Dermatopathology

The Diagnosis: Bullous Leukocytoclastic Vasculitis  

Histopathology with hematoxylin and eosin (H&E) stain showed a perivascular neutrophilic infiltrate, karyorrhexis, red blood cell extravasation, and fibrin deposition in the vessel wall (quiz images). Direct immunofluorescence (DIF) showed fibrin surrounding the vasculature, consistent with vasculitis. The clinical and histopathological evaluation supported the diagnosis of bullous leukocytoclastic vasculitis (LCV). The patient had a full LCV workup including antinuclear antibody, rheumatoid factor, hepatitis B and hepatitis C screening, erythrocyte sedimentation rate, C-reactive protein, and C3/C4/total complement level, which were all within reference range. The patient denied that she had taken any medications prior to the onset of the rash. She was started on a 12-day prednisone taper starting at 60 mg, and the rash resolved in 1 week.  

Although the incidence of LCV is estimated to be 30 cases per million individuals per year,¹ bullous LCV is a rarer entity with only a few cases reported in the literature.^2,3 As in our patient's case, up to 50% of LCV cases are idiopathic or the etiology cannot be determined despite laboratory workup and medication review. Other cases can be secondary to medication, infection, collagen vascular disease, or malignancy.³ Despite the exact pathogenesis of bullous LCV being unknown,⁴ it likely is related to a type III hypersensitivity reaction with immune complex deposition in postcapillary venules leading to endothelial injury, activation of the complement cascade, and development of intraepidermal or subepidermal blister formation depending on location of inflammation and edema.² Clinically, an intraepidermal split would be more flaccid, similar to pemphigus vulgaris, while a subepidermal split, as in our patient, would be taut bullae. The subepidermal split more commonly is seen in bullous LCV.²  

Leukocytoclastic vasculitis on H&E staining characteristically has a perivascular inflammatory infiltrate, neutrophilic fragments called leukocytoclasis, and blood extravasation.³ Extravasated blood presents clinically as petechiae. In this case, the petechiae helped distinguish this entity from the differential diagnosis. Furthermore, DIF would be helpful in distinguishing bullous diseases such as bullous pemphigoid (BP) and pemphigus vulgaris from LCV.² Direct immunofluorescence in bullous LCV would have fibrinogen surrounding the vasculature without C3 and IgG deposition (intraepidermal or subepidermal).  

Mild cases of LCV often resolve with supportive measures including elevation of the legs, ice packs applied to the affected area, and removal of the inciting drug or event.⁴ In the few cases reported in the literature, bullous LCV presented more diffusely than classic LCV with bullous lesions on the forearms and the lower extremities. Oral steroids are efficacious for extensive bullous LCV.⁴ 

The differential diagnosis of bullous LCV includes bullous diseases with subepidermal split including BP and linear IgA bullous dermatosis (LABD). Bullous pemphigoid is an autoimmune subepidermal blistering disease typically affecting patients older than 60 years.⁵ The pathogenesis of BP is related to development of autoantibodies directed against hemidesmosome components, bullous pemphigoid antigen (BPAG) 1 or BPAG2.⁵ Bullous pemphigoid presents clinically as widespread, generally pruritic, erythematous, urticarial plaques with bullae. Histologically, BP characteristically has a subepidermal split with superficial dermal edema and eosinophils at the dermoepidermal junction (Figure 1). Direct immunofluorescence confirms the diagnosis with IgG and C3 deposition in an n-serrated pattern at the dermoepidermal junction.⁶ Bullous pemphigoid can be distinguished from bullous LCV by the older age of presentation, DIF findings, and the absence of purpura.  

Linear IgA bullous dermatosis represents a rare subepidermal vesiculobullous disease occurring in patients in their 60s.⁷ Clinically, this entity presents as tense bullae often located on the periphery of an urticarial plaque, classically called the "string of pearls sign." Histologically, LABD also presents with subepidermal split; however, neutrophils are the predominant cell type vs eosinophils in BP (Figure 2).⁷ Direct immunofluorescence is specific with a linear deposition of IgA at the dermoepidermal junction. Linear IgA bullous dermatosis most commonly is induced by vancomycin. Unlike bullous LCV, the bullae of LABD have an annular peripheral pattern on an erythematous base and lack purpura.  

Stasis dermatitis is inflammation of the dermis due to venous insufficiency that often is present in the bilateral lower extremities. The disorder affects approximately 7% of adults older than 50 years, but it also can occur in younger patients.⁸ The pathophysiology of stasis dermatitis is caused by edema, which leads to extracellular fluid, plasma proteins, macrophages, and erythrocytes passing into the interstitial space. Patients with stasis dermatitis present with scaly erythematous papules and plaques or edematous blisters on the lower extremities. Diagnosis usually can be made clinically; however, a skin biopsy also can be helpful. Hematoxylin and eosin shows a pauci-inflammatory subepidermal bulla with fibrin (Figure 3).⁸ The overlying epidermis is intact. The dermis has cannon ball angiomatosis, red blood cell extravasation, and fibrosis typical of stasis dermatitis. Stasis dermatitis with bullae is cell poor and lacks the perivascular inflammatory infiltrate and neutrophilic fragments that often are present in LCV, making the 2 entities distinguishable. 

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) lies on a spectrum of severe cutaneous drug reactions involving the skin and mucous membranes. Cutaneous involvement typically begins on the trunk and face and later can involve the palms and soles.⁹ Similar drugs have been implicated in bullous LCV and SJS/TEN, including nonsteroidal anti-inflammatory drugs and antibiotics. Histologically, SJS/TEN has full-thickness epidermal necrolysis, vacuolar interface, and keratinocyte apoptosis (Figure 4).⁹ The clinical presentation of sloughing of skin with positive Nikolsky sign, oral involvement, and H&E and DIF findings can help differentiate this entity from bullous LCV.  

The Diagnosis: Bullous Leukocytoclastic Vasculitis  

Histopathology with hematoxylin and eosin (H&E) stain showed a perivascular neutrophilic infiltrate, karyorrhexis, red blood cell extravasation, and fibrin deposition in the vessel wall (quiz images). Direct immunofluorescence (DIF) showed fibrin surrounding the vasculature, consistent with vasculitis. The clinical and histopathological evaluation supported the diagnosis of bullous leukocytoclastic vasculitis (LCV). The patient had a full LCV workup including antinuclear antibody, rheumatoid factor, hepatitis B and hepatitis C screening, erythrocyte sedimentation rate, C-reactive protein, and C3/C4/total complement level, which were all within reference range. The patient denied that she had taken any medications prior to the onset of the rash. She was started on a 12-day prednisone taper starting at 60 mg, and the rash resolved in 1 week.  

Although the incidence of LCV is estimated to be 30 cases per million individuals per year,¹ bullous LCV is a rarer entity with only a few cases reported in the literature.^2,3 As in our patient's case, up to 50% of LCV cases are idiopathic or the etiology cannot be determined despite laboratory workup and medication review. Other cases can be secondary to medication, infection, collagen vascular disease, or malignancy.³ Despite the exact pathogenesis of bullous LCV being unknown,⁴ it likely is related to a type III hypersensitivity reaction with immune complex deposition in postcapillary venules leading to endothelial injury, activation of the complement cascade, and development of intraepidermal or subepidermal blister formation depending on location of inflammation and edema.² Clinically, an intraepidermal split would be more flaccid, similar to pemphigus vulgaris, while a subepidermal split, as in our patient, would be taut bullae. The subepidermal split more commonly is seen in bullous LCV.²  

Leukocytoclastic vasculitis on H&E staining characteristically has a perivascular inflammatory infiltrate, neutrophilic fragments called leukocytoclasis, and blood extravasation.³ Extravasated blood presents clinically as petechiae. In this case, the petechiae helped distinguish this entity from the differential diagnosis. Furthermore, DIF would be helpful in distinguishing bullous diseases such as bullous pemphigoid (BP) and pemphigus vulgaris from LCV.² Direct immunofluorescence in bullous LCV would have fibrinogen surrounding the vasculature without C3 and IgG deposition (intraepidermal or subepidermal).  

Mild cases of LCV often resolve with supportive measures including elevation of the legs, ice packs applied to the affected area, and removal of the inciting drug or event.⁴ In the few cases reported in the literature, bullous LCV presented more diffusely than classic LCV with bullous lesions on the forearms and the lower extremities. Oral steroids are efficacious for extensive bullous LCV.⁴ 

The differential diagnosis of bullous LCV includes bullous diseases with subepidermal split including BP and linear IgA bullous dermatosis (LABD). Bullous pemphigoid is an autoimmune subepidermal blistering disease typically affecting patients older than 60 years.⁵ The pathogenesis of BP is related to development of autoantibodies directed against hemidesmosome components, bullous pemphigoid antigen (BPAG) 1 or BPAG2.⁵ Bullous pemphigoid presents clinically as widespread, generally pruritic, erythematous, urticarial plaques with bullae. Histologically, BP characteristically has a subepidermal split with superficial dermal edema and eosinophils at the dermoepidermal junction (Figure 1). Direct immunofluorescence confirms the diagnosis with IgG and C3 deposition in an n-serrated pattern at the dermoepidermal junction.⁶ Bullous pemphigoid can be distinguished from bullous LCV by the older age of presentation, DIF findings, and the absence of purpura.  

Linear IgA bullous dermatosis represents a rare subepidermal vesiculobullous disease occurring in patients in their 60s.⁷ Clinically, this entity presents as tense bullae often located on the periphery of an urticarial plaque, classically called the "string of pearls sign." Histologically, LABD also presents with subepidermal split; however, neutrophils are the predominant cell type vs eosinophils in BP (Figure 2).⁷ Direct immunofluorescence is specific with a linear deposition of IgA at the dermoepidermal junction. Linear IgA bullous dermatosis most commonly is induced by vancomycin. Unlike bullous LCV, the bullae of LABD have an annular peripheral pattern on an erythematous base and lack purpura.  

Stasis dermatitis is inflammation of the dermis due to venous insufficiency that often is present in the bilateral lower extremities. The disorder affects approximately 7% of adults older than 50 years, but it also can occur in younger patients.⁸ The pathophysiology of stasis dermatitis is caused by edema, which leads to extracellular fluid, plasma proteins, macrophages, and erythrocytes passing into the interstitial space. Patients with stasis dermatitis present with scaly erythematous papules and plaques or edematous blisters on the lower extremities. Diagnosis usually can be made clinically; however, a skin biopsy also can be helpful. Hematoxylin and eosin shows a pauci-inflammatory subepidermal bulla with fibrin (Figure 3).⁸ The overlying epidermis is intact. The dermis has cannon ball angiomatosis, red blood cell extravasation, and fibrosis typical of stasis dermatitis. Stasis dermatitis with bullae is cell poor and lacks the perivascular inflammatory infiltrate and neutrophilic fragments that often are present in LCV, making the 2 entities distinguishable. 

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) lies on a spectrum of severe cutaneous drug reactions involving the skin and mucous membranes. Cutaneous involvement typically begins on the trunk and face and later can involve the palms and soles.⁹ Similar drugs have been implicated in bullous LCV and SJS/TEN, including nonsteroidal anti-inflammatory drugs and antibiotics. Histologically, SJS/TEN has full-thickness epidermal necrolysis, vacuolar interface, and keratinocyte apoptosis (Figure 4).⁹ The clinical presentation of sloughing of skin with positive Nikolsky sign, oral involvement, and H&E and DIF findings can help differentiate this entity from bullous LCV.  

The Diagnosis: Bullous Leukocytoclastic Vasculitis  

Histopathology with hematoxylin and eosin (H&E) stain showed a perivascular neutrophilic infiltrate, karyorrhexis, red blood cell extravasation, and fibrin deposition in the vessel wall (quiz images). Direct immunofluorescence (DIF) showed fibrin surrounding the vasculature, consistent with vasculitis. The clinical and histopathological evaluation supported the diagnosis of bullous leukocytoclastic vasculitis (LCV). The patient had a full LCV workup including antinuclear antibody, rheumatoid factor, hepatitis B and hepatitis C screening, erythrocyte sedimentation rate, C-reactive protein, and C3/C4/total complement level, which were all within reference range. The patient denied that she had taken any medications prior to the onset of the rash. She was started on a 12-day prednisone taper starting at 60 mg, and the rash resolved in 1 week.  

Although the incidence of LCV is estimated to be 30 cases per million individuals per year,¹ bullous LCV is a rarer entity with only a few cases reported in the literature.^2,3 As in our patient's case, up to 50% of LCV cases are idiopathic or the etiology cannot be determined despite laboratory workup and medication review. Other cases can be secondary to medication, infection, collagen vascular disease, or malignancy.³ Despite the exact pathogenesis of bullous LCV being unknown,⁴ it likely is related to a type III hypersensitivity reaction with immune complex deposition in postcapillary venules leading to endothelial injury, activation of the complement cascade, and development of intraepidermal or subepidermal blister formation depending on location of inflammation and edema.² Clinically, an intraepidermal split would be more flaccid, similar to pemphigus vulgaris, while a subepidermal split, as in our patient, would be taut bullae. The subepidermal split more commonly is seen in bullous LCV.²  

Leukocytoclastic vasculitis on H&E staining characteristically has a perivascular inflammatory infiltrate, neutrophilic fragments called leukocytoclasis, and blood extravasation.³ Extravasated blood presents clinically as petechiae. In this case, the petechiae helped distinguish this entity from the differential diagnosis. Furthermore, DIF would be helpful in distinguishing bullous diseases such as bullous pemphigoid (BP) and pemphigus vulgaris from LCV.² Direct immunofluorescence in bullous LCV would have fibrinogen surrounding the vasculature without C3 and IgG deposition (intraepidermal or subepidermal).  

Mild cases of LCV often resolve with supportive measures including elevation of the legs, ice packs applied to the affected area, and removal of the inciting drug or event.⁴ In the few cases reported in the literature, bullous LCV presented more diffusely than classic LCV with bullous lesions on the forearms and the lower extremities. Oral steroids are efficacious for extensive bullous LCV.⁴ 

The differential diagnosis of bullous LCV includes bullous diseases with subepidermal split including BP and linear IgA bullous dermatosis (LABD). Bullous pemphigoid is an autoimmune subepidermal blistering disease typically affecting patients older than 60 years.⁵ The pathogenesis of BP is related to development of autoantibodies directed against hemidesmosome components, bullous pemphigoid antigen (BPAG) 1 or BPAG2.⁵ Bullous pemphigoid presents clinically as widespread, generally pruritic, erythematous, urticarial plaques with bullae. Histologically, BP characteristically has a subepidermal split with superficial dermal edema and eosinophils at the dermoepidermal junction (Figure 1). Direct immunofluorescence confirms the diagnosis with IgG and C3 deposition in an n-serrated pattern at the dermoepidermal junction.⁶ Bullous pemphigoid can be distinguished from bullous LCV by the older age of presentation, DIF findings, and the absence of purpura.  

Linear IgA bullous dermatosis represents a rare subepidermal vesiculobullous disease occurring in patients in their 60s.⁷ Clinically, this entity presents as tense bullae often located on the periphery of an urticarial plaque, classically called the "string of pearls sign." Histologically, LABD also presents with subepidermal split; however, neutrophils are the predominant cell type vs eosinophils in BP (Figure 2).⁷ Direct immunofluorescence is specific with a linear deposition of IgA at the dermoepidermal junction. Linear IgA bullous dermatosis most commonly is induced by vancomycin. Unlike bullous LCV, the bullae of LABD have an annular peripheral pattern on an erythematous base and lack purpura.  

Stasis dermatitis is inflammation of the dermis due to venous insufficiency that often is present in the bilateral lower extremities. The disorder affects approximately 7% of adults older than 50 years, but it also can occur in younger patients.⁸ The pathophysiology of stasis dermatitis is caused by edema, which leads to extracellular fluid, plasma proteins, macrophages, and erythrocytes passing into the interstitial space. Patients with stasis dermatitis present with scaly erythematous papules and plaques or edematous blisters on the lower extremities. Diagnosis usually can be made clinically; however, a skin biopsy also can be helpful. Hematoxylin and eosin shows a pauci-inflammatory subepidermal bulla with fibrin (Figure 3).⁸ The overlying epidermis is intact. The dermis has cannon ball angiomatosis, red blood cell extravasation, and fibrosis typical of stasis dermatitis. Stasis dermatitis with bullae is cell poor and lacks the perivascular inflammatory infiltrate and neutrophilic fragments that often are present in LCV, making the 2 entities distinguishable. 

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) lies on a spectrum of severe cutaneous drug reactions involving the skin and mucous membranes. Cutaneous involvement typically begins on the trunk and face and later can involve the palms and soles.⁹ Similar drugs have been implicated in bullous LCV and SJS/TEN, including nonsteroidal anti-inflammatory drugs and antibiotics. Histologically, SJS/TEN has full-thickness epidermal necrolysis, vacuolar interface, and keratinocyte apoptosis (Figure 4).⁹ The clinical presentation of sloughing of skin with positive Nikolsky sign, oral involvement, and H&E and DIF findings can help differentiate this entity from bullous LCV.  

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (Figure 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (Figures 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (Figure 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (Figure 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulgar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (Figures 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (Figure 3). Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems.

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (Figure 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (Figures 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (Figure 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (Figure 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulgar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (Figures 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (Figure 3). Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems.

To the Editor:

Syringomas are common benign tumors of the eccrine sweat glands that usually manifest clinically as multiple flesh-colored papules. They are most commonly seen on the face, neck, and chest of adolescent girls. Syringomas may appear at any site of the body but are rare in the vulva. We present a case of a 51-year-old woman who was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of a tumor carrying a differential diagnosis of vulvar syringoma vs microcystic adnexal carcinoma (MAC).

A 51-year-old woman presented to dermatology (G.G.) and was referred to the Division of Gynecologic Oncology at the University of Alabama at Birmingham for further management of possible vulvar syringoma vs MAC. The patient previously had been evaluated at an outside community practice due to dyspareunia, vulvar discomfort, and vulvar irregularities of 1 month’s duration. At that time, a small biopsy was performed, and the histologic differential diagnosis included syringoma vs an adnexal carcinoma. Consequently, she was referred to gynecologic oncology for further management.

Pelvic examination revealed multilobular nodular areas overlying the clitoral hood that extended down to the labia majora. The nodular processes did not involve the clitoris, labia minora, or perineum. A mobile isolated lymph node measuring 2.0×1.0 cm in the right inguinal area also was noted. The patient’s clinical history was notable for right breast carcinoma treated with a right mastectomy with axillary lymph node dissection that showed metastatic disease. She also underwent adjuvant chemotherapy with paclitaxel and doxorubicin for breast carcinoma.

After discussing the diagnostic differential and treatment options, the patient elected to undergo a bilateral partial radical vulvectomy with reconstruction and resection of the right inguinal lymph node. Gross examination of the vulvectomy specimen showed multiple flesh-colored papules (Figure 1). Histologic examination revealed a neoplasm with sweat gland differentiation that was broad and poorly circumscribed but confined to the dermis (Figures 2A and 2B). The neoplasm was composed of epithelial cells that formed ductlike structures, lined by 2 layers of cuboidal epithelium within a fibrous stroma (Figure 2C). A toluidine blue special stain was performed and demonstrated an increased amount of mast cells in the tissue (Figure 3). Immunohistochemical stains for gross cystic disease fluid protein, estrogen receptor (ER), and progesterone receptor (PR) were negative in the tumor cells. The lack of cytologic atypia, perineural invasion, and deep infiltration into the subcutis favored a syringoma. One month later, the case was presented at the Tumor Board Conference at the University of Alabama at Birmingham where a final diagnosis of vulvar syringoma was agreed upon and discussed with the patient. At that time, no recurrence was evident and follow-up was recommended.

Syringomas may occur at any site on the body but are prone to occur on the periorbital area, especially the eyelids.¹ Some of the atypical locations for a syringoma include the anterior neck, chest, abdomen, genitals, axillae, groin, and buttocks.² Vulvar syringomas were first reported by Carneiro³ in 1971 as usually affecting adolescent girls and middle-aged women. There have been approximately 40 reported cases affecting women aged 8 to 78 years.^4,5 Vulvar syringomas classically appear as firm or soft, flesh-colored to transparent, papular lesions. The 2 other clinical variants are miliumlike, whitish, cystic papules as well as lichenoid papules.⁶ Pérez-Bustillo et al⁵ reported a case of the lichenoid papule variant on the labia majora of a 78-year-old woman who presented with intermittent vulvar pruritus of 4 years’ duration. Due to this patient’s 9-year history of urinary incontinence, the lesions had been misdiagnosed as irritant dermatitis and associated lichen simplex chronicus (LSC). This case is a reminder to consider vulvar syringoma in patients with LSC who respond poorly to oral antihistamines and topical steroids.⁵ Rarely, multiple clinical variants may coexist. In a case reported by Dereli et al,⁷ a 19-year-old woman presented with concurrent classical and miliumlike forms of vulvar syringoma.

Vulvar syringomas usually present as multiple lesions involving both sides of the labia majora; however, Blasdale and McLelland⁸ reported a single isolated syringoma of the vulva on the anterior right labia minora that measured 1.0×0.5 cm, leading the lesion to be described as a giant syringoma.

Vulvar syringomas usually are asymptomatic and noticed during routine gynecologic examination. Therefore, it is believed that they likely are underdiagnosed.⁵ When symptomatic, they commonly present with constant⁹ or intermittent⁵ pruritus, which may intensify during menstruation, pregnancy, and summertime.^6,10-12 Gerdsen et al¹⁰ documented a 27-year-old woman who presented with a 2-year history of pruritic vulvar skin lesions that became exacerbated during menstruation, which raised the possibility of cyclical hormonal changes being responsible for periodic exacerbation of vulvar pruritus during menstruation. In addition, patients may experience an increase in size and number of the lesions during pregnancy. Bal et al¹¹ reported a 24-year-old primigravida with vulvar papular lesions that intensified during pregnancy. She had experienced intermittent vulvar pruritus for 12 years but had no change in symptoms during menstruation.¹¹ Few studies have attempted to evaluate the presence of ER and PR in the syringomas. A study of 9 nonvulvar syringomas by Wallace and Smoller¹³ showed ER positivity in 1 case and PR positivity in 8 cases, lending support to the hormonal theory; however, in another case series of 15 vulvar syringomas, Huang et al⁶ failed to show ER and PR expression by immunohistochemical staining. A case report published 3 years earlier documented the first case of PR positivity on a vulvar syringoma.¹⁴ Our patient also was negative for ER and PR, which suggested that hormonal status is important in some but not all syringomas.

Patients with vulgar syringomas also might have coexisting extragenital syringomas in the neck,⁴ eyelids,^6,7,10 and periorbital area,⁶ and thorough examination of the body is essential. If an extragenital syringoma is diagnosed, a vulvar syringoma should be considered, especially when the patient presents with unexplained genital symptoms. Although no proven hereditary transmission pattern has been established, family history of syringomas has been established in several cases.¹⁵ In a case series reported by Huang et al,⁶ 4 of 18 patients reported a family history of periorbital syringomas. In our case, the patient did not report a family history of syringomas.

The differential diagnosis of vulvar lesions with pruritus is broad and includes Fox-Fordyce disease, lichen planus, LSC, epidermal cysts, senile angiomas, dystrophic calcinosis, xanthomas, steatocytomas, soft fibromas, condyloma acuminatum, and candidiasis. Vulvar syringomas might have a nonspecific appearance, and histologic examination is essential to confirm the diagnosis and rule out any malignant process such as MAC, vulvar intraepithelial neoplasia, extramammary Paget disease, or other glandular neoplasms of the vulva.

Microcystic adnexal carcinoma was first reported in 1982 by Goldstein et al¹⁶ as a locally aggressive neoplasm that can be confused with benign adnexal neoplasms, particularly desmoplastic trichoepithelioma, trichoadenoma, and syringoma. Microcystic adnexal carcinomas present as slow-growing, flesh-colored papules that may resemble syringomas and appear in similar body sites. Histologic examination is essential to differentiate between these two entities. Syringomas are tumors confined to the dermis and are composed of multiple small ducts lined by 2 layers of cuboidal epithelium within a dense fibrous stroma. Unlike syringomas, MACs usually infiltrate diffusely into the dermis and subcutis and may extend into the underlying muscle. Although bland cytologic features predominate, perineural invasion frequently is present in MACs. A potential pitfall of misdiagnosis can be caused by a superficial biopsy that may reveal benign histologic appearance, particularly in the upper level of the tumor where it may be confused with a syringoma or a benign follicular neoplasm.¹⁷

The initial biopsy performed on our patient was possibly not deep enough to render an unequivocal diagnosis and therefore bilateral partial radical vulvectomy was considered. After surgery, histologic examination of the resection specimen revealed a poorly circumscribed tumor confined to the dermis. The tumor was broad and the lack of deep infiltration into the subcutis and perineural invasion favored a syringoma (Figures 2A and 2B). These findings were consistent with case reports that documented syringomas as being more wide than deep on microscopic examination, whereas the opposite pertained to MAC.¹⁸ Cases of plaque-type syringomas that initially were misdiagnosed as MACs also have been reported.¹⁹ Because misdiagnosis may affect the treatment plan and potentially result in unnecessary surgery, caution should be taken when differentiating between these two entities. When a definitive diagnosis cannot be rendered on a superficial biopsy, a recommendation should be made for a deeper biopsy sampling the subcutis.

For the majority of the patients with vulvar syringomas, treatment is seldom required due to their asymptomatic nature; however, patients who present with symptoms usually report pruritus of variable intensities and patterns. A standardized treatment does not exist for vulvar syringomas, and oral or topical treatment might be used as an initial approach. Commonly prescribed medications with variable results include topical corticosteroids, oral antihistamines, and topical retinoids. In a case reported by Iwao et al,²⁰ vulvar syringomas were successfully treated with tranilast, which has anti-inflammatory and immunomodulatory effects. This medication could have a possible dual action—inhibiting the release of chemical mediators from the mast cells and inhibiting the release of IL-1β from the eccrine duct, which could suppress the proliferation of stromal connective tissue. Our case was stained with toluidine blue and showed an increased number of mast cells in the tissue (Figure 3). Patients who are unresponsive to tranilast or have extensive disease resulting in cosmetic disfigurement might benefit from more invasive treatment methods including a variety of lasers, cryotherapy, electrosurgery, and excision. Excisions should include the entire tumor to avoid recurrence. In a case reported by Garman and Metry,²¹ the lesions were surgically excised using small 2- to 3-mm punches; however, several weeks later the lesions recurred. Our patient presented with a 1-month evolution of dyspareunia, vulvar discomfort, and vulvar irregularities that were probably not treated with oral or topical medications before being referred for surgery.

We report a case of a vulvar syringoma that presented diagnostic challenges in the initial biopsy, which prevented the exclusion of an MAC. After partial radical vulvectomy, histologic examination was more definitive, showing lack of deep infiltration into the subcutis or perineural invasion that are commonly seen in MAC. This case is an example of a notable pitfall in the diagnosis of vulvar syringoma on a limited biopsy leading to overtreatment. Raising awareness of this entity is the only modality to prevent misdiagnosis. We encourage reporting of further cases of syringomas, particularly those with atypical locations or patterns that may cause diagnostic problems.

To the Editor:

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is an uncommon inflammatory skin disorder characterized by sudden onset of fever, leukocytosis, neutrophilia, and tender erythematous papules or plaques or both. Skin biopsy usually reveals extensive infiltration of neutrophils into the epidermis and dermis.^1-3 Although rare, cases of eosinophil-rich SS have been reported in patients with drug-induced and malignancy-associated SS.^4,5 We report a case of a patient with classical SS with dermal eosinophilic infiltration.

An 80-year-old Hispanic man presented with abrupt onset of a rash on the posterior scalp, left ear, back, and hands of 5 days’ duration. The lesions were painful and had progressed to the point of impairing hand grip. The patient’s medical history included a reported common cold the week prior, hyperlipidemia, and hypertension, for which he took metoprolol, simvastatin, aspirin, and clopidogrel. He denied oral lesions and medication changes. He was afebrile and did not experience dietary changes, weight loss, or fatigue. He recently returned from travel to the Dominican Republic.

Physical examination revealed tender, well demarcated, pink to violaceous, pseudovesicular papules and plaques on the palms and dorsal hands (Figure 1), the posterior scalp, left ear, proximal left arm, and back. Pink, juicy, targetoid papules were also found on the scalp, back, and left arm. There was no evidence of lymphadenopathy. Laboratory test results revealed an elevated white blood cell count (11,500/µL [reference range, 3800-10,800/µL]), absolute neutrophil count (8073/µL [reference range, 1500–7800/µL]), and eosinophil count (610/µL [reference range, 15–500/µL]). These results indicated leukocytosis with neutrophilia and mild eosinophilia. The patient also was anemic (hemoglobin, 11.5 g/dL [reference range, 13.2–17.1 g/dL]; hematocrit, 35.1% [reference range, 38.5%–50%]). Urine testing revealed altered renal function (serum creatinine, 2.42 mg/dL [reference range, 0.7–1.1 mg/dL]; blood urea nitrogen, 34 mg/dL [reference range, 7–25 mg/dL]; glomerular filtration rate, 4 mL/min/1.73 m² (reference range, ≥60 mL/min/1.73 m²]), suggesting stage 4 chronic kidney disease. Urinalysis showed mild hematuria and proteinuria.

In our patient, the observed clinical and histological findings were consistent with a diagnosis of SS,^2,10 specifically tender erythematous plaques of sudden onset, fast response to systemic corticosteroid therapy, a dermal neutrophilic infiltrate without evidence of leukocytoclastic vasculitis, and leukocytosis greater than 8000/µL with more than 70% neutrophils. He also exhibited targetoid lesions, which have been reported in 7% to 12% of SS patients.^10,11

The predominant cells involved in the dermis of SS lesions are mature neutrophils; however, eosinophils have been observed in small numbers within dermal infiltrates in skin lesions of patients with either classical SS or drug-induced dermatosis.² In 2 studies of cases of SS (N=73 and N=31), eosinophils were reported in 35% and 41% of skin biopsies, respectively.^4,5 Nevertheless, cases with dense eosinophilic infiltrates are rare. Furthermore, Masuda et al¹² reported a case of eosinophil-rich SS in a 29-year-old woman after treatment of an upper respiratory tract infection with an antibiotic, and Soon et al¹³ described an eosinophil-rich case of SS in the setting of new-onset enteropathy-associated T-cell lymphoma.

Our patient was considered to have classical SS because he had an episode of an upper respiratory tract infection 1 week prior to onset of clinical manifestations. The histologic finding of numerous eosinophils in our case was unusual for idiopathic SS. This finding might suggest a drug hypersensitivity reaction, but the lack of any change in the patient’s long-term medication list and the lack of any other episodes made a diagnosis of drug-induced SS less likely in our patient.

Eosinophilic dermatosis of hematologic malignancy is a rare cutaneous condition in which nodules, pruritic papules, and vesicles arise in patients with a hematologic malignancy, such as chronic lymphocytic leukemia and mantle cell lymphoma,¹³ in which a deep perivascular lymphocytic infiltrate and numerous eosinophils are observed. Malignancy was ruled out in our patient because of the lack of characteristic abnormalities in blood testing, the fast response to corticosteroid therapy, and the lack of recurrence posttreatment or additional systemic concerns.

The typical pathology findings of SS consist of mature neutrophils found in the dermis without evidence of leukocytoclastic vasculitis. Eosinophil-rich infiltration, however rare, has been reported in SS. This report highlights a case of classical SS with a particularly dense eosinophilic infiltrate, which could be mistaken for other eosinophilic dermatoses. Dermatologists should be aware of the possibility of marked eosinophilic infiltration in all subtypes of this disorder.

To the Editor:

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is an uncommon inflammatory skin disorder characterized by sudden onset of fever, leukocytosis, neutrophilia, and tender erythematous papules or plaques or both. Skin biopsy usually reveals extensive infiltration of neutrophils into the epidermis and dermis.^1-3 Although rare, cases of eosinophil-rich SS have been reported in patients with drug-induced and malignancy-associated SS.^4,5 We report a case of a patient with classical SS with dermal eosinophilic infiltration.

An 80-year-old Hispanic man presented with abrupt onset of a rash on the posterior scalp, left ear, back, and hands of 5 days’ duration. The lesions were painful and had progressed to the point of impairing hand grip. The patient’s medical history included a reported common cold the week prior, hyperlipidemia, and hypertension, for which he took metoprolol, simvastatin, aspirin, and clopidogrel. He denied oral lesions and medication changes. He was afebrile and did not experience dietary changes, weight loss, or fatigue. He recently returned from travel to the Dominican Republic.

Physical examination revealed tender, well demarcated, pink to violaceous, pseudovesicular papules and plaques on the palms and dorsal hands (Figure 1), the posterior scalp, left ear, proximal left arm, and back. Pink, juicy, targetoid papules were also found on the scalp, back, and left arm. There was no evidence of lymphadenopathy. Laboratory test results revealed an elevated white blood cell count (11,500/µL [reference range, 3800-10,800/µL]), absolute neutrophil count (8073/µL [reference range, 1500–7800/µL]), and eosinophil count (610/µL [reference range, 15–500/µL]). These results indicated leukocytosis with neutrophilia and mild eosinophilia. The patient also was anemic (hemoglobin, 11.5 g/dL [reference range, 13.2–17.1 g/dL]; hematocrit, 35.1% [reference range, 38.5%–50%]). Urine testing revealed altered renal function (serum creatinine, 2.42 mg/dL [reference range, 0.7–1.1 mg/dL]; blood urea nitrogen, 34 mg/dL [reference range, 7–25 mg/dL]; glomerular filtration rate, 4 mL/min/1.73 m² (reference range, ≥60 mL/min/1.73 m²]), suggesting stage 4 chronic kidney disease. Urinalysis showed mild hematuria and proteinuria.

In our patient, the observed clinical and histological findings were consistent with a diagnosis of SS,^2,10 specifically tender erythematous plaques of sudden onset, fast response to systemic corticosteroid therapy, a dermal neutrophilic infiltrate without evidence of leukocytoclastic vasculitis, and leukocytosis greater than 8000/µL with more than 70% neutrophils. He also exhibited targetoid lesions, which have been reported in 7% to 12% of SS patients.^10,11

The predominant cells involved in the dermis of SS lesions are mature neutrophils; however, eosinophils have been observed in small numbers within dermal infiltrates in skin lesions of patients with either classical SS or drug-induced dermatosis.² In 2 studies of cases of SS (N=73 and N=31), eosinophils were reported in 35% and 41% of skin biopsies, respectively.^4,5 Nevertheless, cases with dense eosinophilic infiltrates are rare. Furthermore, Masuda et al¹² reported a case of eosinophil-rich SS in a 29-year-old woman after treatment of an upper respiratory tract infection with an antibiotic, and Soon et al¹³ described an eosinophil-rich case of SS in the setting of new-onset enteropathy-associated T-cell lymphoma.

Our patient was considered to have classical SS because he had an episode of an upper respiratory tract infection 1 week prior to onset of clinical manifestations. The histologic finding of numerous eosinophils in our case was unusual for idiopathic SS. This finding might suggest a drug hypersensitivity reaction, but the lack of any change in the patient’s long-term medication list and the lack of any other episodes made a diagnosis of drug-induced SS less likely in our patient.

Eosinophilic dermatosis of hematologic malignancy is a rare cutaneous condition in which nodules, pruritic papules, and vesicles arise in patients with a hematologic malignancy, such as chronic lymphocytic leukemia and mantle cell lymphoma,¹³ in which a deep perivascular lymphocytic infiltrate and numerous eosinophils are observed. Malignancy was ruled out in our patient because of the lack of characteristic abnormalities in blood testing, the fast response to corticosteroid therapy, and the lack of recurrence posttreatment or additional systemic concerns.

The typical pathology findings of SS consist of mature neutrophils found in the dermis without evidence of leukocytoclastic vasculitis. Eosinophil-rich infiltration, however rare, has been reported in SS. This report highlights a case of classical SS with a particularly dense eosinophilic infiltrate, which could be mistaken for other eosinophilic dermatoses. Dermatologists should be aware of the possibility of marked eosinophilic infiltration in all subtypes of this disorder.

To the Editor:

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is an uncommon inflammatory skin disorder characterized by sudden onset of fever, leukocytosis, neutrophilia, and tender erythematous papules or plaques or both. Skin biopsy usually reveals extensive infiltration of neutrophils into the epidermis and dermis.^1-3 Although rare, cases of eosinophil-rich SS have been reported in patients with drug-induced and malignancy-associated SS.^4,5 We report a case of a patient with classical SS with dermal eosinophilic infiltration.

An 80-year-old Hispanic man presented with abrupt onset of a rash on the posterior scalp, left ear, back, and hands of 5 days’ duration. The lesions were painful and had progressed to the point of impairing hand grip. The patient’s medical history included a reported common cold the week prior, hyperlipidemia, and hypertension, for which he took metoprolol, simvastatin, aspirin, and clopidogrel. He denied oral lesions and medication changes. He was afebrile and did not experience dietary changes, weight loss, or fatigue. He recently returned from travel to the Dominican Republic.

Physical examination revealed tender, well demarcated, pink to violaceous, pseudovesicular papules and plaques on the palms and dorsal hands (Figure 1), the posterior scalp, left ear, proximal left arm, and back. Pink, juicy, targetoid papules were also found on the scalp, back, and left arm. There was no evidence of lymphadenopathy. Laboratory test results revealed an elevated white blood cell count (11,500/µL [reference range, 3800-10,800/µL]), absolute neutrophil count (8073/µL [reference range, 1500–7800/µL]), and eosinophil count (610/µL [reference range, 15–500/µL]). These results indicated leukocytosis with neutrophilia and mild eosinophilia. The patient also was anemic (hemoglobin, 11.5 g/dL [reference range, 13.2–17.1 g/dL]; hematocrit, 35.1% [reference range, 38.5%–50%]). Urine testing revealed altered renal function (serum creatinine, 2.42 mg/dL [reference range, 0.7–1.1 mg/dL]; blood urea nitrogen, 34 mg/dL [reference range, 7–25 mg/dL]; glomerular filtration rate, 4 mL/min/1.73 m² (reference range, ≥60 mL/min/1.73 m²]), suggesting stage 4 chronic kidney disease. Urinalysis showed mild hematuria and proteinuria.

In our patient, the observed clinical and histological findings were consistent with a diagnosis of SS,^2,10 specifically tender erythematous plaques of sudden onset, fast response to systemic corticosteroid therapy, a dermal neutrophilic infiltrate without evidence of leukocytoclastic vasculitis, and leukocytosis greater than 8000/µL with more than 70% neutrophils. He also exhibited targetoid lesions, which have been reported in 7% to 12% of SS patients.^10,11

The predominant cells involved in the dermis of SS lesions are mature neutrophils; however, eosinophils have been observed in small numbers within dermal infiltrates in skin lesions of patients with either classical SS or drug-induced dermatosis.² In 2 studies of cases of SS (N=73 and N=31), eosinophils were reported in 35% and 41% of skin biopsies, respectively.^4,5 Nevertheless, cases with dense eosinophilic infiltrates are rare. Furthermore, Masuda et al¹² reported a case of eosinophil-rich SS in a 29-year-old woman after treatment of an upper respiratory tract infection with an antibiotic, and Soon et al¹³ described an eosinophil-rich case of SS in the setting of new-onset enteropathy-associated T-cell lymphoma.

Our patient was considered to have classical SS because he had an episode of an upper respiratory tract infection 1 week prior to onset of clinical manifestations. The histologic finding of numerous eosinophils in our case was unusual for idiopathic SS. This finding might suggest a drug hypersensitivity reaction, but the lack of any change in the patient’s long-term medication list and the lack of any other episodes made a diagnosis of drug-induced SS less likely in our patient.

Eosinophilic dermatosis of hematologic malignancy is a rare cutaneous condition in which nodules, pruritic papules, and vesicles arise in patients with a hematologic malignancy, such as chronic lymphocytic leukemia and mantle cell lymphoma,¹³ in which a deep perivascular lymphocytic infiltrate and numerous eosinophils are observed. Malignancy was ruled out in our patient because of the lack of characteristic abnormalities in blood testing, the fast response to corticosteroid therapy, and the lack of recurrence posttreatment or additional systemic concerns.

The typical pathology findings of SS consist of mature neutrophils found in the dermis without evidence of leukocytoclastic vasculitis. Eosinophil-rich infiltration, however rare, has been reported in SS. This report highlights a case of classical SS with a particularly dense eosinophilic infiltrate, which could be mistaken for other eosinophilic dermatoses. Dermatologists should be aware of the possibility of marked eosinophilic infiltration in all subtypes of this disorder.

The Diagnosis: Dermatofibroma With Sebaceous Induction 

The biopsy of the lesion revealed a fibrohistiocytic dermal pattern with overlying benign epidermal and sebaceous hyperplasia with a proliferation of fibroblasts in the dermis. Other sections revealed hyperplastic sebaceous glands of the superficial and mid dermis. These findings were suggestive of a dermatofibroma (DF) that had induced epidermal and sebaceous hyperplasia.  

Dermatofibromas are common benign fibrous soft tissue growths that account for approximately 3% of dermatopathology specimens.¹ The etiology of DFs is unknown; however, they are thought to arise from sites of prior trauma or arthropod bites. Multiple or eruptive DFs have been reported in patients with lupus and atopic dermatitis.² They commonly appear as round firm nodules measuring less than 1 cm in diameter on the extremities of young adults. Eruptive dermatofibromas also have been reported in human immunodeficiency virus-positive and immunosuppressed patients.^3,4 On physical examination, gently pinching the lesion causes a downward movement known as the "dimple sign." If left undisturbed, DFs persist but may undergo partial regression, especially in the center; they also may be excised if symptomatic.  

The clinical differential for this papule included a scar and sebaceous hyperplasia. The lack of history of skin cancer or prior procedure made a scar less likely. Sebaceous glands are less prominent on the shoulders, making sebaceous hyperplasia less likely, though dermoscopy showed pale yellow lobules. Sebaceous adenomas most commonly are seen on the head or neck and present as a flesh-colored papule. Sebaceous induction by DFs is rare but has been reported in the literature.^5,6 

The histology of DFs is described as a nodular proliferation of spindle-shaped fibroblasts and myofibroblasts with short intersecting fascicles. A predilection for sebaceous induction from an underlying DF on the shoulder has been reported.⁵ Sebaceous differentiation has been reported in 16% to 31.6% of DFs.^5,6 Seborrheic keratosis-like epidermal hyperplasia frequently has been seen in DFs with sebaceous induction in comparison to DFs without sebaceous induction.⁵ Immunohistochemical stains are important to help differentiate DF from dermatofibrosarcoma protuberans, especially when approaching the subcutis. Dermatofibromas stain positive for factor XIIIa and negative for CD34, whereas dermatofibrosarcoma protuberans stain negative for factor XIIIa and positive for CD34.⁷ Dermatofibromas also demonstrate positive immunostaining for vimentin, stromelysin 3,⁸ muscle-specific actin, and CD68.  

The Diagnosis: Dermatofibroma With Sebaceous Induction 

The biopsy of the lesion revealed a fibrohistiocytic dermal pattern with overlying benign epidermal and sebaceous hyperplasia with a proliferation of fibroblasts in the dermis. Other sections revealed hyperplastic sebaceous glands of the superficial and mid dermis. These findings were suggestive of a dermatofibroma (DF) that had induced epidermal and sebaceous hyperplasia.  

Dermatofibromas are common benign fibrous soft tissue growths that account for approximately 3% of dermatopathology specimens.¹ The etiology of DFs is unknown; however, they are thought to arise from sites of prior trauma or arthropod bites. Multiple or eruptive DFs have been reported in patients with lupus and atopic dermatitis.² They commonly appear as round firm nodules measuring less than 1 cm in diameter on the extremities of young adults. Eruptive dermatofibromas also have been reported in human immunodeficiency virus-positive and immunosuppressed patients.^3,4 On physical examination, gently pinching the lesion causes a downward movement known as the "dimple sign." If left undisturbed, DFs persist but may undergo partial regression, especially in the center; they also may be excised if symptomatic.  

The clinical differential for this papule included a scar and sebaceous hyperplasia. The lack of history of skin cancer or prior procedure made a scar less likely. Sebaceous glands are less prominent on the shoulders, making sebaceous hyperplasia less likely, though dermoscopy showed pale yellow lobules. Sebaceous adenomas most commonly are seen on the head or neck and present as a flesh-colored papule. Sebaceous induction by DFs is rare but has been reported in the literature.^5,6 

The histology of DFs is described as a nodular proliferation of spindle-shaped fibroblasts and myofibroblasts with short intersecting fascicles. A predilection for sebaceous induction from an underlying DF on the shoulder has been reported.⁵ Sebaceous differentiation has been reported in 16% to 31.6% of DFs.^5,6 Seborrheic keratosis-like epidermal hyperplasia frequently has been seen in DFs with sebaceous induction in comparison to DFs without sebaceous induction.⁵ Immunohistochemical stains are important to help differentiate DF from dermatofibrosarcoma protuberans, especially when approaching the subcutis. Dermatofibromas stain positive for factor XIIIa and negative for CD34, whereas dermatofibrosarcoma protuberans stain negative for factor XIIIa and positive for CD34.⁷ Dermatofibromas also demonstrate positive immunostaining for vimentin, stromelysin 3,⁸ muscle-specific actin, and CD68.  

The Diagnosis: Dermatofibroma With Sebaceous Induction 

The biopsy of the lesion revealed a fibrohistiocytic dermal pattern with overlying benign epidermal and sebaceous hyperplasia with a proliferation of fibroblasts in the dermis. Other sections revealed hyperplastic sebaceous glands of the superficial and mid dermis. These findings were suggestive of a dermatofibroma (DF) that had induced epidermal and sebaceous hyperplasia.  

Dermatofibromas are common benign fibrous soft tissue growths that account for approximately 3% of dermatopathology specimens.¹ The etiology of DFs is unknown; however, they are thought to arise from sites of prior trauma or arthropod bites. Multiple or eruptive DFs have been reported in patients with lupus and atopic dermatitis.² They commonly appear as round firm nodules measuring less than 1 cm in diameter on the extremities of young adults. Eruptive dermatofibromas also have been reported in human immunodeficiency virus-positive and immunosuppressed patients.^3,4 On physical examination, gently pinching the lesion causes a downward movement known as the "dimple sign." If left undisturbed, DFs persist but may undergo partial regression, especially in the center; they also may be excised if symptomatic.  

The clinical differential for this papule included a scar and sebaceous hyperplasia. The lack of history of skin cancer or prior procedure made a scar less likely. Sebaceous glands are less prominent on the shoulders, making sebaceous hyperplasia less likely, though dermoscopy showed pale yellow lobules. Sebaceous adenomas most commonly are seen on the head or neck and present as a flesh-colored papule. Sebaceous induction by DFs is rare but has been reported in the literature.^5,6 

The histology of DFs is described as a nodular proliferation of spindle-shaped fibroblasts and myofibroblasts with short intersecting fascicles. A predilection for sebaceous induction from an underlying DF on the shoulder has been reported.⁵ Sebaceous differentiation has been reported in 16% to 31.6% of DFs.^5,6 Seborrheic keratosis-like epidermal hyperplasia frequently has been seen in DFs with sebaceous induction in comparison to DFs without sebaceous induction.⁵ Immunohistochemical stains are important to help differentiate DF from dermatofibrosarcoma protuberans, especially when approaching the subcutis. Dermatofibromas stain positive for factor XIIIa and negative for CD34, whereas dermatofibrosarcoma protuberans stain negative for factor XIIIa and positive for CD34.⁷ Dermatofibromas also demonstrate positive immunostaining for vimentin, stromelysin 3,⁸ muscle-specific actin, and CD68.  

The Diagnosis: Hypergranulotic Dyscornification 

Hypergranulotic dyscornification (HD) is a rarely reported reaction pattern present in benign solitary keratoses with only few reports to date. It may be an underrecognized reaction pattern based on the paucity of reported cases as well as the histologic similarities to other entities. It has been hypothesized that this pattern reflects an underlying keratin mutation or disorder of keratinization.¹ 

Clinically, HD most commonly presents as a waxy, tan-colored, solitary keratosis generally found on the lower limbs, trunk, or back in individuals aged 20 to 60 years.^1,2 Histopathology shows marked hyperkeratosis, papillomatosis, and clumped basophilic keratohyalin granules within the corneocytes with digitated epidermal hyperplasia. There is abnormal cornification across the entire lesion with papillomatosis and marked hypergranulosis.³ There often are homogeneous orthokeratotic mounds of large, dull, eosinophilic-staining anucleate keratinocytes that are sharply demarcated from the thickened granular layer.^1,2 Within the spinous, granular, and corneal layers, there is a pale, gray-staining, basophilic, cytoplasmic substance intercellularly.¹ 

Histopathologically, HD may be mistaken for several other entities both benign and malignant.¹ Epidermolytic hyperkeratosis can be a genetic disorder, an incidental finding in a variety of skin conditions, or an isolated lesion.⁴ The genetic syndrome, caused by mutation in keratins 1 or 10, clinically presents with hyperkeratosis, erosions, blisters, and thickening of the epidermis, often with a corrugated appearance. Epidermal nevi findings often are seen in conjunction with histologic changes of epidermolytic hyperkeratosis caused by mutation. Solitary lesions also can resemble seborrheic keratosis or verruca. In all examples of epidermolytic hyperkeratosis, the histopathologic findings are identical.⁴ The granular layer is thickened, and coarse keratohyalin granules aggregate in the suprabasal cells.⁵ There is acantholysis with perinuclear vacuolization in the spinous and granular layers with characteristic pale cytoplasmic areas devoid of keratin filaments (Figure 1). The basal layer may be hyperproliferative.⁵ 

Irritated seborrheic keratosis presents as an exophytic, waxy, dark, sharply demarcated plaque with a stuck-on appearance.⁶ There is visible keratinization with comedolike openings, fissures and ridges, and scale; it also can contain milialike cysts. Histopathologically there is papillomatosis with prominent rete ridges, often including keratin pseudohorn cysts and squamous eddies. Enlarged capillaries can be seen in the dermal papillae. There is normal cytology with benign sheets of basaloid cells (Figure 2).⁷ Activating mutation in fibroblast growth factor receptor 3 leads to the growth and thickness of the epidermis that has been identified in these benign lesions.⁸ 

Verruca plana appears as a flesh-colored or reddish, warty, flat-topped papule that often forms clusters. Histopathologically it shows prominent hypergranulosis, thickened stratum spinosum, and vacuolized keratinocytes.⁹ The nuclei demonstrate a characteristic cytopathic effect of the virion, blurring the nuclear chromatin due to viral particle accumulation, known as koilocytes (Figure 3). The cause is the double-stranded DNA human papillomavirus types 2, 3, and 10.¹⁰

Bowen disease is a form of squamous cell carcinoma in situ characterized by an enlarging, well-demarcated, erythematous plaque with an irregular border and crusting or scaling. Histopathology reveals pleomorphic epidermal keratinization that becomes incorporated in the stratum corneum as parakeratotic nuclei. There is acanthosis, elongation of the rete ridges, and disorganized keratinocytes with atypia.¹¹ The granular and spinous layers show an atypical honeycomb pattern with atypical cellular morphology (Figure 4).¹² Bowen disease is a malignant lesion commonly found in older adults on sun-exposed skin that can evolve into invasive squamous cell carcinoma. 

The Diagnosis: Hypergranulotic Dyscornification 

Hypergranulotic dyscornification (HD) is a rarely reported reaction pattern present in benign solitary keratoses with only few reports to date. It may be an underrecognized reaction pattern based on the paucity of reported cases as well as the histologic similarities to other entities. It has been hypothesized that this pattern reflects an underlying keratin mutation or disorder of keratinization.¹ 

Clinically, HD most commonly presents as a waxy, tan-colored, solitary keratosis generally found on the lower limbs, trunk, or back in individuals aged 20 to 60 years.^1,2 Histopathology shows marked hyperkeratosis, papillomatosis, and clumped basophilic keratohyalin granules within the corneocytes with digitated epidermal hyperplasia. There is abnormal cornification across the entire lesion with papillomatosis and marked hypergranulosis.³ There often are homogeneous orthokeratotic mounds of large, dull, eosinophilic-staining anucleate keratinocytes that are sharply demarcated from the thickened granular layer.^1,2 Within the spinous, granular, and corneal layers, there is a pale, gray-staining, basophilic, cytoplasmic substance intercellularly.¹ 

Histopathologically, HD may be mistaken for several other entities both benign and malignant.¹ Epidermolytic hyperkeratosis can be a genetic disorder, an incidental finding in a variety of skin conditions, or an isolated lesion.⁴ The genetic syndrome, caused by mutation in keratins 1 or 10, clinically presents with hyperkeratosis, erosions, blisters, and thickening of the epidermis, often with a corrugated appearance. Epidermal nevi findings often are seen in conjunction with histologic changes of epidermolytic hyperkeratosis caused by mutation. Solitary lesions also can resemble seborrheic keratosis or verruca. In all examples of epidermolytic hyperkeratosis, the histopathologic findings are identical.⁴ The granular layer is thickened, and coarse keratohyalin granules aggregate in the suprabasal cells.⁵ There is acantholysis with perinuclear vacuolization in the spinous and granular layers with characteristic pale cytoplasmic areas devoid of keratin filaments (Figure 1). The basal layer may be hyperproliferative.⁵ 

Irritated seborrheic keratosis presents as an exophytic, waxy, dark, sharply demarcated plaque with a stuck-on appearance.⁶ There is visible keratinization with comedolike openings, fissures and ridges, and scale; it also can contain milialike cysts. Histopathologically there is papillomatosis with prominent rete ridges, often including keratin pseudohorn cysts and squamous eddies. Enlarged capillaries can be seen in the dermal papillae. There is normal cytology with benign sheets of basaloid cells (Figure 2).⁷ Activating mutation in fibroblast growth factor receptor 3 leads to the growth and thickness of the epidermis that has been identified in these benign lesions.⁸ 

Verruca plana appears as a flesh-colored or reddish, warty, flat-topped papule that often forms clusters. Histopathologically it shows prominent hypergranulosis, thickened stratum spinosum, and vacuolized keratinocytes.⁹ The nuclei demonstrate a characteristic cytopathic effect of the virion, blurring the nuclear chromatin due to viral particle accumulation, known as koilocytes (Figure 3). The cause is the double-stranded DNA human papillomavirus types 2, 3, and 10.¹⁰

Bowen disease is a form of squamous cell carcinoma in situ characterized by an enlarging, well-demarcated, erythematous plaque with an irregular border and crusting or scaling. Histopathology reveals pleomorphic epidermal keratinization that becomes incorporated in the stratum corneum as parakeratotic nuclei. There is acanthosis, elongation of the rete ridges, and disorganized keratinocytes with atypia.¹¹ The granular and spinous layers show an atypical honeycomb pattern with atypical cellular morphology (Figure 4).¹² Bowen disease is a malignant lesion commonly found in older adults on sun-exposed skin that can evolve into invasive squamous cell carcinoma. 

The Diagnosis: Hypergranulotic Dyscornification 

Hypergranulotic dyscornification (HD) is a rarely reported reaction pattern present in benign solitary keratoses with only few reports to date. It may be an underrecognized reaction pattern based on the paucity of reported cases as well as the histologic similarities to other entities. It has been hypothesized that this pattern reflects an underlying keratin mutation or disorder of keratinization.¹ 

Clinically, HD most commonly presents as a waxy, tan-colored, solitary keratosis generally found on the lower limbs, trunk, or back in individuals aged 20 to 60 years.^1,2 Histopathology shows marked hyperkeratosis, papillomatosis, and clumped basophilic keratohyalin granules within the corneocytes with digitated epidermal hyperplasia. There is abnormal cornification across the entire lesion with papillomatosis and marked hypergranulosis.³ There often are homogeneous orthokeratotic mounds of large, dull, eosinophilic-staining anucleate keratinocytes that are sharply demarcated from the thickened granular layer.^1,2 Within the spinous, granular, and corneal layers, there is a pale, gray-staining, basophilic, cytoplasmic substance intercellularly.¹ 

Histopathologically, HD may be mistaken for several other entities both benign and malignant.¹ Epidermolytic hyperkeratosis can be a genetic disorder, an incidental finding in a variety of skin conditions, or an isolated lesion.⁴ The genetic syndrome, caused by mutation in keratins 1 or 10, clinically presents with hyperkeratosis, erosions, blisters, and thickening of the epidermis, often with a corrugated appearance. Epidermal nevi findings often are seen in conjunction with histologic changes of epidermolytic hyperkeratosis caused by mutation. Solitary lesions also can resemble seborrheic keratosis or verruca. In all examples of epidermolytic hyperkeratosis, the histopathologic findings are identical.⁴ The granular layer is thickened, and coarse keratohyalin granules aggregate in the suprabasal cells.⁵ There is acantholysis with perinuclear vacuolization in the spinous and granular layers with characteristic pale cytoplasmic areas devoid of keratin filaments (Figure 1). The basal layer may be hyperproliferative.⁵ 

Irritated seborrheic keratosis presents as an exophytic, waxy, dark, sharply demarcated plaque with a stuck-on appearance.⁶ There is visible keratinization with comedolike openings, fissures and ridges, and scale; it also can contain milialike cysts. Histopathologically there is papillomatosis with prominent rete ridges, often including keratin pseudohorn cysts and squamous eddies. Enlarged capillaries can be seen in the dermal papillae. There is normal cytology with benign sheets of basaloid cells (Figure 2).⁷ Activating mutation in fibroblast growth factor receptor 3 leads to the growth and thickness of the epidermis that has been identified in these benign lesions.⁸ 

Verruca plana appears as a flesh-colored or reddish, warty, flat-topped papule that often forms clusters. Histopathologically it shows prominent hypergranulosis, thickened stratum spinosum, and vacuolized keratinocytes.⁹ The nuclei demonstrate a characteristic cytopathic effect of the virion, blurring the nuclear chromatin due to viral particle accumulation, known as koilocytes (Figure 3). The cause is the double-stranded DNA human papillomavirus types 2, 3, and 10.¹⁰

Bowen disease is a form of squamous cell carcinoma in situ characterized by an enlarging, well-demarcated, erythematous plaque with an irregular border and crusting or scaling. Histopathology reveals pleomorphic epidermal keratinization that becomes incorporated in the stratum corneum as parakeratotic nuclei. There is acanthosis, elongation of the rete ridges, and disorganized keratinocytes with atypia.¹¹ The granular and spinous layers show an atypical honeycomb pattern with atypical cellular morphology (Figure 4).¹² Bowen disease is a malignant lesion commonly found in older adults on sun-exposed skin that can evolve into invasive squamous cell carcinoma. 

To the Editor:

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

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

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

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

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

To the Editor:

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

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

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

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

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

To the Editor:

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

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

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

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

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

The Diagnosis: Papuloerythroderma of Ofuji 

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

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

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

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

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

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

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

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

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

The Diagnosis: Papuloerythroderma of Ofuji 

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

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

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

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

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

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

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

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

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

The Diagnosis: Papuloerythroderma of Ofuji 

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

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

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

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

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

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

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

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

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

The Diagnosis: Cutaneous Crohn Disease 

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

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

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

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

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

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

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

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

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

The Diagnosis: Cutaneous Crohn Disease 

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

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

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

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

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

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

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

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

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

The Diagnosis: Cutaneous Crohn Disease 

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

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

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

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

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

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

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

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

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

The Diagnosis: Tophaceous Gout  

Biopsy revealed amorphous pink material within the center of palisading granulomas lined by histiocytes and giant cells. Scattered crystal remnants also were identified within the center of the granulomas; however, the majority of the crystals were dissolved during the formalin processing of the tissue to become the amorphous material. A perivascular mixed inflammatory infiltrate composed of lymphocytes, histiocytes, and plasma cells surrounded the tophi nodules. A biopsy confirmed the diagnosis of tophaceous gout (Figure). 

Gout is a systemic metabolic disease characterized by the supersaturation of monosodium urate (MSU) crystals in joints and bursae. Peripheral joints most commonly are affected due to the poor solubility of MSU crystals at low temperatures.¹ It is one of the most common forms of inflammatory arthritis, with an estimated prevalence of 4% of adults in the United States.² An estimated $1 billion is spent each year on ambulatory care for gout.³ Gout occurs most commonly in men and usually manifests in the fifth or sixth decades of life.⁴ Risk factors for the development of gout include obesity, hypertension, poor dietary habits and kidney function, excessive alcohol intake, and diuretic use.³ 

Disease manifestations range from asymptomatic hyperuricemia to acute gouty arthritis and chronic tophaceous gout. Patients may present with chronic tophaceous gout without a prior clinically apparent acute gout episode.^5,6 Uncontrolled gout may result in large accumulations of MSU crystals, leading to well-circumscribed masses (known as tophi), as demonstrated in our patient.¹ Tophi are pathognomonic features of gout and are the sine qua non of advanced gout (also known as chronic tophaceous gout).² Clinically, these tophi appear as subcutaneous, yellowish white, firm and smooth nodules that are highlighted on the skin.⁴ Tophi most commonly are found on the helix, articular and periarticular tissue, and the tissue of the hands and feet. They usually are visible on physical examination but also may be detected on imaging studies.^2,4 

Gouty tophi have been reported in extraordinary locations, such as in sclerae; vocal cords; heart valves; abdominal striae; nerves; axial skeleton^4,7; and the penis, as in our patient and one other case.² These gouty deposits can appear similarly to lipomas, rheumatoid and osteoarthritic nodules, and infectious and malignant processes.^1,5 When tophi present in unusual locations, tissue biopsy often is necessary to confirm the diagnosis. Tissue preservation in alcohol is required to preserve the urate crystals. Microscopically, urate crystals appear as tightly packed, brown, needle-shaped crystals surrounded by granulomatous inflammation with foreign body giant cells, macrophages, and possibly some fibrosis. When examined under polarized light, the MSU crystals are negatively birefringent. However, when clinical suspicion for gout is low and the tissue is instead formalin fixed, as was performed in our case, the crystals dissolve into fibrillary amorphous deposits within the center of the granulomatous inflammation, which is another characteristic histologic finding in tophaceous gout.⁸ 

Management of gout focuses on urate-lowering therapy including lifestyle changes. Lower serum urate levels are associated with a decreased incidence of acute gout attacks and chronic tophaceous gout.² Urate-lowering drugs often are combined with anti-inflammatory drugs during acute attacks. Lifestyle changes, such as weight loss, exercise, reduced alcohol consumption, high fluid intake, and a low-purine diet also are beneficial.^3,4 Although gout cannot be cured, it can be effectively managed, and appropriate treatment can improve quality of life and reduce the risk for permanent joint damage and structural deformities. If medical treatment and lifestyle changes fail to adequately control tophaceous gout or if tophi become symptomatic, surgical removal of tophi is appropriate.⁴ 

At follow-up, our patient opted for surgical removal of the penile tophi. Using local anesthesia, surgical debulking via curettage was performed. Open defects were closed with fine absorbable sutures, and prophylactic antibiotics were given. Allopurinol also was started. Six weeks following extraction, the patient reported no complications and the area was continuing to heal.

Tophaceous gout would be distinguished from conditions in the differential diagnosis based on histologic findings from hematoxylin and eosin (H&E)-stained sections. Actinomycotic mycetoma is rare in the United States and is characterized by a seropurulent or stringy exudate with grains, ulcerations, melicerous scabs, and retractable scarring.⁹ On H&E-stained sections, actinomyces appear filamentous with deeply basophilic staining and radially oriented acidophilic projections.¹⁰ Calcinosis cutis of the penis has been reported to appear as asymptomatic papules; however, microscopic sections reveal deeply basophilic calcium deposits within the tissue.¹¹ Multinodular syphilis shows characteristic histology with lichenoid or vacuolar interface dermatitis, slender acanthosis, plasma cells, and endothelial swelling of the small vessels. A Treponema pallidum immunoperoxidase stain shows numerous organisms. Planar xanthoma shows xanthomatous or foamy histiocytes throughout the dermis on H&E-stained sections.¹²  

The Diagnosis: Tophaceous Gout  

Biopsy revealed amorphous pink material within the center of palisading granulomas lined by histiocytes and giant cells. Scattered crystal remnants also were identified within the center of the granulomas; however, the majority of the crystals were dissolved during the formalin processing of the tissue to become the amorphous material. A perivascular mixed inflammatory infiltrate composed of lymphocytes, histiocytes, and plasma cells surrounded the tophi nodules. A biopsy confirmed the diagnosis of tophaceous gout (Figure). 

Gout is a systemic metabolic disease characterized by the supersaturation of monosodium urate (MSU) crystals in joints and bursae. Peripheral joints most commonly are affected due to the poor solubility of MSU crystals at low temperatures.¹ It is one of the most common forms of inflammatory arthritis, with an estimated prevalence of 4% of adults in the United States.² An estimated $1 billion is spent each year on ambulatory care for gout.³ Gout occurs most commonly in men and usually manifests in the fifth or sixth decades of life.⁴ Risk factors for the development of gout include obesity, hypertension, poor dietary habits and kidney function, excessive alcohol intake, and diuretic use.³ 

Disease manifestations range from asymptomatic hyperuricemia to acute gouty arthritis and chronic tophaceous gout. Patients may present with chronic tophaceous gout without a prior clinically apparent acute gout episode.^5,6 Uncontrolled gout may result in large accumulations of MSU crystals, leading to well-circumscribed masses (known as tophi), as demonstrated in our patient.¹ Tophi are pathognomonic features of gout and are the sine qua non of advanced gout (also known as chronic tophaceous gout).² Clinically, these tophi appear as subcutaneous, yellowish white, firm and smooth nodules that are highlighted on the skin.⁴ Tophi most commonly are found on the helix, articular and periarticular tissue, and the tissue of the hands and feet. They usually are visible on physical examination but also may be detected on imaging studies.^2,4 

Gouty tophi have been reported in extraordinary locations, such as in sclerae; vocal cords; heart valves; abdominal striae; nerves; axial skeleton^4,7; and the penis, as in our patient and one other case.² These gouty deposits can appear similarly to lipomas, rheumatoid and osteoarthritic nodules, and infectious and malignant processes.^1,5 When tophi present in unusual locations, tissue biopsy often is necessary to confirm the diagnosis. Tissue preservation in alcohol is required to preserve the urate crystals. Microscopically, urate crystals appear as tightly packed, brown, needle-shaped crystals surrounded by granulomatous inflammation with foreign body giant cells, macrophages, and possibly some fibrosis. When examined under polarized light, the MSU crystals are negatively birefringent. However, when clinical suspicion for gout is low and the tissue is instead formalin fixed, as was performed in our case, the crystals dissolve into fibrillary amorphous deposits within the center of the granulomatous inflammation, which is another characteristic histologic finding in tophaceous gout.⁸ 

Management of gout focuses on urate-lowering therapy including lifestyle changes. Lower serum urate levels are associated with a decreased incidence of acute gout attacks and chronic tophaceous gout.² Urate-lowering drugs often are combined with anti-inflammatory drugs during acute attacks. Lifestyle changes, such as weight loss, exercise, reduced alcohol consumption, high fluid intake, and a low-purine diet also are beneficial.^3,4 Although gout cannot be cured, it can be effectively managed, and appropriate treatment can improve quality of life and reduce the risk for permanent joint damage and structural deformities. If medical treatment and lifestyle changes fail to adequately control tophaceous gout or if tophi become symptomatic, surgical removal of tophi is appropriate.⁴ 

At follow-up, our patient opted for surgical removal of the penile tophi. Using local anesthesia, surgical debulking via curettage was performed. Open defects were closed with fine absorbable sutures, and prophylactic antibiotics were given. Allopurinol also was started. Six weeks following extraction, the patient reported no complications and the area was continuing to heal.

Tophaceous gout would be distinguished from conditions in the differential diagnosis based on histologic findings from hematoxylin and eosin (H&E)-stained sections. Actinomycotic mycetoma is rare in the United States and is characterized by a seropurulent or stringy exudate with grains, ulcerations, melicerous scabs, and retractable scarring.⁹ On H&E-stained sections, actinomyces appear filamentous with deeply basophilic staining and radially oriented acidophilic projections.¹⁰ Calcinosis cutis of the penis has been reported to appear as asymptomatic papules; however, microscopic sections reveal deeply basophilic calcium deposits within the tissue.¹¹ Multinodular syphilis shows characteristic histology with lichenoid or vacuolar interface dermatitis, slender acanthosis, plasma cells, and endothelial swelling of the small vessels. A Treponema pallidum immunoperoxidase stain shows numerous organisms. Planar xanthoma shows xanthomatous or foamy histiocytes throughout the dermis on H&E-stained sections.¹²  

The Diagnosis: Tophaceous Gout  

Biopsy revealed amorphous pink material within the center of palisading granulomas lined by histiocytes and giant cells. Scattered crystal remnants also were identified within the center of the granulomas; however, the majority of the crystals were dissolved during the formalin processing of the tissue to become the amorphous material. A perivascular mixed inflammatory infiltrate composed of lymphocytes, histiocytes, and plasma cells surrounded the tophi nodules. A biopsy confirmed the diagnosis of tophaceous gout (Figure). 

Gout is a systemic metabolic disease characterized by the supersaturation of monosodium urate (MSU) crystals in joints and bursae. Peripheral joints most commonly are affected due to the poor solubility of MSU crystals at low temperatures.¹ It is one of the most common forms of inflammatory arthritis, with an estimated prevalence of 4% of adults in the United States.² An estimated $1 billion is spent each year on ambulatory care for gout.³ Gout occurs most commonly in men and usually manifests in the fifth or sixth decades of life.⁴ Risk factors for the development of gout include obesity, hypertension, poor dietary habits and kidney function, excessive alcohol intake, and diuretic use.³ 

Disease manifestations range from asymptomatic hyperuricemia to acute gouty arthritis and chronic tophaceous gout. Patients may present with chronic tophaceous gout without a prior clinically apparent acute gout episode.^5,6 Uncontrolled gout may result in large accumulations of MSU crystals, leading to well-circumscribed masses (known as tophi), as demonstrated in our patient.¹ Tophi are pathognomonic features of gout and are the sine qua non of advanced gout (also known as chronic tophaceous gout).² Clinically, these tophi appear as subcutaneous, yellowish white, firm and smooth nodules that are highlighted on the skin.⁴ Tophi most commonly are found on the helix, articular and periarticular tissue, and the tissue of the hands and feet. They usually are visible on physical examination but also may be detected on imaging studies.^2,4 

Gouty tophi have been reported in extraordinary locations, such as in sclerae; vocal cords; heart valves; abdominal striae; nerves; axial skeleton^4,7; and the penis, as in our patient and one other case.² These gouty deposits can appear similarly to lipomas, rheumatoid and osteoarthritic nodules, and infectious and malignant processes.^1,5 When tophi present in unusual locations, tissue biopsy often is necessary to confirm the diagnosis. Tissue preservation in alcohol is required to preserve the urate crystals. Microscopically, urate crystals appear as tightly packed, brown, needle-shaped crystals surrounded by granulomatous inflammation with foreign body giant cells, macrophages, and possibly some fibrosis. When examined under polarized light, the MSU crystals are negatively birefringent. However, when clinical suspicion for gout is low and the tissue is instead formalin fixed, as was performed in our case, the crystals dissolve into fibrillary amorphous deposits within the center of the granulomatous inflammation, which is another characteristic histologic finding in tophaceous gout.⁸ 

Management of gout focuses on urate-lowering therapy including lifestyle changes. Lower serum urate levels are associated with a decreased incidence of acute gout attacks and chronic tophaceous gout.² Urate-lowering drugs often are combined with anti-inflammatory drugs during acute attacks. Lifestyle changes, such as weight loss, exercise, reduced alcohol consumption, high fluid intake, and a low-purine diet also are beneficial.^3,4 Although gout cannot be cured, it can be effectively managed, and appropriate treatment can improve quality of life and reduce the risk for permanent joint damage and structural deformities. If medical treatment and lifestyle changes fail to adequately control tophaceous gout or if tophi become symptomatic, surgical removal of tophi is appropriate.⁴ 

At follow-up, our patient opted for surgical removal of the penile tophi. Using local anesthesia, surgical debulking via curettage was performed. Open defects were closed with fine absorbable sutures, and prophylactic antibiotics were given. Allopurinol also was started. Six weeks following extraction, the patient reported no complications and the area was continuing to heal.

Tophaceous gout would be distinguished from conditions in the differential diagnosis based on histologic findings from hematoxylin and eosin (H&E)-stained sections. Actinomycotic mycetoma is rare in the United States and is characterized by a seropurulent or stringy exudate with grains, ulcerations, melicerous scabs, and retractable scarring.⁹ On H&E-stained sections, actinomyces appear filamentous with deeply basophilic staining and radially oriented acidophilic projections.¹⁰ Calcinosis cutis of the penis has been reported to appear as asymptomatic papules; however, microscopic sections reveal deeply basophilic calcium deposits within the tissue.¹¹ Multinodular syphilis shows characteristic histology with lichenoid or vacuolar interface dermatitis, slender acanthosis, plasma cells, and endothelial swelling of the small vessels. A Treponema pallidum immunoperoxidase stain shows numerous organisms. Planar xanthoma shows xanthomatous or foamy histiocytes throughout the dermis on H&E-stained sections.¹²  

The Diagnosis: Epidermolysis Bullosa Acquisita 

Epidermolysis bullosa acquisita (EBA) is a rare autoimmune blistering disorder characterized by tense bullae, skin fragility, atrophic scarring, and milia formation.¹ Blisters occur on a noninflammatory base in the classic variant and are trauma induced, hence the predilection for the extensor surfaces.² Mucosal involvement also has been described.¹ The characteristic findings in EBA are IgG autoantibodies directed at the N-terminal collagenous domain of type VII collagen, which composes the anchoring fibrils in the basement membrane zone.¹ Differentiating EBA from other subepidermal bullous diseases, especially bullous pemphigoid (BP), can be difficult, necessitating specialized tests.  

Biopsy of the perilesional skin can help identify the location of the blister formation. Our patient's biopsy showed a subepidermal blister with granulocytes. The differential diagnosis of a subepidermal blister includes BP, herpes gestationis, cicatricial pemphigoid, EBA, bullous systemic lupus erythematosus, dermatitis herpetiformis, linear IgA disease, and porphyria cutanea tarda. 

Direct immunofluorescence (DIF) was performed on the biopsy from our patient, which showed linear/particulate IgG, C3, and IgA deposits in the basement membrane zone, narrowing the differential diagnosis to BP or EBA. To differentiate EBA from BP, DIF of perilesional skin using a salt-split preparation was performed. This test distinguishes the location of the immunoreactants at the basement membrane zone. The antibody complexes in BP are found on the epidermal side of the split, while the antibody complexes in EBA are found on the dermal side of the split. Indirect immunofluorescence on salt-split skin also has been used to distinguish EBA from BP but is only conclusive if there are circulating autoantibodies to the basement membrane zone in the serum, which occurs in approximately 50% of patients with EBA and 15% of patients with BP.³ The immune complexes in our patient were found to be on the dermal side of the split after DIF on salt-split skin, confirming the diagnosis of EBA (Figure).  

Differentiating EBA from BP has great value, as the diagnosis affects treatment options. Bullous pemphigoid is fairly easy to treat, with most patients responding to prednisone.³ Epidermolysis bullosa acquisita usually is resistant to therapy. The disease course is chronic with  exacerbations and remissions. Dapsone often is used to control the disease, though this therapy for EBA is not currently approved by the US Food and Drug Administration. The recommended initial dose of dapsone is 50 mg daily and should be increased by 50 mg each week until remission, usually 100 to 250 mg.⁴ We prescribed dapsone for our patient upon clinical suspicion of EBA before the DIF on salt-split skin was completed. A trial of prednisone may be warranted for EBA if there is no response to dapsone or colchicine, but the response is unpredictable. Cyclosporine usually results in a quick response and may be considered if there is clinically severe disease and other treatment alternatives have failed.⁴ 

The Diagnosis: Epidermolysis Bullosa Acquisita 

Epidermolysis bullosa acquisita (EBA) is a rare autoimmune blistering disorder characterized by tense bullae, skin fragility, atrophic scarring, and milia formation.¹ Blisters occur on a noninflammatory base in the classic variant and are trauma induced, hence the predilection for the extensor surfaces.² Mucosal involvement also has been described.¹ The characteristic findings in EBA are IgG autoantibodies directed at the N-terminal collagenous domain of type VII collagen, which composes the anchoring fibrils in the basement membrane zone.¹ Differentiating EBA from other subepidermal bullous diseases, especially bullous pemphigoid (BP), can be difficult, necessitating specialized tests.  

Biopsy of the perilesional skin can help identify the location of the blister formation. Our patient's biopsy showed a subepidermal blister with granulocytes. The differential diagnosis of a subepidermal blister includes BP, herpes gestationis, cicatricial pemphigoid, EBA, bullous systemic lupus erythematosus, dermatitis herpetiformis, linear IgA disease, and porphyria cutanea tarda. 

Direct immunofluorescence (DIF) was performed on the biopsy from our patient, which showed linear/particulate IgG, C3, and IgA deposits in the basement membrane zone, narrowing the differential diagnosis to BP or EBA. To differentiate EBA from BP, DIF of perilesional skin using a salt-split preparation was performed. This test distinguishes the location of the immunoreactants at the basement membrane zone. The antibody complexes in BP are found on the epidermal side of the split, while the antibody complexes in EBA are found on the dermal side of the split. Indirect immunofluorescence on salt-split skin also has been used to distinguish EBA from BP but is only conclusive if there are circulating autoantibodies to the basement membrane zone in the serum, which occurs in approximately 50% of patients with EBA and 15% of patients with BP.³ The immune complexes in our patient were found to be on the dermal side of the split after DIF on salt-split skin, confirming the diagnosis of EBA (Figure).  

Differentiating EBA from BP has great value, as the diagnosis affects treatment options. Bullous pemphigoid is fairly easy to treat, with most patients responding to prednisone.³ Epidermolysis bullosa acquisita usually is resistant to therapy. The disease course is chronic with  exacerbations and remissions. Dapsone often is used to control the disease, though this therapy for EBA is not currently approved by the US Food and Drug Administration. The recommended initial dose of dapsone is 50 mg daily and should be increased by 50 mg each week until remission, usually 100 to 250 mg.⁴ We prescribed dapsone for our patient upon clinical suspicion of EBA before the DIF on salt-split skin was completed. A trial of prednisone may be warranted for EBA if there is no response to dapsone or colchicine, but the response is unpredictable. Cyclosporine usually results in a quick response and may be considered if there is clinically severe disease and other treatment alternatives have failed.⁴ 

The Diagnosis: Epidermolysis Bullosa Acquisita 

Epidermolysis bullosa acquisita (EBA) is a rare autoimmune blistering disorder characterized by tense bullae, skin fragility, atrophic scarring, and milia formation.¹ Blisters occur on a noninflammatory base in the classic variant and are trauma induced, hence the predilection for the extensor surfaces.² Mucosal involvement also has been described.¹ The characteristic findings in EBA are IgG autoantibodies directed at the N-terminal collagenous domain of type VII collagen, which composes the anchoring fibrils in the basement membrane zone.¹ Differentiating EBA from other subepidermal bullous diseases, especially bullous pemphigoid (BP), can be difficult, necessitating specialized tests.  

Biopsy of the perilesional skin can help identify the location of the blister formation. Our patient's biopsy showed a subepidermal blister with granulocytes. The differential diagnosis of a subepidermal blister includes BP, herpes gestationis, cicatricial pemphigoid, EBA, bullous systemic lupus erythematosus, dermatitis herpetiformis, linear IgA disease, and porphyria cutanea tarda. 

Direct immunofluorescence (DIF) was performed on the biopsy from our patient, which showed linear/particulate IgG, C3, and IgA deposits in the basement membrane zone, narrowing the differential diagnosis to BP or EBA. To differentiate EBA from BP, DIF of perilesional skin using a salt-split preparation was performed. This test distinguishes the location of the immunoreactants at the basement membrane zone. The antibody complexes in BP are found on the epidermal side of the split, while the antibody complexes in EBA are found on the dermal side of the split. Indirect immunofluorescence on salt-split skin also has been used to distinguish EBA from BP but is only conclusive if there are circulating autoantibodies to the basement membrane zone in the serum, which occurs in approximately 50% of patients with EBA and 15% of patients with BP.³ The immune complexes in our patient were found to be on the dermal side of the split after DIF on salt-split skin, confirming the diagnosis of EBA (Figure).  

Differentiating EBA from BP has great value, as the diagnosis affects treatment options. Bullous pemphigoid is fairly easy to treat, with most patients responding to prednisone.³ Epidermolysis bullosa acquisita usually is resistant to therapy. The disease course is chronic with  exacerbations and remissions. Dapsone often is used to control the disease, though this therapy for EBA is not currently approved by the US Food and Drug Administration. The recommended initial dose of dapsone is 50 mg daily and should be increased by 50 mg each week until remission, usually 100 to 250 mg.⁴ We prescribed dapsone for our patient upon clinical suspicion of EBA before the DIF on salt-split skin was completed. A trial of prednisone may be warranted for EBA if there is no response to dapsone or colchicine, but the response is unpredictable. Cyclosporine usually results in a quick response and may be considered if there is clinically severe disease and other treatment alternatives have failed.⁴