Chandra Smart, MD

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.

Six months later the patient returned, presenting with a new central patch of scarring alopecia on the vertex of the scalp (Figure 2). Adjacent to the area of hair loss were areas of prominent perifollicular scale that were slightly violaceous in color. Two 4-mm punch biopsies of the scalp showed dermal scarring with perifollicular lamellar fibrosis surrounded by a rim of lymphoplasmacytic inflammation (Figure 3). Sebaceous glands were found to be reduced in number. These findings were consistent with cicatricial alopecia, which was further classified as LPP in conjunction with the clinical findings. No CD30⁺ lymphocytes were identified in these specimens.

Baseline fasting triglycerides were 123 mg/dL (desirable: <150 mg/dL; borderline: 150–199 mg/dL; high: ≥200 mg/dL) and were stable over the first 4 months on bexarotene. After 5 months of therapy, the triglycerides increased to a high of 255 mg/dL, which corresponded with the onset of LPP. She was treated for the hypertriglyceridemia with omega-3 fatty acids (fish oil), and subsequent triglyceride levels have normalized and been stable. Her alopecia has not progressed but is persistent. She continues to have central hypothyroidism due to bexarotene and is on levothyroxine. The lymphomatoid papulosis also remains stable with no signs of progression to cutaneous T-cell lymphoma.

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.

Six months later the patient returned, presenting with a new central patch of scarring alopecia on the vertex of the scalp (Figure 2). Adjacent to the area of hair loss were areas of prominent perifollicular scale that were slightly violaceous in color. Two 4-mm punch biopsies of the scalp showed dermal scarring with perifollicular lamellar fibrosis surrounded by a rim of lymphoplasmacytic inflammation (Figure 3). Sebaceous glands were found to be reduced in number. These findings were consistent with cicatricial alopecia, which was further classified as LPP in conjunction with the clinical findings. No CD30⁺ lymphocytes were identified in these specimens.

Baseline fasting triglycerides were 123 mg/dL (desirable: <150 mg/dL; borderline: 150–199 mg/dL; high: ≥200 mg/dL) and were stable over the first 4 months on bexarotene. After 5 months of therapy, the triglycerides increased to a high of 255 mg/dL, which corresponded with the onset of LPP. She was treated for the hypertriglyceridemia with omega-3 fatty acids (fish oil), and subsequent triglyceride levels have normalized and been stable. Her alopecia has not progressed but is persistent. She continues to have central hypothyroidism due to bexarotene and is on levothyroxine. The lymphomatoid papulosis also remains stable with no signs of progression to cutaneous T-cell lymphoma.

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.

Six months later the patient returned, presenting with a new central patch of scarring alopecia on the vertex of the scalp (Figure 2). Adjacent to the area of hair loss were areas of prominent perifollicular scale that were slightly violaceous in color. Two 4-mm punch biopsies of the scalp showed dermal scarring with perifollicular lamellar fibrosis surrounded by a rim of lymphoplasmacytic inflammation (Figure 3). Sebaceous glands were found to be reduced in number. These findings were consistent with cicatricial alopecia, which was further classified as LPP in conjunction with the clinical findings. No CD30⁺ lymphocytes were identified in these specimens.

Baseline fasting triglycerides were 123 mg/dL (desirable: <150 mg/dL; borderline: 150–199 mg/dL; high: ≥200 mg/dL) and were stable over the first 4 months on bexarotene. After 5 months of therapy, the triglycerides increased to a high of 255 mg/dL, which corresponded with the onset of LPP. She was treated for the hypertriglyceridemia with omega-3 fatty acids (fish oil), and subsequent triglyceride levels have normalized and been stable. Her alopecia has not progressed but is persistent. She continues to have central hypothyroidism due to bexarotene and is on levothyroxine. The lymphomatoid papulosis also remains stable with no signs of progression to cutaneous T-cell lymphoma.

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: Linear Vesiculobullous Keratosis Follicularis (Darier Disease)

Darier disease (DD), or keratosis follicularis, is typically an autosomal-dominant disorder that is characterized by greasy hyperkeratotic papules that coalesce into warty plaques with a predilection for seborrheic areas. The lesions usually are pruritic; malodorous; and may be exacerbated by sunlight, heat, or sweating. Darier disease may be accompanied by oral mucosal involvement including fine white papules on the palate.¹ The condition also can be accompanied by hand and nail involvement (95% of cases) including palmar pitting, punctate keratoses, hemorrhagic macules, palmoplantar keratoderma, and acrokeratosis verruciformis–like lesions on the dorsal aspects of the hands and feet. Nail changes predominately occur on the fingers, manifesting as longitudinal splitting, subungual hyperkeratosis, or characteristic white and red longitudinal bands with V-shaped nicks at the free margin of the nail. In linear DD, hand and nail involvement is rare and, when present, ipsilateral to the primary lesions.^1,2

The clinical variants of DD are classified by lesion morphology or distribution, or both. Morphological variants include vesiculobullous, cornified, erosive, acral hemorrhagic, and guttate leukodermic macular.^1,2 The clinical features of chronic relapsing vesicular lesions and histologic findings described in this case are consistent with vesiculobullous DD, though genetic testing was not performed.^3,4 As in our case, some patients lack a family history and the disease is thought to be the result of genetic mosaicism or somatic postzygotic mutations that affect a limited number of cells. These mosaic variants are named by their cutaneous distribution (ie, linear, segmental, unilateral, localized) and tend to course along the Blaschko lines, most commonly on the trunk. Studies have shown various types of mutations specific to the ATP2A2 gene in the affected tissue but not in the unaffected skin.⁵ This gene encodes for sarcoplasmic/endoplasmic reticulum ATPase SERCA2, which is responsible for intracellular calcium signaling. These mosaic forms of DD are unlikely to be inherited by offspring, in contrast to patients with mosaic epidermal nevi with epidermolytic hyperkeratosis who have a high likelihood of having children with generalized epidermolytic hyperkeratosis.⁶

Darier disease is a chronic incurable disease. Topical corticosteroid, retinoid, 5-fluorouracil, keratolytics, and laser ablation or excision are used in mild and limited disease with mixed outcomes.⁷ Oral retinoids are effective in severe or systemic cases of DD by inhibiting hyperkeratosis.⁸ Individuals with DD are predisposed to infection, warranting regular surveillance and use of antimicrobials and bleach baths. In addition to prophylaxis for bacterial superinfection, patients also are predisposed to getting disseminated herpes simplex virus in the form of eczema herpeticum.

In our patient, the diagnosis was confirmed by performing a punch biopsy from one of the vesicular lesions. Histopathologic examination revealed suprabasal acantholytic dyskeratosis with superficial perivascular and interstitial inflammation with eosinophils (Figure). Immunohistochemical staining showed no evidence of varicella-zoster virus or herpes simplex virus type 1 or type 2.

Histopathology revealed suprabasal acantholysis forming an intraepidermal cleft with superficial perivascular inflammation (A)(H&E, original magnification ×100) and acantholysis with dyskeratotic keratinocytes floating within the intraepidermal cleft (B)(H&E, original magnification ×200).

Our patient was prescribed tretinoin cream 0.1% daily and was advised to use sun protection and stop valacyclovir. At follow-up she noted decreased frequency of outbreaks after starting the tretinoin cream and the patient has now been free of any outbreaks for 8 months.

The Diagnosis: Linear Vesiculobullous Keratosis Follicularis (Darier Disease)

Darier disease (DD), or keratosis follicularis, is typically an autosomal-dominant disorder that is characterized by greasy hyperkeratotic papules that coalesce into warty plaques with a predilection for seborrheic areas. The lesions usually are pruritic; malodorous; and may be exacerbated by sunlight, heat, or sweating. Darier disease may be accompanied by oral mucosal involvement including fine white papules on the palate.¹ The condition also can be accompanied by hand and nail involvement (95% of cases) including palmar pitting, punctate keratoses, hemorrhagic macules, palmoplantar keratoderma, and acrokeratosis verruciformis–like lesions on the dorsal aspects of the hands and feet. Nail changes predominately occur on the fingers, manifesting as longitudinal splitting, subungual hyperkeratosis, or characteristic white and red longitudinal bands with V-shaped nicks at the free margin of the nail. In linear DD, hand and nail involvement is rare and, when present, ipsilateral to the primary lesions.^1,2

The clinical variants of DD are classified by lesion morphology or distribution, or both. Morphological variants include vesiculobullous, cornified, erosive, acral hemorrhagic, and guttate leukodermic macular.^1,2 The clinical features of chronic relapsing vesicular lesions and histologic findings described in this case are consistent with vesiculobullous DD, though genetic testing was not performed.^3,4 As in our case, some patients lack a family history and the disease is thought to be the result of genetic mosaicism or somatic postzygotic mutations that affect a limited number of cells. These mosaic variants are named by their cutaneous distribution (ie, linear, segmental, unilateral, localized) and tend to course along the Blaschko lines, most commonly on the trunk. Studies have shown various types of mutations specific to the ATP2A2 gene in the affected tissue but not in the unaffected skin.⁵ This gene encodes for sarcoplasmic/endoplasmic reticulum ATPase SERCA2, which is responsible for intracellular calcium signaling. These mosaic forms of DD are unlikely to be inherited by offspring, in contrast to patients with mosaic epidermal nevi with epidermolytic hyperkeratosis who have a high likelihood of having children with generalized epidermolytic hyperkeratosis.⁶

Darier disease is a chronic incurable disease. Topical corticosteroid, retinoid, 5-fluorouracil, keratolytics, and laser ablation or excision are used in mild and limited disease with mixed outcomes.⁷ Oral retinoids are effective in severe or systemic cases of DD by inhibiting hyperkeratosis.⁸ Individuals with DD are predisposed to infection, warranting regular surveillance and use of antimicrobials and bleach baths. In addition to prophylaxis for bacterial superinfection, patients also are predisposed to getting disseminated herpes simplex virus in the form of eczema herpeticum.

In our patient, the diagnosis was confirmed by performing a punch biopsy from one of the vesicular lesions. Histopathologic examination revealed suprabasal acantholytic dyskeratosis with superficial perivascular and interstitial inflammation with eosinophils (Figure). Immunohistochemical staining showed no evidence of varicella-zoster virus or herpes simplex virus type 1 or type 2.

Histopathology revealed suprabasal acantholysis forming an intraepidermal cleft with superficial perivascular inflammation (A)(H&E, original magnification ×100) and acantholysis with dyskeratotic keratinocytes floating within the intraepidermal cleft (B)(H&E, original magnification ×200).

Our patient was prescribed tretinoin cream 0.1% daily and was advised to use sun protection and stop valacyclovir. At follow-up she noted decreased frequency of outbreaks after starting the tretinoin cream and the patient has now been free of any outbreaks for 8 months.

The Diagnosis: Linear Vesiculobullous Keratosis Follicularis (Darier Disease)

Darier disease (DD), or keratosis follicularis, is typically an autosomal-dominant disorder that is characterized by greasy hyperkeratotic papules that coalesce into warty plaques with a predilection for seborrheic areas. The lesions usually are pruritic; malodorous; and may be exacerbated by sunlight, heat, or sweating. Darier disease may be accompanied by oral mucosal involvement including fine white papules on the palate.¹ The condition also can be accompanied by hand and nail involvement (95% of cases) including palmar pitting, punctate keratoses, hemorrhagic macules, palmoplantar keratoderma, and acrokeratosis verruciformis–like lesions on the dorsal aspects of the hands and feet. Nail changes predominately occur on the fingers, manifesting as longitudinal splitting, subungual hyperkeratosis, or characteristic white and red longitudinal bands with V-shaped nicks at the free margin of the nail. In linear DD, hand and nail involvement is rare and, when present, ipsilateral to the primary lesions.^1,2

The clinical variants of DD are classified by lesion morphology or distribution, or both. Morphological variants include vesiculobullous, cornified, erosive, acral hemorrhagic, and guttate leukodermic macular.^1,2 The clinical features of chronic relapsing vesicular lesions and histologic findings described in this case are consistent with vesiculobullous DD, though genetic testing was not performed.^3,4 As in our case, some patients lack a family history and the disease is thought to be the result of genetic mosaicism or somatic postzygotic mutations that affect a limited number of cells. These mosaic variants are named by their cutaneous distribution (ie, linear, segmental, unilateral, localized) and tend to course along the Blaschko lines, most commonly on the trunk. Studies have shown various types of mutations specific to the ATP2A2 gene in the affected tissue but not in the unaffected skin.⁵ This gene encodes for sarcoplasmic/endoplasmic reticulum ATPase SERCA2, which is responsible for intracellular calcium signaling. These mosaic forms of DD are unlikely to be inherited by offspring, in contrast to patients with mosaic epidermal nevi with epidermolytic hyperkeratosis who have a high likelihood of having children with generalized epidermolytic hyperkeratosis.⁶

Darier disease is a chronic incurable disease. Topical corticosteroid, retinoid, 5-fluorouracil, keratolytics, and laser ablation or excision are used in mild and limited disease with mixed outcomes.⁷ Oral retinoids are effective in severe or systemic cases of DD by inhibiting hyperkeratosis.⁸ Individuals with DD are predisposed to infection, warranting regular surveillance and use of antimicrobials and bleach baths. In addition to prophylaxis for bacterial superinfection, patients also are predisposed to getting disseminated herpes simplex virus in the form of eczema herpeticum.

In our patient, the diagnosis was confirmed by performing a punch biopsy from one of the vesicular lesions. Histopathologic examination revealed suprabasal acantholytic dyskeratosis with superficial perivascular and interstitial inflammation with eosinophils (Figure). Immunohistochemical staining showed no evidence of varicella-zoster virus or herpes simplex virus type 1 or type 2.

Histopathology revealed suprabasal acantholysis forming an intraepidermal cleft with superficial perivascular inflammation (A)(H&E, original magnification ×100) and acantholysis with dyskeratotic keratinocytes floating within the intraepidermal cleft (B)(H&E, original magnification ×200).

Our patient was prescribed tretinoin cream 0.1% daily and was advised to use sun protection and stop valacyclovir. At follow-up she noted decreased frequency of outbreaks after starting the tretinoin cream and the patient has now been free of any outbreaks for 8 months.