid-fast bacilli in the biopsy specimen.¹⁶ 

Diagnosis of cutaneous CD requires clinicopathologic correlation, as the clinical and histopathologic differential diagnoses of genital edema and noncaseating granulomas, respectively, are broad. Even though the clinical context was appropriate for cutaneous CD in this case, correct diagnosis required confirmatory histologic findings. Furthermore, taking multiple biopsies is prudent. In our patient, diagnostic findings only were present in the biopsy from the scrotum.  

The Diagnosis: Cutaneous Crohn Disease 

Crohn disease (CD) is an inflammatory bowel disease that can involve any region of the gastrointestinal (GI) tract from the mouth to the anus but most commonly presents in the terminal ileum, colon, or small bowel with transmural inflammation, fistula formation, and knife-cut fissures among the frequently described findings. Extraintestinal manifestations may be found in the liver, eyes, and joints, with cutaneous extraintestinal manifestations occurring in up to one-third of patients.¹ 

Crohn disease can be associated with multiple cutaneous findings, including erythema nodosum, pyoderma gangrenosum, aphthous ulcers, pyodermatitis-pyostomatitis vegetans, necrotizing vasculitis, and metastatic Crohn disease (MCD).² Typical histopathologic findings seen in MCD such as noncaseating granulomatous inflammation in the papillary and reticular dermis, possibly extending to the subcutaneous fat, are not specific to MCD. Associated genital edema is thought to be a consequence of granulomatous inflammation of lymphatics. In one study reviewing specimens from 10 cases of CD, a mean of 46% of all granulomas identified on the slides (264 granulomas in total) were located proximal to lymphatic vessels, suggesting a common pathway for development of intestinal disease and genital edema.³ The differential diagnosis for penile and scrotal swelling is broad, and the diagnosis may be missed if attention is not given to the clinical history of the patient in addition to histopathologic findings.² 

Skin changes in CD also can be separated into perianal disease and true metastatic disease--the former recognized when anal lesions appear associated with segmental involvement of the GI tract and the latter as ulceration of the skin separated from the GI tract by normal tissue.¹ The term sarcoidal reaction often is used to describe histopathologic findings in cutaneous CD, as it refers to the noncaseating granulomas found in approximately 60% of all cases.⁴ Ultimately, the location of noncaseating granulomas within the dermis of our patient's biopsy, taken in conjunction with the clinical history and the lack of defining features for other potential etiologies (eg, polarizable material, organisms on special stains), led to the diagnosis of cutaneous CD.  

Cutaneous manifestations of sarcoidosis most commonly occur as papules, plaques, and subcutaneous nodules predominantly on the face, upper back, arms, and legs. Although the histologic features of sarcoidosis are characterized by lymphocyte-poor noncaseating granulomas (Figure 1), these findings also can be seen as a consequence of multiple granulomatous causes.^5,6 In a review of 48 cutaneous specimens from patients with sarcoidosis, the granulomas were found most frequently in the deep dermis (34/48 [70.8%]), with superficial dermis (21/48) and subcutaneous fat granulomas (20/48) each present in less than 50% of biopsies.⁵ Although less typical, cutaneous sarcoidosis also has been noted in the literature to present in the perianal and gluteal region, demonstrating dermal noncaseating granulomas on biopsy.⁷ One distinction in particular to be noted between sarcoid and CD is that sarcoid lesions in the skin rarely ulcerate, while the lesions of cutaneous CD often are ulcerated.^4,6 

Lesions including abscesses in the groin may raise concern for hidradenitis suppurativa (HS), a disease of the apocrine gland-bearing skin. Typical lesions are tender subcutaneous erythematous nodules, cysts, and comedones that develop rapidly and may rupture to drain suppurative bloody discharge, subsequently healing with an atrophic scar.⁸ More persistent inflammation and rupture of nodules into the dermis may lead to formation of dermal tunnels with palpable cords and sinus tracts.⁸ Typical areas of disease involvement are in the axillae, inframammary folds, groin, or perigenital or perineal regions, with the diagnosis made on a combination of lesion morphology, location, and progression/recurrence frequency.⁹ Histologic examination of HS specimens can demonstrate a perifollicular lymphocytic infiltrate, with more advanced disease characterized by increased inflammatory cells, predominantly neutrophils, monocytes, and mast cells (Figure 2). The presence of granulomas in HS most often is of the foreign body type.⁹ Epithelioid granulomas noted in an area separate from inflammation in a patient with HS serve as a clue to be alert for systemic granulomatous disease.¹⁰  

Mycosis fungoides is the most common primary cutaneous lymphoma to show a granulomatous infiltrate; the granuloma generally is sarcoidal, though other forms are described (Figure 3).¹¹ Beyond these granulomatous foci, the key histopathologic feature of granulomatous mycosis fungoides (GMF) is diffuse dermal infiltration by atypical lymphoid cells. Epidermotropism and sparing of dermal nerves is the most critical finding in the diagnosis of GMF, especially in geographic regions where leprosy is endemic and high on the differential, as the conditions have histopathologic similarities.^11,12 At the same time, lack of epidermotropism does not exclude the diagnosis of GMF.¹³ Clinically, GMF presentation is variable, but common findings include erythematous and hyperpigmented patches and plaques. Given the lack of clear clinical criteria, the diagnosis relies primarily on histopathologic features.¹¹ 

Mycobacterial skin and soft tissue infections may be attributed to both tuberculous and nontuberculous strains (atypical species).¹⁴ Clinical features range from small papules to large deformative plaques and ulcers.¹⁵ Histologic features also distinguish cutaneous tuberculosis (TB) from nontuberculous mycobacterial causes. Cutaneous TB shows caseous granulomas in the upper and mid dermis, while nontuberculous mycobacterial infections have more prominent neutrophil infiltration and interstitial granulomas (Figure 4).¹⁶ 

In cutaneous TB specifically, extrapulmonary manifestations may involve the skin in 1% to 1.5% of all TB cases, and although rare, ulcerative skin TB has been noted in one report as a nonhealing perianal ulcer that showed necrotizing granulomas on biopsy.¹⁷ Ultimately, diagnosis of cutaneous mycobacterial infection is confirmed with detection of acid-fast bacilli in the biopsy specimen.¹⁶ 

Diagnosis of cutaneous CD requires clinicopathologic correlation, as the clinical and histopathologic differential diagnoses of genital edema and noncaseating granulomas, respectively, are broad. Even though the clinical context was appropriate for cutaneous CD in this case, correct diagnosis required confirmatory histologic findings. Furthermore, taking multiple biopsies is prudent. In our patient, diagnostic findings only were present in the biopsy from the scrotum.  

The Diagnosis: Cutaneous Crohn Disease 

Crohn disease (CD) is an inflammatory bowel disease that can involve any region of the gastrointestinal (GI) tract from the mouth to the anus but most commonly presents in the terminal ileum, colon, or small bowel with transmural inflammation, fistula formation, and knife-cut fissures among the frequently described findings. Extraintestinal manifestations may be found in the liver, eyes, and joints, with cutaneous extraintestinal manifestations occurring in up to one-third of patients.¹ 

Crohn disease can be associated with multiple cutaneous findings, including erythema nodosum, pyoderma gangrenosum, aphthous ulcers, pyodermatitis-pyostomatitis vegetans, necrotizing vasculitis, and metastatic Crohn disease (MCD).² Typical histopathologic findings seen in MCD such as noncaseating granulomatous inflammation in the papillary and reticular dermis, possibly extending to the subcutaneous fat, are not specific to MCD. Associated genital edema is thought to be a consequence of granulomatous inflammation of lymphatics. In one study reviewing specimens from 10 cases of CD, a mean of 46% of all granulomas identified on the slides (264 granulomas in total) were located proximal to lymphatic vessels, suggesting a common pathway for development of intestinal disease and genital edema.³ The differential diagnosis for penile and scrotal swelling is broad, and the diagnosis may be missed if attention is not given to the clinical history of the patient in addition to histopathologic findings.² 

Skin changes in CD also can be separated into perianal disease and true metastatic disease--the former recognized when anal lesions appear associated with segmental involvement of the GI tract and the latter as ulceration of the skin separated from the GI tract by normal tissue.¹ The term sarcoidal reaction often is used to describe histopathologic findings in cutaneous CD, as it refers to the noncaseating granulomas found in approximately 60% of all cases.⁴ Ultimately, the location of noncaseating granulomas within the dermis of our patient's biopsy, taken in conjunction with the clinical history and the lack of defining features for other potential etiologies (eg, polarizable material, organisms on special stains), led to the diagnosis of cutaneous CD.  

Cutaneous manifestations of sarcoidosis most commonly occur as papules, plaques, and subcutaneous nodules predominantly on the face, upper back, arms, and legs. Although the histologic features of sarcoidosis are characterized by lymphocyte-poor noncaseating granulomas (Figure 1), these findings also can be seen as a consequence of multiple granulomatous causes.^5,6 In a review of 48 cutaneous specimens from patients with sarcoidosis, the granulomas were found most frequently in the deep dermis (34/48 [70.8%]), with superficial dermis (21/48) and subcutaneous fat granulomas (20/48) each present in less than 50% of biopsies.⁵ Although less typical, cutaneous sarcoidosis also has been noted in the literature to present in the perianal and gluteal region, demonstrating dermal noncaseating granulomas on biopsy.⁷ One distinction in particular to be noted between sarcoid and CD is that sarcoid lesions in the skin rarely ulcerate, while the lesions of cutaneous CD often are ulcerated.^4,6 

Lesions including abscesses in the groin may raise concern for hidradenitis suppurativa (HS), a disease of the apocrine gland-bearing skin. Typical lesions are tender subcutaneous erythematous nodules, cysts, and comedones that develop rapidly and may rupture to drain suppurative bloody discharge, subsequently healing with an atrophic scar.⁸ More persistent inflammation and rupture of nodules into the dermis may lead to formation of dermal tunnels with palpable cords and sinus tracts.⁸ Typical areas of disease involvement are in the axillae, inframammary folds, groin, or perigenital or perineal regions, with the diagnosis made on a combination of lesion morphology, location, and progression/recurrence frequency.⁹ Histologic examination of HS specimens can demonstrate a perifollicular lymphocytic infiltrate, with more advanced disease characterized by increased inflammatory cells, predominantly neutrophils, monocytes, and mast cells (Figure 2). The presence of granulomas in HS most often is of the foreign body type.⁹ Epithelioid granulomas noted in an area separate from inflammation in a patient with HS serve as a clue to be alert for systemic granulomatous disease.¹⁰  

Mycosis fungoides is the most common primary cutaneous lymphoma to show a granulomatous infiltrate; the granuloma generally is sarcoidal, though other forms are described (Figure 3).¹¹ Beyond these granulomatous foci, the key histopathologic feature of granulomatous mycosis fungoides (GMF) is diffuse dermal infiltration by atypical lymphoid cells. Epidermotropism and sparing of dermal nerves is the most critical finding in the diagnosis of GMF, especially in geographic regions where leprosy is endemic and high on the differential, as the conditions have histopathologic similarities.^11,12 At the same time, lack of epidermotropism does not exclude the diagnosis of GMF.¹³ Clinically, GMF presentation is variable, but common findings include erythematous and hyperpigmented patches and plaques. Given the lack of clear clinical criteria, the diagnosis relies primarily on histopathologic features.¹¹ 

Mycobacterial skin and soft tissue infections may be attributed to both tuberculous and nontuberculous strains (atypical species).¹⁴ Clinical features range from small papules to large deformative plaques and ulcers.¹⁵ Histologic features also distinguish cutaneous tuberculosis (TB) from nontuberculous mycobacterial causes. Cutaneous TB shows caseous granulomas in the upper and mid dermis, while nontuberculous mycobacterial infections have more prominent neutrophil infiltration and interstitial granulomas (Figure 4).¹⁶ 

In cutaneous TB specifically, extrapulmonary manifestations may involve the skin in 1% to 1.5% of all TB cases, and although rare, ulcerative skin TB has been noted in one report as a nonhealing perianal ulcer that showed necrotizing granulomas on biopsy.¹⁷ Ultimately, diagnosis of cutaneous mycobacterial infection is confirmed with detection of acid-fast bacilli in the biopsy specimen.¹⁶ 

Diagnosis of cutaneous CD requires clinicopathologic correlation, as the clinical and histopathologic differential diagnoses of genital edema and noncaseating granulomas, respectively, are broad. Even though the clinical context was appropriate for cutaneous CD in this case, correct diagnosis required confirmatory histologic findings. Furthermore, taking multiple biopsies is prudent. In our patient, diagnostic findings only were present in the biopsy from the scrotum.  

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory condition that affects approximately 1% to 4% of the worldwide population and is 3 times more common in females than in males.¹ The condition is characterized by painful inflamed nodules in apocrine gland–bearing regions that can progress to abscesses, sinus tracts, and/or scarring. Hidradenitis suppurativa is associated with intense pain, work disability, and poor quality of life.¹

Recent evidence has suggested that HS is an autoimmune disease resulting from dysregulation of the γ-secretase/Notch pathway, leading to stimulation of the toll-like receptor–mediated innate immunity that contributes to occlusion and inflammation of the hair follicle. Additionally, elevated levels of proinflammatory cytokines such as tumor necrosis factor α and IL-17 are seen in HS lesions.² The autoimmune nature of HS may account for its increased association with other autoimmune disorders such as thyroid disease and potentially with other unexplored conditions such as fibromyalgia.³

Fibromyalgia is a chronic pain condition that primarily affects females and is commonly associated with other autoimmune conditions.⁴ The primary objective of this retrospective study was to determine the prevalence of fibromyalgia in HS patients and assess if there is an association between HS disease severity and development of fibromyalgia.

We conducted a retrospective chart review of patients at Wake Forest Baptist Medical Center (Winston-Salem, North Carolina) who were 18 years and older and had a diagnosis of both HS and fibromyalgia from January 2008 to November 2018. The primary end point was the prevalence of fibromyalgia in the HS population. The secondary end point was the association of HS disease severity with the development of fibromyalgia. Hidradenitis disease severity was defined according to the number of body areas affected by HS: mild disease involved 1 body area, moderate disease involved 2 body areas, and severe disease involved 3 or more body areas. Patient age, sex, and race also were recorded.

A total of 1356 patients were seen during this time period for HS. The prevalence of fibromyalgia in the HS population was 3.2% (n=44). Ninety-five percent (42/44) of patients with HS and fibromyalgia were women; 22 (50%) patients had severe disease, 12 (27%) had moderate disease, 7 (16%) had mild disease, and 3 (7%) had an unknown number of affected body areas. Fifty-seven percent (25/44) of patients were diagnosed with HS prior to the diagnosis of fibromyalgia (Table).

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory condition that affects approximately 1% to 4% of the worldwide population and is 3 times more common in females than in males.¹ The condition is characterized by painful inflamed nodules in apocrine gland–bearing regions that can progress to abscesses, sinus tracts, and/or scarring. Hidradenitis suppurativa is associated with intense pain, work disability, and poor quality of life.¹

Recent evidence has suggested that HS is an autoimmune disease resulting from dysregulation of the γ-secretase/Notch pathway, leading to stimulation of the toll-like receptor–mediated innate immunity that contributes to occlusion and inflammation of the hair follicle. Additionally, elevated levels of proinflammatory cytokines such as tumor necrosis factor α and IL-17 are seen in HS lesions.² The autoimmune nature of HS may account for its increased association with other autoimmune disorders such as thyroid disease and potentially with other unexplored conditions such as fibromyalgia.³

Fibromyalgia is a chronic pain condition that primarily affects females and is commonly associated with other autoimmune conditions.⁴ The primary objective of this retrospective study was to determine the prevalence of fibromyalgia in HS patients and assess if there is an association between HS disease severity and development of fibromyalgia.

We conducted a retrospective chart review of patients at Wake Forest Baptist Medical Center (Winston-Salem, North Carolina) who were 18 years and older and had a diagnosis of both HS and fibromyalgia from January 2008 to November 2018. The primary end point was the prevalence of fibromyalgia in the HS population. The secondary end point was the association of HS disease severity with the development of fibromyalgia. Hidradenitis disease severity was defined according to the number of body areas affected by HS: mild disease involved 1 body area, moderate disease involved 2 body areas, and severe disease involved 3 or more body areas. Patient age, sex, and race also were recorded.

A total of 1356 patients were seen during this time period for HS. The prevalence of fibromyalgia in the HS population was 3.2% (n=44). Ninety-five percent (42/44) of patients with HS and fibromyalgia were women; 22 (50%) patients had severe disease, 12 (27%) had moderate disease, 7 (16%) had mild disease, and 3 (7%) had an unknown number of affected body areas. Fifty-seven percent (25/44) of patients were diagnosed with HS prior to the diagnosis of fibromyalgia (Table).

To the Editor:

Hidradenitis suppurativa (HS) is a chronic inflammatory condition that affects approximately 1% to 4% of the worldwide population and is 3 times more common in females than in males.¹ The condition is characterized by painful inflamed nodules in apocrine gland–bearing regions that can progress to abscesses, sinus tracts, and/or scarring. Hidradenitis suppurativa is associated with intense pain, work disability, and poor quality of life.¹

Recent evidence has suggested that HS is an autoimmune disease resulting from dysregulation of the γ-secretase/Notch pathway, leading to stimulation of the toll-like receptor–mediated innate immunity that contributes to occlusion and inflammation of the hair follicle. Additionally, elevated levels of proinflammatory cytokines such as tumor necrosis factor α and IL-17 are seen in HS lesions.² The autoimmune nature of HS may account for its increased association with other autoimmune disorders such as thyroid disease and potentially with other unexplored conditions such as fibromyalgia.³

Fibromyalgia is a chronic pain condition that primarily affects females and is commonly associated with other autoimmune conditions.⁴ The primary objective of this retrospective study was to determine the prevalence of fibromyalgia in HS patients and assess if there is an association between HS disease severity and development of fibromyalgia.

We conducted a retrospective chart review of patients at Wake Forest Baptist Medical Center (Winston-Salem, North Carolina) who were 18 years and older and had a diagnosis of both HS and fibromyalgia from January 2008 to November 2018. The primary end point was the prevalence of fibromyalgia in the HS population. The secondary end point was the association of HS disease severity with the development of fibromyalgia. Hidradenitis disease severity was defined according to the number of body areas affected by HS: mild disease involved 1 body area, moderate disease involved 2 body areas, and severe disease involved 3 or more body areas. Patient age, sex, and race also were recorded.

A total of 1356 patients were seen during this time period for HS. The prevalence of fibromyalgia in the HS population was 3.2% (n=44). Ninety-five percent (42/44) of patients with HS and fibromyalgia were women; 22 (50%) patients had severe disease, 12 (27%) had moderate disease, 7 (16%) had mild disease, and 3 (7%) had an unknown number of affected body areas. Fifty-seven percent (25/44) of patients were diagnosed with HS prior to the diagnosis of fibromyalgia (Table).

To the Editor:

A 59-year-old man presented with a lesion on the right frontal scalp of 4 months’ duration and a lesion on the left frontal scalp of 1 month’s duration. Both lesions were tender, bleeding, nonhealing, and growing in size. The patient reported no improvement with the use of triple antibiotic ointment. He denied any associated symptoms or trauma to the affected areas. He had a history of stage IV esophageal adenocarcinoma that initially had been surgically removed 6 years prior but metastasized to the lungs and bone. The patient subsequently underwent treatment with FOLFOX (folinic acid, fluorouracil, oxaliplatin), trastuzumab, and radiation therapy.

Physical examination revealed a hyperkeratotic pink nodule with a central erosion and crust on the right frontal scalp measuring 1.5×2 cm in diameter (Figure 1A). The left frontal scalp lesion was a smooth pearly papule measuring 5×5 mm in diameter (Figure 1B). The differential diagnosis included basal cell carcinoma, squamous cell carcinoma, and cutaneous metastases from esophageal adenocarcinoma. Shave biopsies were taken of both scalp lesions.

Our case highlights multiple cutaneous metastases of the scalp from a primary esophageal adenocarcinoma. Although cutaneous scalp metastasis of esophageal adenocarcinoma is rare, it is essential to provide a full-body skin examination, including the scalp, in patients with a history of esophageal cancer and to biopsy any suspicious nodules or plaques. The 1-year survival rate after diagnosis of esophageal carcinoma is less than 50%, and the 5-year survival rate is less than 10%.¹³ Identifying cutaneous metastasis of an esophageal adenocarcinoma can either change the staging of the cancer (if it was the first distant metastasis noted) or indicate an insufficient response to treatment in a patient with known metastatic disease, prompting a potential change in treatment.⁷

This case illustrates a rare site of metastasis of a fairly common cancer and highlights the histopathology and accompanying immunohistochemical stains that can be useful in diagnosis as well as the spectrum of its clinical presentation.

To the Editor:

A 59-year-old man presented with a lesion on the right frontal scalp of 4 months’ duration and a lesion on the left frontal scalp of 1 month’s duration. Both lesions were tender, bleeding, nonhealing, and growing in size. The patient reported no improvement with the use of triple antibiotic ointment. He denied any associated symptoms or trauma to the affected areas. He had a history of stage IV esophageal adenocarcinoma that initially had been surgically removed 6 years prior but metastasized to the lungs and bone. The patient subsequently underwent treatment with FOLFOX (folinic acid, fluorouracil, oxaliplatin), trastuzumab, and radiation therapy.

Physical examination revealed a hyperkeratotic pink nodule with a central erosion and crust on the right frontal scalp measuring 1.5×2 cm in diameter (Figure 1A). The left frontal scalp lesion was a smooth pearly papule measuring 5×5 mm in diameter (Figure 1B). The differential diagnosis included basal cell carcinoma, squamous cell carcinoma, and cutaneous metastases from esophageal adenocarcinoma. Shave biopsies were taken of both scalp lesions.

Our case highlights multiple cutaneous metastases of the scalp from a primary esophageal adenocarcinoma. Although cutaneous scalp metastasis of esophageal adenocarcinoma is rare, it is essential to provide a full-body skin examination, including the scalp, in patients with a history of esophageal cancer and to biopsy any suspicious nodules or plaques. The 1-year survival rate after diagnosis of esophageal carcinoma is less than 50%, and the 5-year survival rate is less than 10%.¹³ Identifying cutaneous metastasis of an esophageal adenocarcinoma can either change the staging of the cancer (if it was the first distant metastasis noted) or indicate an insufficient response to treatment in a patient with known metastatic disease, prompting a potential change in treatment.⁷

This case illustrates a rare site of metastasis of a fairly common cancer and highlights the histopathology and accompanying immunohistochemical stains that can be useful in diagnosis as well as the spectrum of its clinical presentation.

To the Editor:

A 59-year-old man presented with a lesion on the right frontal scalp of 4 months’ duration and a lesion on the left frontal scalp of 1 month’s duration. Both lesions were tender, bleeding, nonhealing, and growing in size. The patient reported no improvement with the use of triple antibiotic ointment. He denied any associated symptoms or trauma to the affected areas. He had a history of stage IV esophageal adenocarcinoma that initially had been surgically removed 6 years prior but metastasized to the lungs and bone. The patient subsequently underwent treatment with FOLFOX (folinic acid, fluorouracil, oxaliplatin), trastuzumab, and radiation therapy.

Physical examination revealed a hyperkeratotic pink nodule with a central erosion and crust on the right frontal scalp measuring 1.5×2 cm in diameter (Figure 1A). The left frontal scalp lesion was a smooth pearly papule measuring 5×5 mm in diameter (Figure 1B). The differential diagnosis included basal cell carcinoma, squamous cell carcinoma, and cutaneous metastases from esophageal adenocarcinoma. Shave biopsies were taken of both scalp lesions.

Our case highlights multiple cutaneous metastases of the scalp from a primary esophageal adenocarcinoma. Although cutaneous scalp metastasis of esophageal adenocarcinoma is rare, it is essential to provide a full-body skin examination, including the scalp, in patients with a history of esophageal cancer and to biopsy any suspicious nodules or plaques. The 1-year survival rate after diagnosis of esophageal carcinoma is less than 50%, and the 5-year survival rate is less than 10%.¹³ Identifying cutaneous metastasis of an esophageal adenocarcinoma can either change the staging of the cancer (if it was the first distant metastasis noted) or indicate an insufficient response to treatment in a patient with known metastatic disease, prompting a potential change in treatment.⁷

This case illustrates a rare site of metastasis of a fairly common cancer and highlights the histopathology and accompanying immunohistochemical stains that can be useful in diagnosis as well as the spectrum of its clinical presentation.