Dermatopathology

The Diagnosis: Eruptive Blue Nevus

All biopsies demonstrated similar histologic features, including an intradermal proliferation of heavily pigmented, spindle-shaped dendritic melanocytes (Figure). The dermal pigment was most pronounced in the grossly darker papules, and there was not a substantial amount of background pigmentation at the stratum basale. Cytologic atypia, foci of necrosis, and mitotic activity were absent from all sections. There was no definitive junctional component identified, no multinucleated giant cells, and there was no overlying epidermal aberration. With some background pigmentation seen histologically, nevus spilus was considered, but because this acute eruption occurred in a young adult without appreciable gross background hyperpigmentation, the clinical context led to a diagnosis of eruptive blue nevus. After communicating the findings to the patient, he declined further treatment.

Eruptive blue nevus is an exceptionally rare subtype of blue nevus with few cases reported since the 1940s.^1-9 Generally, each case report found a triggering event that could possibly have precipitated the acute proliferation and evolution of nevi. Triggering events can include bullous processes such as erythema multiforme² and Stevens-Johnson syndrome,³ severe sunburn,⁴ trauma,⁵ immunosuppression,⁶ and a variety of endocrinopathies. No such history could be identified in our patient, except the biopsy.

Common blue nevi are benign, usually congenital, well-circumscribed, solitary, blue-gray macules or papules. Half of blue nevi cases are found on the dorsal aspects of the hands and feet but can present anywhere (eg, face, scalp, wrists, sacrum, buttocks). The blue-gray color appreciated clinically is attributed to the Tyndall effect, which occurs when long-wavelength light--red, orange, and yellow--is absorbed by the melanin deep in the dermis, while short-wavelength visible light--blue, violet, and indigo--is reflected with backscattering. On polarized dermoscopy, a homogeneous blue-gray hue is appreciated, but lighter segments may be present when collagen deposition is robust. Histopathologic findings confirm spindle-shaped dendritic melanocytes in the dermis without epidermal involvement. It generally is accepted that the etiology of these benign nevi is a failed migration of neural crest cells to the epidermis.^10,11 Although the common blue nevus may be simple to diagnose, several subtypes have been described in the literature, including combined blue nevus, desmoplastic blue nevus, hypomelanotic/amelanotic blue nevus, and epithelioid blue nevus of Carney complex, and excluding a malignant process is of monumental importance.^7,12

Biopsy is recommended for common blue nevi in the evaluation of newly acquired lesions, expansion of previously stable nevi, or for nevi larger than 10 mm in diameter. The nature of eruptive blue nevi warrants a biopsy to exclude melanoma or another malignant process. While the Becker nevus may manifest in adolescent males, it is clinically distinct from an eruptive blue nevus due to the size, relative homogeneity, and presence of hair within the lesion. Cutaneous amyloidosis may appear clinically similar to an eruptive blue nevus, but globular or amorphous material was not present in the papillary dermis of biopsied lesions in our patient. Since there was no cellular atypia or mitotic activity, melanoma and other malignancies were ruled out. Lastly, NAME syndrome by definition must include atrial myxomas, myxoid neurofibromas, and ephelides in addition to the nevi; however, our patient had only nevi and few ephelides. Once the diagnosis is established and benign nature confirmed, treatment is not necessarily required. If the patient elects to remove the lesion for aesthetic reasons, an excision into the subcutaneous fat is required to ensure complete removal of deep dermal melanocytes. Prior excisions of eruptive blue nevi have had no recurrence after more than 10 months.^8,9

The Diagnosis: Eruptive Blue Nevus

All biopsies demonstrated similar histologic features, including an intradermal proliferation of heavily pigmented, spindle-shaped dendritic melanocytes (Figure). The dermal pigment was most pronounced in the grossly darker papules, and there was not a substantial amount of background pigmentation at the stratum basale. Cytologic atypia, foci of necrosis, and mitotic activity were absent from all sections. There was no definitive junctional component identified, no multinucleated giant cells, and there was no overlying epidermal aberration. With some background pigmentation seen histologically, nevus spilus was considered, but because this acute eruption occurred in a young adult without appreciable gross background hyperpigmentation, the clinical context led to a diagnosis of eruptive blue nevus. After communicating the findings to the patient, he declined further treatment.

Eruptive blue nevus is an exceptionally rare subtype of blue nevus with few cases reported since the 1940s.^1-9 Generally, each case report found a triggering event that could possibly have precipitated the acute proliferation and evolution of nevi. Triggering events can include bullous processes such as erythema multiforme² and Stevens-Johnson syndrome,³ severe sunburn,⁴ trauma,⁵ immunosuppression,⁶ and a variety of endocrinopathies. No such history could be identified in our patient, except the biopsy.

Common blue nevi are benign, usually congenital, well-circumscribed, solitary, blue-gray macules or papules. Half of blue nevi cases are found on the dorsal aspects of the hands and feet but can present anywhere (eg, face, scalp, wrists, sacrum, buttocks). The blue-gray color appreciated clinically is attributed to the Tyndall effect, which occurs when long-wavelength light--red, orange, and yellow--is absorbed by the melanin deep in the dermis, while short-wavelength visible light--blue, violet, and indigo--is reflected with backscattering. On polarized dermoscopy, a homogeneous blue-gray hue is appreciated, but lighter segments may be present when collagen deposition is robust. Histopathologic findings confirm spindle-shaped dendritic melanocytes in the dermis without epidermal involvement. It generally is accepted that the etiology of these benign nevi is a failed migration of neural crest cells to the epidermis.^10,11 Although the common blue nevus may be simple to diagnose, several subtypes have been described in the literature, including combined blue nevus, desmoplastic blue nevus, hypomelanotic/amelanotic blue nevus, and epithelioid blue nevus of Carney complex, and excluding a malignant process is of monumental importance.^7,12

Biopsy is recommended for common blue nevi in the evaluation of newly acquired lesions, expansion of previously stable nevi, or for nevi larger than 10 mm in diameter. The nature of eruptive blue nevi warrants a biopsy to exclude melanoma or another malignant process. While the Becker nevus may manifest in adolescent males, it is clinically distinct from an eruptive blue nevus due to the size, relative homogeneity, and presence of hair within the lesion. Cutaneous amyloidosis may appear clinically similar to an eruptive blue nevus, but globular or amorphous material was not present in the papillary dermis of biopsied lesions in our patient. Since there was no cellular atypia or mitotic activity, melanoma and other malignancies were ruled out. Lastly, NAME syndrome by definition must include atrial myxomas, myxoid neurofibromas, and ephelides in addition to the nevi; however, our patient had only nevi and few ephelides. Once the diagnosis is established and benign nature confirmed, treatment is not necessarily required. If the patient elects to remove the lesion for aesthetic reasons, an excision into the subcutaneous fat is required to ensure complete removal of deep dermal melanocytes. Prior excisions of eruptive blue nevi have had no recurrence after more than 10 months.^8,9

The Diagnosis: Eruptive Blue Nevus

All biopsies demonstrated similar histologic features, including an intradermal proliferation of heavily pigmented, spindle-shaped dendritic melanocytes (Figure). The dermal pigment was most pronounced in the grossly darker papules, and there was not a substantial amount of background pigmentation at the stratum basale. Cytologic atypia, foci of necrosis, and mitotic activity were absent from all sections. There was no definitive junctional component identified, no multinucleated giant cells, and there was no overlying epidermal aberration. With some background pigmentation seen histologically, nevus spilus was considered, but because this acute eruption occurred in a young adult without appreciable gross background hyperpigmentation, the clinical context led to a diagnosis of eruptive blue nevus. After communicating the findings to the patient, he declined further treatment.

Eruptive blue nevus is an exceptionally rare subtype of blue nevus with few cases reported since the 1940s.^1-9 Generally, each case report found a triggering event that could possibly have precipitated the acute proliferation and evolution of nevi. Triggering events can include bullous processes such as erythema multiforme² and Stevens-Johnson syndrome,³ severe sunburn,⁴ trauma,⁵ immunosuppression,⁶ and a variety of endocrinopathies. No such history could be identified in our patient, except the biopsy.

Common blue nevi are benign, usually congenital, well-circumscribed, solitary, blue-gray macules or papules. Half of blue nevi cases are found on the dorsal aspects of the hands and feet but can present anywhere (eg, face, scalp, wrists, sacrum, buttocks). The blue-gray color appreciated clinically is attributed to the Tyndall effect, which occurs when long-wavelength light--red, orange, and yellow--is absorbed by the melanin deep in the dermis, while short-wavelength visible light--blue, violet, and indigo--is reflected with backscattering. On polarized dermoscopy, a homogeneous blue-gray hue is appreciated, but lighter segments may be present when collagen deposition is robust. Histopathologic findings confirm spindle-shaped dendritic melanocytes in the dermis without epidermal involvement. It generally is accepted that the etiology of these benign nevi is a failed migration of neural crest cells to the epidermis.^10,11 Although the common blue nevus may be simple to diagnose, several subtypes have been described in the literature, including combined blue nevus, desmoplastic blue nevus, hypomelanotic/amelanotic blue nevus, and epithelioid blue nevus of Carney complex, and excluding a malignant process is of monumental importance.^7,12

Biopsy is recommended for common blue nevi in the evaluation of newly acquired lesions, expansion of previously stable nevi, or for nevi larger than 10 mm in diameter. The nature of eruptive blue nevi warrants a biopsy to exclude melanoma or another malignant process. While the Becker nevus may manifest in adolescent males, it is clinically distinct from an eruptive blue nevus due to the size, relative homogeneity, and presence of hair within the lesion. Cutaneous amyloidosis may appear clinically similar to an eruptive blue nevus, but globular or amorphous material was not present in the papillary dermis of biopsied lesions in our patient. Since there was no cellular atypia or mitotic activity, melanoma and other malignancies were ruled out. Lastly, NAME syndrome by definition must include atrial myxomas, myxoid neurofibromas, and ephelides in addition to the nevi; however, our patient had only nevi and few ephelides. Once the diagnosis is established and benign nature confirmed, treatment is not necessarily required. If the patient elects to remove the lesion for aesthetic reasons, an excision into the subcutaneous fat is required to ensure complete removal of deep dermal melanocytes. Prior excisions of eruptive blue nevi have had no recurrence after more than 10 months.^8,9

The cutaneous manifestations of Crohn disease (CD) are varied, including pyoderma gangrenosum, erythema nodosum, and metastatic CD (MCD). First described by Parks et al,¹ MCD is defined as the occurrence of granulomatous lesions at a skin site distant from the gastrointestinal tract.^1-20 Metastatic CD presents a diagnostic challenge because it is a rare component in the spectrum of inflammatory bowel disease complications, and many physicians are unaware of its existence. It may precede, coincide with, or develop after the diagnosis of intestinal disease.^2-5 Vulvoperineal involvement is particularly problematic because a multitude of other, more likely disease processes are considered first. Typically it is initially diagnosed as a presumed infection prompting reflexive treatment with antivirals, antifungals, and antibiotics. Patients may experience symptoms for years prior to correct diagnosis and institution of proper therapy. A variety of clinical presentations have been described, including nonspecific pain and swelling, erythematous papules and plaques, and nonhealing ulcers. Skin biopsy characteristically confirms the diagnosis and reveals dermal noncaseating granulomas. Multiple oral and parenteral therapies are available, with surgical intervention reserved for resistant cases. We present a case of vulvovaginal MCD in the setting of well-controlled intestinal disease. We also provide a review of the literature regarding genital CD and emphasize the need to keep MCD in the differential of vulvoperineal pathology.

Case Report

A 29-year-old woman was referred to the dermatology clinic with vulvar pain, swelling, and pruritus of 14 months’ duration. Her medical history was remarkable for CD following a colectomy with colostomy. Prior therapies included methotrexate with infliximab for 5 years followed by a 2-year regimen with adalimumab, which induced remission of the intestinal disease.

The patient previously had taken a variety of topical and oral antimicrobials based on treatment from a primary care physician because fungal, bacterial, and viral infections initially were suspected; however, the vulvar disease persisted, and drug-induced immunosuppression was considered to be an underlying factor. Thus, adalimumab was discontinued. Despite elimination of the biologic, the vulvar disease progressed, which prompted referral to the dermatology clinic.

Physical examination revealed diffuse vulvar edema with overlying erythema and scale (Figure 1A). Upon closer inspection, scattered violaceous papules atop a backdrop of lichenification were evident, imparting a cobblestone appearance (Figure 1B). Additionally, a fissure was present on the gluteal cleft. Biopsy from the left labia majora demonstrated well-formed granulomas within a fibrotic reticular dermis (Figures 2A and 2B). The granulomas consisted of both mononucleated and multinucleated histiocytes, rimmed peripherally by lymphocytes and plasma cells (Figure 2C). Periodic acid–Schiff–diastase and acid-fast bacilli stains as well as polarizing microscopy were negative.

Given the patient’s history, a diagnosis of vulvoperineal MCD was rendered. The patient was started on oral metronidazole 250 mg 3 times daily with topical fluocinonide and tacrolimus. She responded well to this treatment regimen and was referred back to the gastroenterologist for management of the intestinal disease.

 

Comment

Crohn disease is an idiopathic chronic inflammatory condition that primarily affects the gastrointestinal tract, anywhere from the mouth to the anus. It is characterized by transmural inflammation and fissures that can extend beyond the muscularis propria.^4,6 Extraintestinal manifestations are common.³

Cutaneous CD often presents as perianal, perifistular, or peristomal inflammation or ulceration.⁷ Other skin manifestations include pyoderma gangrenosum, erythema nodosum, erythema multiforme, epidermolysis bullosa acquisita, and palmar erythema.⁷ Metastatic CD involves skin noncontiguous with the gastrointestinal tract^1-20 and may involve any portion of the cutis. Although rare, MCD is the typical etiology underlying vulvar CD.⁸

Approximately 20% of MCD patients have cutaneous lesions without a history of gastrointestinal disease. More than half of cases in adults and approximately two-thirds in children involve the genitalia. Although more common in adults, vulvar involvement has been reported in children as young as 6 years of age.² Diagnosis is especially challenging when bowel symptoms are absent; those patients should be evaluated and followed for subsequent intestinal involvement.⁶

Clinically, symptoms may include general discomfort, pain, pruritus, and dyspareunia. Psychosocial and sexual dysfunction are prevalent and also should be addressed.⁹ Depending on the stage of the disease, physical examination may reveal erythema, edema, papules, pustules, nodules, condylomatous lesions, abscesses, fissures, fistulas, ulceration, acrochordons, and scarring.^2-6,10,11

A host of infections (ie, mycobacterial, actinomycosis, deep fungal, sexually transmitted, schistosomiasis), inflammatory conditions (ie, sarcoid, hidradenitis suppurativa), foreign body reactions, Melkersson-Rosenthal syndrome, and sexual abuse should be included in the differential diagnosis.^2,6,10-12 Once infection, sarcoid, and foreign body reaction have been ruled out, noncaseating granulomas in skin are highly suggestive of CD.⁷

Histopathologic findings of MCD reveal myriad morphological reaction patterns,^5,13 including high-grade dysplasia and carcinoma of the vulva; therefore, it may be imprudent to withhold diagnosis based on the absence of the historically pathognomonic noncaseating granulomas.⁵

The etiopathogenesis of MCD remains an enigma. Dermatopathologic examinations consistently reveal a vascular injury syndrome,¹³ implicating a possible circulatory system contribution via deposition of immune complexes or antigens in skin.⁷ Bacterial infection has been implicated in the intestinal manifestations of CD; however, failure to detect microbial ribosomal RNA in MCD biopsies refutes theories of hematogenous spread of microbes.¹³ Another plausible explanation is that antibodies are formed to conserved microbial epitopes following loss of tolerance to gut flora, which results in an excessive immunologic response at distinct sites in susceptible individuals.¹³ A T-lymphocyte–mediated type IV hypersensitivity reaction also has been proposed via cross-reactivity of lymphocytes, with skin antigens precipitating extraintestinal granuloma formation and vascular injury.³ Clearly, further investigation is needed.

Magnetic resonanance imaging can identify the extent and anatomy of intestinal and pelvic disease and can assist in the diagnosis of vulvar CD.^10,11,14 For these reasons, some experts propose that imaging should be instituted prior to therapy,^12,15,16 especially when direct extension is suspected.¹⁷

Treatment is challenging and often involves collaboration among several specialties.¹² Many treatment options exist because therapeutic responses vary and genital MCD is frequently recalcitrant to therapy.⁴ Medical therapy includes antibiotics such as metronidazole, corticosteroids (ie, topical, intralesional, systemic), and immune modulators (eg, azathioprine, 6-mercaptopurine, cyclosporine, methotrexate, mycophenolate mofetil, tumor necrosis factor α inhibitors).^{2,3,6,10,16,18} Thalidomide has been used for refractory cases.¹⁹ These treatments can be used alone or in combination. Patients should be monitored for side effects and informed that many treatment regimens may be required before a sustained response is achieved.^4,16,18 Surgery is reserved for the most resistant cases. Extensive radical excision of the involved area is the best approach, as limited local excision often is followed by recurrence.²⁰

Conclusion

Our case highlights that vulvar CD can develop in the setting of well-controlled intestinal disease. Vulvoperineal CD should be considered in the differential diagnosis of chronic vulvar pain, swelling, and pruritus, especially in cases resistant to standard therapies and regardless of whether or not gastrointestinal tract symptoms are present. Physicians must be cognizant that vulvar signs and symptoms may precede, coincide with, or follow the diagnosis of intestinal CD. Increased awareness of this entity may facilitate its early recognition and prompt more timely treatment among women with vulvar disease caused by MCD.

The cutaneous manifestations of Crohn disease (CD) are varied, including pyoderma gangrenosum, erythema nodosum, and metastatic CD (MCD). First described by Parks et al,¹ MCD is defined as the occurrence of granulomatous lesions at a skin site distant from the gastrointestinal tract.^1-20 Metastatic CD presents a diagnostic challenge because it is a rare component in the spectrum of inflammatory bowel disease complications, and many physicians are unaware of its existence. It may precede, coincide with, or develop after the diagnosis of intestinal disease.^2-5 Vulvoperineal involvement is particularly problematic because a multitude of other, more likely disease processes are considered first. Typically it is initially diagnosed as a presumed infection prompting reflexive treatment with antivirals, antifungals, and antibiotics. Patients may experience symptoms for years prior to correct diagnosis and institution of proper therapy. A variety of clinical presentations have been described, including nonspecific pain and swelling, erythematous papules and plaques, and nonhealing ulcers. Skin biopsy characteristically confirms the diagnosis and reveals dermal noncaseating granulomas. Multiple oral and parenteral therapies are available, with surgical intervention reserved for resistant cases. We present a case of vulvovaginal MCD in the setting of well-controlled intestinal disease. We also provide a review of the literature regarding genital CD and emphasize the need to keep MCD in the differential of vulvoperineal pathology.

Case Report

A 29-year-old woman was referred to the dermatology clinic with vulvar pain, swelling, and pruritus of 14 months’ duration. Her medical history was remarkable for CD following a colectomy with colostomy. Prior therapies included methotrexate with infliximab for 5 years followed by a 2-year regimen with adalimumab, which induced remission of the intestinal disease.

The patient previously had taken a variety of topical and oral antimicrobials based on treatment from a primary care physician because fungal, bacterial, and viral infections initially were suspected; however, the vulvar disease persisted, and drug-induced immunosuppression was considered to be an underlying factor. Thus, adalimumab was discontinued. Despite elimination of the biologic, the vulvar disease progressed, which prompted referral to the dermatology clinic.

Physical examination revealed diffuse vulvar edema with overlying erythema and scale (Figure 1A). Upon closer inspection, scattered violaceous papules atop a backdrop of lichenification were evident, imparting a cobblestone appearance (Figure 1B). Additionally, a fissure was present on the gluteal cleft. Biopsy from the left labia majora demonstrated well-formed granulomas within a fibrotic reticular dermis (Figures 2A and 2B). The granulomas consisted of both mononucleated and multinucleated histiocytes, rimmed peripherally by lymphocytes and plasma cells (Figure 2C). Periodic acid–Schiff–diastase and acid-fast bacilli stains as well as polarizing microscopy were negative.

Given the patient’s history, a diagnosis of vulvoperineal MCD was rendered. The patient was started on oral metronidazole 250 mg 3 times daily with topical fluocinonide and tacrolimus. She responded well to this treatment regimen and was referred back to the gastroenterologist for management of the intestinal disease.

 

Comment

Crohn disease is an idiopathic chronic inflammatory condition that primarily affects the gastrointestinal tract, anywhere from the mouth to the anus. It is characterized by transmural inflammation and fissures that can extend beyond the muscularis propria.^4,6 Extraintestinal manifestations are common.³

Cutaneous CD often presents as perianal, perifistular, or peristomal inflammation or ulceration.⁷ Other skin manifestations include pyoderma gangrenosum, erythema nodosum, erythema multiforme, epidermolysis bullosa acquisita, and palmar erythema.⁷ Metastatic CD involves skin noncontiguous with the gastrointestinal tract^1-20 and may involve any portion of the cutis. Although rare, MCD is the typical etiology underlying vulvar CD.⁸

Approximately 20% of MCD patients have cutaneous lesions without a history of gastrointestinal disease. More than half of cases in adults and approximately two-thirds in children involve the genitalia. Although more common in adults, vulvar involvement has been reported in children as young as 6 years of age.² Diagnosis is especially challenging when bowel symptoms are absent; those patients should be evaluated and followed for subsequent intestinal involvement.⁶

Clinically, symptoms may include general discomfort, pain, pruritus, and dyspareunia. Psychosocial and sexual dysfunction are prevalent and also should be addressed.⁹ Depending on the stage of the disease, physical examination may reveal erythema, edema, papules, pustules, nodules, condylomatous lesions, abscesses, fissures, fistulas, ulceration, acrochordons, and scarring.^2-6,10,11

A host of infections (ie, mycobacterial, actinomycosis, deep fungal, sexually transmitted, schistosomiasis), inflammatory conditions (ie, sarcoid, hidradenitis suppurativa), foreign body reactions, Melkersson-Rosenthal syndrome, and sexual abuse should be included in the differential diagnosis.^2,6,10-12 Once infection, sarcoid, and foreign body reaction have been ruled out, noncaseating granulomas in skin are highly suggestive of CD.⁷

Histopathologic findings of MCD reveal myriad morphological reaction patterns,^5,13 including high-grade dysplasia and carcinoma of the vulva; therefore, it may be imprudent to withhold diagnosis based on the absence of the historically pathognomonic noncaseating granulomas.⁵

The etiopathogenesis of MCD remains an enigma. Dermatopathologic examinations consistently reveal a vascular injury syndrome,¹³ implicating a possible circulatory system contribution via deposition of immune complexes or antigens in skin.⁷ Bacterial infection has been implicated in the intestinal manifestations of CD; however, failure to detect microbial ribosomal RNA in MCD biopsies refutes theories of hematogenous spread of microbes.¹³ Another plausible explanation is that antibodies are formed to conserved microbial epitopes following loss of tolerance to gut flora, which results in an excessive immunologic response at distinct sites in susceptible individuals.¹³ A T-lymphocyte–mediated type IV hypersensitivity reaction also has been proposed via cross-reactivity of lymphocytes, with skin antigens precipitating extraintestinal granuloma formation and vascular injury.³ Clearly, further investigation is needed.

Magnetic resonanance imaging can identify the extent and anatomy of intestinal and pelvic disease and can assist in the diagnosis of vulvar CD.^10,11,14 For these reasons, some experts propose that imaging should be instituted prior to therapy,^12,15,16 especially when direct extension is suspected.¹⁷

Treatment is challenging and often involves collaboration among several specialties.¹² Many treatment options exist because therapeutic responses vary and genital MCD is frequently recalcitrant to therapy.⁴ Medical therapy includes antibiotics such as metronidazole, corticosteroids (ie, topical, intralesional, systemic), and immune modulators (eg, azathioprine, 6-mercaptopurine, cyclosporine, methotrexate, mycophenolate mofetil, tumor necrosis factor α inhibitors).^{2,3,6,10,16,18} Thalidomide has been used for refractory cases.¹⁹ These treatments can be used alone or in combination. Patients should be monitored for side effects and informed that many treatment regimens may be required before a sustained response is achieved.^4,16,18 Surgery is reserved for the most resistant cases. Extensive radical excision of the involved area is the best approach, as limited local excision often is followed by recurrence.²⁰

Conclusion

Our case highlights that vulvar CD can develop in the setting of well-controlled intestinal disease. Vulvoperineal CD should be considered in the differential diagnosis of chronic vulvar pain, swelling, and pruritus, especially in cases resistant to standard therapies and regardless of whether or not gastrointestinal tract symptoms are present. Physicians must be cognizant that vulvar signs and symptoms may precede, coincide with, or follow the diagnosis of intestinal CD. Increased awareness of this entity may facilitate its early recognition and prompt more timely treatment among women with vulvar disease caused by MCD.

The cutaneous manifestations of Crohn disease (CD) are varied, including pyoderma gangrenosum, erythema nodosum, and metastatic CD (MCD). First described by Parks et al,¹ MCD is defined as the occurrence of granulomatous lesions at a skin site distant from the gastrointestinal tract.^1-20 Metastatic CD presents a diagnostic challenge because it is a rare component in the spectrum of inflammatory bowel disease complications, and many physicians are unaware of its existence. It may precede, coincide with, or develop after the diagnosis of intestinal disease.^2-5 Vulvoperineal involvement is particularly problematic because a multitude of other, more likely disease processes are considered first. Typically it is initially diagnosed as a presumed infection prompting reflexive treatment with antivirals, antifungals, and antibiotics. Patients may experience symptoms for years prior to correct diagnosis and institution of proper therapy. A variety of clinical presentations have been described, including nonspecific pain and swelling, erythematous papules and plaques, and nonhealing ulcers. Skin biopsy characteristically confirms the diagnosis and reveals dermal noncaseating granulomas. Multiple oral and parenteral therapies are available, with surgical intervention reserved for resistant cases. We present a case of vulvovaginal MCD in the setting of well-controlled intestinal disease. We also provide a review of the literature regarding genital CD and emphasize the need to keep MCD in the differential of vulvoperineal pathology.

Case Report

A 29-year-old woman was referred to the dermatology clinic with vulvar pain, swelling, and pruritus of 14 months’ duration. Her medical history was remarkable for CD following a colectomy with colostomy. Prior therapies included methotrexate with infliximab for 5 years followed by a 2-year regimen with adalimumab, which induced remission of the intestinal disease.

The patient previously had taken a variety of topical and oral antimicrobials based on treatment from a primary care physician because fungal, bacterial, and viral infections initially were suspected; however, the vulvar disease persisted, and drug-induced immunosuppression was considered to be an underlying factor. Thus, adalimumab was discontinued. Despite elimination of the biologic, the vulvar disease progressed, which prompted referral to the dermatology clinic.

Physical examination revealed diffuse vulvar edema with overlying erythema and scale (Figure 1A). Upon closer inspection, scattered violaceous papules atop a backdrop of lichenification were evident, imparting a cobblestone appearance (Figure 1B). Additionally, a fissure was present on the gluteal cleft. Biopsy from the left labia majora demonstrated well-formed granulomas within a fibrotic reticular dermis (Figures 2A and 2B). The granulomas consisted of both mononucleated and multinucleated histiocytes, rimmed peripherally by lymphocytes and plasma cells (Figure 2C). Periodic acid–Schiff–diastase and acid-fast bacilli stains as well as polarizing microscopy were negative.

Given the patient’s history, a diagnosis of vulvoperineal MCD was rendered. The patient was started on oral metronidazole 250 mg 3 times daily with topical fluocinonide and tacrolimus. She responded well to this treatment regimen and was referred back to the gastroenterologist for management of the intestinal disease.

 

Comment

Crohn disease is an idiopathic chronic inflammatory condition that primarily affects the gastrointestinal tract, anywhere from the mouth to the anus. It is characterized by transmural inflammation and fissures that can extend beyond the muscularis propria.^4,6 Extraintestinal manifestations are common.³

Cutaneous CD often presents as perianal, perifistular, or peristomal inflammation or ulceration.⁷ Other skin manifestations include pyoderma gangrenosum, erythema nodosum, erythema multiforme, epidermolysis bullosa acquisita, and palmar erythema.⁷ Metastatic CD involves skin noncontiguous with the gastrointestinal tract^1-20 and may involve any portion of the cutis. Although rare, MCD is the typical etiology underlying vulvar CD.⁸

Approximately 20% of MCD patients have cutaneous lesions without a history of gastrointestinal disease. More than half of cases in adults and approximately two-thirds in children involve the genitalia. Although more common in adults, vulvar involvement has been reported in children as young as 6 years of age.² Diagnosis is especially challenging when bowel symptoms are absent; those patients should be evaluated and followed for subsequent intestinal involvement.⁶

Clinically, symptoms may include general discomfort, pain, pruritus, and dyspareunia. Psychosocial and sexual dysfunction are prevalent and also should be addressed.⁹ Depending on the stage of the disease, physical examination may reveal erythema, edema, papules, pustules, nodules, condylomatous lesions, abscesses, fissures, fistulas, ulceration, acrochordons, and scarring.^2-6,10,11

A host of infections (ie, mycobacterial, actinomycosis, deep fungal, sexually transmitted, schistosomiasis), inflammatory conditions (ie, sarcoid, hidradenitis suppurativa), foreign body reactions, Melkersson-Rosenthal syndrome, and sexual abuse should be included in the differential diagnosis.^2,6,10-12 Once infection, sarcoid, and foreign body reaction have been ruled out, noncaseating granulomas in skin are highly suggestive of CD.⁷

Histopathologic findings of MCD reveal myriad morphological reaction patterns,^5,13 including high-grade dysplasia and carcinoma of the vulva; therefore, it may be imprudent to withhold diagnosis based on the absence of the historically pathognomonic noncaseating granulomas.⁵

The etiopathogenesis of MCD remains an enigma. Dermatopathologic examinations consistently reveal a vascular injury syndrome,¹³ implicating a possible circulatory system contribution via deposition of immune complexes or antigens in skin.⁷ Bacterial infection has been implicated in the intestinal manifestations of CD; however, failure to detect microbial ribosomal RNA in MCD biopsies refutes theories of hematogenous spread of microbes.¹³ Another plausible explanation is that antibodies are formed to conserved microbial epitopes following loss of tolerance to gut flora, which results in an excessive immunologic response at distinct sites in susceptible individuals.¹³ A T-lymphocyte–mediated type IV hypersensitivity reaction also has been proposed via cross-reactivity of lymphocytes, with skin antigens precipitating extraintestinal granuloma formation and vascular injury.³ Clearly, further investigation is needed.

Magnetic resonanance imaging can identify the extent and anatomy of intestinal and pelvic disease and can assist in the diagnosis of vulvar CD.^10,11,14 For these reasons, some experts propose that imaging should be instituted prior to therapy,^12,15,16 especially when direct extension is suspected.¹⁷

Treatment is challenging and often involves collaboration among several specialties.¹² Many treatment options exist because therapeutic responses vary and genital MCD is frequently recalcitrant to therapy.⁴ Medical therapy includes antibiotics such as metronidazole, corticosteroids (ie, topical, intralesional, systemic), and immune modulators (eg, azathioprine, 6-mercaptopurine, cyclosporine, methotrexate, mycophenolate mofetil, tumor necrosis factor α inhibitors).^{2,3,6,10,16,18} Thalidomide has been used for refractory cases.¹⁹ These treatments can be used alone or in combination. Patients should be monitored for side effects and informed that many treatment regimens may be required before a sustained response is achieved.^4,16,18 Surgery is reserved for the most resistant cases. Extensive radical excision of the involved area is the best approach, as limited local excision often is followed by recurrence.²⁰

Conclusion

Our case highlights that vulvar CD can develop in the setting of well-controlled intestinal disease. Vulvoperineal CD should be considered in the differential diagnosis of chronic vulvar pain, swelling, and pruritus, especially in cases resistant to standard therapies and regardless of whether or not gastrointestinal tract symptoms are present. Physicians must be cognizant that vulvar signs and symptoms may precede, coincide with, or follow the diagnosis of intestinal CD. Increased awareness of this entity may facilitate its early recognition and prompt more timely treatment among women with vulvar disease caused by MCD.

To the Editor:

Microcystic adnexal carcinoma (MAC), described by Goldstein et al¹ in 1982, is a relatively uncommon cutaneous neoplasm. This locally aggressive malignant adnexal tumor has high potential for local recurrence. The skin of the head, particularly in the nasolabial and periorbital regions, most often is involved.² Involvement of the external auditory canal (EAC) is relatively rare. We report a case of MAC of the EAC.

A 52-year-old man presented with 1 palpable nodule on the right EAC of approximately 1 year’s duration. The lesion was asymptomatic, and the patient had no history of radiation exposure. The patient was an airport employee required to wear an earplug in the right ear. Endoscopic examination identified a 1×1 cm² erythematous nodule on the anterior inferior quadrant of the right external ear canal orifice (Figure 1). Axial and coronal computed tomography demonstrated a soft tissue mass in the right EAC without any bony erosion. No clinical signs of regional lymphadenopathy or distant metastasis were present. Excision was performed under microscopic visualization.

Histopathology of the nodule showed marked proliferation of multiple keratin-containing cysts, irregular ductal structures, and solid epithelial nests in the deep dermis (Figure 2). Irregular ductal structures with 2 cell layer walls and several epithelial strands or small nests of tumor cells within desmoplastic stroma were noted (Figure 3). No perineural infiltration or tumor infiltration existed at the margin. Based on the clinical and histopathologic findings, the final diagnosis was MAC. Complete resolution was noted after the excision. The patient returned for regular follow-up and no signs of recurrence were noted for 7 years postoperatively.

Microcystic adnexal carcinoma, also known as sclerosing sweat duct (syringomatous) carcinoma, malignant syringoma, and syringoid eccrine carcinoma, is characterized by slow and locally aggressive growth with high likelihood of perineural invasion and frequent recurrence.² Regional lymph node metastasis is uncommon, and systemic metastasis is rare.^2-4

Although the head most often is involved, a PubMed search of articles indexed for MEDLINE using the terms microcystic adnexal carcinoma and external auditory canal revealed 4 cases (Table).^5-8 Our report adds another case of MAC arising solely in the EAC. Although the etiology of MAC is unknown, prior studies indicated that radiotherapy is a risk factor for MAC. Other possible risk factors include UV light exposure and immunodeficiency.² Our patient had no history of these factors and experienced chronic friction caused by use of an occupational unilateral earplug, which may be a notable factor. Locations of MAC arising outside the head region include the axilla, vulva, breast, palm, toe, perianal skin, buttock, chest, and an ovarian cystic teratoma.^3,9 Friction commonly occurs in many of these areas. Therefore, we propose that friction may be a risk factor for MAC.

Microcystic adnexal carcinoma should be included in the differential diagnosis of any slowly growing cutaneous tumor, even in the EAC. Once diagnosed, the tumor should be surgically excised. Because local recurrence is common and may occur several decades after excision, lifetime follow-up for recurrence signs is essential.

To the Editor:

Microcystic adnexal carcinoma (MAC), described by Goldstein et al¹ in 1982, is a relatively uncommon cutaneous neoplasm. This locally aggressive malignant adnexal tumor has high potential for local recurrence. The skin of the head, particularly in the nasolabial and periorbital regions, most often is involved.² Involvement of the external auditory canal (EAC) is relatively rare. We report a case of MAC of the EAC.

A 52-year-old man presented with 1 palpable nodule on the right EAC of approximately 1 year’s duration. The lesion was asymptomatic, and the patient had no history of radiation exposure. The patient was an airport employee required to wear an earplug in the right ear. Endoscopic examination identified a 1×1 cm² erythematous nodule on the anterior inferior quadrant of the right external ear canal orifice (Figure 1). Axial and coronal computed tomography demonstrated a soft tissue mass in the right EAC without any bony erosion. No clinical signs of regional lymphadenopathy or distant metastasis were present. Excision was performed under microscopic visualization.

Histopathology of the nodule showed marked proliferation of multiple keratin-containing cysts, irregular ductal structures, and solid epithelial nests in the deep dermis (Figure 2). Irregular ductal structures with 2 cell layer walls and several epithelial strands or small nests of tumor cells within desmoplastic stroma were noted (Figure 3). No perineural infiltration or tumor infiltration existed at the margin. Based on the clinical and histopathologic findings, the final diagnosis was MAC. Complete resolution was noted after the excision. The patient returned for regular follow-up and no signs of recurrence were noted for 7 years postoperatively.

Microcystic adnexal carcinoma, also known as sclerosing sweat duct (syringomatous) carcinoma, malignant syringoma, and syringoid eccrine carcinoma, is characterized by slow and locally aggressive growth with high likelihood of perineural invasion and frequent recurrence.² Regional lymph node metastasis is uncommon, and systemic metastasis is rare.^2-4

Although the head most often is involved, a PubMed search of articles indexed for MEDLINE using the terms microcystic adnexal carcinoma and external auditory canal revealed 4 cases (Table).^5-8 Our report adds another case of MAC arising solely in the EAC. Although the etiology of MAC is unknown, prior studies indicated that radiotherapy is a risk factor for MAC. Other possible risk factors include UV light exposure and immunodeficiency.² Our patient had no history of these factors and experienced chronic friction caused by use of an occupational unilateral earplug, which may be a notable factor. Locations of MAC arising outside the head region include the axilla, vulva, breast, palm, toe, perianal skin, buttock, chest, and an ovarian cystic teratoma.^3,9 Friction commonly occurs in many of these areas. Therefore, we propose that friction may be a risk factor for MAC.

Microcystic adnexal carcinoma should be included in the differential diagnosis of any slowly growing cutaneous tumor, even in the EAC. Once diagnosed, the tumor should be surgically excised. Because local recurrence is common and may occur several decades after excision, lifetime follow-up for recurrence signs is essential.

To the Editor:

Microcystic adnexal carcinoma (MAC), described by Goldstein et al¹ in 1982, is a relatively uncommon cutaneous neoplasm. This locally aggressive malignant adnexal tumor has high potential for local recurrence. The skin of the head, particularly in the nasolabial and periorbital regions, most often is involved.² Involvement of the external auditory canal (EAC) is relatively rare. We report a case of MAC of the EAC.

A 52-year-old man presented with 1 palpable nodule on the right EAC of approximately 1 year’s duration. The lesion was asymptomatic, and the patient had no history of radiation exposure. The patient was an airport employee required to wear an earplug in the right ear. Endoscopic examination identified a 1×1 cm² erythematous nodule on the anterior inferior quadrant of the right external ear canal orifice (Figure 1). Axial and coronal computed tomography demonstrated a soft tissue mass in the right EAC without any bony erosion. No clinical signs of regional lymphadenopathy or distant metastasis were present. Excision was performed under microscopic visualization.

Histopathology of the nodule showed marked proliferation of multiple keratin-containing cysts, irregular ductal structures, and solid epithelial nests in the deep dermis (Figure 2). Irregular ductal structures with 2 cell layer walls and several epithelial strands or small nests of tumor cells within desmoplastic stroma were noted (Figure 3). No perineural infiltration or tumor infiltration existed at the margin. Based on the clinical and histopathologic findings, the final diagnosis was MAC. Complete resolution was noted after the excision. The patient returned for regular follow-up and no signs of recurrence were noted for 7 years postoperatively.

Microcystic adnexal carcinoma, also known as sclerosing sweat duct (syringomatous) carcinoma, malignant syringoma, and syringoid eccrine carcinoma, is characterized by slow and locally aggressive growth with high likelihood of perineural invasion and frequent recurrence.² Regional lymph node metastasis is uncommon, and systemic metastasis is rare.^2-4

Although the head most often is involved, a PubMed search of articles indexed for MEDLINE using the terms microcystic adnexal carcinoma and external auditory canal revealed 4 cases (Table).^5-8 Our report adds another case of MAC arising solely in the EAC. Although the etiology of MAC is unknown, prior studies indicated that radiotherapy is a risk factor for MAC. Other possible risk factors include UV light exposure and immunodeficiency.² Our patient had no history of these factors and experienced chronic friction caused by use of an occupational unilateral earplug, which may be a notable factor. Locations of MAC arising outside the head region include the axilla, vulva, breast, palm, toe, perianal skin, buttock, chest, and an ovarian cystic teratoma.^3,9 Friction commonly occurs in many of these areas. Therefore, we propose that friction may be a risk factor for MAC.

Microcystic adnexal carcinoma should be included in the differential diagnosis of any slowly growing cutaneous tumor, even in the EAC. Once diagnosed, the tumor should be surgically excised. Because local recurrence is common and may occur several decades after excision, lifetime follow-up for recurrence signs is essential.

Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare entity that presents with linear and pruritic psoriasiform plaques and most commonly occurs during childhood. It represents a dysregulation of keratinocytes exhibiting genetic mosaicism.^1,2 Epidermal nevi may derive from keratinocytic, follicular, sebaceous, apocrine, or eccrine origin. Inflammatory linear verrucous epidermal nevus is classified under the keratinocytic type of epidermal nevus and represents approximately 6% of all epidermal nevi.³ The condition presents as erythematous and verrucous plaques along the lines of Blaschko.^2,4 There is a predilection for the legs, and girls are 4 times more commonly affected than boys.¹ Cases of ILVEN are predominantly sporadic, though rare familial cases have been reported.⁴

Inflammatory linear verrucous epidermal nevus is notoriously refractory to treatment. First-line therapies include topical agents such as corticosteroids, calcipotriol, retinoids, and 5-fluorouracil.^3,4 Other treatments include intralesional corticosteroids, cryotherapy, electrodesiccation and curettage, and surgical excision.³ Several case reports have shown promising results using the pulsed dye and ablative CO2 lasers.^5-8

Case Report

An otherwise healthy 20-year-old woman presented with dry, pruritic, red lesions on the right leg that had been present and stable since she was an infant (2 weeks of age). Her medical history included acne vulgaris, but she denied any personal or family history of psoriasis as well as any arthralgia or arthritis. Physical examination revealed discrete, oval, hyperkeratotic, scaly, red plaques on the lateral right leg with a larger hyperkeratotic, linear, red plaque extending from the right popliteal fossa to the posterior thigh (Figure 1A). The nails, scalp, buttocks, and upper extremities were unaffected. Bacterial culture of the right leg demonstrated Staphylococcus aureus colonization. Biopsy of the right popliteal fossa showed psoriasiform dermatitis with psoriasiform hyperplasia, a slightly verruciform surface, broad zones of superficial pallor, and parakeratosis with conspicuous colonies of bacteria (Figure 2).

Following the positive bacterial culture, the patient was treated with a short course of oral doxycycline, which did not alter the clinical appearance of the lesions or improve symptoms of pruritus. Pruritus improved moderately with topical corticosteroid treatment, but clinically the lesions appeared unchanged. The plaque on the superior right leg was treated with a superpulsed CO₂ laser and the plaque on the inferior right leg was treated with a fractional CO₂ laser, both with minimal improvement.

Because of the clinical and histopathologic similarities of the patient's lesions to psoriasis, a trial of the UV 308-nm excimer laser was initiated. Following initial test spots, she completed a total of 18 treatments to all lesions with noticeable clinical improvement (Figure 1B). Initially, the patient returned for treatment biweekly for approximately 5 weeks with 2 small spots being targeted at each session, with an average surface area of approximately 16 cm². She was started at 225 mJ/cm² with 25% increases at each session and ultimately reached up to 1676 mJ/cm² at the end of the 10 sessions. She tolerated the procedure well with some minor blistering. Treatment was deferred for 3 months due to the patient's schedule, then biweekly treatments resumed for 4 weeks, totaling 8 more sessions. At that time, all lesions on the right leg were targeted, with an average surface area of approximately 100 cm². The laser settings were initiated at 225 mJ/cm² with 20% increases at each session and ultimately reached 560 mJ/cm². The treatment was well tolerated throughout; however, the patient initially reported residual pruritus. The plaques continued to improve, and most notably, there was thinning of the hyperkeratotic scale of the plaques in addition to decreased erythema and complete resolution of pruritus. Ultimately, treatment was discontinued because of lack of insurance coverage and financial burden. The patient was lost to follow-up.

 

Comment

Presentation
Inflammatory linear verrucous epidermal nevus is a rare type of keratinocytic epidermal nevus⁴ that clinically presents as small, discrete, pruritic, scaly plaques coalescing into a linear plaque along the lines of Blaschko.⁹ Considerable pruritus and resistance to treatment are hallmarks of the disease.¹⁰ Histopathologically, ILVEN is characterized by alternating orthokeratosis and parakeratosis with a lack of neutrophils in an acanthotic epidermis.^11-13 Inflammatory linear verrucous epidermal nevus presents at birth or in early childhood. Adult onset is rare.^9,14 Approximately 75% of lesions present by 5 years of age, with a majority occurring within the first 6 months of life.¹⁵ The differential diagnosis includes linear psoriasis, epidermal nevi, linear lichen planus, linear verrucae, linear lichen simplex chronicus, and mycosis fungoides.^4,11

Differentiation From Psoriasis
Despite the histopathologic overlap with psoriasis, ILVEN exhibits fewer Ki-67-positive keratinocyte nuclei (proliferative marker) and more cytokeratin 10-positive cells (epidermal differentiation marker) than psoriasis.¹⁶ Furthermore, ILVEN has demonstrated fewer CD4⁻, CD8⁻, CD45RO⁻, CD2⁻, CD25⁻, CD94⁻, and CD161⁺ cells within the dermis and epidermis than psoriasis.¹⁶

The clinical presentations of ILVEN and psoriasis may be similar, as some patients with linear psoriasis also present with psoriatic plaques along the lines of Blaschko.¹⁷ Additionally, ILVEN may be a precursor to psoriasis. Altman and Mehregan1 found that ILVEN patients who developed psoriasis did so in areas previously affected by ILVEN; however, they continued to distinguish the 2 pathologies as distinct entities. Another early report also hypothesized that the dermoepidermal defect caused by epidermal nevi provided a site for the development of psoriatic lesions because of the Koebner phenomenon.¹⁸

Patients with ILVEN also have been found to have extracutaneous manifestations and symptoms commonly seen in psoriasis patients. A 2012 retrospective review revealed that 37% (7/19) of patients with ILVEN also had psoriatic arthritis, cutaneous psoriatic lesions, and/or nail pitting. The authors concluded that ILVEN may lead to the onset of psoriasis later in life and may indicate an underlying psoriatic predisposition.¹⁹ Genetic theories also have been proposed, stating that ILVEN may be a mosaic of psoriasis2 or that a postzygotic mutation leads to the predisposition for developing psoriasis.²⁰

Treatment
Inflammatory linear verrucous epidermal nevus frequently is refractory to treatment; however, the associated pruritus and distressing cosmesis make treatment attempts worthwhile.¹¹ No single therapy has been found to be successful in all patients. A widely used first-line treatment is topical or intralesional corticosteroids, with the former typically used with occlusion.¹³ Other treatments include adalimumab, calcipotriol,^22,23 tretinoin,²⁴ and 5-fluorouracil.²⁴ Physical modalities such as cryotherapy, electrodesiccation, and dermabrasion have been reported with varying success.^15,24 Surgical treatments include tangential²⁵ and full-thickness excisions.²⁶

The CO₂ laser also has demonstrated success. One study showed considerable improvement of pruritus and partial resolution of lesions only 5 weeks following a single CO₂ laser treatment.⁵ Another study showed promising results when combining CO₂ pulsed laser therapy with fractional CO₂ laser treatment.⁶ Other laser therapies including the argon²⁷ and flashlamp-pumped pulsed dye lasers⁸ have been used with limited success. The use of light therapy and lasers in psoriasis have now increased the treatment options for ILVEN based on the rationale of their shared histopathologic characteristics. Photodynamic therapy also has been attempted because of its successful use in psoriasis patients. It has been found to be successful in diminishing ILVEN lesions and associated pruritus after a few weeks of therapy; however, treatment is limited by the associated pain and requirement for local anesthesia.²⁸

The excimer laser is a form of targeted phototherapy that emits monochromatic light at 308 nm.²⁹ It is ideal for inflammatory skin lesions because the UVB light induces apoptosis.³⁰ Psoriasis lesions treated with the excimer laser show a decrease in keratinocyte proliferation, which in turn reverses epidermal acanthosis and causes T-cell depletion due to upregulation of p53.^29,31 This mechanism of action addresses the overproliferation of keratinocytes mediated by T cells in psoriasis and contributes to the success of excimer laser treatment.³¹ A considerable advantage is its localized treatment, resulting in lower cumulative doses of UVB and reducing the possible carcinogenic and phototoxic risks of whole-body phototherapy.³²

One study examined the antipruritic effects of the excimer laser following the treatment of epidermal hyperinnervation leading to intractable pruritus in patients with atopic dermatitis. The researchers suggested that a potential explanation for the antipruritic effect of the excimer laser may be secondary to nerve degeneration.³³ Additionally, low doses of UVB light also may inhibit mast cell degranulation and prevent histamine release, further supporting the antipruritic properties of excimer laser.³⁴

In our patient, failed treatment with other modalities led to trial of excimer laser therapy because of the overlapping clinical and histopathologic findings with psoriasis. Excimer laser improved the clinical appearance and overall texture of the ILVEN lesions and decreased pruritus. The reasons for treatment success may be two-fold. By decreasing the number of keratinocytes and mast cells, the excimer laser may have improved the epidermal hyperplasia and pruritus in the ILVEN lesions. Alternatively, because the patient had ILVEN lesions since infancy, psoriasis may have developed in the location of the ILVEN lesions due to koebnerization, resulting in the clinical response to excimer therapy; however, she had no other clinical evidence of psoriasis.

Because of the recalcitrance of ILVEN lesions to conventional therapies, it is important to investigate therapies that may be of possible benefit. Our novel case documents successful use of the excimer laser in the treatment of ILVEN. 

Conclusion

Our case of ILVEN in a woman that had been present since infancy highlights the disease pathology as well as a potential new treatment modality. The patient was refractory to first-line treatments and was concerned about the cosmetic appearance of the lesions. The patient was subsequently treated with a trial of a 308-nm excimer laser with clinical improvement of the lesions. It is possible that the similarity of ILVEN and psoriasis may have contributed to the clinical improvement in our patient, but the mechanism of action remains unknown. Due to the paucity of evidence regarding optimal treatment of ILVEN, the current case offers dermatologists an option for patients who are refractory to other treatments.
 

Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare entity that presents with linear and pruritic psoriasiform plaques and most commonly occurs during childhood. It represents a dysregulation of keratinocytes exhibiting genetic mosaicism.^1,2 Epidermal nevi may derive from keratinocytic, follicular, sebaceous, apocrine, or eccrine origin. Inflammatory linear verrucous epidermal nevus is classified under the keratinocytic type of epidermal nevus and represents approximately 6% of all epidermal nevi.³ The condition presents as erythematous and verrucous plaques along the lines of Blaschko.^2,4 There is a predilection for the legs, and girls are 4 times more commonly affected than boys.¹ Cases of ILVEN are predominantly sporadic, though rare familial cases have been reported.⁴

Inflammatory linear verrucous epidermal nevus is notoriously refractory to treatment. First-line therapies include topical agents such as corticosteroids, calcipotriol, retinoids, and 5-fluorouracil.^3,4 Other treatments include intralesional corticosteroids, cryotherapy, electrodesiccation and curettage, and surgical excision.³ Several case reports have shown promising results using the pulsed dye and ablative CO2 lasers.^5-8

Case Report

An otherwise healthy 20-year-old woman presented with dry, pruritic, red lesions on the right leg that had been present and stable since she was an infant (2 weeks of age). Her medical history included acne vulgaris, but she denied any personal or family history of psoriasis as well as any arthralgia or arthritis. Physical examination revealed discrete, oval, hyperkeratotic, scaly, red plaques on the lateral right leg with a larger hyperkeratotic, linear, red plaque extending from the right popliteal fossa to the posterior thigh (Figure 1A). The nails, scalp, buttocks, and upper extremities were unaffected. Bacterial culture of the right leg demonstrated Staphylococcus aureus colonization. Biopsy of the right popliteal fossa showed psoriasiform dermatitis with psoriasiform hyperplasia, a slightly verruciform surface, broad zones of superficial pallor, and parakeratosis with conspicuous colonies of bacteria (Figure 2).

Following the positive bacterial culture, the patient was treated with a short course of oral doxycycline, which did not alter the clinical appearance of the lesions or improve symptoms of pruritus. Pruritus improved moderately with topical corticosteroid treatment, but clinically the lesions appeared unchanged. The plaque on the superior right leg was treated with a superpulsed CO₂ laser and the plaque on the inferior right leg was treated with a fractional CO₂ laser, both with minimal improvement.

Because of the clinical and histopathologic similarities of the patient's lesions to psoriasis, a trial of the UV 308-nm excimer laser was initiated. Following initial test spots, she completed a total of 18 treatments to all lesions with noticeable clinical improvement (Figure 1B). Initially, the patient returned for treatment biweekly for approximately 5 weeks with 2 small spots being targeted at each session, with an average surface area of approximately 16 cm². She was started at 225 mJ/cm² with 25% increases at each session and ultimately reached up to 1676 mJ/cm² at the end of the 10 sessions. She tolerated the procedure well with some minor blistering. Treatment was deferred for 3 months due to the patient's schedule, then biweekly treatments resumed for 4 weeks, totaling 8 more sessions. At that time, all lesions on the right leg were targeted, with an average surface area of approximately 100 cm². The laser settings were initiated at 225 mJ/cm² with 20% increases at each session and ultimately reached 560 mJ/cm². The treatment was well tolerated throughout; however, the patient initially reported residual pruritus. The plaques continued to improve, and most notably, there was thinning of the hyperkeratotic scale of the plaques in addition to decreased erythema and complete resolution of pruritus. Ultimately, treatment was discontinued because of lack of insurance coverage and financial burden. The patient was lost to follow-up.

 

Comment

Presentation
Inflammatory linear verrucous epidermal nevus is a rare type of keratinocytic epidermal nevus⁴ that clinically presents as small, discrete, pruritic, scaly plaques coalescing into a linear plaque along the lines of Blaschko.⁹ Considerable pruritus and resistance to treatment are hallmarks of the disease.¹⁰ Histopathologically, ILVEN is characterized by alternating orthokeratosis and parakeratosis with a lack of neutrophils in an acanthotic epidermis.^11-13 Inflammatory linear verrucous epidermal nevus presents at birth or in early childhood. Adult onset is rare.^9,14 Approximately 75% of lesions present by 5 years of age, with a majority occurring within the first 6 months of life.¹⁵ The differential diagnosis includes linear psoriasis, epidermal nevi, linear lichen planus, linear verrucae, linear lichen simplex chronicus, and mycosis fungoides.^4,11

Differentiation From Psoriasis
Despite the histopathologic overlap with psoriasis, ILVEN exhibits fewer Ki-67-positive keratinocyte nuclei (proliferative marker) and more cytokeratin 10-positive cells (epidermal differentiation marker) than psoriasis.¹⁶ Furthermore, ILVEN has demonstrated fewer CD4⁻, CD8⁻, CD45RO⁻, CD2⁻, CD25⁻, CD94⁻, and CD161⁺ cells within the dermis and epidermis than psoriasis.¹⁶

The clinical presentations of ILVEN and psoriasis may be similar, as some patients with linear psoriasis also present with psoriatic plaques along the lines of Blaschko.¹⁷ Additionally, ILVEN may be a precursor to psoriasis. Altman and Mehregan1 found that ILVEN patients who developed psoriasis did so in areas previously affected by ILVEN; however, they continued to distinguish the 2 pathologies as distinct entities. Another early report also hypothesized that the dermoepidermal defect caused by epidermal nevi provided a site for the development of psoriatic lesions because of the Koebner phenomenon.¹⁸

Patients with ILVEN also have been found to have extracutaneous manifestations and symptoms commonly seen in psoriasis patients. A 2012 retrospective review revealed that 37% (7/19) of patients with ILVEN also had psoriatic arthritis, cutaneous psoriatic lesions, and/or nail pitting. The authors concluded that ILVEN may lead to the onset of psoriasis later in life and may indicate an underlying psoriatic predisposition.¹⁹ Genetic theories also have been proposed, stating that ILVEN may be a mosaic of psoriasis2 or that a postzygotic mutation leads to the predisposition for developing psoriasis.²⁰

Treatment
Inflammatory linear verrucous epidermal nevus frequently is refractory to treatment; however, the associated pruritus and distressing cosmesis make treatment attempts worthwhile.¹¹ No single therapy has been found to be successful in all patients. A widely used first-line treatment is topical or intralesional corticosteroids, with the former typically used with occlusion.¹³ Other treatments include adalimumab, calcipotriol,^22,23 tretinoin,²⁴ and 5-fluorouracil.²⁴ Physical modalities such as cryotherapy, electrodesiccation, and dermabrasion have been reported with varying success.^15,24 Surgical treatments include tangential²⁵ and full-thickness excisions.²⁶

The CO₂ laser also has demonstrated success. One study showed considerable improvement of pruritus and partial resolution of lesions only 5 weeks following a single CO₂ laser treatment.⁵ Another study showed promising results when combining CO₂ pulsed laser therapy with fractional CO₂ laser treatment.⁶ Other laser therapies including the argon²⁷ and flashlamp-pumped pulsed dye lasers⁸ have been used with limited success. The use of light therapy and lasers in psoriasis have now increased the treatment options for ILVEN based on the rationale of their shared histopathologic characteristics. Photodynamic therapy also has been attempted because of its successful use in psoriasis patients. It has been found to be successful in diminishing ILVEN lesions and associated pruritus after a few weeks of therapy; however, treatment is limited by the associated pain and requirement for local anesthesia.²⁸

The excimer laser is a form of targeted phototherapy that emits monochromatic light at 308 nm.²⁹ It is ideal for inflammatory skin lesions because the UVB light induces apoptosis.³⁰ Psoriasis lesions treated with the excimer laser show a decrease in keratinocyte proliferation, which in turn reverses epidermal acanthosis and causes T-cell depletion due to upregulation of p53.^29,31 This mechanism of action addresses the overproliferation of keratinocytes mediated by T cells in psoriasis and contributes to the success of excimer laser treatment.³¹ A considerable advantage is its localized treatment, resulting in lower cumulative doses of UVB and reducing the possible carcinogenic and phototoxic risks of whole-body phototherapy.³²

One study examined the antipruritic effects of the excimer laser following the treatment of epidermal hyperinnervation leading to intractable pruritus in patients with atopic dermatitis. The researchers suggested that a potential explanation for the antipruritic effect of the excimer laser may be secondary to nerve degeneration.³³ Additionally, low doses of UVB light also may inhibit mast cell degranulation and prevent histamine release, further supporting the antipruritic properties of excimer laser.³⁴

In our patient, failed treatment with other modalities led to trial of excimer laser therapy because of the overlapping clinical and histopathologic findings with psoriasis. Excimer laser improved the clinical appearance and overall texture of the ILVEN lesions and decreased pruritus. The reasons for treatment success may be two-fold. By decreasing the number of keratinocytes and mast cells, the excimer laser may have improved the epidermal hyperplasia and pruritus in the ILVEN lesions. Alternatively, because the patient had ILVEN lesions since infancy, psoriasis may have developed in the location of the ILVEN lesions due to koebnerization, resulting in the clinical response to excimer therapy; however, she had no other clinical evidence of psoriasis.

Because of the recalcitrance of ILVEN lesions to conventional therapies, it is important to investigate therapies that may be of possible benefit. Our novel case documents successful use of the excimer laser in the treatment of ILVEN. 

Conclusion

Our case of ILVEN in a woman that had been present since infancy highlights the disease pathology as well as a potential new treatment modality. The patient was refractory to first-line treatments and was concerned about the cosmetic appearance of the lesions. The patient was subsequently treated with a trial of a 308-nm excimer laser with clinical improvement of the lesions. It is possible that the similarity of ILVEN and psoriasis may have contributed to the clinical improvement in our patient, but the mechanism of action remains unknown. Due to the paucity of evidence regarding optimal treatment of ILVEN, the current case offers dermatologists an option for patients who are refractory to other treatments.
 

Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare entity that presents with linear and pruritic psoriasiform plaques and most commonly occurs during childhood. It represents a dysregulation of keratinocytes exhibiting genetic mosaicism.^1,2 Epidermal nevi may derive from keratinocytic, follicular, sebaceous, apocrine, or eccrine origin. Inflammatory linear verrucous epidermal nevus is classified under the keratinocytic type of epidermal nevus and represents approximately 6% of all epidermal nevi.³ The condition presents as erythematous and verrucous plaques along the lines of Blaschko.^2,4 There is a predilection for the legs, and girls are 4 times more commonly affected than boys.¹ Cases of ILVEN are predominantly sporadic, though rare familial cases have been reported.⁴

Inflammatory linear verrucous epidermal nevus is notoriously refractory to treatment. First-line therapies include topical agents such as corticosteroids, calcipotriol, retinoids, and 5-fluorouracil.^3,4 Other treatments include intralesional corticosteroids, cryotherapy, electrodesiccation and curettage, and surgical excision.³ Several case reports have shown promising results using the pulsed dye and ablative CO2 lasers.^5-8

Case Report

An otherwise healthy 20-year-old woman presented with dry, pruritic, red lesions on the right leg that had been present and stable since she was an infant (2 weeks of age). Her medical history included acne vulgaris, but she denied any personal or family history of psoriasis as well as any arthralgia or arthritis. Physical examination revealed discrete, oval, hyperkeratotic, scaly, red plaques on the lateral right leg with a larger hyperkeratotic, linear, red plaque extending from the right popliteal fossa to the posterior thigh (Figure 1A). The nails, scalp, buttocks, and upper extremities were unaffected. Bacterial culture of the right leg demonstrated Staphylococcus aureus colonization. Biopsy of the right popliteal fossa showed psoriasiform dermatitis with psoriasiform hyperplasia, a slightly verruciform surface, broad zones of superficial pallor, and parakeratosis with conspicuous colonies of bacteria (Figure 2).

Following the positive bacterial culture, the patient was treated with a short course of oral doxycycline, which did not alter the clinical appearance of the lesions or improve symptoms of pruritus. Pruritus improved moderately with topical corticosteroid treatment, but clinically the lesions appeared unchanged. The plaque on the superior right leg was treated with a superpulsed CO₂ laser and the plaque on the inferior right leg was treated with a fractional CO₂ laser, both with minimal improvement.

Because of the clinical and histopathologic similarities of the patient's lesions to psoriasis, a trial of the UV 308-nm excimer laser was initiated. Following initial test spots, she completed a total of 18 treatments to all lesions with noticeable clinical improvement (Figure 1B). Initially, the patient returned for treatment biweekly for approximately 5 weeks with 2 small spots being targeted at each session, with an average surface area of approximately 16 cm². She was started at 225 mJ/cm² with 25% increases at each session and ultimately reached up to 1676 mJ/cm² at the end of the 10 sessions. She tolerated the procedure well with some minor blistering. Treatment was deferred for 3 months due to the patient's schedule, then biweekly treatments resumed for 4 weeks, totaling 8 more sessions. At that time, all lesions on the right leg were targeted, with an average surface area of approximately 100 cm². The laser settings were initiated at 225 mJ/cm² with 20% increases at each session and ultimately reached 560 mJ/cm². The treatment was well tolerated throughout; however, the patient initially reported residual pruritus. The plaques continued to improve, and most notably, there was thinning of the hyperkeratotic scale of the plaques in addition to decreased erythema and complete resolution of pruritus. Ultimately, treatment was discontinued because of lack of insurance coverage and financial burden. The patient was lost to follow-up.

 

Comment

Presentation
Inflammatory linear verrucous epidermal nevus is a rare type of keratinocytic epidermal nevus⁴ that clinically presents as small, discrete, pruritic, scaly plaques coalescing into a linear plaque along the lines of Blaschko.⁹ Considerable pruritus and resistance to treatment are hallmarks of the disease.¹⁰ Histopathologically, ILVEN is characterized by alternating orthokeratosis and parakeratosis with a lack of neutrophils in an acanthotic epidermis.^11-13 Inflammatory linear verrucous epidermal nevus presents at birth or in early childhood. Adult onset is rare.^9,14 Approximately 75% of lesions present by 5 years of age, with a majority occurring within the first 6 months of life.¹⁵ The differential diagnosis includes linear psoriasis, epidermal nevi, linear lichen planus, linear verrucae, linear lichen simplex chronicus, and mycosis fungoides.^4,11

Differentiation From Psoriasis
Despite the histopathologic overlap with psoriasis, ILVEN exhibits fewer Ki-67-positive keratinocyte nuclei (proliferative marker) and more cytokeratin 10-positive cells (epidermal differentiation marker) than psoriasis.¹⁶ Furthermore, ILVEN has demonstrated fewer CD4⁻, CD8⁻, CD45RO⁻, CD2⁻, CD25⁻, CD94⁻, and CD161⁺ cells within the dermis and epidermis than psoriasis.¹⁶

The clinical presentations of ILVEN and psoriasis may be similar, as some patients with linear psoriasis also present with psoriatic plaques along the lines of Blaschko.¹⁷ Additionally, ILVEN may be a precursor to psoriasis. Altman and Mehregan1 found that ILVEN patients who developed psoriasis did so in areas previously affected by ILVEN; however, they continued to distinguish the 2 pathologies as distinct entities. Another early report also hypothesized that the dermoepidermal defect caused by epidermal nevi provided a site for the development of psoriatic lesions because of the Koebner phenomenon.¹⁸

Patients with ILVEN also have been found to have extracutaneous manifestations and symptoms commonly seen in psoriasis patients. A 2012 retrospective review revealed that 37% (7/19) of patients with ILVEN also had psoriatic arthritis, cutaneous psoriatic lesions, and/or nail pitting. The authors concluded that ILVEN may lead to the onset of psoriasis later in life and may indicate an underlying psoriatic predisposition.¹⁹ Genetic theories also have been proposed, stating that ILVEN may be a mosaic of psoriasis2 or that a postzygotic mutation leads to the predisposition for developing psoriasis.²⁰

Treatment
Inflammatory linear verrucous epidermal nevus frequently is refractory to treatment; however, the associated pruritus and distressing cosmesis make treatment attempts worthwhile.¹¹ No single therapy has been found to be successful in all patients. A widely used first-line treatment is topical or intralesional corticosteroids, with the former typically used with occlusion.¹³ Other treatments include adalimumab, calcipotriol,^22,23 tretinoin,²⁴ and 5-fluorouracil.²⁴ Physical modalities such as cryotherapy, electrodesiccation, and dermabrasion have been reported with varying success.^15,24 Surgical treatments include tangential²⁵ and full-thickness excisions.²⁶

The CO₂ laser also has demonstrated success. One study showed considerable improvement of pruritus and partial resolution of lesions only 5 weeks following a single CO₂ laser treatment.⁵ Another study showed promising results when combining CO₂ pulsed laser therapy with fractional CO₂ laser treatment.⁶ Other laser therapies including the argon²⁷ and flashlamp-pumped pulsed dye lasers⁸ have been used with limited success. The use of light therapy and lasers in psoriasis have now increased the treatment options for ILVEN based on the rationale of their shared histopathologic characteristics. Photodynamic therapy also has been attempted because of its successful use in psoriasis patients. It has been found to be successful in diminishing ILVEN lesions and associated pruritus after a few weeks of therapy; however, treatment is limited by the associated pain and requirement for local anesthesia.²⁸

The excimer laser is a form of targeted phototherapy that emits monochromatic light at 308 nm.²⁹ It is ideal for inflammatory skin lesions because the UVB light induces apoptosis.³⁰ Psoriasis lesions treated with the excimer laser show a decrease in keratinocyte proliferation, which in turn reverses epidermal acanthosis and causes T-cell depletion due to upregulation of p53.^29,31 This mechanism of action addresses the overproliferation of keratinocytes mediated by T cells in psoriasis and contributes to the success of excimer laser treatment.³¹ A considerable advantage is its localized treatment, resulting in lower cumulative doses of UVB and reducing the possible carcinogenic and phototoxic risks of whole-body phototherapy.³²

One study examined the antipruritic effects of the excimer laser following the treatment of epidermal hyperinnervation leading to intractable pruritus in patients with atopic dermatitis. The researchers suggested that a potential explanation for the antipruritic effect of the excimer laser may be secondary to nerve degeneration.³³ Additionally, low doses of UVB light also may inhibit mast cell degranulation and prevent histamine release, further supporting the antipruritic properties of excimer laser.³⁴

In our patient, failed treatment with other modalities led to trial of excimer laser therapy because of the overlapping clinical and histopathologic findings with psoriasis. Excimer laser improved the clinical appearance and overall texture of the ILVEN lesions and decreased pruritus. The reasons for treatment success may be two-fold. By decreasing the number of keratinocytes and mast cells, the excimer laser may have improved the epidermal hyperplasia and pruritus in the ILVEN lesions. Alternatively, because the patient had ILVEN lesions since infancy, psoriasis may have developed in the location of the ILVEN lesions due to koebnerization, resulting in the clinical response to excimer therapy; however, she had no other clinical evidence of psoriasis.

Because of the recalcitrance of ILVEN lesions to conventional therapies, it is important to investigate therapies that may be of possible benefit. Our novel case documents successful use of the excimer laser in the treatment of ILVEN. 

Conclusion

Our case of ILVEN in a woman that had been present since infancy highlights the disease pathology as well as a potential new treatment modality. The patient was refractory to first-line treatments and was concerned about the cosmetic appearance of the lesions. The patient was subsequently treated with a trial of a 308-nm excimer laser with clinical improvement of the lesions. It is possible that the similarity of ILVEN and psoriasis may have contributed to the clinical improvement in our patient, but the mechanism of action remains unknown. Due to the paucity of evidence regarding optimal treatment of ILVEN, the current case offers dermatologists an option for patients who are refractory to other treatments.
 

The Diagnosis: Monsel Solution Reaction

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

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

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

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

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

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

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

The Diagnosis: Monsel Solution Reaction

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

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

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

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

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

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

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

The Diagnosis: Monsel Solution Reaction

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

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

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

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

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

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

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

The Diagnosis: Superficial Acral Fibromyxoma

A shave biopsy revealed an uninvolved grenz zone and mildly cellular spindle cell dermal proliferation in a collagenous and myxoid background (Figure 1). Spindle cells were seen in a myxoid background among dense coarse collagen (Figure 2A). Spindle cells also were seen in a myxoid background with mast cells and capillary network (Figure 2B). Histopathologic examination of the biopsy specimen revealed spindle cells that were diffusely positive for CD34 (Figure 3); focally positive for epithelial membrane antigen; and negative for melanocytic markers, smooth muscle markers, and cytokeratin. A diagnosis of superficial acral fibromyxoma (SAFM) was made based on clinical, histopathologic, and immunohistochemical findings.

Superficial acral fibromyxomas, also known as digital fibromyxomas, are soft, slow-growing tumors that have a predilection for subungual or periungual regions of the hands and feet. Superficial acral fibromyxomas most frequently occur on the hallux and rarely occur on the ankle or leg. They can present as nodular, dome-shaped, polyploid, or verrucous masses. They can be soft to firm, gelatinous or solid, off-white to gray-white and can have fasciculate cut surfaces. Superficial acral fibromyxomas can be either painful or painless and present with a deformed nail in 9% of cases. Superficial acral fibromyxoma is a superficial lesion with frequent infiltration of the dermal collagen and subcutaneous tissue and may even erode or infiltrate into the underlying bone in rare cases.^1-4 Although SAFMs are rare tumors, documented cases of SAFM have been reported at an increasing rate since the first published report by Fetsch et al² in 2001.

Patients often delay seeking medical treatment and present with a solitary mass that has been slowly growing for months to years. In a study of 124 patients, Hollmann et al1 found that symptoms exist for a mean of 35 months and present with a small mass with a mean tumor size of 1.7 cm before biopsy or excision. Although the age range is broad, SAFM mostly affects middle-aged adults (median age, 49 years).¹ Hollmann et al1 also reported a male predominance (1.3:1 ratio), and preexisting local trauma is reported in 25% of cases.^2-4

The differential for SAFM should include dermatofibroma, keloid, dermatofibrosarcoma protuberans, acquired digital fibrokeratoma, infantile digital fibromatosis, neurolemmoma, sclerosing perineurioma, superficial angiomyxoma, low-grade fibromyxoid sarcoma, and acral myxoinflammatory fibroblastic sarcoma.^1-4

Superficial acral fibromyxomas are composed of CD34⁺ spindle or stellate-shaped cells that are embedded in a myxoid and/or dense hyalinized collagenous stroma in a random or loosely fascicular growth pattern. The spindle or stellate-shaped cells in SAFMs also have been found to be focally positive for epithelial membrane antigen and CD99. Lesions have accentuated microvasculature and increased mast cells.^5-8

Conservative management is reasonable, but patients presenting with persistent pain and/or local deformity should be definitively treated with complete excision and follow-up. Hollmann et al¹ found that 24% of tumors recurred locally upon incomplete excision after a mean interval of 27 months. All recurrent tumors had positive margins at excision or initial biopsy.¹ To date, no reports of tumors metastasizing have been documented.^1-4

The Diagnosis: Superficial Acral Fibromyxoma

A shave biopsy revealed an uninvolved grenz zone and mildly cellular spindle cell dermal proliferation in a collagenous and myxoid background (Figure 1). Spindle cells were seen in a myxoid background among dense coarse collagen (Figure 2A). Spindle cells also were seen in a myxoid background with mast cells and capillary network (Figure 2B). Histopathologic examination of the biopsy specimen revealed spindle cells that were diffusely positive for CD34 (Figure 3); focally positive for epithelial membrane antigen; and negative for melanocytic markers, smooth muscle markers, and cytokeratin. A diagnosis of superficial acral fibromyxoma (SAFM) was made based on clinical, histopathologic, and immunohistochemical findings.

Superficial acral fibromyxomas, also known as digital fibromyxomas, are soft, slow-growing tumors that have a predilection for subungual or periungual regions of the hands and feet. Superficial acral fibromyxomas most frequently occur on the hallux and rarely occur on the ankle or leg. They can present as nodular, dome-shaped, polyploid, or verrucous masses. They can be soft to firm, gelatinous or solid, off-white to gray-white and can have fasciculate cut surfaces. Superficial acral fibromyxomas can be either painful or painless and present with a deformed nail in 9% of cases. Superficial acral fibromyxoma is a superficial lesion with frequent infiltration of the dermal collagen and subcutaneous tissue and may even erode or infiltrate into the underlying bone in rare cases.^1-4 Although SAFMs are rare tumors, documented cases of SAFM have been reported at an increasing rate since the first published report by Fetsch et al² in 2001.

Patients often delay seeking medical treatment and present with a solitary mass that has been slowly growing for months to years. In a study of 124 patients, Hollmann et al1 found that symptoms exist for a mean of 35 months and present with a small mass with a mean tumor size of 1.7 cm before biopsy or excision. Although the age range is broad, SAFM mostly affects middle-aged adults (median age, 49 years).¹ Hollmann et al1 also reported a male predominance (1.3:1 ratio), and preexisting local trauma is reported in 25% of cases.^2-4

The differential for SAFM should include dermatofibroma, keloid, dermatofibrosarcoma protuberans, acquired digital fibrokeratoma, infantile digital fibromatosis, neurolemmoma, sclerosing perineurioma, superficial angiomyxoma, low-grade fibromyxoid sarcoma, and acral myxoinflammatory fibroblastic sarcoma.^1-4

Superficial acral fibromyxomas are composed of CD34⁺ spindle or stellate-shaped cells that are embedded in a myxoid and/or dense hyalinized collagenous stroma in a random or loosely fascicular growth pattern. The spindle or stellate-shaped cells in SAFMs also have been found to be focally positive for epithelial membrane antigen and CD99. Lesions have accentuated microvasculature and increased mast cells.^5-8

Conservative management is reasonable, but patients presenting with persistent pain and/or local deformity should be definitively treated with complete excision and follow-up. Hollmann et al¹ found that 24% of tumors recurred locally upon incomplete excision after a mean interval of 27 months. All recurrent tumors had positive margins at excision or initial biopsy.¹ To date, no reports of tumors metastasizing have been documented.^1-4

The Diagnosis: Superficial Acral Fibromyxoma

A shave biopsy revealed an uninvolved grenz zone and mildly cellular spindle cell dermal proliferation in a collagenous and myxoid background (Figure 1). Spindle cells were seen in a myxoid background among dense coarse collagen (Figure 2A). Spindle cells also were seen in a myxoid background with mast cells and capillary network (Figure 2B). Histopathologic examination of the biopsy specimen revealed spindle cells that were diffusely positive for CD34 (Figure 3); focally positive for epithelial membrane antigen; and negative for melanocytic markers, smooth muscle markers, and cytokeratin. A diagnosis of superficial acral fibromyxoma (SAFM) was made based on clinical, histopathologic, and immunohistochemical findings.

Superficial acral fibromyxomas, also known as digital fibromyxomas, are soft, slow-growing tumors that have a predilection for subungual or periungual regions of the hands and feet. Superficial acral fibromyxomas most frequently occur on the hallux and rarely occur on the ankle or leg. They can present as nodular, dome-shaped, polyploid, or verrucous masses. They can be soft to firm, gelatinous or solid, off-white to gray-white and can have fasciculate cut surfaces. Superficial acral fibromyxomas can be either painful or painless and present with a deformed nail in 9% of cases. Superficial acral fibromyxoma is a superficial lesion with frequent infiltration of the dermal collagen and subcutaneous tissue and may even erode or infiltrate into the underlying bone in rare cases.^1-4 Although SAFMs are rare tumors, documented cases of SAFM have been reported at an increasing rate since the first published report by Fetsch et al² in 2001.

Patients often delay seeking medical treatment and present with a solitary mass that has been slowly growing for months to years. In a study of 124 patients, Hollmann et al1 found that symptoms exist for a mean of 35 months and present with a small mass with a mean tumor size of 1.7 cm before biopsy or excision. Although the age range is broad, SAFM mostly affects middle-aged adults (median age, 49 years).¹ Hollmann et al1 also reported a male predominance (1.3:1 ratio), and preexisting local trauma is reported in 25% of cases.^2-4

The differential for SAFM should include dermatofibroma, keloid, dermatofibrosarcoma protuberans, acquired digital fibrokeratoma, infantile digital fibromatosis, neurolemmoma, sclerosing perineurioma, superficial angiomyxoma, low-grade fibromyxoid sarcoma, and acral myxoinflammatory fibroblastic sarcoma.^1-4

Superficial acral fibromyxomas are composed of CD34⁺ spindle or stellate-shaped cells that are embedded in a myxoid and/or dense hyalinized collagenous stroma in a random or loosely fascicular growth pattern. The spindle or stellate-shaped cells in SAFMs also have been found to be focally positive for epithelial membrane antigen and CD99. Lesions have accentuated microvasculature and increased mast cells.^5-8

Conservative management is reasonable, but patients presenting with persistent pain and/or local deformity should be definitively treated with complete excision and follow-up. Hollmann et al¹ found that 24% of tumors recurred locally upon incomplete excision after a mean interval of 27 months. All recurrent tumors had positive margins at excision or initial biopsy.¹ To date, no reports of tumors metastasizing have been documented.^1-4

CHICAGO – Among the many difficult decisions dermatologists have to make, some of the more challenging involve caring for patients with atypical melanocytic lesions. A session at the summer meeting of the American Academy of Dermatology provided some guidance for surveillance of these patients.

Caroline C. Kim, MD, directs the pigmented lesion clinic at Beth Israel Deaconess Medical Center, Boston, and shared the evidence base for her management schema, along with some clinical pearls. No dermatologist ever wants to miss a melanoma, she acknowledged. “We want to avoid those scenarios but not make people feel like Swiss cheese” from multiple biopsies, she said during her presentation.

One key concept that can help physicians find the balance, she said, is that although the presence of atypical or dysplastic nevi increases the risk for melanoma in a given patient, the actual transformation rate of dysplastic nevi to melanomas is not known. In fact, she said, between 50% and 75% of melanomas may arise de novo.

From a dermatopathologic perspective, nevi exist along a continuum of mild to moderate to severe dysplasia, and some lesions are melanomas. But mildly dysplastic nevi are not fated to continue a transformation to increasingly severely dysplastic ones, or to melanomas.

Bringing these ideas to the patient discussion means that one should avoid ever calling a dysplastic nevus “precancerous,” said Dr. Kim; not only is this inaccurate, but it is unnecessarily anxiety provoking, she said.

Within this framework, the initial exam can begin with a search for signature patterns – and ugly ducklings. Each patient will have a pattern, or several patterns, that typify their nevi. Though the markings may be “atypical,” they’ll have some consistency; if the nevus has several neighbors that look just like it, it’s much less likely to be melanoma. “If they are matching partners, it’s more likely that it’s your typical nevus pattern,” said Dr. Kim, also an assistant professor of dermatology at Harvard Medical School, Boston.

By contrast, some lesions stand out from the patient’s other atypical nevi. They may be larger, darker, more elevated, but sometimes, “Even from the doorway, they just stand out,” Dr. Kim said. And these dual concepts of signature patterns and ugly ducklings are useful to talk over with patients, she said. “It’s so easy for patients to grab on to – they totally get it.”

“Use dermoscopy” when you get to the detailed skin exam, she said. “Data have shown that as clinicians, we are pretty good at picking up melanomas ... But with dermoscopy, our detection rate goes up to 70%-95%,” Dr. Kim said. The caveat is that dermoscopy without proper training is a dangerous tool: Several studies have shown that melanoma detection rates drop compared to the naked eye when dermoscopy is performed by untrained users, she said. “Training matters.”

A further tool to help train the eye and mind to recognize benign and malignant patterns when performing dermoscopy of atypical nevi is a now-classic paper that maps these patterns out, she said (Dermatol Surg. 2007;33[11]:1388-91).

“Beware of de novo and changing lesions,” Dr. Kim said. “A picture truly is worth a thousand words” for tracking these, she said.

Total body digital photography, if it’s available, is the best way to track subtle changes, and to spot new lesions as they crop up, said Dr. Kim. In head-to-head studies with dermoscopy and visual exam alone, digital photography can reduce the number of lesions excised, detect early melanoma, and reduce patient anxiety. One study found a 3.8-fold reduction in the mean rate of nevus biopsies when total body digital photography was used, she said (J Am Acad Dermatol. 2016 Mar. doi: 10.1016/j.jaad.2016.02.1152).

A patient care pearl Dr. Kim shared is that she’ll ask patients for their smartphones and take a photograph of the patients’ backs with those phones. This lets them have a handy reference image for monitoring their own skin in the intervals between visits. But make sure, she said, that patients know that “all change is not bad change – you can get new nevi through your 50s.

“Consider sharing care with a local pigmented lesion clinic” if digital photography is not available at your site, said Dr. Kim. She does this for several of her patients, alternating visits with the primary dermatologist.

When should you perform a biopsy?

“You don’t need to biopsy an atypical nevus to call it atypical. You biopsy lesions if you’re suspicious for calling it melanoma,” Dr. Kim said. Removal also can be considered if, for example, a patient lives alone and the nevi of concern are on her back so home monitoring is a challenge, she said.

Once you’ve decided to biopsy, a narrow excisional biopsy with saucerization and 1- to 3-mm margins is preferred when there’s a high suspicion for melanoma, said Dr. Kim, citing a study that found that 2-mm margins using this method yielded an 87% rate of clear pathologic specimen margins in dysplastic nevi (J Am Acad Dermatol. 2017 Dec;77[6]:1096-9). There is some leeway in the guidelines, but “the preferred technique is a narrow excisional biopsy when you are worried,” she said.

There may be times when a partial or incisional biopsy is a rational choice, as when lesions are very large, located on the face or acral areas, or when suspicion for melanoma is low. “If you do partial biopsies, you really have to be aware of the limitations” of the technique since it may miss the nidus of melanoma within an otherwise bland lesion, Dr. Kim pointed out.

And don’t forget to plan your closure with future follow-up in mind: Dr. Kim related that she’d seen a patient for melanoma who’d had the large excisional biopsy performed elsewhere; the patient’s site was closed with an advancement flap, which made sentinel node biopsy impossible.

When the results come back, then what?

Studies have found that atypical nevi are characterized differently at different sites and that management strategies vary geographically, Dr. Kim said. “There’s a need for large-scale data to further investigate the role of observation versus re-excision of dysplastic nevi,” and a multicenter study is underway to do just that, she said, under the auspices of the Pigmented Lesion Subcommittee of the Melanoma Prevention Working Group (ECOG/SWOG).

That same subcommittee has issued a consensus statement for dealing with histologically positive excisional biopsy margins. For mildly dysplastic lesions without clinically observable residual pigment, observation is preferred. Severely dysplastic lesions with unpigmented margins should be re-excised, says the statement (JAMA Dermatol. 2015;151[2]:212-18).

For the intermediate lesions, the group recommended that a reasonable option is to observe a moderately dysplastic nevus site that’s been excisionally biopsied with a finding of positive margins, while acknowledging that more data are needed.

All biopsy sites should be followed for regrowth, though recurrence of pigment alone doesn’t necessarily mean another excision is in the patient’s future, Dr. Kim said.

She reported no conflicts of interest.

koakes@mdedge.com

SOURCE: Kim C. Summer AAD 2018, Presentation F014.

CHICAGO – Among the many difficult decisions dermatologists have to make, some of the more challenging involve caring for patients with atypical melanocytic lesions. A session at the summer meeting of the American Academy of Dermatology provided some guidance for surveillance of these patients.

Caroline C. Kim, MD, directs the pigmented lesion clinic at Beth Israel Deaconess Medical Center, Boston, and shared the evidence base for her management schema, along with some clinical pearls. No dermatologist ever wants to miss a melanoma, she acknowledged. “We want to avoid those scenarios but not make people feel like Swiss cheese” from multiple biopsies, she said during her presentation.

One key concept that can help physicians find the balance, she said, is that although the presence of atypical or dysplastic nevi increases the risk for melanoma in a given patient, the actual transformation rate of dysplastic nevi to melanomas is not known. In fact, she said, between 50% and 75% of melanomas may arise de novo.

From a dermatopathologic perspective, nevi exist along a continuum of mild to moderate to severe dysplasia, and some lesions are melanomas. But mildly dysplastic nevi are not fated to continue a transformation to increasingly severely dysplastic ones, or to melanomas.

Bringing these ideas to the patient discussion means that one should avoid ever calling a dysplastic nevus “precancerous,” said Dr. Kim; not only is this inaccurate, but it is unnecessarily anxiety provoking, she said.

Within this framework, the initial exam can begin with a search for signature patterns – and ugly ducklings. Each patient will have a pattern, or several patterns, that typify their nevi. Though the markings may be “atypical,” they’ll have some consistency; if the nevus has several neighbors that look just like it, it’s much less likely to be melanoma. “If they are matching partners, it’s more likely that it’s your typical nevus pattern,” said Dr. Kim, also an assistant professor of dermatology at Harvard Medical School, Boston.

By contrast, some lesions stand out from the patient’s other atypical nevi. They may be larger, darker, more elevated, but sometimes, “Even from the doorway, they just stand out,” Dr. Kim said. And these dual concepts of signature patterns and ugly ducklings are useful to talk over with patients, she said. “It’s so easy for patients to grab on to – they totally get it.”

“Use dermoscopy” when you get to the detailed skin exam, she said. “Data have shown that as clinicians, we are pretty good at picking up melanomas ... But with dermoscopy, our detection rate goes up to 70%-95%,” Dr. Kim said. The caveat is that dermoscopy without proper training is a dangerous tool: Several studies have shown that melanoma detection rates drop compared to the naked eye when dermoscopy is performed by untrained users, she said. “Training matters.”

A further tool to help train the eye and mind to recognize benign and malignant patterns when performing dermoscopy of atypical nevi is a now-classic paper that maps these patterns out, she said (Dermatol Surg. 2007;33[11]:1388-91).

“Beware of de novo and changing lesions,” Dr. Kim said. “A picture truly is worth a thousand words” for tracking these, she said.

Total body digital photography, if it’s available, is the best way to track subtle changes, and to spot new lesions as they crop up, said Dr. Kim. In head-to-head studies with dermoscopy and visual exam alone, digital photography can reduce the number of lesions excised, detect early melanoma, and reduce patient anxiety. One study found a 3.8-fold reduction in the mean rate of nevus biopsies when total body digital photography was used, she said (J Am Acad Dermatol. 2016 Mar. doi: 10.1016/j.jaad.2016.02.1152).

A patient care pearl Dr. Kim shared is that she’ll ask patients for their smartphones and take a photograph of the patients’ backs with those phones. This lets them have a handy reference image for monitoring their own skin in the intervals between visits. But make sure, she said, that patients know that “all change is not bad change – you can get new nevi through your 50s.

“Consider sharing care with a local pigmented lesion clinic” if digital photography is not available at your site, said Dr. Kim. She does this for several of her patients, alternating visits with the primary dermatologist.

When should you perform a biopsy?

“You don’t need to biopsy an atypical nevus to call it atypical. You biopsy lesions if you’re suspicious for calling it melanoma,” Dr. Kim said. Removal also can be considered if, for example, a patient lives alone and the nevi of concern are on her back so home monitoring is a challenge, she said.

Once you’ve decided to biopsy, a narrow excisional biopsy with saucerization and 1- to 3-mm margins is preferred when there’s a high suspicion for melanoma, said Dr. Kim, citing a study that found that 2-mm margins using this method yielded an 87% rate of clear pathologic specimen margins in dysplastic nevi (J Am Acad Dermatol. 2017 Dec;77[6]:1096-9). There is some leeway in the guidelines, but “the preferred technique is a narrow excisional biopsy when you are worried,” she said.

There may be times when a partial or incisional biopsy is a rational choice, as when lesions are very large, located on the face or acral areas, or when suspicion for melanoma is low. “If you do partial biopsies, you really have to be aware of the limitations” of the technique since it may miss the nidus of melanoma within an otherwise bland lesion, Dr. Kim pointed out.

And don’t forget to plan your closure with future follow-up in mind: Dr. Kim related that she’d seen a patient for melanoma who’d had the large excisional biopsy performed elsewhere; the patient’s site was closed with an advancement flap, which made sentinel node biopsy impossible.

When the results come back, then what?

Studies have found that atypical nevi are characterized differently at different sites and that management strategies vary geographically, Dr. Kim said. “There’s a need for large-scale data to further investigate the role of observation versus re-excision of dysplastic nevi,” and a multicenter study is underway to do just that, she said, under the auspices of the Pigmented Lesion Subcommittee of the Melanoma Prevention Working Group (ECOG/SWOG).

That same subcommittee has issued a consensus statement for dealing with histologically positive excisional biopsy margins. For mildly dysplastic lesions without clinically observable residual pigment, observation is preferred. Severely dysplastic lesions with unpigmented margins should be re-excised, says the statement (JAMA Dermatol. 2015;151[2]:212-18).

For the intermediate lesions, the group recommended that a reasonable option is to observe a moderately dysplastic nevus site that’s been excisionally biopsied with a finding of positive margins, while acknowledging that more data are needed.

All biopsy sites should be followed for regrowth, though recurrence of pigment alone doesn’t necessarily mean another excision is in the patient’s future, Dr. Kim said.

She reported no conflicts of interest.

koakes@mdedge.com

SOURCE: Kim C. Summer AAD 2018, Presentation F014.

CHICAGO – Among the many difficult decisions dermatologists have to make, some of the more challenging involve caring for patients with atypical melanocytic lesions. A session at the summer meeting of the American Academy of Dermatology provided some guidance for surveillance of these patients.

Caroline C. Kim, MD, directs the pigmented lesion clinic at Beth Israel Deaconess Medical Center, Boston, and shared the evidence base for her management schema, along with some clinical pearls. No dermatologist ever wants to miss a melanoma, she acknowledged. “We want to avoid those scenarios but not make people feel like Swiss cheese” from multiple biopsies, she said during her presentation.

One key concept that can help physicians find the balance, she said, is that although the presence of atypical or dysplastic nevi increases the risk for melanoma in a given patient, the actual transformation rate of dysplastic nevi to melanomas is not known. In fact, she said, between 50% and 75% of melanomas may arise de novo.

From a dermatopathologic perspective, nevi exist along a continuum of mild to moderate to severe dysplasia, and some lesions are melanomas. But mildly dysplastic nevi are not fated to continue a transformation to increasingly severely dysplastic ones, or to melanomas.

Bringing these ideas to the patient discussion means that one should avoid ever calling a dysplastic nevus “precancerous,” said Dr. Kim; not only is this inaccurate, but it is unnecessarily anxiety provoking, she said.

Within this framework, the initial exam can begin with a search for signature patterns – and ugly ducklings. Each patient will have a pattern, or several patterns, that typify their nevi. Though the markings may be “atypical,” they’ll have some consistency; if the nevus has several neighbors that look just like it, it’s much less likely to be melanoma. “If they are matching partners, it’s more likely that it’s your typical nevus pattern,” said Dr. Kim, also an assistant professor of dermatology at Harvard Medical School, Boston.

By contrast, some lesions stand out from the patient’s other atypical nevi. They may be larger, darker, more elevated, but sometimes, “Even from the doorway, they just stand out,” Dr. Kim said. And these dual concepts of signature patterns and ugly ducklings are useful to talk over with patients, she said. “It’s so easy for patients to grab on to – they totally get it.”

“Use dermoscopy” when you get to the detailed skin exam, she said. “Data have shown that as clinicians, we are pretty good at picking up melanomas ... But with dermoscopy, our detection rate goes up to 70%-95%,” Dr. Kim said. The caveat is that dermoscopy without proper training is a dangerous tool: Several studies have shown that melanoma detection rates drop compared to the naked eye when dermoscopy is performed by untrained users, she said. “Training matters.”

A further tool to help train the eye and mind to recognize benign and malignant patterns when performing dermoscopy of atypical nevi is a now-classic paper that maps these patterns out, she said (Dermatol Surg. 2007;33[11]:1388-91).

“Beware of de novo and changing lesions,” Dr. Kim said. “A picture truly is worth a thousand words” for tracking these, she said.

Total body digital photography, if it’s available, is the best way to track subtle changes, and to spot new lesions as they crop up, said Dr. Kim. In head-to-head studies with dermoscopy and visual exam alone, digital photography can reduce the number of lesions excised, detect early melanoma, and reduce patient anxiety. One study found a 3.8-fold reduction in the mean rate of nevus biopsies when total body digital photography was used, she said (J Am Acad Dermatol. 2016 Mar. doi: 10.1016/j.jaad.2016.02.1152).

A patient care pearl Dr. Kim shared is that she’ll ask patients for their smartphones and take a photograph of the patients’ backs with those phones. This lets them have a handy reference image for monitoring their own skin in the intervals between visits. But make sure, she said, that patients know that “all change is not bad change – you can get new nevi through your 50s.

“Consider sharing care with a local pigmented lesion clinic” if digital photography is not available at your site, said Dr. Kim. She does this for several of her patients, alternating visits with the primary dermatologist.

When should you perform a biopsy?

“You don’t need to biopsy an atypical nevus to call it atypical. You biopsy lesions if you’re suspicious for calling it melanoma,” Dr. Kim said. Removal also can be considered if, for example, a patient lives alone and the nevi of concern are on her back so home monitoring is a challenge, she said.

Once you’ve decided to biopsy, a narrow excisional biopsy with saucerization and 1- to 3-mm margins is preferred when there’s a high suspicion for melanoma, said Dr. Kim, citing a study that found that 2-mm margins using this method yielded an 87% rate of clear pathologic specimen margins in dysplastic nevi (J Am Acad Dermatol. 2017 Dec;77[6]:1096-9). There is some leeway in the guidelines, but “the preferred technique is a narrow excisional biopsy when you are worried,” she said.

There may be times when a partial or incisional biopsy is a rational choice, as when lesions are very large, located on the face or acral areas, or when suspicion for melanoma is low. “If you do partial biopsies, you really have to be aware of the limitations” of the technique since it may miss the nidus of melanoma within an otherwise bland lesion, Dr. Kim pointed out.

And don’t forget to plan your closure with future follow-up in mind: Dr. Kim related that she’d seen a patient for melanoma who’d had the large excisional biopsy performed elsewhere; the patient’s site was closed with an advancement flap, which made sentinel node biopsy impossible.

When the results come back, then what?

Studies have found that atypical nevi are characterized differently at different sites and that management strategies vary geographically, Dr. Kim said. “There’s a need for large-scale data to further investigate the role of observation versus re-excision of dysplastic nevi,” and a multicenter study is underway to do just that, she said, under the auspices of the Pigmented Lesion Subcommittee of the Melanoma Prevention Working Group (ECOG/SWOG).

That same subcommittee has issued a consensus statement for dealing with histologically positive excisional biopsy margins. For mildly dysplastic lesions without clinically observable residual pigment, observation is preferred. Severely dysplastic lesions with unpigmented margins should be re-excised, says the statement (JAMA Dermatol. 2015;151[2]:212-18).

For the intermediate lesions, the group recommended that a reasonable option is to observe a moderately dysplastic nevus site that’s been excisionally biopsied with a finding of positive margins, while acknowledging that more data are needed.

All biopsy sites should be followed for regrowth, though recurrence of pigment alone doesn’t necessarily mean another excision is in the patient’s future, Dr. Kim said.

She reported no conflicts of interest.

koakes@mdedge.com

SOURCE: Kim C. Summer AAD 2018, Presentation F014.

To the Editor:

An 11-year-old girl presented to the dermatology clinic with an asymptomatic rash on the bilateral forearms, dorsal hands, and ears of 1 month’s duration. Recent history was notable for persistent low-grade fevers, dizziness, headaches, arthralgia, and swelling of multiple joints, as well as difficulty ambulating due to the joint pain. A thorough review of systems revealed no photosensitivity, oral sores, weight loss, pulmonary symptoms, Raynaud phenomenon, or dysphagia.

Medical history was notable for presumed viral pancreatitis and transaminitis requiring inpatient hospitalization 1 year prior to presentation. The patient underwent extensive workup at that time, which was notable for a positive antinuclear antibody level of 1:2560, an elevated erythrocyte sedimentation rate level of 75 mm/h (reference range, 0–22 mm/h), hemolytic anemia with a hemoglobin of 10.9 g/dL (14.0–17.5 g/dL), and leukopenia with a white blood cell count of 3700/µL (4500–11,000/µL). Additional laboratory tests were performed and were found to be within reference range, including creatine kinase, aldolase, complete metabolic panel, extractable nuclear antigen, complement levels, C-reactive protein level, antiphospholipid antibodies,partial thromboplastin time, prothrombin time, anti–double-stranded DNA, rheumatoid factor, β₂-glycoprotein, and antineutrophil cytoplasmic antibody tests. Skin purified protein derivative (tuberculin) test and chest radiograph also were unremarkable. The patient also was evaluated and found negative for Wilson disease, hemochromatosis, α₁-antitrypsin disease, and autoimmune hepatitis.

Physical examination revealed erythematous plaques with crusted hyperpigmented erosions and central hypopigmentation on the bilateral conchal bowls and antihelices, findings characteristic of discoid lupus erythematosus (Figure 1A). On the bilateral elbows, metacarpophalangeal (MCP) joints, and proximal interphalangeal (PIP) joints, there were firm, erythematous to violaceous, keratotic papules that were clinically suggestive of Gottron-like papules (Figures 1B and 1C). However, there were no lesions on the skin between the MCP, PIP, and distal interphalangeal joints. The MCP joints were associated with swelling and were tender to palpation. Examination of the fingernails showed dilated telangiectasia of the proximal nail folds and ragged hyperkeratotic cuticles of all 10 digits (Figure 1D). On the extensor aspects of the bilateral forearms, there were erythematous excoriated papules and papulovesicular lesions with central hemorrhagic crusting. The patient showed no shawl sign, heliotrope rash, calcinosis, malar rash, oral lesions, or hair loss.

Additional physical examinations performed by the neufigrology and rheumatology departments revealed no impairment of muscle strength, soreness of muscles, and muscular atrophy. Joint examination was notable for restriction in range of motion of the hands, hips, and ankles due to swelling and pain of the joints. Radiographs and ultrasound of the feet showed fluid accumulation and synovial thickening of the metatarsal phalangeal joints and one of the PIP joints of the right hand without erosion.

The patient did not undergo magnetic resonance imaging of muscles due to the lack of muscular symptoms and normal myositis laboratory markers. Dermatomyositis-specific antibody testing, such as anti–Jo-1 and anti–Mi-2, also was not performed.

After reviewing the biopsy results, laboratory findings, and clinical presentation, the patient was diagnosed with systemic lupus erythematosus (SLE), as she met American College of Rheumatology criteria¹ with the following: discoid rash, hemolytic anemia, positive antinuclear antibodies, and nonerosive arthritis. Due to her abnormal constellation of laboratory values and symptoms, she was evaluated by 2 pediatric rheumatologists at 2 different medical centers who agreed with a primary diagnosis of SLE rather than dermatomyositis sine myositis. The hemolytic anemia was attributed to underlying connective tissue disease, as the hemoglobin levels were found to be persistently low for 1 year prior to the diagnosis of systemic lupus, and there was no alternative cause of the hematologic disorder.

A punch biopsy obtained from a Gottron-like papule on the dorsal aspect of the left hand revealed lymphocytic interface dermatitis and slight thickening of the basement membrane zone (Figure 2A). There was a dense superficial and deep periadnexal and perivascular lymphocytic inflammation as well as increased dermal mucin, which can be seen in both lupus erythematosus and dermatomyositis (Figure 2B). Perniosis also was considered from histologic findings but was excluded based on clinical history and physical findings. A second biopsy of the left conchal bowl showed hyperkeratosis, epidermal atrophy, interface changes, follicular plugging, and basement membrane thickening. These findings can be seen in dermatomyositis, but when considered together with the clinical appearance of the patient’s eruption on the ears, they were more consistent with discoid lupus erythematosus (Figures 2C and 2D).

Finally, although ragged cuticles and proximal nail fold telangiectasia typically are seen in dermatomyositis, nail fold hyperkeratosis, ragged cuticles, and nail bed telangiectasia also have been reported in lupus erythematosus.^2,3 Therefore, the findings overlying our patient’s knuckles and elbows can be considered Gottron-like papules in the setting of SLE.

Dermatomyositis has several characteristic dermatologic manifestations, including Gottron papules, shawl sign, facial heliotrope rash, periungual telangiectasia, and mechanic’s hands. Of them, Gottron papules have been the most pathognomonic, while the other skin findings are less specific and can be seen in other disease entities.^4,5

The pathogenesis of Gottron papules in dermatomyositis remains largely unknown. Prior molecular studies have proposed that stretch CD44 variant 7 and abnormal osteopontin levels may contribute to the pathogenesis of Gottron papules by increasing local inflammation.⁶ Studies also have linked abnormal osteopontin levels and CD44 variant 7 expression with other diseases of autoimmunity, including lupus erythematosus.⁷ Because lupus erythematosus can have a large variety of cutaneous findings, Gottron-like papules may be considered a rare dermatologic presentation of lupus erythematosus.

We present a case of Gottron-like papules as an unusual dermatologic manifestation of SLE, challenging the concept of Gottron papules as a pathognomonic finding of dermatomyositis.

To the Editor:

An 11-year-old girl presented to the dermatology clinic with an asymptomatic rash on the bilateral forearms, dorsal hands, and ears of 1 month’s duration. Recent history was notable for persistent low-grade fevers, dizziness, headaches, arthralgia, and swelling of multiple joints, as well as difficulty ambulating due to the joint pain. A thorough review of systems revealed no photosensitivity, oral sores, weight loss, pulmonary symptoms, Raynaud phenomenon, or dysphagia.

Medical history was notable for presumed viral pancreatitis and transaminitis requiring inpatient hospitalization 1 year prior to presentation. The patient underwent extensive workup at that time, which was notable for a positive antinuclear antibody level of 1:2560, an elevated erythrocyte sedimentation rate level of 75 mm/h (reference range, 0–22 mm/h), hemolytic anemia with a hemoglobin of 10.9 g/dL (14.0–17.5 g/dL), and leukopenia with a white blood cell count of 3700/µL (4500–11,000/µL). Additional laboratory tests were performed and were found to be within reference range, including creatine kinase, aldolase, complete metabolic panel, extractable nuclear antigen, complement levels, C-reactive protein level, antiphospholipid antibodies,partial thromboplastin time, prothrombin time, anti–double-stranded DNA, rheumatoid factor, β₂-glycoprotein, and antineutrophil cytoplasmic antibody tests. Skin purified protein derivative (tuberculin) test and chest radiograph also were unremarkable. The patient also was evaluated and found negative for Wilson disease, hemochromatosis, α₁-antitrypsin disease, and autoimmune hepatitis.

Physical examination revealed erythematous plaques with crusted hyperpigmented erosions and central hypopigmentation on the bilateral conchal bowls and antihelices, findings characteristic of discoid lupus erythematosus (Figure 1A). On the bilateral elbows, metacarpophalangeal (MCP) joints, and proximal interphalangeal (PIP) joints, there were firm, erythematous to violaceous, keratotic papules that were clinically suggestive of Gottron-like papules (Figures 1B and 1C). However, there were no lesions on the skin between the MCP, PIP, and distal interphalangeal joints. The MCP joints were associated with swelling and were tender to palpation. Examination of the fingernails showed dilated telangiectasia of the proximal nail folds and ragged hyperkeratotic cuticles of all 10 digits (Figure 1D). On the extensor aspects of the bilateral forearms, there were erythematous excoriated papules and papulovesicular lesions with central hemorrhagic crusting. The patient showed no shawl sign, heliotrope rash, calcinosis, malar rash, oral lesions, or hair loss.

Additional physical examinations performed by the neufigrology and rheumatology departments revealed no impairment of muscle strength, soreness of muscles, and muscular atrophy. Joint examination was notable for restriction in range of motion of the hands, hips, and ankles due to swelling and pain of the joints. Radiographs and ultrasound of the feet showed fluid accumulation and synovial thickening of the metatarsal phalangeal joints and one of the PIP joints of the right hand without erosion.

The patient did not undergo magnetic resonance imaging of muscles due to the lack of muscular symptoms and normal myositis laboratory markers. Dermatomyositis-specific antibody testing, such as anti–Jo-1 and anti–Mi-2, also was not performed.

After reviewing the biopsy results, laboratory findings, and clinical presentation, the patient was diagnosed with systemic lupus erythematosus (SLE), as she met American College of Rheumatology criteria¹ with the following: discoid rash, hemolytic anemia, positive antinuclear antibodies, and nonerosive arthritis. Due to her abnormal constellation of laboratory values and symptoms, she was evaluated by 2 pediatric rheumatologists at 2 different medical centers who agreed with a primary diagnosis of SLE rather than dermatomyositis sine myositis. The hemolytic anemia was attributed to underlying connective tissue disease, as the hemoglobin levels were found to be persistently low for 1 year prior to the diagnosis of systemic lupus, and there was no alternative cause of the hematologic disorder.

A punch biopsy obtained from a Gottron-like papule on the dorsal aspect of the left hand revealed lymphocytic interface dermatitis and slight thickening of the basement membrane zone (Figure 2A). There was a dense superficial and deep periadnexal and perivascular lymphocytic inflammation as well as increased dermal mucin, which can be seen in both lupus erythematosus and dermatomyositis (Figure 2B). Perniosis also was considered from histologic findings but was excluded based on clinical history and physical findings. A second biopsy of the left conchal bowl showed hyperkeratosis, epidermal atrophy, interface changes, follicular plugging, and basement membrane thickening. These findings can be seen in dermatomyositis, but when considered together with the clinical appearance of the patient’s eruption on the ears, they were more consistent with discoid lupus erythematosus (Figures 2C and 2D).

Finally, although ragged cuticles and proximal nail fold telangiectasia typically are seen in dermatomyositis, nail fold hyperkeratosis, ragged cuticles, and nail bed telangiectasia also have been reported in lupus erythematosus.^2,3 Therefore, the findings overlying our patient’s knuckles and elbows can be considered Gottron-like papules in the setting of SLE.

Dermatomyositis has several characteristic dermatologic manifestations, including Gottron papules, shawl sign, facial heliotrope rash, periungual telangiectasia, and mechanic’s hands. Of them, Gottron papules have been the most pathognomonic, while the other skin findings are less specific and can be seen in other disease entities.^4,5

The pathogenesis of Gottron papules in dermatomyositis remains largely unknown. Prior molecular studies have proposed that stretch CD44 variant 7 and abnormal osteopontin levels may contribute to the pathogenesis of Gottron papules by increasing local inflammation.⁶ Studies also have linked abnormal osteopontin levels and CD44 variant 7 expression with other diseases of autoimmunity, including lupus erythematosus.⁷ Because lupus erythematosus can have a large variety of cutaneous findings, Gottron-like papules may be considered a rare dermatologic presentation of lupus erythematosus.

We present a case of Gottron-like papules as an unusual dermatologic manifestation of SLE, challenging the concept of Gottron papules as a pathognomonic finding of dermatomyositis.

To the Editor:

An 11-year-old girl presented to the dermatology clinic with an asymptomatic rash on the bilateral forearms, dorsal hands, and ears of 1 month’s duration. Recent history was notable for persistent low-grade fevers, dizziness, headaches, arthralgia, and swelling of multiple joints, as well as difficulty ambulating due to the joint pain. A thorough review of systems revealed no photosensitivity, oral sores, weight loss, pulmonary symptoms, Raynaud phenomenon, or dysphagia.

Medical history was notable for presumed viral pancreatitis and transaminitis requiring inpatient hospitalization 1 year prior to presentation. The patient underwent extensive workup at that time, which was notable for a positive antinuclear antibody level of 1:2560, an elevated erythrocyte sedimentation rate level of 75 mm/h (reference range, 0–22 mm/h), hemolytic anemia with a hemoglobin of 10.9 g/dL (14.0–17.5 g/dL), and leukopenia with a white blood cell count of 3700/µL (4500–11,000/µL). Additional laboratory tests were performed and were found to be within reference range, including creatine kinase, aldolase, complete metabolic panel, extractable nuclear antigen, complement levels, C-reactive protein level, antiphospholipid antibodies,partial thromboplastin time, prothrombin time, anti–double-stranded DNA, rheumatoid factor, β₂-glycoprotein, and antineutrophil cytoplasmic antibody tests. Skin purified protein derivative (tuberculin) test and chest radiograph also were unremarkable. The patient also was evaluated and found negative for Wilson disease, hemochromatosis, α₁-antitrypsin disease, and autoimmune hepatitis.

Physical examination revealed erythematous plaques with crusted hyperpigmented erosions and central hypopigmentation on the bilateral conchal bowls and antihelices, findings characteristic of discoid lupus erythematosus (Figure 1A). On the bilateral elbows, metacarpophalangeal (MCP) joints, and proximal interphalangeal (PIP) joints, there were firm, erythematous to violaceous, keratotic papules that were clinically suggestive of Gottron-like papules (Figures 1B and 1C). However, there were no lesions on the skin between the MCP, PIP, and distal interphalangeal joints. The MCP joints were associated with swelling and were tender to palpation. Examination of the fingernails showed dilated telangiectasia of the proximal nail folds and ragged hyperkeratotic cuticles of all 10 digits (Figure 1D). On the extensor aspects of the bilateral forearms, there were erythematous excoriated papules and papulovesicular lesions with central hemorrhagic crusting. The patient showed no shawl sign, heliotrope rash, calcinosis, malar rash, oral lesions, or hair loss.

Additional physical examinations performed by the neufigrology and rheumatology departments revealed no impairment of muscle strength, soreness of muscles, and muscular atrophy. Joint examination was notable for restriction in range of motion of the hands, hips, and ankles due to swelling and pain of the joints. Radiographs and ultrasound of the feet showed fluid accumulation and synovial thickening of the metatarsal phalangeal joints and one of the PIP joints of the right hand without erosion.

The patient did not undergo magnetic resonance imaging of muscles due to the lack of muscular symptoms and normal myositis laboratory markers. Dermatomyositis-specific antibody testing, such as anti–Jo-1 and anti–Mi-2, also was not performed.

After reviewing the biopsy results, laboratory findings, and clinical presentation, the patient was diagnosed with systemic lupus erythematosus (SLE), as she met American College of Rheumatology criteria¹ with the following: discoid rash, hemolytic anemia, positive antinuclear antibodies, and nonerosive arthritis. Due to her abnormal constellation of laboratory values and symptoms, she was evaluated by 2 pediatric rheumatologists at 2 different medical centers who agreed with a primary diagnosis of SLE rather than dermatomyositis sine myositis. The hemolytic anemia was attributed to underlying connective tissue disease, as the hemoglobin levels were found to be persistently low for 1 year prior to the diagnosis of systemic lupus, and there was no alternative cause of the hematologic disorder.

A punch biopsy obtained from a Gottron-like papule on the dorsal aspect of the left hand revealed lymphocytic interface dermatitis and slight thickening of the basement membrane zone (Figure 2A). There was a dense superficial and deep periadnexal and perivascular lymphocytic inflammation as well as increased dermal mucin, which can be seen in both lupus erythematosus and dermatomyositis (Figure 2B). Perniosis also was considered from histologic findings but was excluded based on clinical history and physical findings. A second biopsy of the left conchal bowl showed hyperkeratosis, epidermal atrophy, interface changes, follicular plugging, and basement membrane thickening. These findings can be seen in dermatomyositis, but when considered together with the clinical appearance of the patient’s eruption on the ears, they were more consistent with discoid lupus erythematosus (Figures 2C and 2D).

Finally, although ragged cuticles and proximal nail fold telangiectasia typically are seen in dermatomyositis, nail fold hyperkeratosis, ragged cuticles, and nail bed telangiectasia also have been reported in lupus erythematosus.^2,3 Therefore, the findings overlying our patient’s knuckles and elbows can be considered Gottron-like papules in the setting of SLE.

Dermatomyositis has several characteristic dermatologic manifestations, including Gottron papules, shawl sign, facial heliotrope rash, periungual telangiectasia, and mechanic’s hands. Of them, Gottron papules have been the most pathognomonic, while the other skin findings are less specific and can be seen in other disease entities.^4,5

The pathogenesis of Gottron papules in dermatomyositis remains largely unknown. Prior molecular studies have proposed that stretch CD44 variant 7 and abnormal osteopontin levels may contribute to the pathogenesis of Gottron papules by increasing local inflammation.⁶ Studies also have linked abnormal osteopontin levels and CD44 variant 7 expression with other diseases of autoimmunity, including lupus erythematosus.⁷ Because lupus erythematosus can have a large variety of cutaneous findings, Gottron-like papules may be considered a rare dermatologic presentation of lupus erythematosus.

We present a case of Gottron-like papules as an unusual dermatologic manifestation of SLE, challenging the concept of Gottron papules as a pathognomonic finding of dermatomyositis.

To the Editor:

A 50-year-old female farmer with diabetes mellitus, paroxysmal atrial fibrillation, and treatment-refractory systemic lupus erythematosus presented with worsening erythema, ecchymoses, edema, and tenderness in the bilateral legs of 3 weeks’ duration. The patient was taking oral methylprednisolone 12 mg daily (8 mg in the morning, 4 mg in the evening) for systemic lupus erythematosus. She previously was treated with mycophenolate mofetil, mycophenolic acid, methotrexate, azathioprine, hydroxychloroquine, etanercept, and cyclosporine without success. Cyclophosphamide was helpful in the past, but the last dose was more than 1 year prior to the current presentation. Physical examination showed no fever and 1+ pitting edema to the mid shin. Multiple warm, tender, erythematous to gray plaques were present on the bilateral lower extremities, and a 2-cm ulcerated plaque with a violaceous border was present on the medial surface of the lower left leg (Figure 1). The surrounding erythematous tissue was markedly tender to palpation. No popliteal or inguinal lymphadenopathy was appreciated.

Punch biopsies were obtained from the periphery and center of the ulcerated plaque on the left leg. Histopathologic analysis revealed an ulcerated necrotic epidermis with scant diffuse acute and chronic inflammation (Figure 2A). Leukocytoclastic vasculitis was present at the periphery of the lesion (Figure 2B). Colloidal iron stain revealed a marked increase in dermal mucin. Gram stain showed both gram-positive and gram-negative organisms (Figure 2C). Fungal and hyphal elements were seen in the superficial epidermis. Tissue cultures revealed a predominance of Pseudomonas fluorescens, along with Candida albicans, Klebsiella oxytoca, and Staphylococcus and Enterococcus species. Bacterial and fungal blood cultures were negative.

The patient was treated with ciprofloxacin, vancomycin, and voriconazole based on culture sensitivities. Although double coverage often is recommended for pseudomonal infections,¹ the patient could not be started on a second antipseudomonal agent due to multiple severe antibiotic allergies. She continued home administration of methylprednisolone in the setting of active lupus; additional immunosuppression was avoided. Over the course of 1 week, the patient’s preexisting ulcerated plaque on the medial surface of the lower left leg gradually improved, and no new lesions developed. Ciprofloxacin, vancomycin, and voriconazole were continued along with insulin, aspirin, warfarin, metoprolol, furosemide, and bumetanide at discharge. The patient subsequently was readmitted to the hospital several more times over the next 4 months for multiple bacterial infections and ultimately died of overwhelming septic shock several months later.

Ecthyma gangrenosum (EG) is a rare cutaneous infection that results from either direct inoculation or hematogenous dissemination. It classically is caused by infection with Pseudomonas aeruginosa in immunocompromised or neutropenic patients. However, other bacteria and fungi, mucormycosis, and herpes simplex virus also have been reported to cause EG.¹ Skin lesions often start as erythematous or purpuric macules, develop into vesicles and bullae, and eventually become necrotic ulcers with central eschars.² Histopathologic findings reveal necrotizing hemorrhagic vasculitis; gram-negative rods often are found in the medial and adventitial walls of deeper vessels.^3,4 The case mortality rate is high, ranging from 15% in nonbacteremic patients to 38% to 96% in patients with bacteremia.³

The leukocytoclastic vasculitis seen on biopsy in our patient was a reaction pattern, likely a direct result of the soft tissue infection. Biopsy showed hyphal or pseudohyphal elements in the superficial epidermis, corresponding to the positive C albicans growth on fungal culture. Candida albicans has been reported to cause lesions that mimic bacterial EG.¹ However, the marked predominance of P fluorescens on biopsy and culture suggests that the Candida likely were opportunistic and managed to invade secondary to the vascular damage caused by P fluorescens.

Pseudomonas fluorescens is an aerobic gram-negative rod-shaped bacterium found in soil that rarely is implicated in human disease. This bacterium is unable to ferment lactose and grows best on MacConkey agar between 30°C and 37°C but also can grow at temperatures as low as 4°C.⁵ The ability of P fluorescens to rapidly proliferate at low temperatures (ie, in refrigerated blood products, saline solutions, water dispensers, ice baths, humidifier water) is thought to explain a number of reported clinical consequences, ranging from asymptomatic colonization to fatal bacteremia.^6-10 This opportunistic pathogen also has been linked to Crohn disease and has been reported to cause pelvic inflammatory disease with the use of intrauterine contraception devices and nosocomial respiratory tract infections due to contaminated spirometers.^11-14 In our case, the patient was part of a family of farmers and worked in an agricultural setting. She often handled the produce and worked at the family’s produce stand at the local farmer’s market. Her exposure to soil and soil pathogens may have been the source of the P fluorescens infection.

This case introduces P fluorescens as a causative agent of EG, suggests that exposure to agricultural products may predispose an immunosuppressed patient to this type of infection, and emphasizes the importance of timely diagnosis through tissue culture and histopathology so that immunosuppressive medications can be withheld and appropriate antibiotics can be initiated.

To the Editor:

A 50-year-old female farmer with diabetes mellitus, paroxysmal atrial fibrillation, and treatment-refractory systemic lupus erythematosus presented with worsening erythema, ecchymoses, edema, and tenderness in the bilateral legs of 3 weeks’ duration. The patient was taking oral methylprednisolone 12 mg daily (8 mg in the morning, 4 mg in the evening) for systemic lupus erythematosus. She previously was treated with mycophenolate mofetil, mycophenolic acid, methotrexate, azathioprine, hydroxychloroquine, etanercept, and cyclosporine without success. Cyclophosphamide was helpful in the past, but the last dose was more than 1 year prior to the current presentation. Physical examination showed no fever and 1+ pitting edema to the mid shin. Multiple warm, tender, erythematous to gray plaques were present on the bilateral lower extremities, and a 2-cm ulcerated plaque with a violaceous border was present on the medial surface of the lower left leg (Figure 1). The surrounding erythematous tissue was markedly tender to palpation. No popliteal or inguinal lymphadenopathy was appreciated.

Punch biopsies were obtained from the periphery and center of the ulcerated plaque on the left leg. Histopathologic analysis revealed an ulcerated necrotic epidermis with scant diffuse acute and chronic inflammation (Figure 2A). Leukocytoclastic vasculitis was present at the periphery of the lesion (Figure 2B). Colloidal iron stain revealed a marked increase in dermal mucin. Gram stain showed both gram-positive and gram-negative organisms (Figure 2C). Fungal and hyphal elements were seen in the superficial epidermis. Tissue cultures revealed a predominance of Pseudomonas fluorescens, along with Candida albicans, Klebsiella oxytoca, and Staphylococcus and Enterococcus species. Bacterial and fungal blood cultures were negative.

The patient was treated with ciprofloxacin, vancomycin, and voriconazole based on culture sensitivities. Although double coverage often is recommended for pseudomonal infections,¹ the patient could not be started on a second antipseudomonal agent due to multiple severe antibiotic allergies. She continued home administration of methylprednisolone in the setting of active lupus; additional immunosuppression was avoided. Over the course of 1 week, the patient’s preexisting ulcerated plaque on the medial surface of the lower left leg gradually improved, and no new lesions developed. Ciprofloxacin, vancomycin, and voriconazole were continued along with insulin, aspirin, warfarin, metoprolol, furosemide, and bumetanide at discharge. The patient subsequently was readmitted to the hospital several more times over the next 4 months for multiple bacterial infections and ultimately died of overwhelming septic shock several months later.

Ecthyma gangrenosum (EG) is a rare cutaneous infection that results from either direct inoculation or hematogenous dissemination. It classically is caused by infection with Pseudomonas aeruginosa in immunocompromised or neutropenic patients. However, other bacteria and fungi, mucormycosis, and herpes simplex virus also have been reported to cause EG.¹ Skin lesions often start as erythematous or purpuric macules, develop into vesicles and bullae, and eventually become necrotic ulcers with central eschars.² Histopathologic findings reveal necrotizing hemorrhagic vasculitis; gram-negative rods often are found in the medial and adventitial walls of deeper vessels.^3,4 The case mortality rate is high, ranging from 15% in nonbacteremic patients to 38% to 96% in patients with bacteremia.³

The leukocytoclastic vasculitis seen on biopsy in our patient was a reaction pattern, likely a direct result of the soft tissue infection. Biopsy showed hyphal or pseudohyphal elements in the superficial epidermis, corresponding to the positive C albicans growth on fungal culture. Candida albicans has been reported to cause lesions that mimic bacterial EG.¹ However, the marked predominance of P fluorescens on biopsy and culture suggests that the Candida likely were opportunistic and managed to invade secondary to the vascular damage caused by P fluorescens.

Pseudomonas fluorescens is an aerobic gram-negative rod-shaped bacterium found in soil that rarely is implicated in human disease. This bacterium is unable to ferment lactose and grows best on MacConkey agar between 30°C and 37°C but also can grow at temperatures as low as 4°C.⁵ The ability of P fluorescens to rapidly proliferate at low temperatures (ie, in refrigerated blood products, saline solutions, water dispensers, ice baths, humidifier water) is thought to explain a number of reported clinical consequences, ranging from asymptomatic colonization to fatal bacteremia.^6-10 This opportunistic pathogen also has been linked to Crohn disease and has been reported to cause pelvic inflammatory disease with the use of intrauterine contraception devices and nosocomial respiratory tract infections due to contaminated spirometers.^11-14 In our case, the patient was part of a family of farmers and worked in an agricultural setting. She often handled the produce and worked at the family’s produce stand at the local farmer’s market. Her exposure to soil and soil pathogens may have been the source of the P fluorescens infection.

This case introduces P fluorescens as a causative agent of EG, suggests that exposure to agricultural products may predispose an immunosuppressed patient to this type of infection, and emphasizes the importance of timely diagnosis through tissue culture and histopathology so that immunosuppressive medications can be withheld and appropriate antibiotics can be initiated.

To the Editor:

A 50-year-old female farmer with diabetes mellitus, paroxysmal atrial fibrillation, and treatment-refractory systemic lupus erythematosus presented with worsening erythema, ecchymoses, edema, and tenderness in the bilateral legs of 3 weeks’ duration. The patient was taking oral methylprednisolone 12 mg daily (8 mg in the morning, 4 mg in the evening) for systemic lupus erythematosus. She previously was treated with mycophenolate mofetil, mycophenolic acid, methotrexate, azathioprine, hydroxychloroquine, etanercept, and cyclosporine without success. Cyclophosphamide was helpful in the past, but the last dose was more than 1 year prior to the current presentation. Physical examination showed no fever and 1+ pitting edema to the mid shin. Multiple warm, tender, erythematous to gray plaques were present on the bilateral lower extremities, and a 2-cm ulcerated plaque with a violaceous border was present on the medial surface of the lower left leg (Figure 1). The surrounding erythematous tissue was markedly tender to palpation. No popliteal or inguinal lymphadenopathy was appreciated.

Punch biopsies were obtained from the periphery and center of the ulcerated plaque on the left leg. Histopathologic analysis revealed an ulcerated necrotic epidermis with scant diffuse acute and chronic inflammation (Figure 2A). Leukocytoclastic vasculitis was present at the periphery of the lesion (Figure 2B). Colloidal iron stain revealed a marked increase in dermal mucin. Gram stain showed both gram-positive and gram-negative organisms (Figure 2C). Fungal and hyphal elements were seen in the superficial epidermis. Tissue cultures revealed a predominance of Pseudomonas fluorescens, along with Candida albicans, Klebsiella oxytoca, and Staphylococcus and Enterococcus species. Bacterial and fungal blood cultures were negative.

The patient was treated with ciprofloxacin, vancomycin, and voriconazole based on culture sensitivities. Although double coverage often is recommended for pseudomonal infections,¹ the patient could not be started on a second antipseudomonal agent due to multiple severe antibiotic allergies. She continued home administration of methylprednisolone in the setting of active lupus; additional immunosuppression was avoided. Over the course of 1 week, the patient’s preexisting ulcerated plaque on the medial surface of the lower left leg gradually improved, and no new lesions developed. Ciprofloxacin, vancomycin, and voriconazole were continued along with insulin, aspirin, warfarin, metoprolol, furosemide, and bumetanide at discharge. The patient subsequently was readmitted to the hospital several more times over the next 4 months for multiple bacterial infections and ultimately died of overwhelming septic shock several months later.

Ecthyma gangrenosum (EG) is a rare cutaneous infection that results from either direct inoculation or hematogenous dissemination. It classically is caused by infection with Pseudomonas aeruginosa in immunocompromised or neutropenic patients. However, other bacteria and fungi, mucormycosis, and herpes simplex virus also have been reported to cause EG.¹ Skin lesions often start as erythematous or purpuric macules, develop into vesicles and bullae, and eventually become necrotic ulcers with central eschars.² Histopathologic findings reveal necrotizing hemorrhagic vasculitis; gram-negative rods often are found in the medial and adventitial walls of deeper vessels.^3,4 The case mortality rate is high, ranging from 15% in nonbacteremic patients to 38% to 96% in patients with bacteremia.³

The leukocytoclastic vasculitis seen on biopsy in our patient was a reaction pattern, likely a direct result of the soft tissue infection. Biopsy showed hyphal or pseudohyphal elements in the superficial epidermis, corresponding to the positive C albicans growth on fungal culture. Candida albicans has been reported to cause lesions that mimic bacterial EG.¹ However, the marked predominance of P fluorescens on biopsy and culture suggests that the Candida likely were opportunistic and managed to invade secondary to the vascular damage caused by P fluorescens.

Pseudomonas fluorescens is an aerobic gram-negative rod-shaped bacterium found in soil that rarely is implicated in human disease. This bacterium is unable to ferment lactose and grows best on MacConkey agar between 30°C and 37°C but also can grow at temperatures as low as 4°C.⁵ The ability of P fluorescens to rapidly proliferate at low temperatures (ie, in refrigerated blood products, saline solutions, water dispensers, ice baths, humidifier water) is thought to explain a number of reported clinical consequences, ranging from asymptomatic colonization to fatal bacteremia.^6-10 This opportunistic pathogen also has been linked to Crohn disease and has been reported to cause pelvic inflammatory disease with the use of intrauterine contraception devices and nosocomial respiratory tract infections due to contaminated spirometers.^11-14 In our case, the patient was part of a family of farmers and worked in an agricultural setting. She often handled the produce and worked at the family’s produce stand at the local farmer’s market. Her exposure to soil and soil pathogens may have been the source of the P fluorescens infection.

This case introduces P fluorescens as a causative agent of EG, suggests that exposure to agricultural products may predispose an immunosuppressed patient to this type of infection, and emphasizes the importance of timely diagnosis through tissue culture and histopathology so that immunosuppressive medications can be withheld and appropriate antibiotics can be initiated.

To the Editor:

A 38-year-old woman was diagnosed with common variable immune deficiency (CVID) by an immunologist at an outside institution 1 year prior to the current presentation. The diagnosis was based on history of severe recurrent sinopulmonary tract, inner ear, Clostridium difficile, urinary tract, and herpes zoster infections of approximately 6 years’ duration, as well as persistently low IgG, IgA, and IgM levels of 530 mg/dL (reference range, 690–1400 mg/dL), 29 mg/dL (reference range, 88–410 mg/dL), and 30 mg/dL (reference range, 34–210 mg/dL), respectively, with failure to respond to vaccinations (ie, Haemophilus influenzae type B, Streptococcus pneumoniae, diphtheria IgG antibody, tetanus antibody). She was started on replacement intravenous immunoglobulin (IVIG) 40 g monthly (400 mg/kg) for CVID. She had a family history of CVID diagnosed in her son and sister.

One year after the CVID diagnosis, she was diagnosed with Sweet syndrome (SS) by a physician at our institution via biopsy of a lesion on the left arm (Figure 1) that showed dense dermal infiltrate of neutrophils with scattered background apoptotic nuclear debris without evidence of vasculitis (Figure 2). Gram stain and microbial biopsy cultures were negative for mycobacterial, fungal, and bacterial organisms. Cutaneous lesions failed to respond to courses of intravenous antibiotics. Sarcoidosis workup was unremarkable and was pursued to exclude the association with SS. Other negative testing included antinuclear antibody, human immunodeficiency virus, rheumatoid factor, thyroid-stimulating hormone, Ro and La autoantibodies, cytoplasmic antineutrophil cytoplasmic antibody, perinuclear antineutrophil cytoplasmic antibody, antimitochondrial antibody, and urinalysis. Occult malignancy was excluded with negative bone marrow biopsy; cerebrospinal fluid analysis; esophagogastroduodenoscopy; colonoscopy; and computed tomography of the chest, abdomen, and pelvis.

Sweet syndrome flares in this patient began with a prodromal syndrome of fever, chills, fatigue, diarrhea, and severe local neuropathic pain. Cutaneous lesions erupted 2 days later, most frequently on the arms and fingers. Preemptive treatment with prednisone 30 to 40 mg when the prodrome was present did not arrest cutaneous lesion development. Flares initially occurred every 3 to 5 weeks.

She initially was successfully treated with high-dose prednisone 100 mg daily during SS flares. Prolonged low-dose prednisone maintenance (10–20 mg) and hydroxychloroquine failed to control her frequent exacerbations. Dapsone was intolerable secondary to an adverse reaction. She continued to have frequent exacerbations of the SS requiring hospitalizations.

During SS flares, CVID was stable with infrequent systemic infections. Although a causal relationship between CVID and SS was unclear, an empiric increase in IVIG dose was made by her immunologist to test if it would decrease the frequency of the cutaneous flares. Subsequently, the IVIG dose was increased to 60 g monthly followed by 200 g monthly after approximately 4 months with a partial initial response in the beginning of therapy for the first 6 months. However, episodes resumed with increasing frequency with cutaneous lesion flares every 2 to 3 weeks. In a 3-month period, the patient had at least 4 hospitalizations for SS flares. Finally, 18 months after the diagnosis of SS was made, she was started on metronomic cyclophosphamide at a daily oral dose of 100 mg, later reduced to 50 mg daily after she developed mild neutropenia. She was continued on monthly IVIG replacement at a higher dose of 200 g divided over 2 days for CVID throughout the course of the disease and to the present time. Since then, the frequency of SS flares has notably reduced. She required 1 hospitalization after cyclophosphamide was initiated. She uses short-pulse prednisone (1 mg/kg) for 3 to 5 days when new skin lesions appear in addition to cyclophosphamide.

Common variable immune deficiency, the most common primary immunodeficiency, initially can present in adulthood.^1,2 Its hallmarks include low levels of serum immunoglobulin, most notably IgG with most patients having concurrent deficiencies of IgA and IgM, and impaired antibody responses with recurrent or atypical infections. It has been associated with autoimmune diseases, granulomatous disease, and inflammatory disorders.² Failure to mount protective levels of antibody titer after vaccination demonstrates the deficiency of antibody production.¹ Lack of recognition of this clinical spectrum may lead to delayed diagnosis and more importantly stalls the initiation of immunoglobulin replacement therapy.¹ The customary dose of immunoglobulin replacement is 400 mg/kg given in a single monthly infusion²; however, doses should be individualized and based on clinical response.¹

 

Sweet syndrome is characterized by the constellation of pyrexia; leukocytosis; and eruption of painful, edematous, dermal, and neutrophil-dense plaques that occur in the setting of infection or malignancy or are drug induced.^3,4 Although not fully elucidated, the pathogenesis is thought to involve the effects of cytokines that precipitate neutrophil activation and infiltration inducing a hypersensitivity reaction and escalation of the immunologic cascade.³ Because SS can represent a paraneoplastic phenomenon or a dermal manifestation of a solid neoplasm or hematologic dyscrasia, it is important to rule out occult malignancy.³ The mainstay of treatment is systemic corticosteroids to which classical SS lesions readily respond. Alternatively, topical or intralesional corticosteroids may be used as adjuvant therapy. Alternate first-line treatments include potassium iodide and colchicine. Second-line therapies include indomethacin, cyclosporine, dapsone, and other immunosuppressive agents.⁵ The lesions may become superinfected with bacterial pathogens requiring antimicrobials.³ Spontaneous resolution seldom occurs. The risk for relapse is lifelong following spontaneous or therapy-induced clinical remission.³ There is a growing body of literature of SS-associated conditions.

Common variable immune deficiency is a collection of disorders resulting in antibody deficiency and recurrent infections.⁶ Despite the humeral defects in CVID, patients paradoxically may develop various autoimmune, hematologic, and inflammatory disorders.⁷ Sweet syndrome, first described in 1964, is a constellation of fever, neutrophilia, and neutrophilic dermatosis of unknown pathogenesis.⁸ Copresentation of CVID and SS has not been commonly reported. O’Regan et al⁸ described a 17-year-old adolescent boy with both SS and CVID but SS preceded the diagnosis of CVID. In our case, the patient presented with CVID first and then manifested SS 1 year later.

Common variable immune deficiency is the most frequent symptomatic primary immunodeficiency in adults. Because adults with CVID have varied manifestations, CVID is thought to be late-onset antibody failure. The genetic basis of these disorders has not been identified in the majority of individuals. More than 100 genetic defects have been ascribed to primary immunodeficiencies,⁹ though none are consistently found to be associated with CVID. The majority of CVID cases are sporadic, but the positive family history in our patient suggests a familial form. Approximately 10% to 20% of patients have an identified heritable cause of CVID.¹⁰ Our patient’s diagnosis of CVID was confirmed by meeting the diagnostic triad set by the European Society for Immunodeficiencies¹¹ of marked reduction of IgG and IgA or IgM plus onset after 2 years of age, recurrent infections, and defective vaccination response. Additional complications including autoimmunity, malignancy, and granulomatous inflammation were extensively ruled out.

The etiology of SS is unknown and its pathogenesis not fully elucidated, though it is presumed to be a hypersensitivity reaction.¹² Sweet syndrome can be classified into 3 major subtypes: classical or idiopathic, malignancy associated, or drug induced.³ Our patient’s presentation is consistent with the classical variant, as malignancy was ruled out and the patient was not on any medication other than IVIG at the time of diagnosis. The treatment of SS consists of systemic steroids, initially high dose followed by a prolonged taper over 4 to 6 weeks.³ This treatment causes a pronounced and sustained decrease in serum IgG due to increased catabolism during drug administration and decreased synthesis during and for a variable time after drug administration.¹³ In refractory cases, intravenous pulse administration of methylprednisolone sodium succinate for 3 to 5 days may enhance the response to standard therapies.⁵

The concurrent development of neutrophilic dermatoses/SS in an individual with CVID has not been fully described. There is a credible association of SS with infections, inflammatory bowel disease, pregnancy, malignancy, and medications, as well as a possible association with Behçet disease, erythema nodosum, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, and thyroid disease.⁵ The association between immunoglobulin deficiencies and SS is markedly unusual. Despite regular IVIG replacement, adequate treatment of CVID did not seem to modulate SS flares in our patient. A case report in a pediatric patient does not provide specific guidance regarding treatment options.⁸

A particularly challenging aspect of our case was tailoring a treatment regimen to suppress SS flares. We have attained partial response to the refractory cutaneous lesions (decreased frequency and amplitude of outbreaks) with IVIG replacement 200 g every 4 weeks in combination with metronomic cyclophosphamide 50 mg daily (use of a repetitive, low-dose daily chemotherapy regimen to minimize side effects). Intermittent SS flares were managed acutely with pulse high-dose steroids. We report a case of SS with CVID, raising the plausibility of correlated pathogenesis. However, the exact mechanisms remain undefined.

To the Editor:

A 38-year-old woman was diagnosed with common variable immune deficiency (CVID) by an immunologist at an outside institution 1 year prior to the current presentation. The diagnosis was based on history of severe recurrent sinopulmonary tract, inner ear, Clostridium difficile, urinary tract, and herpes zoster infections of approximately 6 years’ duration, as well as persistently low IgG, IgA, and IgM levels of 530 mg/dL (reference range, 690–1400 mg/dL), 29 mg/dL (reference range, 88–410 mg/dL), and 30 mg/dL (reference range, 34–210 mg/dL), respectively, with failure to respond to vaccinations (ie, Haemophilus influenzae type B, Streptococcus pneumoniae, diphtheria IgG antibody, tetanus antibody). She was started on replacement intravenous immunoglobulin (IVIG) 40 g monthly (400 mg/kg) for CVID. She had a family history of CVID diagnosed in her son and sister.

One year after the CVID diagnosis, she was diagnosed with Sweet syndrome (SS) by a physician at our institution via biopsy of a lesion on the left arm (Figure 1) that showed dense dermal infiltrate of neutrophils with scattered background apoptotic nuclear debris without evidence of vasculitis (Figure 2). Gram stain and microbial biopsy cultures were negative for mycobacterial, fungal, and bacterial organisms. Cutaneous lesions failed to respond to courses of intravenous antibiotics. Sarcoidosis workup was unremarkable and was pursued to exclude the association with SS. Other negative testing included antinuclear antibody, human immunodeficiency virus, rheumatoid factor, thyroid-stimulating hormone, Ro and La autoantibodies, cytoplasmic antineutrophil cytoplasmic antibody, perinuclear antineutrophil cytoplasmic antibody, antimitochondrial antibody, and urinalysis. Occult malignancy was excluded with negative bone marrow biopsy; cerebrospinal fluid analysis; esophagogastroduodenoscopy; colonoscopy; and computed tomography of the chest, abdomen, and pelvis.

Sweet syndrome flares in this patient began with a prodromal syndrome of fever, chills, fatigue, diarrhea, and severe local neuropathic pain. Cutaneous lesions erupted 2 days later, most frequently on the arms and fingers. Preemptive treatment with prednisone 30 to 40 mg when the prodrome was present did not arrest cutaneous lesion development. Flares initially occurred every 3 to 5 weeks.

She initially was successfully treated with high-dose prednisone 100 mg daily during SS flares. Prolonged low-dose prednisone maintenance (10–20 mg) and hydroxychloroquine failed to control her frequent exacerbations. Dapsone was intolerable secondary to an adverse reaction. She continued to have frequent exacerbations of the SS requiring hospitalizations.

During SS flares, CVID was stable with infrequent systemic infections. Although a causal relationship between CVID and SS was unclear, an empiric increase in IVIG dose was made by her immunologist to test if it would decrease the frequency of the cutaneous flares. Subsequently, the IVIG dose was increased to 60 g monthly followed by 200 g monthly after approximately 4 months with a partial initial response in the beginning of therapy for the first 6 months. However, episodes resumed with increasing frequency with cutaneous lesion flares every 2 to 3 weeks. In a 3-month period, the patient had at least 4 hospitalizations for SS flares. Finally, 18 months after the diagnosis of SS was made, she was started on metronomic cyclophosphamide at a daily oral dose of 100 mg, later reduced to 50 mg daily after she developed mild neutropenia. She was continued on monthly IVIG replacement at a higher dose of 200 g divided over 2 days for CVID throughout the course of the disease and to the present time. Since then, the frequency of SS flares has notably reduced. She required 1 hospitalization after cyclophosphamide was initiated. She uses short-pulse prednisone (1 mg/kg) for 3 to 5 days when new skin lesions appear in addition to cyclophosphamide.

Common variable immune deficiency, the most common primary immunodeficiency, initially can present in adulthood.^1,2 Its hallmarks include low levels of serum immunoglobulin, most notably IgG with most patients having concurrent deficiencies of IgA and IgM, and impaired antibody responses with recurrent or atypical infections. It has been associated with autoimmune diseases, granulomatous disease, and inflammatory disorders.² Failure to mount protective levels of antibody titer after vaccination demonstrates the deficiency of antibody production.¹ Lack of recognition of this clinical spectrum may lead to delayed diagnosis and more importantly stalls the initiation of immunoglobulin replacement therapy.¹ The customary dose of immunoglobulin replacement is 400 mg/kg given in a single monthly infusion²; however, doses should be individualized and based on clinical response.¹

 

Sweet syndrome is characterized by the constellation of pyrexia; leukocytosis; and eruption of painful, edematous, dermal, and neutrophil-dense plaques that occur in the setting of infection or malignancy or are drug induced.^3,4 Although not fully elucidated, the pathogenesis is thought to involve the effects of cytokines that precipitate neutrophil activation and infiltration inducing a hypersensitivity reaction and escalation of the immunologic cascade.³ Because SS can represent a paraneoplastic phenomenon or a dermal manifestation of a solid neoplasm or hematologic dyscrasia, it is important to rule out occult malignancy.³ The mainstay of treatment is systemic corticosteroids to which classical SS lesions readily respond. Alternatively, topical or intralesional corticosteroids may be used as adjuvant therapy. Alternate first-line treatments include potassium iodide and colchicine. Second-line therapies include indomethacin, cyclosporine, dapsone, and other immunosuppressive agents.⁵ The lesions may become superinfected with bacterial pathogens requiring antimicrobials.³ Spontaneous resolution seldom occurs. The risk for relapse is lifelong following spontaneous or therapy-induced clinical remission.³ There is a growing body of literature of SS-associated conditions.

Common variable immune deficiency is a collection of disorders resulting in antibody deficiency and recurrent infections.⁶ Despite the humeral defects in CVID, patients paradoxically may develop various autoimmune, hematologic, and inflammatory disorders.⁷ Sweet syndrome, first described in 1964, is a constellation of fever, neutrophilia, and neutrophilic dermatosis of unknown pathogenesis.⁸ Copresentation of CVID and SS has not been commonly reported. O’Regan et al⁸ described a 17-year-old adolescent boy with both SS and CVID but SS preceded the diagnosis of CVID. In our case, the patient presented with CVID first and then manifested SS 1 year later.

Common variable immune deficiency is the most frequent symptomatic primary immunodeficiency in adults. Because adults with CVID have varied manifestations, CVID is thought to be late-onset antibody failure. The genetic basis of these disorders has not been identified in the majority of individuals. More than 100 genetic defects have been ascribed to primary immunodeficiencies,⁹ though none are consistently found to be associated with CVID. The majority of CVID cases are sporadic, but the positive family history in our patient suggests a familial form. Approximately 10% to 20% of patients have an identified heritable cause of CVID.¹⁰ Our patient’s diagnosis of CVID was confirmed by meeting the diagnostic triad set by the European Society for Immunodeficiencies¹¹ of marked reduction of IgG and IgA or IgM plus onset after 2 years of age, recurrent infections, and defective vaccination response. Additional complications including autoimmunity, malignancy, and granulomatous inflammation were extensively ruled out.

The etiology of SS is unknown and its pathogenesis not fully elucidated, though it is presumed to be a hypersensitivity reaction.¹² Sweet syndrome can be classified into 3 major subtypes: classical or idiopathic, malignancy associated, or drug induced.³ Our patient’s presentation is consistent with the classical variant, as malignancy was ruled out and the patient was not on any medication other than IVIG at the time of diagnosis. The treatment of SS consists of systemic steroids, initially high dose followed by a prolonged taper over 4 to 6 weeks.³ This treatment causes a pronounced and sustained decrease in serum IgG due to increased catabolism during drug administration and decreased synthesis during and for a variable time after drug administration.¹³ In refractory cases, intravenous pulse administration of methylprednisolone sodium succinate for 3 to 5 days may enhance the response to standard therapies.⁵

The concurrent development of neutrophilic dermatoses/SS in an individual with CVID has not been fully described. There is a credible association of SS with infections, inflammatory bowel disease, pregnancy, malignancy, and medications, as well as a possible association with Behçet disease, erythema nodosum, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, and thyroid disease.⁵ The association between immunoglobulin deficiencies and SS is markedly unusual. Despite regular IVIG replacement, adequate treatment of CVID did not seem to modulate SS flares in our patient. A case report in a pediatric patient does not provide specific guidance regarding treatment options.⁸

A particularly challenging aspect of our case was tailoring a treatment regimen to suppress SS flares. We have attained partial response to the refractory cutaneous lesions (decreased frequency and amplitude of outbreaks) with IVIG replacement 200 g every 4 weeks in combination with metronomic cyclophosphamide 50 mg daily (use of a repetitive, low-dose daily chemotherapy regimen to minimize side effects). Intermittent SS flares were managed acutely with pulse high-dose steroids. We report a case of SS with CVID, raising the plausibility of correlated pathogenesis. However, the exact mechanisms remain undefined.

To the Editor:

A 38-year-old woman was diagnosed with common variable immune deficiency (CVID) by an immunologist at an outside institution 1 year prior to the current presentation. The diagnosis was based on history of severe recurrent sinopulmonary tract, inner ear, Clostridium difficile, urinary tract, and herpes zoster infections of approximately 6 years’ duration, as well as persistently low IgG, IgA, and IgM levels of 530 mg/dL (reference range, 690–1400 mg/dL), 29 mg/dL (reference range, 88–410 mg/dL), and 30 mg/dL (reference range, 34–210 mg/dL), respectively, with failure to respond to vaccinations (ie, Haemophilus influenzae type B, Streptococcus pneumoniae, diphtheria IgG antibody, tetanus antibody). She was started on replacement intravenous immunoglobulin (IVIG) 40 g monthly (400 mg/kg) for CVID. She had a family history of CVID diagnosed in her son and sister.

One year after the CVID diagnosis, she was diagnosed with Sweet syndrome (SS) by a physician at our institution via biopsy of a lesion on the left arm (Figure 1) that showed dense dermal infiltrate of neutrophils with scattered background apoptotic nuclear debris without evidence of vasculitis (Figure 2). Gram stain and microbial biopsy cultures were negative for mycobacterial, fungal, and bacterial organisms. Cutaneous lesions failed to respond to courses of intravenous antibiotics. Sarcoidosis workup was unremarkable and was pursued to exclude the association with SS. Other negative testing included antinuclear antibody, human immunodeficiency virus, rheumatoid factor, thyroid-stimulating hormone, Ro and La autoantibodies, cytoplasmic antineutrophil cytoplasmic antibody, perinuclear antineutrophil cytoplasmic antibody, antimitochondrial antibody, and urinalysis. Occult malignancy was excluded with negative bone marrow biopsy; cerebrospinal fluid analysis; esophagogastroduodenoscopy; colonoscopy; and computed tomography of the chest, abdomen, and pelvis.

Sweet syndrome flares in this patient began with a prodromal syndrome of fever, chills, fatigue, diarrhea, and severe local neuropathic pain. Cutaneous lesions erupted 2 days later, most frequently on the arms and fingers. Preemptive treatment with prednisone 30 to 40 mg when the prodrome was present did not arrest cutaneous lesion development. Flares initially occurred every 3 to 5 weeks.

She initially was successfully treated with high-dose prednisone 100 mg daily during SS flares. Prolonged low-dose prednisone maintenance (10–20 mg) and hydroxychloroquine failed to control her frequent exacerbations. Dapsone was intolerable secondary to an adverse reaction. She continued to have frequent exacerbations of the SS requiring hospitalizations.

During SS flares, CVID was stable with infrequent systemic infections. Although a causal relationship between CVID and SS was unclear, an empiric increase in IVIG dose was made by her immunologist to test if it would decrease the frequency of the cutaneous flares. Subsequently, the IVIG dose was increased to 60 g monthly followed by 200 g monthly after approximately 4 months with a partial initial response in the beginning of therapy for the first 6 months. However, episodes resumed with increasing frequency with cutaneous lesion flares every 2 to 3 weeks. In a 3-month period, the patient had at least 4 hospitalizations for SS flares. Finally, 18 months after the diagnosis of SS was made, she was started on metronomic cyclophosphamide at a daily oral dose of 100 mg, later reduced to 50 mg daily after she developed mild neutropenia. She was continued on monthly IVIG replacement at a higher dose of 200 g divided over 2 days for CVID throughout the course of the disease and to the present time. Since then, the frequency of SS flares has notably reduced. She required 1 hospitalization after cyclophosphamide was initiated. She uses short-pulse prednisone (1 mg/kg) for 3 to 5 days when new skin lesions appear in addition to cyclophosphamide.

Common variable immune deficiency, the most common primary immunodeficiency, initially can present in adulthood.^1,2 Its hallmarks include low levels of serum immunoglobulin, most notably IgG with most patients having concurrent deficiencies of IgA and IgM, and impaired antibody responses with recurrent or atypical infections. It has been associated with autoimmune diseases, granulomatous disease, and inflammatory disorders.² Failure to mount protective levels of antibody titer after vaccination demonstrates the deficiency of antibody production.¹ Lack of recognition of this clinical spectrum may lead to delayed diagnosis and more importantly stalls the initiation of immunoglobulin replacement therapy.¹ The customary dose of immunoglobulin replacement is 400 mg/kg given in a single monthly infusion²; however, doses should be individualized and based on clinical response.¹

 

Sweet syndrome is characterized by the constellation of pyrexia; leukocytosis; and eruption of painful, edematous, dermal, and neutrophil-dense plaques that occur in the setting of infection or malignancy or are drug induced.^3,4 Although not fully elucidated, the pathogenesis is thought to involve the effects of cytokines that precipitate neutrophil activation and infiltration inducing a hypersensitivity reaction and escalation of the immunologic cascade.³ Because SS can represent a paraneoplastic phenomenon or a dermal manifestation of a solid neoplasm or hematologic dyscrasia, it is important to rule out occult malignancy.³ The mainstay of treatment is systemic corticosteroids to which classical SS lesions readily respond. Alternatively, topical or intralesional corticosteroids may be used as adjuvant therapy. Alternate first-line treatments include potassium iodide and colchicine. Second-line therapies include indomethacin, cyclosporine, dapsone, and other immunosuppressive agents.⁵ The lesions may become superinfected with bacterial pathogens requiring antimicrobials.³ Spontaneous resolution seldom occurs. The risk for relapse is lifelong following spontaneous or therapy-induced clinical remission.³ There is a growing body of literature of SS-associated conditions.

Common variable immune deficiency is a collection of disorders resulting in antibody deficiency and recurrent infections.⁶ Despite the humeral defects in CVID, patients paradoxically may develop various autoimmune, hematologic, and inflammatory disorders.⁷ Sweet syndrome, first described in 1964, is a constellation of fever, neutrophilia, and neutrophilic dermatosis of unknown pathogenesis.⁸ Copresentation of CVID and SS has not been commonly reported. O’Regan et al⁸ described a 17-year-old adolescent boy with both SS and CVID but SS preceded the diagnosis of CVID. In our case, the patient presented with CVID first and then manifested SS 1 year later.

Common variable immune deficiency is the most frequent symptomatic primary immunodeficiency in adults. Because adults with CVID have varied manifestations, CVID is thought to be late-onset antibody failure. The genetic basis of these disorders has not been identified in the majority of individuals. More than 100 genetic defects have been ascribed to primary immunodeficiencies,⁹ though none are consistently found to be associated with CVID. The majority of CVID cases are sporadic, but the positive family history in our patient suggests a familial form. Approximately 10% to 20% of patients have an identified heritable cause of CVID.¹⁰ Our patient’s diagnosis of CVID was confirmed by meeting the diagnostic triad set by the European Society for Immunodeficiencies¹¹ of marked reduction of IgG and IgA or IgM plus onset after 2 years of age, recurrent infections, and defective vaccination response. Additional complications including autoimmunity, malignancy, and granulomatous inflammation were extensively ruled out.

The etiology of SS is unknown and its pathogenesis not fully elucidated, though it is presumed to be a hypersensitivity reaction.¹² Sweet syndrome can be classified into 3 major subtypes: classical or idiopathic, malignancy associated, or drug induced.³ Our patient’s presentation is consistent with the classical variant, as malignancy was ruled out and the patient was not on any medication other than IVIG at the time of diagnosis. The treatment of SS consists of systemic steroids, initially high dose followed by a prolonged taper over 4 to 6 weeks.³ This treatment causes a pronounced and sustained decrease in serum IgG due to increased catabolism during drug administration and decreased synthesis during and for a variable time after drug administration.¹³ In refractory cases, intravenous pulse administration of methylprednisolone sodium succinate for 3 to 5 days may enhance the response to standard therapies.⁵

The concurrent development of neutrophilic dermatoses/SS in an individual with CVID has not been fully described. There is a credible association of SS with infections, inflammatory bowel disease, pregnancy, malignancy, and medications, as well as a possible association with Behçet disease, erythema nodosum, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, and thyroid disease.⁵ The association between immunoglobulin deficiencies and SS is markedly unusual. Despite regular IVIG replacement, adequate treatment of CVID did not seem to modulate SS flares in our patient. A case report in a pediatric patient does not provide specific guidance regarding treatment options.⁸

A particularly challenging aspect of our case was tailoring a treatment regimen to suppress SS flares. We have attained partial response to the refractory cutaneous lesions (decreased frequency and amplitude of outbreaks) with IVIG replacement 200 g every 4 weeks in combination with metronomic cyclophosphamide 50 mg daily (use of a repetitive, low-dose daily chemotherapy regimen to minimize side effects). Intermittent SS flares were managed acutely with pulse high-dose steroids. We report a case of SS with CVID, raising the plausibility of correlated pathogenesis. However, the exact mechanisms remain undefined.