Dermatopathology

The Diagnosis: Lichen Nitidus 

Our patient represents a case of lichen nitidus (LN) that was diagnosed through clinicopathologic correlation, with the pathology results showing a lymphohistiocytic infiltrate in the papillary dermis enclosed by acanthotic rete ridges on either side. Lichen nitidus was first described by Pinkus in 1901 as a variant of lichen planus.¹ It is a rare chronic inflammatory disease that is most prevalent in children and adolescents.² Clinically, the lesions appear as 1- to 2-mm, shiny, flesh-colored papules with central umbilication.³ Typically, lesions are localized and discrete; however, vesicular, hemorrhagic, perforating, spinous follicular, linear, generalized, and actinic variants all have been reported in the literature. Lichen nitidus has a predilection for the lower abdomen, medial thighs, penis, forearms, ventral wrists, and hands.⁴ Cases of LN have been reported on the palms, soles, nails, and mucosa, presenting a diagnostic challenge.⁵ The pathogenesis of LN is unknown, and all races and sexes are affected equally.⁶  

Histopathologically, LN has distinct findings including a well-circumscribed lymphohistiocytic infiltrate in the papillary dermis embraced by elongated and acanthotic rete ridges.² These histopathologic characteristics were seen in our patient's biopsy specimen (Figure) and have been described as the ball-and-claw configuration. Lichen nitidus may be pruritic but typically is asymptomatic.⁷ It often spontaneously regresses within months to years without any treatment⁷; however, successful outcomes have been seen with topical steroids, UVA/UVB phototherapy, and retinoids.² Our patient was treated with topical steroids. 

The differential diagnosis for LN includes verruca plana, dyshidrotic eczema, acral persistent papular mucinosis (APPM), and molluscum contagiosum. Verruca plana can occur as 1- to 5-mm, grouped, flesh-colored papules on the face, neck, dorsal hands, wrists, or knees.⁸ Most commonly, verruca plana occurs due to human papillomavirus type 3 and less commonly human papillomavirus types 10, 27, and 41. Verruca plana is easily differentiated from LN on pathology with findings of epidermal hyperkeratosis, irregular acanthosis, and koilocytic changes.⁸  

Dyshidrotic eczema is a pruritic vesicular rash that is classically distributed symmetrically on the palmar aspects of the hands and lateral fingers.⁹ Histopathology of the lesions reveals spongiosis with an epidermal lymphocytic infiltrate. Exacerbating factors include exposure to allergens, stress, fungal infections, and genetic predisposition.⁹ 

Acral persistent papular mucinosis can present as multiple, 2- to 5-mm, flesh-colored papules on the dorsal aspects of the hands.¹⁰ However, the demographic is different from LN, as APPM most commonly affects middle-aged females versus adolescents. Lesions of APPM may multiply or spontaneously remit over time. Acral persistent papular mucinosis generally is asymptomatic but can be treated with cryotherapy, topical corticosteroids, electrodesiccation, or CO₂ lasers for cosmetic purposes. Acral persistent papular mucinosis can be easily distinguished from LN on histology, as it will show areas of focal, well-circumscribed mucin in the papillary dermis and a spared Grenz zone.¹⁰ 

Molluscum contagiosum is a common viral skin infection caused by the poxvirus that affects children and adults.¹¹ The skin lesions appear as 2- to 4-mm, dome-shaped, flesh-colored papules with central umbilication on the limbs, trunk, or face. Clinicians may choose to monitor lesions of molluscum contagiosum, as it is a self-limited condition, or it may be treated with cryotherapy, salicylic acid, imiquimod, curettage, laser, or cimetidine.¹¹ On histology, epidermal budlike proliferations can be appreciated in the dermis, and characteristic large, eosinophilic, intracytoplasmic inclusion or molluscum bodies are found in the epidermis.¹² 

The Diagnosis: Lichen Nitidus 

Our patient represents a case of lichen nitidus (LN) that was diagnosed through clinicopathologic correlation, with the pathology results showing a lymphohistiocytic infiltrate in the papillary dermis enclosed by acanthotic rete ridges on either side. Lichen nitidus was first described by Pinkus in 1901 as a variant of lichen planus.¹ It is a rare chronic inflammatory disease that is most prevalent in children and adolescents.² Clinically, the lesions appear as 1- to 2-mm, shiny, flesh-colored papules with central umbilication.³ Typically, lesions are localized and discrete; however, vesicular, hemorrhagic, perforating, spinous follicular, linear, generalized, and actinic variants all have been reported in the literature. Lichen nitidus has a predilection for the lower abdomen, medial thighs, penis, forearms, ventral wrists, and hands.⁴ Cases of LN have been reported on the palms, soles, nails, and mucosa, presenting a diagnostic challenge.⁵ The pathogenesis of LN is unknown, and all races and sexes are affected equally.⁶  

Histopathologically, LN has distinct findings including a well-circumscribed lymphohistiocytic infiltrate in the papillary dermis embraced by elongated and acanthotic rete ridges.² These histopathologic characteristics were seen in our patient's biopsy specimen (Figure) and have been described as the ball-and-claw configuration. Lichen nitidus may be pruritic but typically is asymptomatic.⁷ It often spontaneously regresses within months to years without any treatment⁷; however, successful outcomes have been seen with topical steroids, UVA/UVB phototherapy, and retinoids.² Our patient was treated with topical steroids. 

The differential diagnosis for LN includes verruca plana, dyshidrotic eczema, acral persistent papular mucinosis (APPM), and molluscum contagiosum. Verruca plana can occur as 1- to 5-mm, grouped, flesh-colored papules on the face, neck, dorsal hands, wrists, or knees.⁸ Most commonly, verruca plana occurs due to human papillomavirus type 3 and less commonly human papillomavirus types 10, 27, and 41. Verruca plana is easily differentiated from LN on pathology with findings of epidermal hyperkeratosis, irregular acanthosis, and koilocytic changes.⁸  

Dyshidrotic eczema is a pruritic vesicular rash that is classically distributed symmetrically on the palmar aspects of the hands and lateral fingers.⁹ Histopathology of the lesions reveals spongiosis with an epidermal lymphocytic infiltrate. Exacerbating factors include exposure to allergens, stress, fungal infections, and genetic predisposition.⁹ 

Acral persistent papular mucinosis can present as multiple, 2- to 5-mm, flesh-colored papules on the dorsal aspects of the hands.¹⁰ However, the demographic is different from LN, as APPM most commonly affects middle-aged females versus adolescents. Lesions of APPM may multiply or spontaneously remit over time. Acral persistent papular mucinosis generally is asymptomatic but can be treated with cryotherapy, topical corticosteroids, electrodesiccation, or CO₂ lasers for cosmetic purposes. Acral persistent papular mucinosis can be easily distinguished from LN on histology, as it will show areas of focal, well-circumscribed mucin in the papillary dermis and a spared Grenz zone.¹⁰ 

Molluscum contagiosum is a common viral skin infection caused by the poxvirus that affects children and adults.¹¹ The skin lesions appear as 2- to 4-mm, dome-shaped, flesh-colored papules with central umbilication on the limbs, trunk, or face. Clinicians may choose to monitor lesions of molluscum contagiosum, as it is a self-limited condition, or it may be treated with cryotherapy, salicylic acid, imiquimod, curettage, laser, or cimetidine.¹¹ On histology, epidermal budlike proliferations can be appreciated in the dermis, and characteristic large, eosinophilic, intracytoplasmic inclusion or molluscum bodies are found in the epidermis.¹² 

The Diagnosis: Lichen Nitidus 

Our patient represents a case of lichen nitidus (LN) that was diagnosed through clinicopathologic correlation, with the pathology results showing a lymphohistiocytic infiltrate in the papillary dermis enclosed by acanthotic rete ridges on either side. Lichen nitidus was first described by Pinkus in 1901 as a variant of lichen planus.¹ It is a rare chronic inflammatory disease that is most prevalent in children and adolescents.² Clinically, the lesions appear as 1- to 2-mm, shiny, flesh-colored papules with central umbilication.³ Typically, lesions are localized and discrete; however, vesicular, hemorrhagic, perforating, spinous follicular, linear, generalized, and actinic variants all have been reported in the literature. Lichen nitidus has a predilection for the lower abdomen, medial thighs, penis, forearms, ventral wrists, and hands.⁴ Cases of LN have been reported on the palms, soles, nails, and mucosa, presenting a diagnostic challenge.⁵ The pathogenesis of LN is unknown, and all races and sexes are affected equally.⁶  

Histopathologically, LN has distinct findings including a well-circumscribed lymphohistiocytic infiltrate in the papillary dermis embraced by elongated and acanthotic rete ridges.² These histopathologic characteristics were seen in our patient's biopsy specimen (Figure) and have been described as the ball-and-claw configuration. Lichen nitidus may be pruritic but typically is asymptomatic.⁷ It often spontaneously regresses within months to years without any treatment⁷; however, successful outcomes have been seen with topical steroids, UVA/UVB phototherapy, and retinoids.² Our patient was treated with topical steroids. 

The differential diagnosis for LN includes verruca plana, dyshidrotic eczema, acral persistent papular mucinosis (APPM), and molluscum contagiosum. Verruca plana can occur as 1- to 5-mm, grouped, flesh-colored papules on the face, neck, dorsal hands, wrists, or knees.⁸ Most commonly, verruca plana occurs due to human papillomavirus type 3 and less commonly human papillomavirus types 10, 27, and 41. Verruca plana is easily differentiated from LN on pathology with findings of epidermal hyperkeratosis, irregular acanthosis, and koilocytic changes.⁸  

Dyshidrotic eczema is a pruritic vesicular rash that is classically distributed symmetrically on the palmar aspects of the hands and lateral fingers.⁹ Histopathology of the lesions reveals spongiosis with an epidermal lymphocytic infiltrate. Exacerbating factors include exposure to allergens, stress, fungal infections, and genetic predisposition.⁹ 

Acral persistent papular mucinosis can present as multiple, 2- to 5-mm, flesh-colored papules on the dorsal aspects of the hands.¹⁰ However, the demographic is different from LN, as APPM most commonly affects middle-aged females versus adolescents. Lesions of APPM may multiply or spontaneously remit over time. Acral persistent papular mucinosis generally is asymptomatic but can be treated with cryotherapy, topical corticosteroids, electrodesiccation, or CO₂ lasers for cosmetic purposes. Acral persistent papular mucinosis can be easily distinguished from LN on histology, as it will show areas of focal, well-circumscribed mucin in the papillary dermis and a spared Grenz zone.¹⁰ 

Molluscum contagiosum is a common viral skin infection caused by the poxvirus that affects children and adults.¹¹ The skin lesions appear as 2- to 4-mm, dome-shaped, flesh-colored papules with central umbilication on the limbs, trunk, or face. Clinicians may choose to monitor lesions of molluscum contagiosum, as it is a self-limited condition, or it may be treated with cryotherapy, salicylic acid, imiquimod, curettage, laser, or cimetidine.¹¹ On histology, epidermal budlike proliferations can be appreciated in the dermis, and characteristic large, eosinophilic, intracytoplasmic inclusion or molluscum bodies are found in the epidermis.¹² 

The Diagnosis: Unilateral Dermatomal Trichoepithelioma  

Adnexal lesions presenting with a linear and/or dermatomal pattern rarely have been reported. Bolognia et al¹ performed a comprehensive review of Blaschko lines and skin conditions that follow such a pattern. The authors found that adnexal-related lesions included linear nevus comedonicus, linear basal cell nevus with comedones (linear basaloid follicular hamartoma), unilateral nevoid basal cell carcinoma (BCC), linear trichoepithelioma, linear trichodiscoma, linear hamartoma of the follicular infundibulum, nevus sebaceous, syringocystadenoma papilliferum, porokeratotic eccrine ostial and dermal duct nevus, linear eccrine poroma, linear spiradenoma, linear syringoma, and linear eccrine syringofibroadenoma.¹  

Trichoepithelioma is a hair follicle-related neoplastic lesion presenting most commonly as the autosomal-dominant multiple familial type with lesions mainly centered on the face. Initial genetic studies associated the disease with loss of heterozygosity in the 9p21 region and further studies identified mutations in the CYLD (cylindromatosis [turban tumor syndrome]) gene on chromosome 16q12-q13.^2,3 Unilateral, linear, and dermatomal forms of trichoepithelioma rarely are reported. In 1986, Geffner et al⁴ reported a case of linear and dermatomal trichoepithelioma in a 10-year-old girl. In addition to discrete solitary lesions affecting the face, she developed lesions on the left shoulder, left side of the trunk, and left lower leg following dermatomal distribution. In 2006, 2 cases of dermatomal trichoepitheliomas affecting the face in children, as in our case, were reported.^5,6 Another case involving the neck was reported in 2016.⁷ Although classic multiple familial trichoepithelioma can be part of conditions such as Brooke-Spiegler⁸ and Rombo syndromes,⁹ no syndromal association has been reported thus far with the unilateral, linear, or dermatomal variants.  

Our case showed typical histopathologic features of trichoepithelioma, including discrete islands of basaloid cells in the dermis set in a conspicuous fibroblastic stroma. Focal connection with the epidermis was present. Most of the islands showed peripheral palisading and horn cysts lined by eosinophilic cells. The fibroblastic component was tightly adherent to the epithelial component, and only stromal clefts were detected. Papillary mesenchymal bodies also were detected as oval aggregates of fibroblastic cells invaginating into epithelial islands to form hair papillae. 

Histopathologically, the 2 most important differential diagnoses of trichoepithelioma include BCC and basaloid follicular hamartoma. In differentiating BCC from trichoepithelioma, the presence of dense fibroblastic stroma and papillary mesenchymal bodies characterize trichoepithelioma, while a fibromucinous stroma with mucinous retraction artifacts and clefting between the basaloid islands and the stroma characterize BCC (Figure 1).¹⁰ Immunohistochemical studies using antibodies against Bcl-2, CD34, CD10, androgen receptor, Ki-67, cytokeratin 19, and PHLDA1 (pleckstrin homologylike domain family A member 1) have reportedly been utilized to differentiate trichoepithelioma from BCC.^11,12 Basaloid follicular hamartoma is characterized by thin anastomosing strands and branching cords of undifferentiated basaloid cells that replace or associate hair follicles in a latticelike pattern (Figure 2). The strands usually are vertically oriented perpendicular to the epidermis. Peripheral palisading is possible, and the basaloid strands are surrounded with cellular connective tissue stroma.¹³ Tumor islands in eccrine poroma show broad connections with the epidermis and are composed of poroid cells that show evident ductal differentiation with eosinophilic cuticles (Figure 3).¹⁴ Spiradenoma is characterized by capsulated deep-seated tumorous nodules not connected with the epidermis and composed of light and dark cells with ductal differentiation and vascular stroma (Figure 4). Scattered lymphocytes within the tumor lobules and in the stroma also are seen. Eosinophilic hyaline globules rarely can be present.¹⁵ 

Many pathologists consider trichoepithelioma as the superficial variant of trichoblastoma. According to the recent World Health Organization classification of benign tumors with follicular differentiation, trichoepithelioma is considered synonymous with trichoblastoma.¹⁶ 

Trichoepitheliomas are benign tumors, and therapy is mainly directed at removal for cosmetic purposes. Several methods of removal are available including electrocautery, laser therapy, and surgery. Awareness of the possible dermatomal distribution of hair follicle and other adnexal-related conditions is important, and such lesions should be thought of in the differential diagnosis of unilateral and/or dermatomal lesions.

The Diagnosis: Unilateral Dermatomal Trichoepithelioma  

Adnexal lesions presenting with a linear and/or dermatomal pattern rarely have been reported. Bolognia et al¹ performed a comprehensive review of Blaschko lines and skin conditions that follow such a pattern. The authors found that adnexal-related lesions included linear nevus comedonicus, linear basal cell nevus with comedones (linear basaloid follicular hamartoma), unilateral nevoid basal cell carcinoma (BCC), linear trichoepithelioma, linear trichodiscoma, linear hamartoma of the follicular infundibulum, nevus sebaceous, syringocystadenoma papilliferum, porokeratotic eccrine ostial and dermal duct nevus, linear eccrine poroma, linear spiradenoma, linear syringoma, and linear eccrine syringofibroadenoma.¹  

Trichoepithelioma is a hair follicle-related neoplastic lesion presenting most commonly as the autosomal-dominant multiple familial type with lesions mainly centered on the face. Initial genetic studies associated the disease with loss of heterozygosity in the 9p21 region and further studies identified mutations in the CYLD (cylindromatosis [turban tumor syndrome]) gene on chromosome 16q12-q13.^2,3 Unilateral, linear, and dermatomal forms of trichoepithelioma rarely are reported. In 1986, Geffner et al⁴ reported a case of linear and dermatomal trichoepithelioma in a 10-year-old girl. In addition to discrete solitary lesions affecting the face, she developed lesions on the left shoulder, left side of the trunk, and left lower leg following dermatomal distribution. In 2006, 2 cases of dermatomal trichoepitheliomas affecting the face in children, as in our case, were reported.^5,6 Another case involving the neck was reported in 2016.⁷ Although classic multiple familial trichoepithelioma can be part of conditions such as Brooke-Spiegler⁸ and Rombo syndromes,⁹ no syndromal association has been reported thus far with the unilateral, linear, or dermatomal variants.  

Our case showed typical histopathologic features of trichoepithelioma, including discrete islands of basaloid cells in the dermis set in a conspicuous fibroblastic stroma. Focal connection with the epidermis was present. Most of the islands showed peripheral palisading and horn cysts lined by eosinophilic cells. The fibroblastic component was tightly adherent to the epithelial component, and only stromal clefts were detected. Papillary mesenchymal bodies also were detected as oval aggregates of fibroblastic cells invaginating into epithelial islands to form hair papillae. 

Histopathologically, the 2 most important differential diagnoses of trichoepithelioma include BCC and basaloid follicular hamartoma. In differentiating BCC from trichoepithelioma, the presence of dense fibroblastic stroma and papillary mesenchymal bodies characterize trichoepithelioma, while a fibromucinous stroma with mucinous retraction artifacts and clefting between the basaloid islands and the stroma characterize BCC (Figure 1).¹⁰ Immunohistochemical studies using antibodies against Bcl-2, CD34, CD10, androgen receptor, Ki-67, cytokeratin 19, and PHLDA1 (pleckstrin homologylike domain family A member 1) have reportedly been utilized to differentiate trichoepithelioma from BCC.^11,12 Basaloid follicular hamartoma is characterized by thin anastomosing strands and branching cords of undifferentiated basaloid cells that replace or associate hair follicles in a latticelike pattern (Figure 2). The strands usually are vertically oriented perpendicular to the epidermis. Peripheral palisading is possible, and the basaloid strands are surrounded with cellular connective tissue stroma.¹³ Tumor islands in eccrine poroma show broad connections with the epidermis and are composed of poroid cells that show evident ductal differentiation with eosinophilic cuticles (Figure 3).¹⁴ Spiradenoma is characterized by capsulated deep-seated tumorous nodules not connected with the epidermis and composed of light and dark cells with ductal differentiation and vascular stroma (Figure 4). Scattered lymphocytes within the tumor lobules and in the stroma also are seen. Eosinophilic hyaline globules rarely can be present.¹⁵ 

Many pathologists consider trichoepithelioma as the superficial variant of trichoblastoma. According to the recent World Health Organization classification of benign tumors with follicular differentiation, trichoepithelioma is considered synonymous with trichoblastoma.¹⁶ 

Trichoepitheliomas are benign tumors, and therapy is mainly directed at removal for cosmetic purposes. Several methods of removal are available including electrocautery, laser therapy, and surgery. Awareness of the possible dermatomal distribution of hair follicle and other adnexal-related conditions is important, and such lesions should be thought of in the differential diagnosis of unilateral and/or dermatomal lesions.

The Diagnosis: Unilateral Dermatomal Trichoepithelioma  

Adnexal lesions presenting with a linear and/or dermatomal pattern rarely have been reported. Bolognia et al¹ performed a comprehensive review of Blaschko lines and skin conditions that follow such a pattern. The authors found that adnexal-related lesions included linear nevus comedonicus, linear basal cell nevus with comedones (linear basaloid follicular hamartoma), unilateral nevoid basal cell carcinoma (BCC), linear trichoepithelioma, linear trichodiscoma, linear hamartoma of the follicular infundibulum, nevus sebaceous, syringocystadenoma papilliferum, porokeratotic eccrine ostial and dermal duct nevus, linear eccrine poroma, linear spiradenoma, linear syringoma, and linear eccrine syringofibroadenoma.¹  

Trichoepithelioma is a hair follicle-related neoplastic lesion presenting most commonly as the autosomal-dominant multiple familial type with lesions mainly centered on the face. Initial genetic studies associated the disease with loss of heterozygosity in the 9p21 region and further studies identified mutations in the CYLD (cylindromatosis [turban tumor syndrome]) gene on chromosome 16q12-q13.^2,3 Unilateral, linear, and dermatomal forms of trichoepithelioma rarely are reported. In 1986, Geffner et al⁴ reported a case of linear and dermatomal trichoepithelioma in a 10-year-old girl. In addition to discrete solitary lesions affecting the face, she developed lesions on the left shoulder, left side of the trunk, and left lower leg following dermatomal distribution. In 2006, 2 cases of dermatomal trichoepitheliomas affecting the face in children, as in our case, were reported.^5,6 Another case involving the neck was reported in 2016.⁷ Although classic multiple familial trichoepithelioma can be part of conditions such as Brooke-Spiegler⁸ and Rombo syndromes,⁹ no syndromal association has been reported thus far with the unilateral, linear, or dermatomal variants.  

Our case showed typical histopathologic features of trichoepithelioma, including discrete islands of basaloid cells in the dermis set in a conspicuous fibroblastic stroma. Focal connection with the epidermis was present. Most of the islands showed peripheral palisading and horn cysts lined by eosinophilic cells. The fibroblastic component was tightly adherent to the epithelial component, and only stromal clefts were detected. Papillary mesenchymal bodies also were detected as oval aggregates of fibroblastic cells invaginating into epithelial islands to form hair papillae. 

Histopathologically, the 2 most important differential diagnoses of trichoepithelioma include BCC and basaloid follicular hamartoma. In differentiating BCC from trichoepithelioma, the presence of dense fibroblastic stroma and papillary mesenchymal bodies characterize trichoepithelioma, while a fibromucinous stroma with mucinous retraction artifacts and clefting between the basaloid islands and the stroma characterize BCC (Figure 1).¹⁰ Immunohistochemical studies using antibodies against Bcl-2, CD34, CD10, androgen receptor, Ki-67, cytokeratin 19, and PHLDA1 (pleckstrin homologylike domain family A member 1) have reportedly been utilized to differentiate trichoepithelioma from BCC.^11,12 Basaloid follicular hamartoma is characterized by thin anastomosing strands and branching cords of undifferentiated basaloid cells that replace or associate hair follicles in a latticelike pattern (Figure 2). The strands usually are vertically oriented perpendicular to the epidermis. Peripheral palisading is possible, and the basaloid strands are surrounded with cellular connective tissue stroma.¹³ Tumor islands in eccrine poroma show broad connections with the epidermis and are composed of poroid cells that show evident ductal differentiation with eosinophilic cuticles (Figure 3).¹⁴ Spiradenoma is characterized by capsulated deep-seated tumorous nodules not connected with the epidermis and composed of light and dark cells with ductal differentiation and vascular stroma (Figure 4). Scattered lymphocytes within the tumor lobules and in the stroma also are seen. Eosinophilic hyaline globules rarely can be present.¹⁵ 

Many pathologists consider trichoepithelioma as the superficial variant of trichoblastoma. According to the recent World Health Organization classification of benign tumors with follicular differentiation, trichoepithelioma is considered synonymous with trichoblastoma.¹⁶ 

Trichoepitheliomas are benign tumors, and therapy is mainly directed at removal for cosmetic purposes. Several methods of removal are available including electrocautery, laser therapy, and surgery. Awareness of the possible dermatomal distribution of hair follicle and other adnexal-related conditions is important, and such lesions should be thought of in the differential diagnosis of unilateral and/or dermatomal lesions.

To the Editor:

Epidermolysis bullosa (EB) was first described in 1886, with the first classification scheme proposed in 1962 utilizing transmission electron microscopy (TEM) findings to delineate categories: epidermolytic (EB simplex [EBS]), lucidolytic (junctional EB), and dermolytic (dystrophic EB).¹ Localized EBS (EBS-loc) is an autosomal-dominant disorder caused by negative mutations in keratin-5 and keratin-14, proteins expressed in the intermediate filaments of basal keratinocytes, which result in fragility of the skin in response to minor trauma.² The incidence of EBS-loc is approximately 10 to 30 cases per million live births, with the age of presentation typically between the first and third decades of life.^3,4 Because EBS-loc is the most common and often mildest form of EB, not all patients present for medical evaluation and true prevalence may be underestimated.⁴ We report a case of EBS-loc.

A 26-year-old woman with no notable medical history presented to the dermatology clinic for evaluation of skin blisters that had been intermittently present since infancy. The blisters primarily occurred on the feet, but she did occasionally develop blisters on the hands, knees, and elbows and at sites of friction or trauma (eg, bra line, medial thighs) following exercise. The blisters were worsened by heat and tight-fitting shoes. Because of the painful nature of the blisters, she would lance them with a needle. On the medial thighs, she utilized nonstick and gauze bandage roll dressings to minimize friction. A review of systems was positive for hyperhidrosis. Her family history revealed multiple family members with blisters involving the feet and areas of friction or trauma for 4 generations with no known diagnosis.

Physical examination revealed multiple tense bullae and calluses scattered over the bilateral plantar and distal dorsal feet with a few healing, superficially eroded, erythematous papules and plaques on the bilateral medial thighs (Figure 1). A biopsy from an induced blister on the right dorsal second toe was performed and sent in glutaraldehyde to the Epidermolysis Bullosa Clinic at Stanford University (Redwood City, California) for electron microscopy, which revealed lysis within the basal keratinocytes through the tonofilaments with continuous and intact lamina densa and lamina lucida (Figure 2). In this clinical context with the relevant family history, the findings were consistent with the diagnosis of EBS-loc (formerly Weber-Cockayne syndrome).²

Light microscopy does not have a notable role in diagnosis of classic forms of inherited EB unless another autoimmune blistering disorder is suspected.^2,5 Both TEM and immunofluorescence mapping are used to diagnose EB.¹ DNA mutational analysis is not considered a first-line diagnostic test for EB given it is a costly labor-intensive technique with limited access at present, but it may be considered in settings of prenatal diagnosis or in vitro fertilization.¹ Biopsy of a freshly induced blister should be performed, as early reepithelialization of an existing blister makes it difficult to establish the level of cleavage.⁵ Applying firm pressure using a pencil eraser and rotating it on intact skin induces a subclinical blister. Two punch biopsies (4 mm) at the edge of the blister with one-third lesional and two-thirds perilesional skin should be obtained, with one biopsy sent for immunofluorescence mapping in Michel fixative and the other for TEM in glutaraldehyde.^3,5 Transmission electron microscopy of an induced blister in EBS-loc shows cleavage within the most inferior portion of the basilar keratinocyte.² Immunofluorescence mapping with anti–epidermal basement membrane monoclonal antibodies can distinguish between EB subtypes and assess expression of specific skin-associated proteins on both a qualitative or semiquantitative basis, providing insight on which structural protein is mutated.^1,5

No specific treatments are available for EBS-loc. Mainstays of treatment include prevention of mechanical trauma and secondary infection. Hyperhidrosis of thepalms and soles may be treated with topical aluminum chloride hexahydrate or injections of botulinum toxin type A.^2,6 Patients have normal life expectancy, though some cases may have complications with substantial morbidity.¹ Awareness of this disease, its clinical course, and therapeutic options will allow physicians to more appropriately counsel patients on the disease process.

Localized EBS may be more common than previously thought, as not all patients seek medical care. Given its impact on patient quality of life, it is important for clinicians to recognize EBS-loc. Although no specific treatments are available, wound care counseling and explanation of the genetics of the disease should be provided to patients.

To the Editor:

Epidermolysis bullosa (EB) was first described in 1886, with the first classification scheme proposed in 1962 utilizing transmission electron microscopy (TEM) findings to delineate categories: epidermolytic (EB simplex [EBS]), lucidolytic (junctional EB), and dermolytic (dystrophic EB).¹ Localized EBS (EBS-loc) is an autosomal-dominant disorder caused by negative mutations in keratin-5 and keratin-14, proteins expressed in the intermediate filaments of basal keratinocytes, which result in fragility of the skin in response to minor trauma.² The incidence of EBS-loc is approximately 10 to 30 cases per million live births, with the age of presentation typically between the first and third decades of life.^3,4 Because EBS-loc is the most common and often mildest form of EB, not all patients present for medical evaluation and true prevalence may be underestimated.⁴ We report a case of EBS-loc.

A 26-year-old woman with no notable medical history presented to the dermatology clinic for evaluation of skin blisters that had been intermittently present since infancy. The blisters primarily occurred on the feet, but she did occasionally develop blisters on the hands, knees, and elbows and at sites of friction or trauma (eg, bra line, medial thighs) following exercise. The blisters were worsened by heat and tight-fitting shoes. Because of the painful nature of the blisters, she would lance them with a needle. On the medial thighs, she utilized nonstick and gauze bandage roll dressings to minimize friction. A review of systems was positive for hyperhidrosis. Her family history revealed multiple family members with blisters involving the feet and areas of friction or trauma for 4 generations with no known diagnosis.

Physical examination revealed multiple tense bullae and calluses scattered over the bilateral plantar and distal dorsal feet with a few healing, superficially eroded, erythematous papules and plaques on the bilateral medial thighs (Figure 1). A biopsy from an induced blister on the right dorsal second toe was performed and sent in glutaraldehyde to the Epidermolysis Bullosa Clinic at Stanford University (Redwood City, California) for electron microscopy, which revealed lysis within the basal keratinocytes through the tonofilaments with continuous and intact lamina densa and lamina lucida (Figure 2). In this clinical context with the relevant family history, the findings were consistent with the diagnosis of EBS-loc (formerly Weber-Cockayne syndrome).²

Light microscopy does not have a notable role in diagnosis of classic forms of inherited EB unless another autoimmune blistering disorder is suspected.^2,5 Both TEM and immunofluorescence mapping are used to diagnose EB.¹ DNA mutational analysis is not considered a first-line diagnostic test for EB given it is a costly labor-intensive technique with limited access at present, but it may be considered in settings of prenatal diagnosis or in vitro fertilization.¹ Biopsy of a freshly induced blister should be performed, as early reepithelialization of an existing blister makes it difficult to establish the level of cleavage.⁵ Applying firm pressure using a pencil eraser and rotating it on intact skin induces a subclinical blister. Two punch biopsies (4 mm) at the edge of the blister with one-third lesional and two-thirds perilesional skin should be obtained, with one biopsy sent for immunofluorescence mapping in Michel fixative and the other for TEM in glutaraldehyde.^3,5 Transmission electron microscopy of an induced blister in EBS-loc shows cleavage within the most inferior portion of the basilar keratinocyte.² Immunofluorescence mapping with anti–epidermal basement membrane monoclonal antibodies can distinguish between EB subtypes and assess expression of specific skin-associated proteins on both a qualitative or semiquantitative basis, providing insight on which structural protein is mutated.^1,5

No specific treatments are available for EBS-loc. Mainstays of treatment include prevention of mechanical trauma and secondary infection. Hyperhidrosis of thepalms and soles may be treated with topical aluminum chloride hexahydrate or injections of botulinum toxin type A.^2,6 Patients have normal life expectancy, though some cases may have complications with substantial morbidity.¹ Awareness of this disease, its clinical course, and therapeutic options will allow physicians to more appropriately counsel patients on the disease process.

Localized EBS may be more common than previously thought, as not all patients seek medical care. Given its impact on patient quality of life, it is important for clinicians to recognize EBS-loc. Although no specific treatments are available, wound care counseling and explanation of the genetics of the disease should be provided to patients.

To the Editor:

Epidermolysis bullosa (EB) was first described in 1886, with the first classification scheme proposed in 1962 utilizing transmission electron microscopy (TEM) findings to delineate categories: epidermolytic (EB simplex [EBS]), lucidolytic (junctional EB), and dermolytic (dystrophic EB).¹ Localized EBS (EBS-loc) is an autosomal-dominant disorder caused by negative mutations in keratin-5 and keratin-14, proteins expressed in the intermediate filaments of basal keratinocytes, which result in fragility of the skin in response to minor trauma.² The incidence of EBS-loc is approximately 10 to 30 cases per million live births, with the age of presentation typically between the first and third decades of life.^3,4 Because EBS-loc is the most common and often mildest form of EB, not all patients present for medical evaluation and true prevalence may be underestimated.⁴ We report a case of EBS-loc.

A 26-year-old woman with no notable medical history presented to the dermatology clinic for evaluation of skin blisters that had been intermittently present since infancy. The blisters primarily occurred on the feet, but she did occasionally develop blisters on the hands, knees, and elbows and at sites of friction or trauma (eg, bra line, medial thighs) following exercise. The blisters were worsened by heat and tight-fitting shoes. Because of the painful nature of the blisters, she would lance them with a needle. On the medial thighs, she utilized nonstick and gauze bandage roll dressings to minimize friction. A review of systems was positive for hyperhidrosis. Her family history revealed multiple family members with blisters involving the feet and areas of friction or trauma for 4 generations with no known diagnosis.

Physical examination revealed multiple tense bullae and calluses scattered over the bilateral plantar and distal dorsal feet with a few healing, superficially eroded, erythematous papules and plaques on the bilateral medial thighs (Figure 1). A biopsy from an induced blister on the right dorsal second toe was performed and sent in glutaraldehyde to the Epidermolysis Bullosa Clinic at Stanford University (Redwood City, California) for electron microscopy, which revealed lysis within the basal keratinocytes through the tonofilaments with continuous and intact lamina densa and lamina lucida (Figure 2). In this clinical context with the relevant family history, the findings were consistent with the diagnosis of EBS-loc (formerly Weber-Cockayne syndrome).²

Light microscopy does not have a notable role in diagnosis of classic forms of inherited EB unless another autoimmune blistering disorder is suspected.^2,5 Both TEM and immunofluorescence mapping are used to diagnose EB.¹ DNA mutational analysis is not considered a first-line diagnostic test for EB given it is a costly labor-intensive technique with limited access at present, but it may be considered in settings of prenatal diagnosis or in vitro fertilization.¹ Biopsy of a freshly induced blister should be performed, as early reepithelialization of an existing blister makes it difficult to establish the level of cleavage.⁵ Applying firm pressure using a pencil eraser and rotating it on intact skin induces a subclinical blister. Two punch biopsies (4 mm) at the edge of the blister with one-third lesional and two-thirds perilesional skin should be obtained, with one biopsy sent for immunofluorescence mapping in Michel fixative and the other for TEM in glutaraldehyde.^3,5 Transmission electron microscopy of an induced blister in EBS-loc shows cleavage within the most inferior portion of the basilar keratinocyte.² Immunofluorescence mapping with anti–epidermal basement membrane monoclonal antibodies can distinguish between EB subtypes and assess expression of specific skin-associated proteins on both a qualitative or semiquantitative basis, providing insight on which structural protein is mutated.^1,5

No specific treatments are available for EBS-loc. Mainstays of treatment include prevention of mechanical trauma and secondary infection. Hyperhidrosis of thepalms and soles may be treated with topical aluminum chloride hexahydrate or injections of botulinum toxin type A.^2,6 Patients have normal life expectancy, though some cases may have complications with substantial morbidity.¹ Awareness of this disease, its clinical course, and therapeutic options will allow physicians to more appropriately counsel patients on the disease process.

Localized EBS may be more common than previously thought, as not all patients seek medical care. Given its impact on patient quality of life, it is important for clinicians to recognize EBS-loc. Although no specific treatments are available, wound care counseling and explanation of the genetics of the disease should be provided to patients.

Relapsing polychondritis (RP) is a recurrent inflammatory condition involving primarily cartilaginous structures. The disease, first described as a clinical entity in 1960 by Pearson et al,¹ is rare with an estimated incidence of 3.5 cases per 1 million individuals.² The pathogenesis of RP is widely accepted as being autoimmune in nature, largely due to the identification of circulating autoantibodies seen in the sera of patients with similar clinical pictures.³

Although in most patients the primary process involves inflammation of cartilage, a subset of patients experience involvement of noncartilaginous sites.⁴ The degree of systemic involvement varies from none to notable, affecting the cardiovascular and respiratory systems and potentially leading to life-threatening complications, including cardiac valve compromise and airway collapse. Relapsing polychondritis is considered to be a progressive disease with the ultimate potential to be life-threatening.⁵

Human immunodeficiency virus (HIV) infection leads to a profound state of immune dysregulation, affecting innate, adaptive, and natural killer components of the immune system.⁶ There is variability in the development of autoimmune disease in HIV patients depending on the stage of infection. The frequency of rheumatologic disease in HIV patients might be as high as 60%.⁶ Relapsing polychondritis is rare in patients with HIV.^7-9 Of 4 reported cases, 2 patients had other coexisting autoimmune disease—sarcoidosis and Behçet disease.^8,9

Case Report

A 36-year-old man presented to the clinic with a concern of recurrent ear pain and swelling of approximately 2 years’ duration. Onset was sudden without inciting event. Symptoms initially involved the right ear with eventual progression to both ears. Additional symptoms included an auditory perception of underwater submersion, intermittent vertigo, and 3 episodes of throat closure sensation.

The patient’s medical history was notable for asthma; gastritis; depression; and HIV infection, which was diagnosed 4 years earlier and adequately managed with highly active antiretroviral therapy. His family history was notable for systemic lupus erythematosus in his mother, maternal aunt, and maternal cousin.

At presentation, the patient’s CD4 count was 799 cells/mm³ with an undetectable viral load. Medications included abacavir-dolutegravir-lamivudine, hydroxyzine, meclizine, mometasone, and quetiapine. Physical examination showed erythema, swelling, and tenderness of the left and right auricles with sparing of the earlobe that was more noticeable on the left ear (Figure 1). Bacterial culture from the external auditory meatus was positive for methicillin-resistant Staphylococcus aureus. Biopsy revealed chronic inflammatory perichondritis with mild to moderate fibrosis and chronic lymphocytic inflammation at the dermal cartilaginous junction (Figure 2). A direct immunofluorescent biopsy was unremarkable, but subsequent type II collagen antibodies were positive (35.5 endotoxin units/mL [reference range, <20 endotoxin units/mL]).

Comment

Relapsing polychondritis is an uncommon progressive disease characterized by recurrent inflammatory insults to cartilaginous and proteoglycan-rich structures.⁴ The most consistent clinical features of RP are ear inflammation that involves the auricle and spares the lobe, nasal chondritis, and arthralgia.¹⁰ Laryngotracheal compromise may occur from tracheal cartilage inflammation. The involvement of these specific structures is due to commonality between their component collagens.⁵ Although any organ system can be affected, as many as 50% of patients have respiratory tract involvement, which may affect any portion of the respiratory tree.¹¹ If involving the larynx, this inflammation can lead to severe edema warranting intubation. Cardiovascular involvement is present in 24% to 52% of patients,¹⁰ which most commonly manifests as valvular impairment affecting the aortic valve more frequently than the mitral valve.⁵

Pathogenesis
Although the etiology of RP remains undetermined, multiple hypotheses have been proposed. One is that a certain subset of patients is predisposed to autoimmunity, and a secondary triggering event in the form of infection, malignancy, or medication catalyzes development of RP. A second hypothesis is that mechanical trauma to cartilage exposes the immune system to certain antigens that would have otherwise remained hidden, prompting autosensitization.^12,13

Regardless of cause, an autoimmune pathogenesis is favored based on the following observations: RP is frequently associated with other autoimmune diseases in the same patient, glucocorticosteroids and other immunosuppressive therapies are effective for treatment, and histopathologic findings include an infiltrate of CD4⁺ T lymphocytes with detection of immunoglobulins and plasma cells in different lesions.⁵ The detection of autoantibodies against collagen in the serum of patients with RP further supports an autoimmune pathogenesis.³ The earliest identified autoantibodies in patients with RP were against type II collagen. Subsequent studies have identified autoantibodies against type IV and type XI collagens as well as other cartilage-related proteins such as matrilin 1¹⁴ and cartilage oligomeric matrix proteins.¹⁵ Although circulating antibodies to type II collagen are present in a variable number of patients with the disease (30%–70%), levels likely correlate with disease activity and are highest at times of acute inflammation.³ Additionally, titers of type II collagen antibodies have been shown to decrease upon institution of immunosuppressive therapy.¹⁶

Although a humoral response dominates the picture of RP, there also is an associated T cell–mediated response.¹³ Histopathologically, biopsy of an active lesion of auricular cartilage shows a mixed inflammatory infiltrate composed primarily of lymphocytes, with variable numbers of polymorphonuclear cells, monocytes, and plasma cells. Loss of basophilia of the cartilage matrix can be observed, thought to be the result of proteoglycan depletion.¹³ Later, lesions classically display apoptosis of chondrocytes, focal calcification, or fibrosis.⁵

Diagnosis
Relapsing polychondritis acts classically as an autoimmune disease with a variable presentation, making diagnosis a challenge. Many sets of diagnostic criteria have been proposed. The most referenced remains the original criteria described by McAdam et al.¹⁷ In 2012, the Relapsing Polychondritis Disease Activity Index modified criteria set forth by Michet et al¹⁸ and might serve as the standard for diagnosis going forward.¹⁹

McAdam et al¹⁷ proposed that 3 of 6 clinical features are necessary for diagnosis: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, and audiovestibular damage. Michet et al¹⁸ proposed that 1 of 2 conditions are necessary for diagnosis of RP: (1) proven inflammation in 2 of 3 of the auricular, nasal, or laryngotracheal cartilages; or (2) proven inflammation in 1 of 3 of the auricular, nasal, or laryngotracheal cartilages, plus 2 other signs, including ocular inflammation, vestibular dysfunction, seronegative inflammatory arthritis, and hearing loss.

These criteria were proposed originally in 1976¹⁷ and modified in 1986.¹⁸ No further updates have been offered since then. As such, serologic findings, such as antibodies against type II collagen, are not included in the diagnostic criteria. Additionally, these antibodies are not specific for RP and can be seen in other conditions such as rheumatoid arthritis.²⁰

More recently, imaging analysis has been employed in conjunction with clinical and serologic data to diagnose the disease and evaluate its severity. The use of imaging modalities for these purposes is most beneficial in patients with notable disease and respiratory involvement.²¹

Although the clinical picture is typified by the classic findings described above, the clinician must be aware of more subtle clues to diagnosis,¹¹ which is of particular importance to the dermatologist because 35% of patients with RP alone will have skin manifestations that can precede onset of chondritis.¹⁰ Most commonly, dermatologic manifestations are nonspecific and can include nodules on the limbs, purpura, and urticarial lesions.²² Individual case reports have noted the coexistence of RP with erythema multiforme,¹⁸ erythema annulare centrifugum,²³ pyoderma gangrenosum,²⁴ and panniculitis,¹⁸ among other disorders.

Severe systemic involvement leads to increased mortality and warrants more aggressive treatment.²² Commonly used agents include the immunosuppressants cyclophosphamide, cyclosporine, and methotrexate. Tumor necrosis factor α inhibitors have been the most widely utilized immunomodulatory agent for treatment of RP.^25,26 Abatacept and rituximab also have been used with variable efficacy in patients with severe disease. Recently, the IL-6 receptor blocker tocilizumab has been used with some success.²⁷

Prognosis
The prognosis for patients with RP largely depends on the severity of disease and degree of internal involvement. With improved management, largely due to awareness and recognition of disease, the survival rate among RP patients has increased from 55% at 10 years to 94% at the end of 8 years.¹⁸ The main cause of death in RP patients is airway complications related to laryngotracheal involvement.¹⁰ The second most common cause of death is cardiovascular complications in which valvular disease predominates.⁵

Concomitant Illness
Thirty-five percent of RP patients have coexisting autoimmune disease, the most common being antineutrophil cytoplasmic antibody–associated vasculitis.^5,28 Although this association with autoimmune disease is well described, reports of RP occurring in other states of immune dysfunction are sparse. One case of RP has been reported in a child with common variable immunodeficiency thought to be related to underlying abnormal immune regulation and immunodeficiency.²⁹ Relapsing polychondritis has been described in 4 patients with HIV, 2 of whom had concomitant autoimmune disease.^7-9

Human immunodeficiency virus infection is a well-established cause of immune dysregulation and has variable association with autoimmunity. This variability depends largely on the stage of infection. When divided into stages, autoimmune diseases develop predominantly in stage I, during acute infection with an intact immune system; in stage III, with immunosuppression, a low CD4 count, and development of AIDS; and in stage IV, when the immune system is restored with the institution of highly active antiretroviral therapy.⁶ The interplay between HIV infection and development of autoimmune disease is complex, and pathogenesis remains speculative.

Conclusion

Our patient represents a case of RP in an HIV-positive patient. Additionally, our patient had no other identifiable autoimmune conditions but did have a strong family history of them. It is important for providers to be aware of the potential for development of RP as well as other autoimmune disease in the setting of HIV infection. The implications of a missed diagnosis could be dire because the disease course of RP is progressive and has the potential to decrease survival.

Relapsing polychondritis (RP) is a recurrent inflammatory condition involving primarily cartilaginous structures. The disease, first described as a clinical entity in 1960 by Pearson et al,¹ is rare with an estimated incidence of 3.5 cases per 1 million individuals.² The pathogenesis of RP is widely accepted as being autoimmune in nature, largely due to the identification of circulating autoantibodies seen in the sera of patients with similar clinical pictures.³

Although in most patients the primary process involves inflammation of cartilage, a subset of patients experience involvement of noncartilaginous sites.⁴ The degree of systemic involvement varies from none to notable, affecting the cardiovascular and respiratory systems and potentially leading to life-threatening complications, including cardiac valve compromise and airway collapse. Relapsing polychondritis is considered to be a progressive disease with the ultimate potential to be life-threatening.⁵

Human immunodeficiency virus (HIV) infection leads to a profound state of immune dysregulation, affecting innate, adaptive, and natural killer components of the immune system.⁶ There is variability in the development of autoimmune disease in HIV patients depending on the stage of infection. The frequency of rheumatologic disease in HIV patients might be as high as 60%.⁶ Relapsing polychondritis is rare in patients with HIV.^7-9 Of 4 reported cases, 2 patients had other coexisting autoimmune disease—sarcoidosis and Behçet disease.^8,9

Case Report

A 36-year-old man presented to the clinic with a concern of recurrent ear pain and swelling of approximately 2 years’ duration. Onset was sudden without inciting event. Symptoms initially involved the right ear with eventual progression to both ears. Additional symptoms included an auditory perception of underwater submersion, intermittent vertigo, and 3 episodes of throat closure sensation.

The patient’s medical history was notable for asthma; gastritis; depression; and HIV infection, which was diagnosed 4 years earlier and adequately managed with highly active antiretroviral therapy. His family history was notable for systemic lupus erythematosus in his mother, maternal aunt, and maternal cousin.

At presentation, the patient’s CD4 count was 799 cells/mm³ with an undetectable viral load. Medications included abacavir-dolutegravir-lamivudine, hydroxyzine, meclizine, mometasone, and quetiapine. Physical examination showed erythema, swelling, and tenderness of the left and right auricles with sparing of the earlobe that was more noticeable on the left ear (Figure 1). Bacterial culture from the external auditory meatus was positive for methicillin-resistant Staphylococcus aureus. Biopsy revealed chronic inflammatory perichondritis with mild to moderate fibrosis and chronic lymphocytic inflammation at the dermal cartilaginous junction (Figure 2). A direct immunofluorescent biopsy was unremarkable, but subsequent type II collagen antibodies were positive (35.5 endotoxin units/mL [reference range, <20 endotoxin units/mL]).

Comment

Relapsing polychondritis is an uncommon progressive disease characterized by recurrent inflammatory insults to cartilaginous and proteoglycan-rich structures.⁴ The most consistent clinical features of RP are ear inflammation that involves the auricle and spares the lobe, nasal chondritis, and arthralgia.¹⁰ Laryngotracheal compromise may occur from tracheal cartilage inflammation. The involvement of these specific structures is due to commonality between their component collagens.⁵ Although any organ system can be affected, as many as 50% of patients have respiratory tract involvement, which may affect any portion of the respiratory tree.¹¹ If involving the larynx, this inflammation can lead to severe edema warranting intubation. Cardiovascular involvement is present in 24% to 52% of patients,¹⁰ which most commonly manifests as valvular impairment affecting the aortic valve more frequently than the mitral valve.⁵

Pathogenesis
Although the etiology of RP remains undetermined, multiple hypotheses have been proposed. One is that a certain subset of patients is predisposed to autoimmunity, and a secondary triggering event in the form of infection, malignancy, or medication catalyzes development of RP. A second hypothesis is that mechanical trauma to cartilage exposes the immune system to certain antigens that would have otherwise remained hidden, prompting autosensitization.^12,13

Regardless of cause, an autoimmune pathogenesis is favored based on the following observations: RP is frequently associated with other autoimmune diseases in the same patient, glucocorticosteroids and other immunosuppressive therapies are effective for treatment, and histopathologic findings include an infiltrate of CD4⁺ T lymphocytes with detection of immunoglobulins and plasma cells in different lesions.⁵ The detection of autoantibodies against collagen in the serum of patients with RP further supports an autoimmune pathogenesis.³ The earliest identified autoantibodies in patients with RP were against type II collagen. Subsequent studies have identified autoantibodies against type IV and type XI collagens as well as other cartilage-related proteins such as matrilin 1¹⁴ and cartilage oligomeric matrix proteins.¹⁵ Although circulating antibodies to type II collagen are present in a variable number of patients with the disease (30%–70%), levels likely correlate with disease activity and are highest at times of acute inflammation.³ Additionally, titers of type II collagen antibodies have been shown to decrease upon institution of immunosuppressive therapy.¹⁶

Although a humoral response dominates the picture of RP, there also is an associated T cell–mediated response.¹³ Histopathologically, biopsy of an active lesion of auricular cartilage shows a mixed inflammatory infiltrate composed primarily of lymphocytes, with variable numbers of polymorphonuclear cells, monocytes, and plasma cells. Loss of basophilia of the cartilage matrix can be observed, thought to be the result of proteoglycan depletion.¹³ Later, lesions classically display apoptosis of chondrocytes, focal calcification, or fibrosis.⁵

Diagnosis
Relapsing polychondritis acts classically as an autoimmune disease with a variable presentation, making diagnosis a challenge. Many sets of diagnostic criteria have been proposed. The most referenced remains the original criteria described by McAdam et al.¹⁷ In 2012, the Relapsing Polychondritis Disease Activity Index modified criteria set forth by Michet et al¹⁸ and might serve as the standard for diagnosis going forward.¹⁹

McAdam et al¹⁷ proposed that 3 of 6 clinical features are necessary for diagnosis: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, and audiovestibular damage. Michet et al¹⁸ proposed that 1 of 2 conditions are necessary for diagnosis of RP: (1) proven inflammation in 2 of 3 of the auricular, nasal, or laryngotracheal cartilages; or (2) proven inflammation in 1 of 3 of the auricular, nasal, or laryngotracheal cartilages, plus 2 other signs, including ocular inflammation, vestibular dysfunction, seronegative inflammatory arthritis, and hearing loss.

These criteria were proposed originally in 1976¹⁷ and modified in 1986.¹⁸ No further updates have been offered since then. As such, serologic findings, such as antibodies against type II collagen, are not included in the diagnostic criteria. Additionally, these antibodies are not specific for RP and can be seen in other conditions such as rheumatoid arthritis.²⁰

More recently, imaging analysis has been employed in conjunction with clinical and serologic data to diagnose the disease and evaluate its severity. The use of imaging modalities for these purposes is most beneficial in patients with notable disease and respiratory involvement.²¹

Although the clinical picture is typified by the classic findings described above, the clinician must be aware of more subtle clues to diagnosis,¹¹ which is of particular importance to the dermatologist because 35% of patients with RP alone will have skin manifestations that can precede onset of chondritis.¹⁰ Most commonly, dermatologic manifestations are nonspecific and can include nodules on the limbs, purpura, and urticarial lesions.²² Individual case reports have noted the coexistence of RP with erythema multiforme,¹⁸ erythema annulare centrifugum,²³ pyoderma gangrenosum,²⁴ and panniculitis,¹⁸ among other disorders.

Severe systemic involvement leads to increased mortality and warrants more aggressive treatment.²² Commonly used agents include the immunosuppressants cyclophosphamide, cyclosporine, and methotrexate. Tumor necrosis factor α inhibitors have been the most widely utilized immunomodulatory agent for treatment of RP.^25,26 Abatacept and rituximab also have been used with variable efficacy in patients with severe disease. Recently, the IL-6 receptor blocker tocilizumab has been used with some success.²⁷

Prognosis
The prognosis for patients with RP largely depends on the severity of disease and degree of internal involvement. With improved management, largely due to awareness and recognition of disease, the survival rate among RP patients has increased from 55% at 10 years to 94% at the end of 8 years.¹⁸ The main cause of death in RP patients is airway complications related to laryngotracheal involvement.¹⁰ The second most common cause of death is cardiovascular complications in which valvular disease predominates.⁵

Concomitant Illness
Thirty-five percent of RP patients have coexisting autoimmune disease, the most common being antineutrophil cytoplasmic antibody–associated vasculitis.^5,28 Although this association with autoimmune disease is well described, reports of RP occurring in other states of immune dysfunction are sparse. One case of RP has been reported in a child with common variable immunodeficiency thought to be related to underlying abnormal immune regulation and immunodeficiency.²⁹ Relapsing polychondritis has been described in 4 patients with HIV, 2 of whom had concomitant autoimmune disease.^7-9

Human immunodeficiency virus infection is a well-established cause of immune dysregulation and has variable association with autoimmunity. This variability depends largely on the stage of infection. When divided into stages, autoimmune diseases develop predominantly in stage I, during acute infection with an intact immune system; in stage III, with immunosuppression, a low CD4 count, and development of AIDS; and in stage IV, when the immune system is restored with the institution of highly active antiretroviral therapy.⁶ The interplay between HIV infection and development of autoimmune disease is complex, and pathogenesis remains speculative.

Conclusion

Our patient represents a case of RP in an HIV-positive patient. Additionally, our patient had no other identifiable autoimmune conditions but did have a strong family history of them. It is important for providers to be aware of the potential for development of RP as well as other autoimmune disease in the setting of HIV infection. The implications of a missed diagnosis could be dire because the disease course of RP is progressive and has the potential to decrease survival.

Relapsing polychondritis (RP) is a recurrent inflammatory condition involving primarily cartilaginous structures. The disease, first described as a clinical entity in 1960 by Pearson et al,¹ is rare with an estimated incidence of 3.5 cases per 1 million individuals.² The pathogenesis of RP is widely accepted as being autoimmune in nature, largely due to the identification of circulating autoantibodies seen in the sera of patients with similar clinical pictures.³

Although in most patients the primary process involves inflammation of cartilage, a subset of patients experience involvement of noncartilaginous sites.⁴ The degree of systemic involvement varies from none to notable, affecting the cardiovascular and respiratory systems and potentially leading to life-threatening complications, including cardiac valve compromise and airway collapse. Relapsing polychondritis is considered to be a progressive disease with the ultimate potential to be life-threatening.⁵

Human immunodeficiency virus (HIV) infection leads to a profound state of immune dysregulation, affecting innate, adaptive, and natural killer components of the immune system.⁶ There is variability in the development of autoimmune disease in HIV patients depending on the stage of infection. The frequency of rheumatologic disease in HIV patients might be as high as 60%.⁶ Relapsing polychondritis is rare in patients with HIV.^7-9 Of 4 reported cases, 2 patients had other coexisting autoimmune disease—sarcoidosis and Behçet disease.^8,9

Case Report

A 36-year-old man presented to the clinic with a concern of recurrent ear pain and swelling of approximately 2 years’ duration. Onset was sudden without inciting event. Symptoms initially involved the right ear with eventual progression to both ears. Additional symptoms included an auditory perception of underwater submersion, intermittent vertigo, and 3 episodes of throat closure sensation.

The patient’s medical history was notable for asthma; gastritis; depression; and HIV infection, which was diagnosed 4 years earlier and adequately managed with highly active antiretroviral therapy. His family history was notable for systemic lupus erythematosus in his mother, maternal aunt, and maternal cousin.

At presentation, the patient’s CD4 count was 799 cells/mm³ with an undetectable viral load. Medications included abacavir-dolutegravir-lamivudine, hydroxyzine, meclizine, mometasone, and quetiapine. Physical examination showed erythema, swelling, and tenderness of the left and right auricles with sparing of the earlobe that was more noticeable on the left ear (Figure 1). Bacterial culture from the external auditory meatus was positive for methicillin-resistant Staphylococcus aureus. Biopsy revealed chronic inflammatory perichondritis with mild to moderate fibrosis and chronic lymphocytic inflammation at the dermal cartilaginous junction (Figure 2). A direct immunofluorescent biopsy was unremarkable, but subsequent type II collagen antibodies were positive (35.5 endotoxin units/mL [reference range, <20 endotoxin units/mL]).

Comment

Relapsing polychondritis is an uncommon progressive disease characterized by recurrent inflammatory insults to cartilaginous and proteoglycan-rich structures.⁴ The most consistent clinical features of RP are ear inflammation that involves the auricle and spares the lobe, nasal chondritis, and arthralgia.¹⁰ Laryngotracheal compromise may occur from tracheal cartilage inflammation. The involvement of these specific structures is due to commonality between their component collagens.⁵ Although any organ system can be affected, as many as 50% of patients have respiratory tract involvement, which may affect any portion of the respiratory tree.¹¹ If involving the larynx, this inflammation can lead to severe edema warranting intubation. Cardiovascular involvement is present in 24% to 52% of patients,¹⁰ which most commonly manifests as valvular impairment affecting the aortic valve more frequently than the mitral valve.⁵

Pathogenesis
Although the etiology of RP remains undetermined, multiple hypotheses have been proposed. One is that a certain subset of patients is predisposed to autoimmunity, and a secondary triggering event in the form of infection, malignancy, or medication catalyzes development of RP. A second hypothesis is that mechanical trauma to cartilage exposes the immune system to certain antigens that would have otherwise remained hidden, prompting autosensitization.^12,13

Regardless of cause, an autoimmune pathogenesis is favored based on the following observations: RP is frequently associated with other autoimmune diseases in the same patient, glucocorticosteroids and other immunosuppressive therapies are effective for treatment, and histopathologic findings include an infiltrate of CD4⁺ T lymphocytes with detection of immunoglobulins and plasma cells in different lesions.⁵ The detection of autoantibodies against collagen in the serum of patients with RP further supports an autoimmune pathogenesis.³ The earliest identified autoantibodies in patients with RP were against type II collagen. Subsequent studies have identified autoantibodies against type IV and type XI collagens as well as other cartilage-related proteins such as matrilin 1¹⁴ and cartilage oligomeric matrix proteins.¹⁵ Although circulating antibodies to type II collagen are present in a variable number of patients with the disease (30%–70%), levels likely correlate with disease activity and are highest at times of acute inflammation.³ Additionally, titers of type II collagen antibodies have been shown to decrease upon institution of immunosuppressive therapy.¹⁶

Although a humoral response dominates the picture of RP, there also is an associated T cell–mediated response.¹³ Histopathologically, biopsy of an active lesion of auricular cartilage shows a mixed inflammatory infiltrate composed primarily of lymphocytes, with variable numbers of polymorphonuclear cells, monocytes, and plasma cells. Loss of basophilia of the cartilage matrix can be observed, thought to be the result of proteoglycan depletion.¹³ Later, lesions classically display apoptosis of chondrocytes, focal calcification, or fibrosis.⁵

Diagnosis
Relapsing polychondritis acts classically as an autoimmune disease with a variable presentation, making diagnosis a challenge. Many sets of diagnostic criteria have been proposed. The most referenced remains the original criteria described by McAdam et al.¹⁷ In 2012, the Relapsing Polychondritis Disease Activity Index modified criteria set forth by Michet et al¹⁸ and might serve as the standard for diagnosis going forward.¹⁹

McAdam et al¹⁷ proposed that 3 of 6 clinical features are necessary for diagnosis: bilateral auricular chondritis, nonerosive seronegative inflammatory polyarthritis, nasal chondritis, ocular inflammation, respiratory tract chondritis, and audiovestibular damage. Michet et al¹⁸ proposed that 1 of 2 conditions are necessary for diagnosis of RP: (1) proven inflammation in 2 of 3 of the auricular, nasal, or laryngotracheal cartilages; or (2) proven inflammation in 1 of 3 of the auricular, nasal, or laryngotracheal cartilages, plus 2 other signs, including ocular inflammation, vestibular dysfunction, seronegative inflammatory arthritis, and hearing loss.

These criteria were proposed originally in 1976¹⁷ and modified in 1986.¹⁸ No further updates have been offered since then. As such, serologic findings, such as antibodies against type II collagen, are not included in the diagnostic criteria. Additionally, these antibodies are not specific for RP and can be seen in other conditions such as rheumatoid arthritis.²⁰

More recently, imaging analysis has been employed in conjunction with clinical and serologic data to diagnose the disease and evaluate its severity. The use of imaging modalities for these purposes is most beneficial in patients with notable disease and respiratory involvement.²¹

Although the clinical picture is typified by the classic findings described above, the clinician must be aware of more subtle clues to diagnosis,¹¹ which is of particular importance to the dermatologist because 35% of patients with RP alone will have skin manifestations that can precede onset of chondritis.¹⁰ Most commonly, dermatologic manifestations are nonspecific and can include nodules on the limbs, purpura, and urticarial lesions.²² Individual case reports have noted the coexistence of RP with erythema multiforme,¹⁸ erythema annulare centrifugum,²³ pyoderma gangrenosum,²⁴ and panniculitis,¹⁸ among other disorders.

Severe systemic involvement leads to increased mortality and warrants more aggressive treatment.²² Commonly used agents include the immunosuppressants cyclophosphamide, cyclosporine, and methotrexate. Tumor necrosis factor α inhibitors have been the most widely utilized immunomodulatory agent for treatment of RP.^25,26 Abatacept and rituximab also have been used with variable efficacy in patients with severe disease. Recently, the IL-6 receptor blocker tocilizumab has been used with some success.²⁷

Prognosis
The prognosis for patients with RP largely depends on the severity of disease and degree of internal involvement. With improved management, largely due to awareness and recognition of disease, the survival rate among RP patients has increased from 55% at 10 years to 94% at the end of 8 years.¹⁸ The main cause of death in RP patients is airway complications related to laryngotracheal involvement.¹⁰ The second most common cause of death is cardiovascular complications in which valvular disease predominates.⁵

Concomitant Illness
Thirty-five percent of RP patients have coexisting autoimmune disease, the most common being antineutrophil cytoplasmic antibody–associated vasculitis.^5,28 Although this association with autoimmune disease is well described, reports of RP occurring in other states of immune dysfunction are sparse. One case of RP has been reported in a child with common variable immunodeficiency thought to be related to underlying abnormal immune regulation and immunodeficiency.²⁹ Relapsing polychondritis has been described in 4 patients with HIV, 2 of whom had concomitant autoimmune disease.^7-9

Human immunodeficiency virus infection is a well-established cause of immune dysregulation and has variable association with autoimmunity. This variability depends largely on the stage of infection. When divided into stages, autoimmune diseases develop predominantly in stage I, during acute infection with an intact immune system; in stage III, with immunosuppression, a low CD4 count, and development of AIDS; and in stage IV, when the immune system is restored with the institution of highly active antiretroviral therapy.⁶ The interplay between HIV infection and development of autoimmune disease is complex, and pathogenesis remains speculative.

Conclusion

Our patient represents a case of RP in an HIV-positive patient. Additionally, our patient had no other identifiable autoimmune conditions but did have a strong family history of them. It is important for providers to be aware of the potential for development of RP as well as other autoimmune disease in the setting of HIV infection. The implications of a missed diagnosis could be dire because the disease course of RP is progressive and has the potential to decrease survival.

Herpes zoster (HZ) is a painful skin condition caused by reactivation of latent varicella-zoster virus (VZV) in dorsal root ganglion cells.¹ Upon reactivation, VZV replicates in the dorsal root ganglion, which ultimately results in inflammation and necrosis of the neuron and intense neuralgia. Reactivation of latent VZV may occur spontaneously or may be induced by various factors including immunosuppression, stress, illness, and trauma. Prior to the development of skin lesions, many patients experience a prodrome of tingling, pain, or pruritus. Herpes zoster classically presents with grouped vesicles on an erythematous base in a unilateral dermatomal distribution; however, more than one adjacent dermatome may be involved, and the lesions can cross the midline. Furthermore, the development of vesicles may be preceded by the development of edematous papules or plaques.¹

On histology, VZV closely resembles herpes simplex virus type 1 and herpes simplex virus type 2 infections.² Classic histologic findings include ballooning degeneration of keratinocytes, acantholysis, nuclear molding, ground-glass nuclear inclusions, marginated chromatin, and multinucleated keratinocytes, as well as necrosis of follicles and sebaceous glands.² Varicella-zoster virus polymerase chain reaction or immunostaining can be used to confirm the diagnosis.²

Classic mycosis fungoides (MF) presents with well-circumscribed erythematous patches in non–sun-exposed areas and eventually may progress to plaques and tumors.³ Patients with cutaneous T-cell lymphomas, such as MF, are at a higher risk for skin infections including HZ^4,5; however, immunocompromised patients, such as those with cutaneous lymphomas, can have atypical clinical presentations of HZ that may be concerning for cutaneous lymphoma.⁶ Furthermore, cutaneous malignancies can occur in dermatomal distributions that may mimic HZ.⁷ Therefore, the threshold for biopsy should be lowered in those patients with dermatomal lesions and history concerning for possible malignancy.

Classically, histologic examination of MF demonstrates an infiltrate of haloed cells at the dermoepidermal junction, which are atypical T cells with hyperchromatic cerebriform nuclei that are larger, darker, and more angulated than the benign recruited lymphocytes in the perivascular infiltrate seen in VZV infection (Figure 1).³ Papillary dermal fibrosis typically is present, and the perivascular infiltrate is denser above the postcapillary venule rather than being symmetrical around the vessel (bare underbelly sign). Clusters of these cells may form within the epidermis, which are called Pautrier microabscesses.³ Mycosis fungoides also can exhibit large cell transformation in which small lymphocytes transform into larger cells, thereby associated with a poorer prognosis.⁸

Lymphomatoid papulosis is a CD30+-predominant form of cutaneous T-cell lymphoma characterized by papules and nodules that spontaneously involute.⁹ This condition is most commonly associated with MF but can be associated with other lymphomas. This condition may be mistaken for HZ clinically, but histology classically demonstrates large atypical lymphocytes resembling Reed-Sternberg cells in small clusters rather than follicular necrosis (Figure 2).⁹

Patients with lymphoma may sequentially develop a secondary lymphoma. There have been reports of secondary B-cell lymphomas associated with MF, but this phenomenon is rare.¹⁰ The histology depends on the type of B-cell lymphoma present, but follicular necrosis would not be expected (Figure 3).

Unusual hypersensitivity reactions to arthropod attacks have been described in patients with lymphoproliferative disorders and could be mistaken for HZ. Histology may demonstrate a wedge-shaped perivascular and/or interstitial infiltrate containing eosinophils with endothelial swelling (Figure 4), but these findings may vary depending on the type of arthropod involved.¹¹

Our case provided a unique example of HZ in a patient with a known history of MF. Clinically, there was concern for progression of the patient’s underlying disease; however, histology demonstrated ballooning keratinocytes and follicular necrosis, which are classically seen in HZ infection.

Herpes zoster (HZ) is a painful skin condition caused by reactivation of latent varicella-zoster virus (VZV) in dorsal root ganglion cells.¹ Upon reactivation, VZV replicates in the dorsal root ganglion, which ultimately results in inflammation and necrosis of the neuron and intense neuralgia. Reactivation of latent VZV may occur spontaneously or may be induced by various factors including immunosuppression, stress, illness, and trauma. Prior to the development of skin lesions, many patients experience a prodrome of tingling, pain, or pruritus. Herpes zoster classically presents with grouped vesicles on an erythematous base in a unilateral dermatomal distribution; however, more than one adjacent dermatome may be involved, and the lesions can cross the midline. Furthermore, the development of vesicles may be preceded by the development of edematous papules or plaques.¹

On histology, VZV closely resembles herpes simplex virus type 1 and herpes simplex virus type 2 infections.² Classic histologic findings include ballooning degeneration of keratinocytes, acantholysis, nuclear molding, ground-glass nuclear inclusions, marginated chromatin, and multinucleated keratinocytes, as well as necrosis of follicles and sebaceous glands.² Varicella-zoster virus polymerase chain reaction or immunostaining can be used to confirm the diagnosis.²

Classic mycosis fungoides (MF) presents with well-circumscribed erythematous patches in non–sun-exposed areas and eventually may progress to plaques and tumors.³ Patients with cutaneous T-cell lymphomas, such as MF, are at a higher risk for skin infections including HZ^4,5; however, immunocompromised patients, such as those with cutaneous lymphomas, can have atypical clinical presentations of HZ that may be concerning for cutaneous lymphoma.⁶ Furthermore, cutaneous malignancies can occur in dermatomal distributions that may mimic HZ.⁷ Therefore, the threshold for biopsy should be lowered in those patients with dermatomal lesions and history concerning for possible malignancy.

Classically, histologic examination of MF demonstrates an infiltrate of haloed cells at the dermoepidermal junction, which are atypical T cells with hyperchromatic cerebriform nuclei that are larger, darker, and more angulated than the benign recruited lymphocytes in the perivascular infiltrate seen in VZV infection (Figure 1).³ Papillary dermal fibrosis typically is present, and the perivascular infiltrate is denser above the postcapillary venule rather than being symmetrical around the vessel (bare underbelly sign). Clusters of these cells may form within the epidermis, which are called Pautrier microabscesses.³ Mycosis fungoides also can exhibit large cell transformation in which small lymphocytes transform into larger cells, thereby associated with a poorer prognosis.⁸

Lymphomatoid papulosis is a CD30+-predominant form of cutaneous T-cell lymphoma characterized by papules and nodules that spontaneously involute.⁹ This condition is most commonly associated with MF but can be associated with other lymphomas. This condition may be mistaken for HZ clinically, but histology classically demonstrates large atypical lymphocytes resembling Reed-Sternberg cells in small clusters rather than follicular necrosis (Figure 2).⁹

Patients with lymphoma may sequentially develop a secondary lymphoma. There have been reports of secondary B-cell lymphomas associated with MF, but this phenomenon is rare.¹⁰ The histology depends on the type of B-cell lymphoma present, but follicular necrosis would not be expected (Figure 3).

Unusual hypersensitivity reactions to arthropod attacks have been described in patients with lymphoproliferative disorders and could be mistaken for HZ. Histology may demonstrate a wedge-shaped perivascular and/or interstitial infiltrate containing eosinophils with endothelial swelling (Figure 4), but these findings may vary depending on the type of arthropod involved.¹¹

Our case provided a unique example of HZ in a patient with a known history of MF. Clinically, there was concern for progression of the patient’s underlying disease; however, histology demonstrated ballooning keratinocytes and follicular necrosis, which are classically seen in HZ infection.

Herpes zoster (HZ) is a painful skin condition caused by reactivation of latent varicella-zoster virus (VZV) in dorsal root ganglion cells.¹ Upon reactivation, VZV replicates in the dorsal root ganglion, which ultimately results in inflammation and necrosis of the neuron and intense neuralgia. Reactivation of latent VZV may occur spontaneously or may be induced by various factors including immunosuppression, stress, illness, and trauma. Prior to the development of skin lesions, many patients experience a prodrome of tingling, pain, or pruritus. Herpes zoster classically presents with grouped vesicles on an erythematous base in a unilateral dermatomal distribution; however, more than one adjacent dermatome may be involved, and the lesions can cross the midline. Furthermore, the development of vesicles may be preceded by the development of edematous papules or plaques.¹

On histology, VZV closely resembles herpes simplex virus type 1 and herpes simplex virus type 2 infections.² Classic histologic findings include ballooning degeneration of keratinocytes, acantholysis, nuclear molding, ground-glass nuclear inclusions, marginated chromatin, and multinucleated keratinocytes, as well as necrosis of follicles and sebaceous glands.² Varicella-zoster virus polymerase chain reaction or immunostaining can be used to confirm the diagnosis.²

Classic mycosis fungoides (MF) presents with well-circumscribed erythematous patches in non–sun-exposed areas and eventually may progress to plaques and tumors.³ Patients with cutaneous T-cell lymphomas, such as MF, are at a higher risk for skin infections including HZ^4,5; however, immunocompromised patients, such as those with cutaneous lymphomas, can have atypical clinical presentations of HZ that may be concerning for cutaneous lymphoma.⁶ Furthermore, cutaneous malignancies can occur in dermatomal distributions that may mimic HZ.⁷ Therefore, the threshold for biopsy should be lowered in those patients with dermatomal lesions and history concerning for possible malignancy.

Classically, histologic examination of MF demonstrates an infiltrate of haloed cells at the dermoepidermal junction, which are atypical T cells with hyperchromatic cerebriform nuclei that are larger, darker, and more angulated than the benign recruited lymphocytes in the perivascular infiltrate seen in VZV infection (Figure 1).³ Papillary dermal fibrosis typically is present, and the perivascular infiltrate is denser above the postcapillary venule rather than being symmetrical around the vessel (bare underbelly sign). Clusters of these cells may form within the epidermis, which are called Pautrier microabscesses.³ Mycosis fungoides also can exhibit large cell transformation in which small lymphocytes transform into larger cells, thereby associated with a poorer prognosis.⁸

Lymphomatoid papulosis is a CD30+-predominant form of cutaneous T-cell lymphoma characterized by papules and nodules that spontaneously involute.⁹ This condition is most commonly associated with MF but can be associated with other lymphomas. This condition may be mistaken for HZ clinically, but histology classically demonstrates large atypical lymphocytes resembling Reed-Sternberg cells in small clusters rather than follicular necrosis (Figure 2).⁹

Patients with lymphoma may sequentially develop a secondary lymphoma. There have been reports of secondary B-cell lymphomas associated with MF, but this phenomenon is rare.¹⁰ The histology depends on the type of B-cell lymphoma present, but follicular necrosis would not be expected (Figure 3).

Unusual hypersensitivity reactions to arthropod attacks have been described in patients with lymphoproliferative disorders and could be mistaken for HZ. Histology may demonstrate a wedge-shaped perivascular and/or interstitial infiltrate containing eosinophils with endothelial swelling (Figure 4), but these findings may vary depending on the type of arthropod involved.¹¹

Our case provided a unique example of HZ in a patient with a known history of MF. Clinically, there was concern for progression of the patient’s underlying disease; however, histology demonstrated ballooning keratinocytes and follicular necrosis, which are classically seen in HZ infection.

WASHINGTON – The 31-gene expression profile test has met the highest level of evidence under the Strength of Recommendation Taxonomy (SORT) method as a prognostic marker for accurately predicting recurrence-free survival and distant metastasis-free survival and melanoma-specific survival, according to results presented by Bradley N. Greenhaw, MD, at a late-breaking research session at the annual meeting of the American Academy of Dermatology.

Dr. Greenhaw, a dermatologist affiliated with the North Mississippi Medical Center-Tupelo, and his colleagues pooled together 1,268 patients from the following studies that analyzed results from melanoma patients who had their disease classified with the 31-gene expression profile (31-GEP) test.

• A single-center study, conducted by Dr. Greenhaw and his associates (Greenhaw BN et al. Dermatol Surg. 2018 Dec. doi: 10.1097/DSS.0000000000001588.
• A multicenter prospective study (J Hematol Oncol. 2017 Aug. doi: 10.1186/s13045-017-0520-1.
• A retrospective archival study (J Am Acad Dermatol. 2019 Jan. doi: 10.1016/j.jaad.2018.07.028.

The 31-GEP test stratifies an individual’s likelihood of developing metastasis within 5 years as low and high risk. In the three studies, the test was used to identify tumors with low-risk (class 1A, class 1B), higher-risk (class 2A), and highest-risk (class 2B) melanoma based on tumor gene expression. In these individual studies, class 2B melanoma independently predicted recurrence-free survival (RFS), distant metastasis–free, and melanoma-specific survival.

Dr. Greenhaw and colleagues performed a meta-analysis of 1,268 patients with stage I through stage III melanoma from those three studies, using fixed and random effects weighting to account for study differences and heterogeneity, respectively. For class 2B tumors, they found a 2.96 increased risk for recurrent metastases and a 2.88 increased risk for distant metastases. The researchers also found no heterogeneity across the studies.

Melanoma-specific survival was not included in the meta-analysis because one paper did not contain any mortality events in class 1A melanoma patients.

“The meta-analysis demonstrated that the GEP test was able to accurately identify those melanoma patients who were at higher risk of metastasis, and we saw a consistent effect across multiple studies,” Dr. Greenhaw said.

Since publication of the 2019 JAAD paper, there were an additional 211 patients who met inclusion criteria and were included in an additional meta-analysis to determine whether inclusion of these patients affected the results. Dr. Greenhaw and colleagues found a 91.4% recurrence-free survival rate and a 94.1% distant metastasis–free survival rate for class 1A melanomas, compared with 45.7% and 55.5% , respectively, for class 2B tumors.

“You can see a big divergence,” Dr. Greenhaw said at the meeting. “Just by using this one test, it’s able to separate out melanomas that otherwise may be grouped in together under current AJCC [American Joint Committee on Cancer] staging,” he added. “The class 2B designation really did confirm a higher risk for recurrence in distant metastasis.”

The researchers used the SORT method to rate the quality of the data across all three studies. Level 1 evidence under the SORT method represents a systematic review or meta-analysis of good-quality studies and/or a prospective study with good follow-up, while an A-level recommendation represents good, quality evidence. Based on the meta-analysis results, the 31-GEP test meets level 1A evidence under the SORT method, Dr. Greenhaw said.

As a prognostic tool, 31-GEP has the potential to change how dermatologists manage their patients with regard to follow-up and adjuvant therapy. “It is being used not just as this novel test that gives us more information, it’s being used clinically,” said Dr. Greenhaw, who noted he regularly uses the 31-GEP test in his practice.

This is the first time that a meta-analysis has been performed for this test, he noted.

Dr. Greenhaw reports a pending relationship with Castle Biosciences.

SOURCE: Greenhaw BN et al. AAD 19. Session F055, Abstract 11370.

WASHINGTON – The 31-gene expression profile test has met the highest level of evidence under the Strength of Recommendation Taxonomy (SORT) method as a prognostic marker for accurately predicting recurrence-free survival and distant metastasis-free survival and melanoma-specific survival, according to results presented by Bradley N. Greenhaw, MD, at a late-breaking research session at the annual meeting of the American Academy of Dermatology.

Dr. Greenhaw, a dermatologist affiliated with the North Mississippi Medical Center-Tupelo, and his colleagues pooled together 1,268 patients from the following studies that analyzed results from melanoma patients who had their disease classified with the 31-gene expression profile (31-GEP) test.

• A single-center study, conducted by Dr. Greenhaw and his associates (Greenhaw BN et al. Dermatol Surg. 2018 Dec. doi: 10.1097/DSS.0000000000001588.
• A multicenter prospective study (J Hematol Oncol. 2017 Aug. doi: 10.1186/s13045-017-0520-1.
• A retrospective archival study (J Am Acad Dermatol. 2019 Jan. doi: 10.1016/j.jaad.2018.07.028.

The 31-GEP test stratifies an individual’s likelihood of developing metastasis within 5 years as low and high risk. In the three studies, the test was used to identify tumors with low-risk (class 1A, class 1B), higher-risk (class 2A), and highest-risk (class 2B) melanoma based on tumor gene expression. In these individual studies, class 2B melanoma independently predicted recurrence-free survival (RFS), distant metastasis–free, and melanoma-specific survival.

Dr. Greenhaw and colleagues performed a meta-analysis of 1,268 patients with stage I through stage III melanoma from those three studies, using fixed and random effects weighting to account for study differences and heterogeneity, respectively. For class 2B tumors, they found a 2.96 increased risk for recurrent metastases and a 2.88 increased risk for distant metastases. The researchers also found no heterogeneity across the studies.

Melanoma-specific survival was not included in the meta-analysis because one paper did not contain any mortality events in class 1A melanoma patients.

“The meta-analysis demonstrated that the GEP test was able to accurately identify those melanoma patients who were at higher risk of metastasis, and we saw a consistent effect across multiple studies,” Dr. Greenhaw said.

Since publication of the 2019 JAAD paper, there were an additional 211 patients who met inclusion criteria and were included in an additional meta-analysis to determine whether inclusion of these patients affected the results. Dr. Greenhaw and colleagues found a 91.4% recurrence-free survival rate and a 94.1% distant metastasis–free survival rate for class 1A melanomas, compared with 45.7% and 55.5% , respectively, for class 2B tumors.

“You can see a big divergence,” Dr. Greenhaw said at the meeting. “Just by using this one test, it’s able to separate out melanomas that otherwise may be grouped in together under current AJCC [American Joint Committee on Cancer] staging,” he added. “The class 2B designation really did confirm a higher risk for recurrence in distant metastasis.”

The researchers used the SORT method to rate the quality of the data across all three studies. Level 1 evidence under the SORT method represents a systematic review or meta-analysis of good-quality studies and/or a prospective study with good follow-up, while an A-level recommendation represents good, quality evidence. Based on the meta-analysis results, the 31-GEP test meets level 1A evidence under the SORT method, Dr. Greenhaw said.

As a prognostic tool, 31-GEP has the potential to change how dermatologists manage their patients with regard to follow-up and adjuvant therapy. “It is being used not just as this novel test that gives us more information, it’s being used clinically,” said Dr. Greenhaw, who noted he regularly uses the 31-GEP test in his practice.

This is the first time that a meta-analysis has been performed for this test, he noted.

Dr. Greenhaw reports a pending relationship with Castle Biosciences.

SOURCE: Greenhaw BN et al. AAD 19. Session F055, Abstract 11370.

WASHINGTON – The 31-gene expression profile test has met the highest level of evidence under the Strength of Recommendation Taxonomy (SORT) method as a prognostic marker for accurately predicting recurrence-free survival and distant metastasis-free survival and melanoma-specific survival, according to results presented by Bradley N. Greenhaw, MD, at a late-breaking research session at the annual meeting of the American Academy of Dermatology.

Dr. Greenhaw, a dermatologist affiliated with the North Mississippi Medical Center-Tupelo, and his colleagues pooled together 1,268 patients from the following studies that analyzed results from melanoma patients who had their disease classified with the 31-gene expression profile (31-GEP) test.

• A single-center study, conducted by Dr. Greenhaw and his associates (Greenhaw BN et al. Dermatol Surg. 2018 Dec. doi: 10.1097/DSS.0000000000001588.
• A multicenter prospective study (J Hematol Oncol. 2017 Aug. doi: 10.1186/s13045-017-0520-1.
• A retrospective archival study (J Am Acad Dermatol. 2019 Jan. doi: 10.1016/j.jaad.2018.07.028.

The 31-GEP test stratifies an individual’s likelihood of developing metastasis within 5 years as low and high risk. In the three studies, the test was used to identify tumors with low-risk (class 1A, class 1B), higher-risk (class 2A), and highest-risk (class 2B) melanoma based on tumor gene expression. In these individual studies, class 2B melanoma independently predicted recurrence-free survival (RFS), distant metastasis–free, and melanoma-specific survival.

Dr. Greenhaw and colleagues performed a meta-analysis of 1,268 patients with stage I through stage III melanoma from those three studies, using fixed and random effects weighting to account for study differences and heterogeneity, respectively. For class 2B tumors, they found a 2.96 increased risk for recurrent metastases and a 2.88 increased risk for distant metastases. The researchers also found no heterogeneity across the studies.

Melanoma-specific survival was not included in the meta-analysis because one paper did not contain any mortality events in class 1A melanoma patients.

“The meta-analysis demonstrated that the GEP test was able to accurately identify those melanoma patients who were at higher risk of metastasis, and we saw a consistent effect across multiple studies,” Dr. Greenhaw said.

Since publication of the 2019 JAAD paper, there were an additional 211 patients who met inclusion criteria and were included in an additional meta-analysis to determine whether inclusion of these patients affected the results. Dr. Greenhaw and colleagues found a 91.4% recurrence-free survival rate and a 94.1% distant metastasis–free survival rate for class 1A melanomas, compared with 45.7% and 55.5% , respectively, for class 2B tumors.

“You can see a big divergence,” Dr. Greenhaw said at the meeting. “Just by using this one test, it’s able to separate out melanomas that otherwise may be grouped in together under current AJCC [American Joint Committee on Cancer] staging,” he added. “The class 2B designation really did confirm a higher risk for recurrence in distant metastasis.”

The researchers used the SORT method to rate the quality of the data across all three studies. Level 1 evidence under the SORT method represents a systematic review or meta-analysis of good-quality studies and/or a prospective study with good follow-up, while an A-level recommendation represents good, quality evidence. Based on the meta-analysis results, the 31-GEP test meets level 1A evidence under the SORT method, Dr. Greenhaw said.

As a prognostic tool, 31-GEP has the potential to change how dermatologists manage their patients with regard to follow-up and adjuvant therapy. “It is being used not just as this novel test that gives us more information, it’s being used clinically,” said Dr. Greenhaw, who noted he regularly uses the 31-GEP test in his practice.

This is the first time that a meta-analysis has been performed for this test, he noted.

Dr. Greenhaw reports a pending relationship with Castle Biosciences.

SOURCE: Greenhaw BN et al. AAD 19. Session F055, Abstract 11370.

Hailey-Hailey disease (HHD), also known as benign familial chronic pemphigus, is an autosomal-dominant genodermatosis caused by mutations of the ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1.¹ It is characterized by crusted macerated erosions and velvety, fissured, hypertrophic plaques classically involving the intertriginous areas. The diagnosis is suggested by characteristic clinical morphology, involvement of the intertriginous areas, and a positive family history. Histology often confirms the diagnosis and demonstrates a characteristic dilapidated brick wall appearance. If there is a need to distinguish HHD from pemphigus, direct immunofluorescence studies also should be performed, which would be negative.^2,3 However, HHD often is misdiagnosed due to lack of knowledge of this uncommon disorder and its resemblance to other dermatoses of the intertriginous areas.⁴ We present an unusual presentation of HHD with late onset and involvement of the skin of the abdomen and foot.

Case Report

A 61-year-old woman presented with a 3×4-cm fissured plaque with erosions and a peripheral yellow crust on the left side of the anterior abdomen (Figure 1A). There was another fissured plaque with surrounding erythema and scaling on the fifth digit of the right foot (Figure 1B). For the last 11 years, she periodically experienced erosive and scabbing skin plaques under the breasts and on the axillae and groin. Her mother and maternal grandfather had a history of similar skin lesions. Due to a suspicion of HHD, a skin biopsy specimen of the abdominal plaque was performed, which demonstrated epidermal acanthosis and suprabasal acantholysis with lacunae formation (Figure 2). There was uneven thickening of the epidermal keratin layer with parakeratotic nests. The upper layer of the dermis demonstrated edema and focal fibrosis, enlarged capillaries, and pericapillary lymphohistiocytic infiltration with eosinophils and neutrophils. Accordingly, a diagnosis of HHD was established.

Comment

Hailey-Hailey disease occurs in 1 to 4 per 100,000 individuals without predilection for sex or ethnic group.^5-9 Onset usually occurs after puberty, most commonly in the third decade of life.^8,10-12 Mutations of the ATP2C1 gene on band 3q22.1 cause haploinsufficiency of Ca²⁺/Mn²⁺−ATPase protein 1 (hSPCA1) that alters the intracellular calcium gradient, leading to disruptions in assembly and trafficking of desmosomal proteins to the cell membrane. Consequently, altered intercellular connections and acantholysis of the epidermis occur.^1,13-16

Hailey-Hailey disease initially manifests as grouped flaccid vesicles that rupture easily, leaving behind crusted erosions and dry, scaly, eczematous patches.^17,18 Over time, velvety, fissured, and hypertrophic plaques develop. Up to 80% of patients experience secondary bacterial and fungal superinfections that may cause vegetative or malodorous plaques.⁹ Although HHD has no specific treatment, symptoms are managed with topical corticosteroids and antimicrobial agents. Patients should be advised to avoid irritants such as friction, sunlight, or sweat. For severe cases, botulinum toxin type A, laser therapy, dermabrasion, and surgery have been utilized with variable success.^19-22 The responsiveness of HHD to corticosteroids and antimicrobial agents facilitates misdiagnosis as intertrigo, erythrasma, or dermatophytosis.

Our patient presented with late-onset HHD (age, 50 years) compared to the typical age of onset in the third decade of life.⁸ Furthermore, her presentation was atypical for HHD, which characteristically affects intertriginous areas due to sweat, heat, friction, and microorganisms. Hailey-Hailey disease involving the abdominal skin is unusual, as it typically occurs in regions of friction such as the belt area.²³ Our patient lacked a history of friction or trauma at the site of the abdominal plaque. In addition, HHD involving the feet is exceedingly rare. It is plausible that friction and heat caused by footwear may have predisposed her to these skin changes.

Conclusion

This case highlights the difficulties of diagnosing HHD, especially if it appears in atypical locations.²⁴ Obtaining a thorough family history and detailed dermatologic examination as well as maintaining a high level of suspicion can assist in diagnosing this uncommon disorder.

Hailey-Hailey disease (HHD), also known as benign familial chronic pemphigus, is an autosomal-dominant genodermatosis caused by mutations of the ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1.¹ It is characterized by crusted macerated erosions and velvety, fissured, hypertrophic plaques classically involving the intertriginous areas. The diagnosis is suggested by characteristic clinical morphology, involvement of the intertriginous areas, and a positive family history. Histology often confirms the diagnosis and demonstrates a characteristic dilapidated brick wall appearance. If there is a need to distinguish HHD from pemphigus, direct immunofluorescence studies also should be performed, which would be negative.^2,3 However, HHD often is misdiagnosed due to lack of knowledge of this uncommon disorder and its resemblance to other dermatoses of the intertriginous areas.⁴ We present an unusual presentation of HHD with late onset and involvement of the skin of the abdomen and foot.

Case Report

A 61-year-old woman presented with a 3×4-cm fissured plaque with erosions and a peripheral yellow crust on the left side of the anterior abdomen (Figure 1A). There was another fissured plaque with surrounding erythema and scaling on the fifth digit of the right foot (Figure 1B). For the last 11 years, she periodically experienced erosive and scabbing skin plaques under the breasts and on the axillae and groin. Her mother and maternal grandfather had a history of similar skin lesions. Due to a suspicion of HHD, a skin biopsy specimen of the abdominal plaque was performed, which demonstrated epidermal acanthosis and suprabasal acantholysis with lacunae formation (Figure 2). There was uneven thickening of the epidermal keratin layer with parakeratotic nests. The upper layer of the dermis demonstrated edema and focal fibrosis, enlarged capillaries, and pericapillary lymphohistiocytic infiltration with eosinophils and neutrophils. Accordingly, a diagnosis of HHD was established.

Comment

Hailey-Hailey disease occurs in 1 to 4 per 100,000 individuals without predilection for sex or ethnic group.^5-9 Onset usually occurs after puberty, most commonly in the third decade of life.^8,10-12 Mutations of the ATP2C1 gene on band 3q22.1 cause haploinsufficiency of Ca²⁺/Mn²⁺−ATPase protein 1 (hSPCA1) that alters the intracellular calcium gradient, leading to disruptions in assembly and trafficking of desmosomal proteins to the cell membrane. Consequently, altered intercellular connections and acantholysis of the epidermis occur.^1,13-16

Hailey-Hailey disease initially manifests as grouped flaccid vesicles that rupture easily, leaving behind crusted erosions and dry, scaly, eczematous patches.^17,18 Over time, velvety, fissured, and hypertrophic plaques develop. Up to 80% of patients experience secondary bacterial and fungal superinfections that may cause vegetative or malodorous plaques.⁹ Although HHD has no specific treatment, symptoms are managed with topical corticosteroids and antimicrobial agents. Patients should be advised to avoid irritants such as friction, sunlight, or sweat. For severe cases, botulinum toxin type A, laser therapy, dermabrasion, and surgery have been utilized with variable success.^19-22 The responsiveness of HHD to corticosteroids and antimicrobial agents facilitates misdiagnosis as intertrigo, erythrasma, or dermatophytosis.

Our patient presented with late-onset HHD (age, 50 years) compared to the typical age of onset in the third decade of life.⁸ Furthermore, her presentation was atypical for HHD, which characteristically affects intertriginous areas due to sweat, heat, friction, and microorganisms. Hailey-Hailey disease involving the abdominal skin is unusual, as it typically occurs in regions of friction such as the belt area.²³ Our patient lacked a history of friction or trauma at the site of the abdominal plaque. In addition, HHD involving the feet is exceedingly rare. It is plausible that friction and heat caused by footwear may have predisposed her to these skin changes.

Conclusion

This case highlights the difficulties of diagnosing HHD, especially if it appears in atypical locations.²⁴ Obtaining a thorough family history and detailed dermatologic examination as well as maintaining a high level of suspicion can assist in diagnosing this uncommon disorder.

Hailey-Hailey disease (HHD), also known as benign familial chronic pemphigus, is an autosomal-dominant genodermatosis caused by mutations of the ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1.¹ It is characterized by crusted macerated erosions and velvety, fissured, hypertrophic plaques classically involving the intertriginous areas. The diagnosis is suggested by characteristic clinical morphology, involvement of the intertriginous areas, and a positive family history. Histology often confirms the diagnosis and demonstrates a characteristic dilapidated brick wall appearance. If there is a need to distinguish HHD from pemphigus, direct immunofluorescence studies also should be performed, which would be negative.^2,3 However, HHD often is misdiagnosed due to lack of knowledge of this uncommon disorder and its resemblance to other dermatoses of the intertriginous areas.⁴ We present an unusual presentation of HHD with late onset and involvement of the skin of the abdomen and foot.

Case Report

A 61-year-old woman presented with a 3×4-cm fissured plaque with erosions and a peripheral yellow crust on the left side of the anterior abdomen (Figure 1A). There was another fissured plaque with surrounding erythema and scaling on the fifth digit of the right foot (Figure 1B). For the last 11 years, she periodically experienced erosive and scabbing skin plaques under the breasts and on the axillae and groin. Her mother and maternal grandfather had a history of similar skin lesions. Due to a suspicion of HHD, a skin biopsy specimen of the abdominal plaque was performed, which demonstrated epidermal acanthosis and suprabasal acantholysis with lacunae formation (Figure 2). There was uneven thickening of the epidermal keratin layer with parakeratotic nests. The upper layer of the dermis demonstrated edema and focal fibrosis, enlarged capillaries, and pericapillary lymphohistiocytic infiltration with eosinophils and neutrophils. Accordingly, a diagnosis of HHD was established.

Comment

Hailey-Hailey disease occurs in 1 to 4 per 100,000 individuals without predilection for sex or ethnic group.^5-9 Onset usually occurs after puberty, most commonly in the third decade of life.^8,10-12 Mutations of the ATP2C1 gene on band 3q22.1 cause haploinsufficiency of Ca²⁺/Mn²⁺−ATPase protein 1 (hSPCA1) that alters the intracellular calcium gradient, leading to disruptions in assembly and trafficking of desmosomal proteins to the cell membrane. Consequently, altered intercellular connections and acantholysis of the epidermis occur.^1,13-16

Hailey-Hailey disease initially manifests as grouped flaccid vesicles that rupture easily, leaving behind crusted erosions and dry, scaly, eczematous patches.^17,18 Over time, velvety, fissured, and hypertrophic plaques develop. Up to 80% of patients experience secondary bacterial and fungal superinfections that may cause vegetative or malodorous plaques.⁹ Although HHD has no specific treatment, symptoms are managed with topical corticosteroids and antimicrobial agents. Patients should be advised to avoid irritants such as friction, sunlight, or sweat. For severe cases, botulinum toxin type A, laser therapy, dermabrasion, and surgery have been utilized with variable success.^19-22 The responsiveness of HHD to corticosteroids and antimicrobial agents facilitates misdiagnosis as intertrigo, erythrasma, or dermatophytosis.

Our patient presented with late-onset HHD (age, 50 years) compared to the typical age of onset in the third decade of life.⁸ Furthermore, her presentation was atypical for HHD, which characteristically affects intertriginous areas due to sweat, heat, friction, and microorganisms. Hailey-Hailey disease involving the abdominal skin is unusual, as it typically occurs in regions of friction such as the belt area.²³ Our patient lacked a history of friction or trauma at the site of the abdominal plaque. In addition, HHD involving the feet is exceedingly rare. It is plausible that friction and heat caused by footwear may have predisposed her to these skin changes.

Conclusion

This case highlights the difficulties of diagnosing HHD, especially if it appears in atypical locations.²⁴ Obtaining a thorough family history and detailed dermatologic examination as well as maintaining a high level of suspicion can assist in diagnosing this uncommon disorder.

ORLANDO – When caring for individuals with sun-damaged skin, dermatologists need comfort with the full spectrum of photo-related skin disease. From assessment and treatment of actinic keratoses (AKs) and field cancerization, to long-term follow-up of cutaneous squamous cell carcinomas (SCCs), appropriate treatment and staging can improve patient quality of life and reduce health care costs, Vishal Patel, MD, said at the Orlando Dermatology Aesthetic and Clinical Conference.

Kari Oakes/MDedge News

“Actinic keratosis/squamous cell carcinoma in situ is not a disease; it’s a symptom of cutaneous carcinogenesis or field cancerization,” said Dr. Patel, director of cutaneous oncology at George Washington University Cancer Center, Washington. On the other hand, he added, “field disease can be a marker for invasive squamous cell carcinoma risk, and it requires field treatment.” Treatment that reduces field disease is primary prevention because it decreases the formation of invasive SCC, he noted.

“But this level of disease – AKs and SCC in situ – doesn’t kill people,” he emphasized. “I want to leave you with an ability to stage this disease,” said Dr. Patel, noting that SCC mortality may eventually surpass melanoma mortality as deaths from the latter decline and numbers of older Americans with high ultraviolet light exposure and other risk factors climb.

While the majority of AKs regress within 5 years, he looks at the total burden of AKs as a marker for field cancerization “because having less than five in situ or actinic lesions puts you at less than a 1% risk of squamous cell carcinoma formation. Having more than 20 increases that risk 20-fold to 20%,” he said. “That’s the way we need to start thinking about this: Is this a disease – or a symptom?”

Rather than thinking of each AK or SCC in situ as a separate disease event, “the disease we need to be focusing on and treating is field cancerization,” he continued. Within this context, “we should not be thinking that … we need to be aggressive in our management,” which is what results in high costs.

“The reality is that this is a big quality of life issue for our patients. So what do we do?” Field treatment is appropriate for field disease, he said. Dr. Patel said that at GW only field treatment is used; destructive treatment for AKs and SCC in situ is not used. In the absence of patient and lesion characteristics that elevate risk,“surgery is really not the standard of care for in situ lesions for us,” he commented.

“We start by discerning the field disease from the invasive disease” with an initial round of field treatment and, if needed, adjunctive oral chemoprophylaxis. “We lather, rinse, and repeat” the field therapy, continuously if needed, Dr. Patel said.

“We like to do that because we can then identify those specific lesions we want to go after. No cryosurgery, no destructive therapy, because we run the risk of burying those tumors under the scar. They may recur and make it more difficult to accurately stage them in the future,” he noted.

“I like to be more sophisticated in thinking about our approach to the outcomes of these individual lesions,” he said. When it comes to excising lesions that have been biopsied and show invasive SCC, “disc excision may be a more cost-effective way to treat many low-risk SCCs,” he noted. In any case, “removal with clear surgical margins is key.”

Primary tumors with such low-risk attributes as diameter under a centimeter and thickness under 2 mm; well-defined borders; location on the trunk, neck, or extremities; well-differentiated histology; and lack of perineural invasion can all be considered for a disc technique, especially if the patient is immunocompetent without background chronic inflammation or a history of prior radiation therapy.

Staging SCCs, said Dr. Patel, is where things really get tricky. Older staging systems for SCC “led us to overtreat nonaggressive disease and undertreat aggressive disease. I think we have the responsibility to lead the charge to having a more sophisticated approach.” For example, patients whose tumors were staged T2 in the American Joint Commission on Cancer (AJCC) 7 classification system were most likely to have poor outcomes – in part because so few tumors were staged higher – which meant AJCC 7 didn’t provide adequate differentiation for useful risk prognostication.

A group of researchers at the Brigham and Women’s Hospital (BWH), Boston, “came up with a better system to better differentiate those T2 tumors into a high-risk and a low-risk subtype,” according to Dr. Patel.

With use of validated risk factors, the investigators applied a long list of risk factors to 2,000 tumors to see which risk factors, taken individually, were really contributing to poor outcomes. Eventually, four risk factors that made the most difference were identified: size greater than 2 cm, poor tumor differentiation, perineural invasion greater than 0.1 mm in diameter, and tumor invasion beyond subcutaneous fat. “I really want to highlight the size portion of those risk factors,” said Dr. Patel. “Something I’d like you to do in your clinical practice is to measure and document the size of the lesion. … That really, clearly helps” with risk prognostication.

These four factors were then used to break out a T2a stage for tumors with one risk factor and a T2b stage for tumors with two or three risk factors. Tumors with no risk factors are stage T1, and those with all four risk factors are stage T3. In situ SCC is T0.

Applying this new staging system to a 2,000-patient cohort with SCC yielded clear separation in outcomes including recurrence, nodal metastasis, disease-specific death, and overall survival between patients with the T2a and T2b tumors (P less than .001 for all; J Clin Oncol. 2014 Feb 1;32[4]:327-34).

While AJCC 8 is “significantly better” than AJCC 7 in its incorporation of meaningful risk factors into the SCC staging system, “it still underperforms in comparison” with the BWH staging system using the 2000 patient cohort, he said. Recent work has shown the BWH classification system to have superior specificity and positive predictive value in detecting nodal metastasis and disease-specific death in higher-grade tumors. But both BWH and AJCC 8 need further refinement.

“So what are the staging pearls to take home?” Dr. Patel asked. “First, utilize a staging system.” “Staging of SCC utilizing should be done routinely. Most data seems to suggest that the BWH system appears to outperform AJCC 8, and it is what we currently use routinely at GW,” he said.

Patients who are T1 by BWH criteria, with no risk factors, are at low or even no risk, he noted. He pointed out that of the nearly 1,400 patients who met T1 criteria, there were just eight local recurrences, one nodal metastasis, and no distant metastases or deaths. Knowing this should guide physicians on a treatment path that will reduce costs and provide patients with peace of mind, he said.

In the BWH schema, T2a patients fared almost as well, with a 2% risk of nodal metastasis and an overall 1% risk of disease-specific death. “T2a disease is low risk, in my mind. Most of these patients will go on to do well,” he said.

By contrast, “there may be a number of tumors that you are missing” that are candidates for close follow-up if the BWH criteria are not being used, said Dr. Patel. These are the T2b tumors. “For those patients, we want to aggressively follow them and think about a more aggressive management plan.”

The bottom line is that BWH T2b and T3 tumors are both high risk, and management needs to acknowledge this, he said. The current protocol in our cutaneous oncology program includes using routine radiologic nodal staging in patients with BWH stage 2b and above SCCs and considering sentinel lymph node biopsy for certain individuals.

For patients with BWH T2b and T3 tumors, dermatologists should give consideration to tertiary care or cancer center referrals so they have access to the full spectrum of diagnostic and therapeutic modalities and the opportunity to participate in clinical trials, Dr. Patel said.

Dr. Patel reported that he is a speaker for Regeneron/Sanofi and a cofounder of the Skin Cancer Outcomes (SCOUT) consortium.

This article was updated 2/9/2019

[email protected]

ORLANDO – When caring for individuals with sun-damaged skin, dermatologists need comfort with the full spectrum of photo-related skin disease. From assessment and treatment of actinic keratoses (AKs) and field cancerization, to long-term follow-up of cutaneous squamous cell carcinomas (SCCs), appropriate treatment and staging can improve patient quality of life and reduce health care costs, Vishal Patel, MD, said at the Orlando Dermatology Aesthetic and Clinical Conference.

Kari Oakes/MDedge News

“Actinic keratosis/squamous cell carcinoma in situ is not a disease; it’s a symptom of cutaneous carcinogenesis or field cancerization,” said Dr. Patel, director of cutaneous oncology at George Washington University Cancer Center, Washington. On the other hand, he added, “field disease can be a marker for invasive squamous cell carcinoma risk, and it requires field treatment.” Treatment that reduces field disease is primary prevention because it decreases the formation of invasive SCC, he noted.

“But this level of disease – AKs and SCC in situ – doesn’t kill people,” he emphasized. “I want to leave you with an ability to stage this disease,” said Dr. Patel, noting that SCC mortality may eventually surpass melanoma mortality as deaths from the latter decline and numbers of older Americans with high ultraviolet light exposure and other risk factors climb.

While the majority of AKs regress within 5 years, he looks at the total burden of AKs as a marker for field cancerization “because having less than five in situ or actinic lesions puts you at less than a 1% risk of squamous cell carcinoma formation. Having more than 20 increases that risk 20-fold to 20%,” he said. “That’s the way we need to start thinking about this: Is this a disease – or a symptom?”

Rather than thinking of each AK or SCC in situ as a separate disease event, “the disease we need to be focusing on and treating is field cancerization,” he continued. Within this context, “we should not be thinking that … we need to be aggressive in our management,” which is what results in high costs.

“The reality is that this is a big quality of life issue for our patients. So what do we do?” Field treatment is appropriate for field disease, he said. Dr. Patel said that at GW only field treatment is used; destructive treatment for AKs and SCC in situ is not used. In the absence of patient and lesion characteristics that elevate risk,“surgery is really not the standard of care for in situ lesions for us,” he commented.

“We start by discerning the field disease from the invasive disease” with an initial round of field treatment and, if needed, adjunctive oral chemoprophylaxis. “We lather, rinse, and repeat” the field therapy, continuously if needed, Dr. Patel said.

“We like to do that because we can then identify those specific lesions we want to go after. No cryosurgery, no destructive therapy, because we run the risk of burying those tumors under the scar. They may recur and make it more difficult to accurately stage them in the future,” he noted.

“I like to be more sophisticated in thinking about our approach to the outcomes of these individual lesions,” he said. When it comes to excising lesions that have been biopsied and show invasive SCC, “disc excision may be a more cost-effective way to treat many low-risk SCCs,” he noted. In any case, “removal with clear surgical margins is key.”

Primary tumors with such low-risk attributes as diameter under a centimeter and thickness under 2 mm; well-defined borders; location on the trunk, neck, or extremities; well-differentiated histology; and lack of perineural invasion can all be considered for a disc technique, especially if the patient is immunocompetent without background chronic inflammation or a history of prior radiation therapy.

Staging SCCs, said Dr. Patel, is where things really get tricky. Older staging systems for SCC “led us to overtreat nonaggressive disease and undertreat aggressive disease. I think we have the responsibility to lead the charge to having a more sophisticated approach.” For example, patients whose tumors were staged T2 in the American Joint Commission on Cancer (AJCC) 7 classification system were most likely to have poor outcomes – in part because so few tumors were staged higher – which meant AJCC 7 didn’t provide adequate differentiation for useful risk prognostication.

A group of researchers at the Brigham and Women’s Hospital (BWH), Boston, “came up with a better system to better differentiate those T2 tumors into a high-risk and a low-risk subtype,” according to Dr. Patel.

With use of validated risk factors, the investigators applied a long list of risk factors to 2,000 tumors to see which risk factors, taken individually, were really contributing to poor outcomes. Eventually, four risk factors that made the most difference were identified: size greater than 2 cm, poor tumor differentiation, perineural invasion greater than 0.1 mm in diameter, and tumor invasion beyond subcutaneous fat. “I really want to highlight the size portion of those risk factors,” said Dr. Patel. “Something I’d like you to do in your clinical practice is to measure and document the size of the lesion. … That really, clearly helps” with risk prognostication.

These four factors were then used to break out a T2a stage for tumors with one risk factor and a T2b stage for tumors with two or three risk factors. Tumors with no risk factors are stage T1, and those with all four risk factors are stage T3. In situ SCC is T0.

Applying this new staging system to a 2,000-patient cohort with SCC yielded clear separation in outcomes including recurrence, nodal metastasis, disease-specific death, and overall survival between patients with the T2a and T2b tumors (P less than .001 for all; J Clin Oncol. 2014 Feb 1;32[4]:327-34).

While AJCC 8 is “significantly better” than AJCC 7 in its incorporation of meaningful risk factors into the SCC staging system, “it still underperforms in comparison” with the BWH staging system using the 2000 patient cohort, he said. Recent work has shown the BWH classification system to have superior specificity and positive predictive value in detecting nodal metastasis and disease-specific death in higher-grade tumors. But both BWH and AJCC 8 need further refinement.

“So what are the staging pearls to take home?” Dr. Patel asked. “First, utilize a staging system.” “Staging of SCC utilizing should be done routinely. Most data seems to suggest that the BWH system appears to outperform AJCC 8, and it is what we currently use routinely at GW,” he said.

Patients who are T1 by BWH criteria, with no risk factors, are at low or even no risk, he noted. He pointed out that of the nearly 1,400 patients who met T1 criteria, there were just eight local recurrences, one nodal metastasis, and no distant metastases or deaths. Knowing this should guide physicians on a treatment path that will reduce costs and provide patients with peace of mind, he said.

In the BWH schema, T2a patients fared almost as well, with a 2% risk of nodal metastasis and an overall 1% risk of disease-specific death. “T2a disease is low risk, in my mind. Most of these patients will go on to do well,” he said.

By contrast, “there may be a number of tumors that you are missing” that are candidates for close follow-up if the BWH criteria are not being used, said Dr. Patel. These are the T2b tumors. “For those patients, we want to aggressively follow them and think about a more aggressive management plan.”

The bottom line is that BWH T2b and T3 tumors are both high risk, and management needs to acknowledge this, he said. The current protocol in our cutaneous oncology program includes using routine radiologic nodal staging in patients with BWH stage 2b and above SCCs and considering sentinel lymph node biopsy for certain individuals.

For patients with BWH T2b and T3 tumors, dermatologists should give consideration to tertiary care or cancer center referrals so they have access to the full spectrum of diagnostic and therapeutic modalities and the opportunity to participate in clinical trials, Dr. Patel said.

Dr. Patel reported that he is a speaker for Regeneron/Sanofi and a cofounder of the Skin Cancer Outcomes (SCOUT) consortium.

This article was updated 2/9/2019

[email protected]

ORLANDO – When caring for individuals with sun-damaged skin, dermatologists need comfort with the full spectrum of photo-related skin disease. From assessment and treatment of actinic keratoses (AKs) and field cancerization, to long-term follow-up of cutaneous squamous cell carcinomas (SCCs), appropriate treatment and staging can improve patient quality of life and reduce health care costs, Vishal Patel, MD, said at the Orlando Dermatology Aesthetic and Clinical Conference.

Kari Oakes/MDedge News

“Actinic keratosis/squamous cell carcinoma in situ is not a disease; it’s a symptom of cutaneous carcinogenesis or field cancerization,” said Dr. Patel, director of cutaneous oncology at George Washington University Cancer Center, Washington. On the other hand, he added, “field disease can be a marker for invasive squamous cell carcinoma risk, and it requires field treatment.” Treatment that reduces field disease is primary prevention because it decreases the formation of invasive SCC, he noted.

“But this level of disease – AKs and SCC in situ – doesn’t kill people,” he emphasized. “I want to leave you with an ability to stage this disease,” said Dr. Patel, noting that SCC mortality may eventually surpass melanoma mortality as deaths from the latter decline and numbers of older Americans with high ultraviolet light exposure and other risk factors climb.

While the majority of AKs regress within 5 years, he looks at the total burden of AKs as a marker for field cancerization “because having less than five in situ or actinic lesions puts you at less than a 1% risk of squamous cell carcinoma formation. Having more than 20 increases that risk 20-fold to 20%,” he said. “That’s the way we need to start thinking about this: Is this a disease – or a symptom?”

Rather than thinking of each AK or SCC in situ as a separate disease event, “the disease we need to be focusing on and treating is field cancerization,” he continued. Within this context, “we should not be thinking that … we need to be aggressive in our management,” which is what results in high costs.

“The reality is that this is a big quality of life issue for our patients. So what do we do?” Field treatment is appropriate for field disease, he said. Dr. Patel said that at GW only field treatment is used; destructive treatment for AKs and SCC in situ is not used. In the absence of patient and lesion characteristics that elevate risk,“surgery is really not the standard of care for in situ lesions for us,” he commented.

“We start by discerning the field disease from the invasive disease” with an initial round of field treatment and, if needed, adjunctive oral chemoprophylaxis. “We lather, rinse, and repeat” the field therapy, continuously if needed, Dr. Patel said.

“We like to do that because we can then identify those specific lesions we want to go after. No cryosurgery, no destructive therapy, because we run the risk of burying those tumors under the scar. They may recur and make it more difficult to accurately stage them in the future,” he noted.

“I like to be more sophisticated in thinking about our approach to the outcomes of these individual lesions,” he said. When it comes to excising lesions that have been biopsied and show invasive SCC, “disc excision may be a more cost-effective way to treat many low-risk SCCs,” he noted. In any case, “removal with clear surgical margins is key.”

Primary tumors with such low-risk attributes as diameter under a centimeter and thickness under 2 mm; well-defined borders; location on the trunk, neck, or extremities; well-differentiated histology; and lack of perineural invasion can all be considered for a disc technique, especially if the patient is immunocompetent without background chronic inflammation or a history of prior radiation therapy.

Staging SCCs, said Dr. Patel, is where things really get tricky. Older staging systems for SCC “led us to overtreat nonaggressive disease and undertreat aggressive disease. I think we have the responsibility to lead the charge to having a more sophisticated approach.” For example, patients whose tumors were staged T2 in the American Joint Commission on Cancer (AJCC) 7 classification system were most likely to have poor outcomes – in part because so few tumors were staged higher – which meant AJCC 7 didn’t provide adequate differentiation for useful risk prognostication.

A group of researchers at the Brigham and Women’s Hospital (BWH), Boston, “came up with a better system to better differentiate those T2 tumors into a high-risk and a low-risk subtype,” according to Dr. Patel.

With use of validated risk factors, the investigators applied a long list of risk factors to 2,000 tumors to see which risk factors, taken individually, were really contributing to poor outcomes. Eventually, four risk factors that made the most difference were identified: size greater than 2 cm, poor tumor differentiation, perineural invasion greater than 0.1 mm in diameter, and tumor invasion beyond subcutaneous fat. “I really want to highlight the size portion of those risk factors,” said Dr. Patel. “Something I’d like you to do in your clinical practice is to measure and document the size of the lesion. … That really, clearly helps” with risk prognostication.

These four factors were then used to break out a T2a stage for tumors with one risk factor and a T2b stage for tumors with two or three risk factors. Tumors with no risk factors are stage T1, and those with all four risk factors are stage T3. In situ SCC is T0.

Applying this new staging system to a 2,000-patient cohort with SCC yielded clear separation in outcomes including recurrence, nodal metastasis, disease-specific death, and overall survival between patients with the T2a and T2b tumors (P less than .001 for all; J Clin Oncol. 2014 Feb 1;32[4]:327-34).

While AJCC 8 is “significantly better” than AJCC 7 in its incorporation of meaningful risk factors into the SCC staging system, “it still underperforms in comparison” with the BWH staging system using the 2000 patient cohort, he said. Recent work has shown the BWH classification system to have superior specificity and positive predictive value in detecting nodal metastasis and disease-specific death in higher-grade tumors. But both BWH and AJCC 8 need further refinement.

“So what are the staging pearls to take home?” Dr. Patel asked. “First, utilize a staging system.” “Staging of SCC utilizing should be done routinely. Most data seems to suggest that the BWH system appears to outperform AJCC 8, and it is what we currently use routinely at GW,” he said.

Patients who are T1 by BWH criteria, with no risk factors, are at low or even no risk, he noted. He pointed out that of the nearly 1,400 patients who met T1 criteria, there were just eight local recurrences, one nodal metastasis, and no distant metastases or deaths. Knowing this should guide physicians on a treatment path that will reduce costs and provide patients with peace of mind, he said.

In the BWH schema, T2a patients fared almost as well, with a 2% risk of nodal metastasis and an overall 1% risk of disease-specific death. “T2a disease is low risk, in my mind. Most of these patients will go on to do well,” he said.

By contrast, “there may be a number of tumors that you are missing” that are candidates for close follow-up if the BWH criteria are not being used, said Dr. Patel. These are the T2b tumors. “For those patients, we want to aggressively follow them and think about a more aggressive management plan.”

The bottom line is that BWH T2b and T3 tumors are both high risk, and management needs to acknowledge this, he said. The current protocol in our cutaneous oncology program includes using routine radiologic nodal staging in patients with BWH stage 2b and above SCCs and considering sentinel lymph node biopsy for certain individuals.

For patients with BWH T2b and T3 tumors, dermatologists should give consideration to tertiary care or cancer center referrals so they have access to the full spectrum of diagnostic and therapeutic modalities and the opportunity to participate in clinical trials, Dr. Patel said.

Dr. Patel reported that he is a speaker for Regeneron/Sanofi and a cofounder of the Skin Cancer Outcomes (SCOUT) consortium.

This article was updated 2/9/2019

[email protected]

To the Editor:

We report an interesting clinical case of dermatomyositis (DM) that presented with an associated malignancy (small cell lung cancer). This patient also had an unusual clinical finding of predominantly unilateral, confluent, erythematous papules on the knee, a cutaneous sign that is seldom described in the DM literature. This case serves to reinforce the classic findings and associations of DM, in addition to the uncommon manifestation of predominantly unilateral papules on the knee.

A 68-year-old woman presented with several cutaneous manifestations including the classic findings of photo distributed erythema on the arms and face, a heliotrope rash, Gottron papules, and confluent pink papules on the left knee (Figure 1). The patient also had one of the more rare manifestations of DM, flagellate erythema on the back (Figure 2). She had a history of breast cancer and was found to have metastatic small cell lung cancer at the time of the DM diagnosis.

To the Editor:

We report an interesting clinical case of dermatomyositis (DM) that presented with an associated malignancy (small cell lung cancer). This patient also had an unusual clinical finding of predominantly unilateral, confluent, erythematous papules on the knee, a cutaneous sign that is seldom described in the DM literature. This case serves to reinforce the classic findings and associations of DM, in addition to the uncommon manifestation of predominantly unilateral papules on the knee.

A 68-year-old woman presented with several cutaneous manifestations including the classic findings of photo distributed erythema on the arms and face, a heliotrope rash, Gottron papules, and confluent pink papules on the left knee (Figure 1). The patient also had one of the more rare manifestations of DM, flagellate erythema on the back (Figure 2). She had a history of breast cancer and was found to have metastatic small cell lung cancer at the time of the DM diagnosis.

To the Editor:

We report an interesting clinical case of dermatomyositis (DM) that presented with an associated malignancy (small cell lung cancer). This patient also had an unusual clinical finding of predominantly unilateral, confluent, erythematous papules on the knee, a cutaneous sign that is seldom described in the DM literature. This case serves to reinforce the classic findings and associations of DM, in addition to the uncommon manifestation of predominantly unilateral papules on the knee.

A 68-year-old woman presented with several cutaneous manifestations including the classic findings of photo distributed erythema on the arms and face, a heliotrope rash, Gottron papules, and confluent pink papules on the left knee (Figure 1). The patient also had one of the more rare manifestations of DM, flagellate erythema on the back (Figure 2). She had a history of breast cancer and was found to have metastatic small cell lung cancer at the time of the DM diagnosis.

To the Editor:
A 52-year-old woman with a medical history of migraines and cervicalgia presented with lesions on the right arm, back, and right calf. The patient stated that the lesions began as small papules that had grown over 13 months, with the largest papule on the right forearm. She reported no itching, bleeding, pain, discharge, or other symptoms associated with the lesions. She had a multiple-year history of similar lesions that did not respond to treatment with antifungals, moderate-potency steroids, and other over-the-counter creams. The lesions would resolve spontaneously with scarring and subsequently recur. Prior skin biopsies were inconclusive. The patient did not report any systemic symptoms or a personal or family history of connective tissue diseases.

Physical examination revealed a 4-cm asymmetric, annular, erythematous plaque with central clearing on the right dorsal forearm with defined margins except over the distal aspect (Figure 1). She also had several 1- to 2-cm erythematous, nummular, asymmetric plaques on the right upper arm with well-defined margins. She had several lesions over the central and left sides of the upper back that were similar to the lesions on the upper arm.

Two 4-mm punch biopsies of the right dorsal forearm and left side of the upper back revealed similar histologic features with a predominantly unremarkable epidermis. The dermis revealed a lymphohistiocytic infiltrate with prominent multinucleated giant cells organized into foreign body–type granulomas that extended into the deep dermis and subcutaneous tissue (Figure 2). In the granulomatous areas, there was a near-complete loss of elastic fibers with focal elastophagocytosis highlighted with Verhoeff-van Gieson (elastin) stain (Figure 3). Grocott-Gomori methenamine-silver and Fite stains for microorganisms were negative, and there was an absence of necrobiosis, lipids, and mucin.

The histologic findings of a granulomatous dermatitis with loss of elastic fibers and elastophagocytosis in addition to the patient’s clinical presentation and history were consistent with the diagnosis of annular elastolytic giant cell granuloma (AEGCG). Infectious and other granulomatous diseases including sarcoidosis were ruled out via clinical history, unremarkable laboratory analysis (ie, complete blood cell count, chemistry panel, antinuclear antibody, urinalysis), and a normal chest radiograph. The histologic findings via the various stains were instrumental to the diagnosis. The patient was treated with fluocinonide and subsequently lost to follow-up.

Annular elastolytic giant cell granuloma is an uncommon cutaneous disease that presents with recurring annular plaques with raised erythematous borders and subsequent residual scarring.¹ O’Brien² originally described this condition in 1975 as an actinic granuloma due to similar histologic findings in areas of the patient’s sun-exposed skin. Ragaz and Ackerman³ disputed O’Brien’s² description, claiming granulomatous inflammation was a primary pathologic process and not a consequence to damaged elastotic material. In 1979, Hanke et al⁴ termed the lesions as AEGCG because he did not find a correlation to the sun-exposed areas of the patients and did not see solar elastosis.

Although AEGCG has an unclear pathogenesis, cellular immunologic reactions induced by modified function of elastic fibers’ antigenicity contribute to AEGCG formation.⁵ Therefore, environmental and host factors may play a role in its etiopathogenesis. In one study, 37% of 38 Japanese patients with AEGCG were found to have definitive or latent diabetes mellitus, raising the possible role of diabetes in the structural damage of the elastic fibers.⁶

Patients typically are middle-aged women who present clinically with red or atrophic plaques that have slightly elevated borders. They have centripetal spread with a resulting atrophic center.⁷ Clinically, the differential diagnosis of this condition includes actinic granuloma, granuloma annulare, and granuloma multiforme.⁸

Histologically, AEGCG has a granulomatous component with multinucleated giant cells in the upper and mid dermis. This component typically is distributed peripherally to a central zone that lacks elastic tissue. Elastophagocytosis, a classic finding in AEGCG, is the phagocytosis of elastic fibers that can microscopically be seen in the cytoplasm of histiocytes and multinucleated giant cells. There also is an absence of necrobiosis, lipids, mucin, and a palisading arrangement of the granulomas. These findings distinguish AEGCG from granuloma annulare and necrobiosis lipoidica, the primary histologic differential diagnoses.⁹ In addition, consideration of entities consistently exhibiting elastophagocytosis such as mid-dermal elastolysis, papillary dermal elastolysis, actinic granuloma, and granulomatous slack skin should be considered.^5,10,11

Therapy for AEGCG is broad and includes topical, intralesional, and systemic corticosteroids. Hydroxychloroquine, isotretinoin, clofazimine, dapsone, photochemotherapy, and cyclosporine also have been utilized with varying results. Other reports show improvement with surgical excision, cryotherapy, or cauterization of small lesions.^12-15

To the Editor:
A 52-year-old woman with a medical history of migraines and cervicalgia presented with lesions on the right arm, back, and right calf. The patient stated that the lesions began as small papules that had grown over 13 months, with the largest papule on the right forearm. She reported no itching, bleeding, pain, discharge, or other symptoms associated with the lesions. She had a multiple-year history of similar lesions that did not respond to treatment with antifungals, moderate-potency steroids, and other over-the-counter creams. The lesions would resolve spontaneously with scarring and subsequently recur. Prior skin biopsies were inconclusive. The patient did not report any systemic symptoms or a personal or family history of connective tissue diseases.

Physical examination revealed a 4-cm asymmetric, annular, erythematous plaque with central clearing on the right dorsal forearm with defined margins except over the distal aspect (Figure 1). She also had several 1- to 2-cm erythematous, nummular, asymmetric plaques on the right upper arm with well-defined margins. She had several lesions over the central and left sides of the upper back that were similar to the lesions on the upper arm.

Two 4-mm punch biopsies of the right dorsal forearm and left side of the upper back revealed similar histologic features with a predominantly unremarkable epidermis. The dermis revealed a lymphohistiocytic infiltrate with prominent multinucleated giant cells organized into foreign body–type granulomas that extended into the deep dermis and subcutaneous tissue (Figure 2). In the granulomatous areas, there was a near-complete loss of elastic fibers with focal elastophagocytosis highlighted with Verhoeff-van Gieson (elastin) stain (Figure 3). Grocott-Gomori methenamine-silver and Fite stains for microorganisms were negative, and there was an absence of necrobiosis, lipids, and mucin.

The histologic findings of a granulomatous dermatitis with loss of elastic fibers and elastophagocytosis in addition to the patient’s clinical presentation and history were consistent with the diagnosis of annular elastolytic giant cell granuloma (AEGCG). Infectious and other granulomatous diseases including sarcoidosis were ruled out via clinical history, unremarkable laboratory analysis (ie, complete blood cell count, chemistry panel, antinuclear antibody, urinalysis), and a normal chest radiograph. The histologic findings via the various stains were instrumental to the diagnosis. The patient was treated with fluocinonide and subsequently lost to follow-up.

Annular elastolytic giant cell granuloma is an uncommon cutaneous disease that presents with recurring annular plaques with raised erythematous borders and subsequent residual scarring.¹ O’Brien² originally described this condition in 1975 as an actinic granuloma due to similar histologic findings in areas of the patient’s sun-exposed skin. Ragaz and Ackerman³ disputed O’Brien’s² description, claiming granulomatous inflammation was a primary pathologic process and not a consequence to damaged elastotic material. In 1979, Hanke et al⁴ termed the lesions as AEGCG because he did not find a correlation to the sun-exposed areas of the patients and did not see solar elastosis.

Although AEGCG has an unclear pathogenesis, cellular immunologic reactions induced by modified function of elastic fibers’ antigenicity contribute to AEGCG formation.⁵ Therefore, environmental and host factors may play a role in its etiopathogenesis. In one study, 37% of 38 Japanese patients with AEGCG were found to have definitive or latent diabetes mellitus, raising the possible role of diabetes in the structural damage of the elastic fibers.⁶

Patients typically are middle-aged women who present clinically with red or atrophic plaques that have slightly elevated borders. They have centripetal spread with a resulting atrophic center.⁷ Clinically, the differential diagnosis of this condition includes actinic granuloma, granuloma annulare, and granuloma multiforme.⁸

Histologically, AEGCG has a granulomatous component with multinucleated giant cells in the upper and mid dermis. This component typically is distributed peripherally to a central zone that lacks elastic tissue. Elastophagocytosis, a classic finding in AEGCG, is the phagocytosis of elastic fibers that can microscopically be seen in the cytoplasm of histiocytes and multinucleated giant cells. There also is an absence of necrobiosis, lipids, mucin, and a palisading arrangement of the granulomas. These findings distinguish AEGCG from granuloma annulare and necrobiosis lipoidica, the primary histologic differential diagnoses.⁹ In addition, consideration of entities consistently exhibiting elastophagocytosis such as mid-dermal elastolysis, papillary dermal elastolysis, actinic granuloma, and granulomatous slack skin should be considered.^5,10,11

Therapy for AEGCG is broad and includes topical, intralesional, and systemic corticosteroids. Hydroxychloroquine, isotretinoin, clofazimine, dapsone, photochemotherapy, and cyclosporine also have been utilized with varying results. Other reports show improvement with surgical excision, cryotherapy, or cauterization of small lesions.^12-15

To the Editor:
A 52-year-old woman with a medical history of migraines and cervicalgia presented with lesions on the right arm, back, and right calf. The patient stated that the lesions began as small papules that had grown over 13 months, with the largest papule on the right forearm. She reported no itching, bleeding, pain, discharge, or other symptoms associated with the lesions. She had a multiple-year history of similar lesions that did not respond to treatment with antifungals, moderate-potency steroids, and other over-the-counter creams. The lesions would resolve spontaneously with scarring and subsequently recur. Prior skin biopsies were inconclusive. The patient did not report any systemic symptoms or a personal or family history of connective tissue diseases.

Physical examination revealed a 4-cm asymmetric, annular, erythematous plaque with central clearing on the right dorsal forearm with defined margins except over the distal aspect (Figure 1). She also had several 1- to 2-cm erythematous, nummular, asymmetric plaques on the right upper arm with well-defined margins. She had several lesions over the central and left sides of the upper back that were similar to the lesions on the upper arm.

Two 4-mm punch biopsies of the right dorsal forearm and left side of the upper back revealed similar histologic features with a predominantly unremarkable epidermis. The dermis revealed a lymphohistiocytic infiltrate with prominent multinucleated giant cells organized into foreign body–type granulomas that extended into the deep dermis and subcutaneous tissue (Figure 2). In the granulomatous areas, there was a near-complete loss of elastic fibers with focal elastophagocytosis highlighted with Verhoeff-van Gieson (elastin) stain (Figure 3). Grocott-Gomori methenamine-silver and Fite stains for microorganisms were negative, and there was an absence of necrobiosis, lipids, and mucin.

The histologic findings of a granulomatous dermatitis with loss of elastic fibers and elastophagocytosis in addition to the patient’s clinical presentation and history were consistent with the diagnosis of annular elastolytic giant cell granuloma (AEGCG). Infectious and other granulomatous diseases including sarcoidosis were ruled out via clinical history, unremarkable laboratory analysis (ie, complete blood cell count, chemistry panel, antinuclear antibody, urinalysis), and a normal chest radiograph. The histologic findings via the various stains were instrumental to the diagnosis. The patient was treated with fluocinonide and subsequently lost to follow-up.

Annular elastolytic giant cell granuloma is an uncommon cutaneous disease that presents with recurring annular plaques with raised erythematous borders and subsequent residual scarring.¹ O’Brien² originally described this condition in 1975 as an actinic granuloma due to similar histologic findings in areas of the patient’s sun-exposed skin. Ragaz and Ackerman³ disputed O’Brien’s² description, claiming granulomatous inflammation was a primary pathologic process and not a consequence to damaged elastotic material. In 1979, Hanke et al⁴ termed the lesions as AEGCG because he did not find a correlation to the sun-exposed areas of the patients and did not see solar elastosis.

Although AEGCG has an unclear pathogenesis, cellular immunologic reactions induced by modified function of elastic fibers’ antigenicity contribute to AEGCG formation.⁵ Therefore, environmental and host factors may play a role in its etiopathogenesis. In one study, 37% of 38 Japanese patients with AEGCG were found to have definitive or latent diabetes mellitus, raising the possible role of diabetes in the structural damage of the elastic fibers.⁶

Patients typically are middle-aged women who present clinically with red or atrophic plaques that have slightly elevated borders. They have centripetal spread with a resulting atrophic center.⁷ Clinically, the differential diagnosis of this condition includes actinic granuloma, granuloma annulare, and granuloma multiforme.⁸

Histologically, AEGCG has a granulomatous component with multinucleated giant cells in the upper and mid dermis. This component typically is distributed peripherally to a central zone that lacks elastic tissue. Elastophagocytosis, a classic finding in AEGCG, is the phagocytosis of elastic fibers that can microscopically be seen in the cytoplasm of histiocytes and multinucleated giant cells. There also is an absence of necrobiosis, lipids, mucin, and a palisading arrangement of the granulomas. These findings distinguish AEGCG from granuloma annulare and necrobiosis lipoidica, the primary histologic differential diagnoses.⁹ In addition, consideration of entities consistently exhibiting elastophagocytosis such as mid-dermal elastolysis, papillary dermal elastolysis, actinic granuloma, and granulomatous slack skin should be considered.^5,10,11

Therapy for AEGCG is broad and includes topical, intralesional, and systemic corticosteroids. Hydroxychloroquine, isotretinoin, clofazimine, dapsone, photochemotherapy, and cyclosporine also have been utilized with varying results. Other reports show improvement with surgical excision, cryotherapy, or cauterization of small lesions.^12-15