Dermatopathology

THE DIAGNOSIS: White Fibrous Papulosis

Given the histopathology findings, location on a sun-exposed site, lack of any additional systemic signs or symptoms, and no family history of similar lesions to suggest an underlying genetic condition, a diagnosis of white fibrous papulosis (WFP) was made. White fibrous papulosis is a relatively rare cutaneous disorder that was first reported by Shimizu et al¹ in 1985. It is characterized by numerous grouped, 2- to 3-mm, white to flesh-colored papules that in most cases are confined to the neck in middle-aged to elderly individuals; however, cases involving the upper trunk and axillae also have been reported.^1-3 The etiology of this condition is unclear but is thought to be related to aging and chronic exposure to UV light. Although treatment is not required, various modalities including tretinoin, excision, and laser therapy have been trialed with varying success.^2,4 Our patient elected not to proceed with treatment.

Histologically, WFP may manifest similarly to connective tissue nevi; the overall architecture is nonspecific with focally thickened collagen and often elastic fibers that may be normal to reduced and/or fragmented, as well as an overall decrease in superficial dermal elastic tissue.^3,5 Therefore, the differential diagnosis may include connective tissue nevi and require clinical correlation to make a correct diagnosis.

Pseudoxanthoma elasticum (PXE) is an autosomalrecessive disorder most commonly related to mutations in the ATP binding cassette subfamily C member 6 (ABCC6) gene that tends to manifest clinically on the neck and flexural extremities.⁶ This disease affects elastic fibers, which may become calcified over time. Pseudoxanthoma elasticum is associated with ocular complications relating to the Bruch membrane of the retina and angioid streaks; choroidal neovascularization involving the damaged Bruch membrane and episodes of acute retinopathy may result in vision loss in later stages of the disease.⁷ Involvement of the elastic laminae of arteries can be associated with cardiovascular and cerebrovascular complications such as stroke, coronary artery disease, claudication, and aneurysms. Involvement of the gastrointestinal or genitourinary tracts also may occur and most commonly manifests with bleeding. Pathologic alterations in the elastic fibers of the lungs also have been reported in patients with PXE.⁸ Histologically, PXE exhibits increased abnormally clumped and fragmented elastic fibers in the superficial dermis, often with calcification (Figure 1). Pseudo-PXE related to D-penicillamine use often lacks calcification and has a bramble bush appearance.⁹

Fibrofolliculomas may manifest alone or in association with an underlying condition such as Birt-Hogg-Dubé syndrome, in which lesions are most frequently seen scattered on the scalp, face, ears, neck, or upper trunk.¹⁰ This condition is related to a folliculin (FLCN) gene germline mutation. Birt-Hogg-Dubé syndrome also may be associated with acrochordons, trichodiscomas, renal cancer, and lung cysts with or without spontaneous pneumothorax. Less frequently noted findings include oral papules, epidermal cysts, angiofibromas, lipomas/angiolipomas, parotid gland tumors, and thyroid neoplasms. Connective tissue nevi/collagenomas can appear clinically similar to fibrofolliculomas; true connective tissue nevi are reported less commonly in Birt-Hogg-Dubé syndrome.¹¹ Histologically, a fibrofolliculoma manifests with epidermal strands originating from a hair follicle associated with prominent surrounding connective tissue (Figure 2).

Elastofibroma dorsi is a benign tumor of connective tissue that most commonly manifests clinically as a solitary subcutaneous mass on the back near the inferior angle of the scapula; it typically develops below the rhomboid major and latissimus dorsi muscles.¹² The pathogenesis is uncertain, but some patients have reported a family history of the condition or a history of repetitive shoulder movement/trauma prior to onset; the mass may be asymptomatic or associated with pain and/or swelling. Those affected tend to be older than 50 years.¹³ Histologically, thickened and rounded to beaded elastic fibers are seen admixed with collagen (Figure 3).

Actinic (solar) elastosis frequently is encountered in many skin biopsies and is caused by chronic photodamage. More hypertrophic variants, such as papular or nodular solar elastosis, may clinically manifest similarly to WFP.¹⁴ Histologically, actinic elastosis manifests as a considerable increase in elastic tissue in the papillary and superficial reticular dermis (Figure 4).

THE DIAGNOSIS: White Fibrous Papulosis

Given the histopathology findings, location on a sun-exposed site, lack of any additional systemic signs or symptoms, and no family history of similar lesions to suggest an underlying genetic condition, a diagnosis of white fibrous papulosis (WFP) was made. White fibrous papulosis is a relatively rare cutaneous disorder that was first reported by Shimizu et al¹ in 1985. It is characterized by numerous grouped, 2- to 3-mm, white to flesh-colored papules that in most cases are confined to the neck in middle-aged to elderly individuals; however, cases involving the upper trunk and axillae also have been reported.^1-3 The etiology of this condition is unclear but is thought to be related to aging and chronic exposure to UV light. Although treatment is not required, various modalities including tretinoin, excision, and laser therapy have been trialed with varying success.^2,4 Our patient elected not to proceed with treatment.

Histologically, WFP may manifest similarly to connective tissue nevi; the overall architecture is nonspecific with focally thickened collagen and often elastic fibers that may be normal to reduced and/or fragmented, as well as an overall decrease in superficial dermal elastic tissue.^3,5 Therefore, the differential diagnosis may include connective tissue nevi and require clinical correlation to make a correct diagnosis.

Pseudoxanthoma elasticum (PXE) is an autosomalrecessive disorder most commonly related to mutations in the ATP binding cassette subfamily C member 6 (ABCC6) gene that tends to manifest clinically on the neck and flexural extremities.⁶ This disease affects elastic fibers, which may become calcified over time. Pseudoxanthoma elasticum is associated with ocular complications relating to the Bruch membrane of the retina and angioid streaks; choroidal neovascularization involving the damaged Bruch membrane and episodes of acute retinopathy may result in vision loss in later stages of the disease.⁷ Involvement of the elastic laminae of arteries can be associated with cardiovascular and cerebrovascular complications such as stroke, coronary artery disease, claudication, and aneurysms. Involvement of the gastrointestinal or genitourinary tracts also may occur and most commonly manifests with bleeding. Pathologic alterations in the elastic fibers of the lungs also have been reported in patients with PXE.⁸ Histologically, PXE exhibits increased abnormally clumped and fragmented elastic fibers in the superficial dermis, often with calcification (Figure 1). Pseudo-PXE related to D-penicillamine use often lacks calcification and has a bramble bush appearance.⁹

Fibrofolliculomas may manifest alone or in association with an underlying condition such as Birt-Hogg-Dubé syndrome, in which lesions are most frequently seen scattered on the scalp, face, ears, neck, or upper trunk.¹⁰ This condition is related to a folliculin (FLCN) gene germline mutation. Birt-Hogg-Dubé syndrome also may be associated with acrochordons, trichodiscomas, renal cancer, and lung cysts with or without spontaneous pneumothorax. Less frequently noted findings include oral papules, epidermal cysts, angiofibromas, lipomas/angiolipomas, parotid gland tumors, and thyroid neoplasms. Connective tissue nevi/collagenomas can appear clinically similar to fibrofolliculomas; true connective tissue nevi are reported less commonly in Birt-Hogg-Dubé syndrome.¹¹ Histologically, a fibrofolliculoma manifests with epidermal strands originating from a hair follicle associated with prominent surrounding connective tissue (Figure 2).

Elastofibroma dorsi is a benign tumor of connective tissue that most commonly manifests clinically as a solitary subcutaneous mass on the back near the inferior angle of the scapula; it typically develops below the rhomboid major and latissimus dorsi muscles.¹² The pathogenesis is uncertain, but some patients have reported a family history of the condition or a history of repetitive shoulder movement/trauma prior to onset; the mass may be asymptomatic or associated with pain and/or swelling. Those affected tend to be older than 50 years.¹³ Histologically, thickened and rounded to beaded elastic fibers are seen admixed with collagen (Figure 3).

Actinic (solar) elastosis frequently is encountered in many skin biopsies and is caused by chronic photodamage. More hypertrophic variants, such as papular or nodular solar elastosis, may clinically manifest similarly to WFP.¹⁴ Histologically, actinic elastosis manifests as a considerable increase in elastic tissue in the papillary and superficial reticular dermis (Figure 4).

THE DIAGNOSIS: White Fibrous Papulosis

Given the histopathology findings, location on a sun-exposed site, lack of any additional systemic signs or symptoms, and no family history of similar lesions to suggest an underlying genetic condition, a diagnosis of white fibrous papulosis (WFP) was made. White fibrous papulosis is a relatively rare cutaneous disorder that was first reported by Shimizu et al¹ in 1985. It is characterized by numerous grouped, 2- to 3-mm, white to flesh-colored papules that in most cases are confined to the neck in middle-aged to elderly individuals; however, cases involving the upper trunk and axillae also have been reported.^1-3 The etiology of this condition is unclear but is thought to be related to aging and chronic exposure to UV light. Although treatment is not required, various modalities including tretinoin, excision, and laser therapy have been trialed with varying success.^2,4 Our patient elected not to proceed with treatment.

Histologically, WFP may manifest similarly to connective tissue nevi; the overall architecture is nonspecific with focally thickened collagen and often elastic fibers that may be normal to reduced and/or fragmented, as well as an overall decrease in superficial dermal elastic tissue.^3,5 Therefore, the differential diagnosis may include connective tissue nevi and require clinical correlation to make a correct diagnosis.

Pseudoxanthoma elasticum (PXE) is an autosomalrecessive disorder most commonly related to mutations in the ATP binding cassette subfamily C member 6 (ABCC6) gene that tends to manifest clinically on the neck and flexural extremities.⁶ This disease affects elastic fibers, which may become calcified over time. Pseudoxanthoma elasticum is associated with ocular complications relating to the Bruch membrane of the retina and angioid streaks; choroidal neovascularization involving the damaged Bruch membrane and episodes of acute retinopathy may result in vision loss in later stages of the disease.⁷ Involvement of the elastic laminae of arteries can be associated with cardiovascular and cerebrovascular complications such as stroke, coronary artery disease, claudication, and aneurysms. Involvement of the gastrointestinal or genitourinary tracts also may occur and most commonly manifests with bleeding. Pathologic alterations in the elastic fibers of the lungs also have been reported in patients with PXE.⁸ Histologically, PXE exhibits increased abnormally clumped and fragmented elastic fibers in the superficial dermis, often with calcification (Figure 1). Pseudo-PXE related to D-penicillamine use often lacks calcification and has a bramble bush appearance.⁹

Fibrofolliculomas may manifest alone or in association with an underlying condition such as Birt-Hogg-Dubé syndrome, in which lesions are most frequently seen scattered on the scalp, face, ears, neck, or upper trunk.¹⁰ This condition is related to a folliculin (FLCN) gene germline mutation. Birt-Hogg-Dubé syndrome also may be associated with acrochordons, trichodiscomas, renal cancer, and lung cysts with or without spontaneous pneumothorax. Less frequently noted findings include oral papules, epidermal cysts, angiofibromas, lipomas/angiolipomas, parotid gland tumors, and thyroid neoplasms. Connective tissue nevi/collagenomas can appear clinically similar to fibrofolliculomas; true connective tissue nevi are reported less commonly in Birt-Hogg-Dubé syndrome.¹¹ Histologically, a fibrofolliculoma manifests with epidermal strands originating from a hair follicle associated with prominent surrounding connective tissue (Figure 2).

Elastofibroma dorsi is a benign tumor of connective tissue that most commonly manifests clinically as a solitary subcutaneous mass on the back near the inferior angle of the scapula; it typically develops below the rhomboid major and latissimus dorsi muscles.¹² The pathogenesis is uncertain, but some patients have reported a family history of the condition or a history of repetitive shoulder movement/trauma prior to onset; the mass may be asymptomatic or associated with pain and/or swelling. Those affected tend to be older than 50 years.¹³ Histologically, thickened and rounded to beaded elastic fibers are seen admixed with collagen (Figure 3).

Actinic (solar) elastosis frequently is encountered in many skin biopsies and is caused by chronic photodamage. More hypertrophic variants, such as papular or nodular solar elastosis, may clinically manifest similarly to WFP.¹⁴ Histologically, actinic elastosis manifests as a considerable increase in elastic tissue in the papillary and superficial reticular dermis (Figure 4).

THE DIAGNOSIS: Papular Acantholytic Dyskeratosis

Histopathology of the lesion in our patient revealed hyperkeratosis, parakeratosis, dyskeratosis, and acantholysis of keratinocytes. The dermis showed variable chronic inflammatory cells. Corps ronds and grains in the acantholytic layer of the epidermis were identified. Hair follicles were not affected by acantholysis. Anti–desmoglein 1 and anti–desmoglein 3 serum antibodies were negative. Based on the combined clinical and histologic findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD) of the genitocrural area.

Although its typical histopathologic pattern mimics both Hailey-Hailey disease and Darier disease, PAD is a rare unique clinicopathologic entity recognized by dermatopathologists. It usually occurs in middle-aged women with no family history of similar conditions. The multiple localized, flesh-colored to whitish papules of PAD tend to coalesce into plaques in the anogenital and genitocrural regions. Plaques usually are asymptomatic but may be pruritic. Histopathologically, PAD will demonstrate hyperkeratosis, dyskeratosis, and acantholysis. Corps ronds and grains will be present in the acantholytic layer of the epidermis.^1,2

The differential diagnosis for PAD includes pemphigus vegetans, Hailey-Hailey disease, Darier disease, and Grover disease. Patients usually develop pemphigus vegetans at an older age (typically 50–70 years).³ Histopathologically, it is characterized by pseudoepitheliomatous hyperplasia with an eosinophilic microabscess as well as acantholysis that involves the follicular epithelium (Figure 1),⁴ which were not seen in our patient. Direct immunofluorescence will show the intercellular pattern of the pemphigus group, and antidesmoglein antibodies can be detected by enzyme-linked immunosorbent assay.^4,5

Hailey-Hailey disease (also known as benign familial pemphigus) typically manifests as itchy malodorous vesicles and erosions, especially in intertriginous areas. The most commonly affected sites are the groin, neck, under the breasts, and between the buttocks. In one study, two-thirds of affected patients reported a relevant family history.⁴ Histopathology will show minimal dyskeratosis and suprabasilar acantholysis with loss of intercellular bridges, classically described as resembling a dilapidated brick wall (Figure 2).^4,5 There is no notable follicular involvement with acantholysis.⁴

Darier disease (also known as keratosis follicularis) typically is inherited in an autosomal-dominant pattern.⁴ It is found on the seborrheic areas such as the scalp, forehead, nasolabial folds, and upper chest. Characteristic features include distal notching of the nails, mucosal lesions, and palmoplantar papules. Histopathology will reveal acantholysis, dyskeratosis, suprabasilar acantholysis, and corps ronds and grains.⁴ Acantholysis in Darier disease can be in discrete foci and/or widespread (Figure 3).⁴ Darier disease demonstrates more dyskeratosis than Hailey-Hailey disease.^4,5

Grover disease (also referred to as transient acantholytic dermatosis) is observed predominantly in individuals who are middle-aged or older, though occurrence in children has been rarely reported.⁴ It affects the trunk, neck, and proximal limbs but spares the genital area. Histopathology may reveal acantholysis (similar to Hailey-Hailey disease or pemphigus vulgaris), dyskeratosis (resembling Darier disease), spongiosis, parakeratosis, and a superficial perivascular lymphocytic infiltrate with eosinophils.⁴ A histologic clue to the diagnosis is small lesion size (1–3 mm). Usually, only 1 or 2 small discrete lesions that span a few rete ridges are noted (Figure 4).⁴ Grover disease can cause follicular or acrosyringeal involvement.⁴

THE DIAGNOSIS: Papular Acantholytic Dyskeratosis

Histopathology of the lesion in our patient revealed hyperkeratosis, parakeratosis, dyskeratosis, and acantholysis of keratinocytes. The dermis showed variable chronic inflammatory cells. Corps ronds and grains in the acantholytic layer of the epidermis were identified. Hair follicles were not affected by acantholysis. Anti–desmoglein 1 and anti–desmoglein 3 serum antibodies were negative. Based on the combined clinical and histologic findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD) of the genitocrural area.

Although its typical histopathologic pattern mimics both Hailey-Hailey disease and Darier disease, PAD is a rare unique clinicopathologic entity recognized by dermatopathologists. It usually occurs in middle-aged women with no family history of similar conditions. The multiple localized, flesh-colored to whitish papules of PAD tend to coalesce into plaques in the anogenital and genitocrural regions. Plaques usually are asymptomatic but may be pruritic. Histopathologically, PAD will demonstrate hyperkeratosis, dyskeratosis, and acantholysis. Corps ronds and grains will be present in the acantholytic layer of the epidermis.^1,2

The differential diagnosis for PAD includes pemphigus vegetans, Hailey-Hailey disease, Darier disease, and Grover disease. Patients usually develop pemphigus vegetans at an older age (typically 50–70 years).³ Histopathologically, it is characterized by pseudoepitheliomatous hyperplasia with an eosinophilic microabscess as well as acantholysis that involves the follicular epithelium (Figure 1),⁴ which were not seen in our patient. Direct immunofluorescence will show the intercellular pattern of the pemphigus group, and antidesmoglein antibodies can be detected by enzyme-linked immunosorbent assay.^4,5

Hailey-Hailey disease (also known as benign familial pemphigus) typically manifests as itchy malodorous vesicles and erosions, especially in intertriginous areas. The most commonly affected sites are the groin, neck, under the breasts, and between the buttocks. In one study, two-thirds of affected patients reported a relevant family history.⁴ Histopathology will show minimal dyskeratosis and suprabasilar acantholysis with loss of intercellular bridges, classically described as resembling a dilapidated brick wall (Figure 2).^4,5 There is no notable follicular involvement with acantholysis.⁴

Darier disease (also known as keratosis follicularis) typically is inherited in an autosomal-dominant pattern.⁴ It is found on the seborrheic areas such as the scalp, forehead, nasolabial folds, and upper chest. Characteristic features include distal notching of the nails, mucosal lesions, and palmoplantar papules. Histopathology will reveal acantholysis, dyskeratosis, suprabasilar acantholysis, and corps ronds and grains.⁴ Acantholysis in Darier disease can be in discrete foci and/or widespread (Figure 3).⁴ Darier disease demonstrates more dyskeratosis than Hailey-Hailey disease.^4,5

Grover disease (also referred to as transient acantholytic dermatosis) is observed predominantly in individuals who are middle-aged or older, though occurrence in children has been rarely reported.⁴ It affects the trunk, neck, and proximal limbs but spares the genital area. Histopathology may reveal acantholysis (similar to Hailey-Hailey disease or pemphigus vulgaris), dyskeratosis (resembling Darier disease), spongiosis, parakeratosis, and a superficial perivascular lymphocytic infiltrate with eosinophils.⁴ A histologic clue to the diagnosis is small lesion size (1–3 mm). Usually, only 1 or 2 small discrete lesions that span a few rete ridges are noted (Figure 4).⁴ Grover disease can cause follicular or acrosyringeal involvement.⁴

THE DIAGNOSIS: Papular Acantholytic Dyskeratosis

Histopathology of the lesion in our patient revealed hyperkeratosis, parakeratosis, dyskeratosis, and acantholysis of keratinocytes. The dermis showed variable chronic inflammatory cells. Corps ronds and grains in the acantholytic layer of the epidermis were identified. Hair follicles were not affected by acantholysis. Anti–desmoglein 1 and anti–desmoglein 3 serum antibodies were negative. Based on the combined clinical and histologic findings, the patient was diagnosed with papular acantholytic dyskeratosis (PAD) of the genitocrural area.

Although its typical histopathologic pattern mimics both Hailey-Hailey disease and Darier disease, PAD is a rare unique clinicopathologic entity recognized by dermatopathologists. It usually occurs in middle-aged women with no family history of similar conditions. The multiple localized, flesh-colored to whitish papules of PAD tend to coalesce into plaques in the anogenital and genitocrural regions. Plaques usually are asymptomatic but may be pruritic. Histopathologically, PAD will demonstrate hyperkeratosis, dyskeratosis, and acantholysis. Corps ronds and grains will be present in the acantholytic layer of the epidermis.^1,2

The differential diagnosis for PAD includes pemphigus vegetans, Hailey-Hailey disease, Darier disease, and Grover disease. Patients usually develop pemphigus vegetans at an older age (typically 50–70 years).³ Histopathologically, it is characterized by pseudoepitheliomatous hyperplasia with an eosinophilic microabscess as well as acantholysis that involves the follicular epithelium (Figure 1),⁴ which were not seen in our patient. Direct immunofluorescence will show the intercellular pattern of the pemphigus group, and antidesmoglein antibodies can be detected by enzyme-linked immunosorbent assay.^4,5

Hailey-Hailey disease (also known as benign familial pemphigus) typically manifests as itchy malodorous vesicles and erosions, especially in intertriginous areas. The most commonly affected sites are the groin, neck, under the breasts, and between the buttocks. In one study, two-thirds of affected patients reported a relevant family history.⁴ Histopathology will show minimal dyskeratosis and suprabasilar acantholysis with loss of intercellular bridges, classically described as resembling a dilapidated brick wall (Figure 2).^4,5 There is no notable follicular involvement with acantholysis.⁴

Darier disease (also known as keratosis follicularis) typically is inherited in an autosomal-dominant pattern.⁴ It is found on the seborrheic areas such as the scalp, forehead, nasolabial folds, and upper chest. Characteristic features include distal notching of the nails, mucosal lesions, and palmoplantar papules. Histopathology will reveal acantholysis, dyskeratosis, suprabasilar acantholysis, and corps ronds and grains.⁴ Acantholysis in Darier disease can be in discrete foci and/or widespread (Figure 3).⁴ Darier disease demonstrates more dyskeratosis than Hailey-Hailey disease.^4,5

Grover disease (also referred to as transient acantholytic dermatosis) is observed predominantly in individuals who are middle-aged or older, though occurrence in children has been rarely reported.⁴ It affects the trunk, neck, and proximal limbs but spares the genital area. Histopathology may reveal acantholysis (similar to Hailey-Hailey disease or pemphigus vulgaris), dyskeratosis (resembling Darier disease), spongiosis, parakeratosis, and a superficial perivascular lymphocytic infiltrate with eosinophils.⁴ A histologic clue to the diagnosis is small lesion size (1–3 mm). Usually, only 1 or 2 small discrete lesions that span a few rete ridges are noted (Figure 4).⁴ Grover disease can cause follicular or acrosyringeal involvement.⁴

THE DIAGNOSIS: Dengue Hemorrhagic Fever

The retiform purpura observed in our patient was suggestive of a vasculitic, thrombotic, or embolic etiology. Dengue IgM serologic testing performed based on her extensive travel history and recent return from a dengue-endemic area was positive, indicating acute infection. A clinical diagnosis of dengue hemorrhagic fever (DHF) was made based on the hemorrhagic appearance of the lesion. Histopathology revealed leukocytoclastic vasculitis (Figure). Anti–double-stranded DNA, antideoxyribonuclease, C3 and C4, CH50 (total hemolytic complement), antineutrophil cytoplasmic antibodies, HIV, and hepatitis B virus tests were normal. Direct immunofluorescence was negative.

Dengue virus is a single-stranded RNA virus transmitted by Aedes aegypti and Aedes albopictus mosquitoes and is one of the most prevalent arthropod-borne viruses affecting humans today.^1,2 Infection with the dengue virus generally is seen in travelers visiting tropical regions of Africa, Mexico, South America, South and Central Asia, Southeast Asia, and the Caribbean.¹ The Table shows the global distribution of dengue serotypes from 2000 to 2014.^3,4 There are 4 serotypes of the dengue virus: DENV-1 to DENV-4. Infection with 1 strain elicits longlasting immunity to that strain, but subsequent infection with another strain can result in severe DHF due to antibody cross-reaction.¹

Dengue virus infection ranges from mildly symptomatic to a spectrum of increasingly severe conditions that comprise dengue fever (DF) and DHF, as well as dengue shock syndrome and brain stem hemorrhage, which may be fatal.^2,5 Dengue fever manifests as severe myalgia, fever, headache (usually retro-orbital), arthralgia, erythema, and rubelliform exanthema.⁶ The frequency of skin eruptions in patients with DF varies with the virus strain and outbreaks.⁷ The lesions initially develop with the onset of fever and manifest as flushing or erythematous mottling of the face, neck, and chest areas.^1,7 The morbilliform eruption develops 2 to 6 days after the onset of the fever, beginning on the trunk and spreading to the face and extremities.^1,7 The rash may become confluent with characteristic sparing of small round areas of normal skin described as white islands in a sea of red.² Verrucous papules on the ears also have been described and may resemble those seen in Cowden syndrome. In patients with prior infection with a different strain of the virus, hemorrhagic lesions may develop, including characteristic retiform purpura, a positive tourniquet test, and the appearance of petechiae on the lower legs. Pruritus and desquamation, especially on the palms and soles, may follow the termination of the eruption.⁷

The differential diagnosis of DF includes measles, rubella, enteroviruses, and influenza. Chikungunya and West Nile viruses in Asia and Africa and the O’nyong-nyong virus in Africa are also arboviruses that cause a clinical picture similar to DF but not DHF. Other diagnostic considerations include phases of scarlet fever, typhoid, malaria, leptospirosis, hepatitis A, and trypanosomal and rickettsial diseases.⁷ The differential diagnosis of DHF includes antineutrophil cytoplasmic antibody–associated vasculitis, rheumatoid vasculitis, and bacterial septic vasculitis.

Acute clinical diagnosis of DF can be challenging because of the nonspecific symptoms that can be seen in almost every infectious disease. Clinical presentation assessment should be confirmed with laboratory testing.⁶ Dengue virus infection usually is confirmed by the identification of viral genomic RNA, antigens, or the antibodies it elicits. Enzyme-linked immunosorbent assay–based serologic tests are cost-effective and easy to perform.⁵ IgM antibodies usually show cross-reactivity with platelets, but the antibody levels are not positively correlated with the severity of DF.⁸ Primary infection with the dengue virus is characterized by the elevation of specific IgM levels that usually occurs 3 to 5 days after symptom onset and persists during the postfebrile stage (up to 30 to 60 days). In secondary infections, the IgM levels usually rise more slowly and reach a lower level than in primary infections.⁹ For both primary and secondary infections, testing IgM levels after the febrile stage may be helpful with the laboratory diagnosis.

Currently, there is no antiviral drug available for dengue. Treatment of dengue infection is symptomatic and supportive.²

Dengue hemorrhagic fever is indicated by a rising hematocrit (≥20%) and a falling platelet count (>100,000/mm³) accompanying clinical signs of hemorrhage. Treatment includes intravenous fluid replacement and careful clinical monitoring of hematocrit levels, platelet count, vitals, urine output, and other signs of shock.⁵ For patients with a history of dengue infection, travel to areas with other serotypes is not recommended.

If any travel to a high-risk area is planned, countryspecific travel recommendations and warnings should be reviewed from the Centers for Disease Control and Prevention’s website (https://wwwnc.cdc.gov/travel/notices/level1/dengue-global). Use of an Environmental Protection Agency–registered insect repellent to avoid mosquito bites and acetaminophen for managing symptoms is advised. During travel, staying in places with window and door screens and using a bed net during sleep are suggested. Long-sleeved shirts and long pants also are preferred. Travelers should see a health care provider if they have symptoms of dengue.¹⁰

African tick bite fever (ATBF) is caused by Rickettsia africae transmitted by Amblyomma ticks. Skin findings in ATBF include erythematous, firm, tender papules with central eschars consistent with the feeding patterns of ticks.¹¹ Histopathology of ATBF usually includes fibrinoid necrosis of vessels in the dermis with a perivascular inflammatory infiltrate and coagulation necrosis of the surrounding dermis consistent with eschar formation.¹² The lack of an eschar weighs against this diagnosis.

African trypanosomiasis (also known as sleeping sickness) is caused by protozoa transmitted by the tsetse fly. A chancrelike, circumscribed, rubbery, indurated red or violaceous nodule measuring 2 to 5 cm in diameter often develops as the earliest cutaneous sign of the disease.¹³ Nonspecific histopathologic findings, such as infiltration of lymphocytes and macrophages and proliferation of endothelial cells and fibroblasts, may be observed.¹⁴ Extravascular parasites have been noted in skin biopsies.¹⁵ In later stages, skin lesions called trypanids may be observed as macular, papular, annular, targetoid, purpuric, and erythematous lesions, and histopathologic findings consistent with vasculitis also may be seen.¹³

Chikungunya virus infection is an acute-onset, mosquito-borne viral disease. Skin manifestations may start with nonspecific, generalized, morbilliform, maculopapular rashes coinciding with fever, which also may be seen initially with DHF. Skin hyperpigmentation, mostly centrofacial and involving the nose (chik sign); purpuric and ecchymotic lesions over the trunk and flexors of limbs in adults, often surmounted by subepidermal bullae and lesions resembling toxic epidermal necrolysis; and nonhealing ulcers in the genital and groin areas are common skin manifestations of chikungunya infection.¹⁶ Intraepithelial splitting with acantholysis and perivascular lymphohistiocytic infiltration may be observed in the histopathology of blistering lesions, which are not consistent with DHF.¹⁷

Zika virus infection is caused by an arbovirus within the Flaviviridae family, which also includes the dengue virus. Initial mucocutaneous findings of the Zika virus include nonspecific diffuse maculopapular eruptions. The eruption generally spares the palms and soles; however, various manifestations including involvement of the palms and soles have been reported.¹⁸ The morbilliform eruption begins on the face and extends to the trunk and extremities. Mild hemorrhagic manifestations, including petechiae and bleeding gums, may be observed. Distinguishing between dengue and Zika virus infection relies on the severity of symptoms and laboratory tests, including polymerase chain reaction or IgM antibody testing.¹⁹ The other conditions listed do not produce hemorrhagic fever.

THE DIAGNOSIS: Dengue Hemorrhagic Fever

The retiform purpura observed in our patient was suggestive of a vasculitic, thrombotic, or embolic etiology. Dengue IgM serologic testing performed based on her extensive travel history and recent return from a dengue-endemic area was positive, indicating acute infection. A clinical diagnosis of dengue hemorrhagic fever (DHF) was made based on the hemorrhagic appearance of the lesion. Histopathology revealed leukocytoclastic vasculitis (Figure). Anti–double-stranded DNA, antideoxyribonuclease, C3 and C4, CH50 (total hemolytic complement), antineutrophil cytoplasmic antibodies, HIV, and hepatitis B virus tests were normal. Direct immunofluorescence was negative.

Dengue virus is a single-stranded RNA virus transmitted by Aedes aegypti and Aedes albopictus mosquitoes and is one of the most prevalent arthropod-borne viruses affecting humans today.^1,2 Infection with the dengue virus generally is seen in travelers visiting tropical regions of Africa, Mexico, South America, South and Central Asia, Southeast Asia, and the Caribbean.¹ The Table shows the global distribution of dengue serotypes from 2000 to 2014.^3,4 There are 4 serotypes of the dengue virus: DENV-1 to DENV-4. Infection with 1 strain elicits longlasting immunity to that strain, but subsequent infection with another strain can result in severe DHF due to antibody cross-reaction.¹

Dengue virus infection ranges from mildly symptomatic to a spectrum of increasingly severe conditions that comprise dengue fever (DF) and DHF, as well as dengue shock syndrome and brain stem hemorrhage, which may be fatal.^2,5 Dengue fever manifests as severe myalgia, fever, headache (usually retro-orbital), arthralgia, erythema, and rubelliform exanthema.⁶ The frequency of skin eruptions in patients with DF varies with the virus strain and outbreaks.⁷ The lesions initially develop with the onset of fever and manifest as flushing or erythematous mottling of the face, neck, and chest areas.^1,7 The morbilliform eruption develops 2 to 6 days after the onset of the fever, beginning on the trunk and spreading to the face and extremities.^1,7 The rash may become confluent with characteristic sparing of small round areas of normal skin described as white islands in a sea of red.² Verrucous papules on the ears also have been described and may resemble those seen in Cowden syndrome. In patients with prior infection with a different strain of the virus, hemorrhagic lesions may develop, including characteristic retiform purpura, a positive tourniquet test, and the appearance of petechiae on the lower legs. Pruritus and desquamation, especially on the palms and soles, may follow the termination of the eruption.⁷

The differential diagnosis of DF includes measles, rubella, enteroviruses, and influenza. Chikungunya and West Nile viruses in Asia and Africa and the O’nyong-nyong virus in Africa are also arboviruses that cause a clinical picture similar to DF but not DHF. Other diagnostic considerations include phases of scarlet fever, typhoid, malaria, leptospirosis, hepatitis A, and trypanosomal and rickettsial diseases.⁷ The differential diagnosis of DHF includes antineutrophil cytoplasmic antibody–associated vasculitis, rheumatoid vasculitis, and bacterial septic vasculitis.

Acute clinical diagnosis of DF can be challenging because of the nonspecific symptoms that can be seen in almost every infectious disease. Clinical presentation assessment should be confirmed with laboratory testing.⁶ Dengue virus infection usually is confirmed by the identification of viral genomic RNA, antigens, or the antibodies it elicits. Enzyme-linked immunosorbent assay–based serologic tests are cost-effective and easy to perform.⁵ IgM antibodies usually show cross-reactivity with platelets, but the antibody levels are not positively correlated with the severity of DF.⁸ Primary infection with the dengue virus is characterized by the elevation of specific IgM levels that usually occurs 3 to 5 days after symptom onset and persists during the postfebrile stage (up to 30 to 60 days). In secondary infections, the IgM levels usually rise more slowly and reach a lower level than in primary infections.⁹ For both primary and secondary infections, testing IgM levels after the febrile stage may be helpful with the laboratory diagnosis.

Currently, there is no antiviral drug available for dengue. Treatment of dengue infection is symptomatic and supportive.²

Dengue hemorrhagic fever is indicated by a rising hematocrit (≥20%) and a falling platelet count (>100,000/mm³) accompanying clinical signs of hemorrhage. Treatment includes intravenous fluid replacement and careful clinical monitoring of hematocrit levels, platelet count, vitals, urine output, and other signs of shock.⁵ For patients with a history of dengue infection, travel to areas with other serotypes is not recommended.

If any travel to a high-risk area is planned, countryspecific travel recommendations and warnings should be reviewed from the Centers for Disease Control and Prevention’s website (https://wwwnc.cdc.gov/travel/notices/level1/dengue-global). Use of an Environmental Protection Agency–registered insect repellent to avoid mosquito bites and acetaminophen for managing symptoms is advised. During travel, staying in places with window and door screens and using a bed net during sleep are suggested. Long-sleeved shirts and long pants also are preferred. Travelers should see a health care provider if they have symptoms of dengue.¹⁰

African tick bite fever (ATBF) is caused by Rickettsia africae transmitted by Amblyomma ticks. Skin findings in ATBF include erythematous, firm, tender papules with central eschars consistent with the feeding patterns of ticks.¹¹ Histopathology of ATBF usually includes fibrinoid necrosis of vessels in the dermis with a perivascular inflammatory infiltrate and coagulation necrosis of the surrounding dermis consistent with eschar formation.¹² The lack of an eschar weighs against this diagnosis.

African trypanosomiasis (also known as sleeping sickness) is caused by protozoa transmitted by the tsetse fly. A chancrelike, circumscribed, rubbery, indurated red or violaceous nodule measuring 2 to 5 cm in diameter often develops as the earliest cutaneous sign of the disease.¹³ Nonspecific histopathologic findings, such as infiltration of lymphocytes and macrophages and proliferation of endothelial cells and fibroblasts, may be observed.¹⁴ Extravascular parasites have been noted in skin biopsies.¹⁵ In later stages, skin lesions called trypanids may be observed as macular, papular, annular, targetoid, purpuric, and erythematous lesions, and histopathologic findings consistent with vasculitis also may be seen.¹³

Chikungunya virus infection is an acute-onset, mosquito-borne viral disease. Skin manifestations may start with nonspecific, generalized, morbilliform, maculopapular rashes coinciding with fever, which also may be seen initially with DHF. Skin hyperpigmentation, mostly centrofacial and involving the nose (chik sign); purpuric and ecchymotic lesions over the trunk and flexors of limbs in adults, often surmounted by subepidermal bullae and lesions resembling toxic epidermal necrolysis; and nonhealing ulcers in the genital and groin areas are common skin manifestations of chikungunya infection.¹⁶ Intraepithelial splitting with acantholysis and perivascular lymphohistiocytic infiltration may be observed in the histopathology of blistering lesions, which are not consistent with DHF.¹⁷

Zika virus infection is caused by an arbovirus within the Flaviviridae family, which also includes the dengue virus. Initial mucocutaneous findings of the Zika virus include nonspecific diffuse maculopapular eruptions. The eruption generally spares the palms and soles; however, various manifestations including involvement of the palms and soles have been reported.¹⁸ The morbilliform eruption begins on the face and extends to the trunk and extremities. Mild hemorrhagic manifestations, including petechiae and bleeding gums, may be observed. Distinguishing between dengue and Zika virus infection relies on the severity of symptoms and laboratory tests, including polymerase chain reaction or IgM antibody testing.¹⁹ The other conditions listed do not produce hemorrhagic fever.

THE DIAGNOSIS: Dengue Hemorrhagic Fever

The retiform purpura observed in our patient was suggestive of a vasculitic, thrombotic, or embolic etiology. Dengue IgM serologic testing performed based on her extensive travel history and recent return from a dengue-endemic area was positive, indicating acute infection. A clinical diagnosis of dengue hemorrhagic fever (DHF) was made based on the hemorrhagic appearance of the lesion. Histopathology revealed leukocytoclastic vasculitis (Figure). Anti–double-stranded DNA, antideoxyribonuclease, C3 and C4, CH50 (total hemolytic complement), antineutrophil cytoplasmic antibodies, HIV, and hepatitis B virus tests were normal. Direct immunofluorescence was negative.

Dengue virus is a single-stranded RNA virus transmitted by Aedes aegypti and Aedes albopictus mosquitoes and is one of the most prevalent arthropod-borne viruses affecting humans today.^1,2 Infection with the dengue virus generally is seen in travelers visiting tropical regions of Africa, Mexico, South America, South and Central Asia, Southeast Asia, and the Caribbean.¹ The Table shows the global distribution of dengue serotypes from 2000 to 2014.^3,4 There are 4 serotypes of the dengue virus: DENV-1 to DENV-4. Infection with 1 strain elicits longlasting immunity to that strain, but subsequent infection with another strain can result in severe DHF due to antibody cross-reaction.¹

Dengue virus infection ranges from mildly symptomatic to a spectrum of increasingly severe conditions that comprise dengue fever (DF) and DHF, as well as dengue shock syndrome and brain stem hemorrhage, which may be fatal.^2,5 Dengue fever manifests as severe myalgia, fever, headache (usually retro-orbital), arthralgia, erythema, and rubelliform exanthema.⁶ The frequency of skin eruptions in patients with DF varies with the virus strain and outbreaks.⁷ The lesions initially develop with the onset of fever and manifest as flushing or erythematous mottling of the face, neck, and chest areas.^1,7 The morbilliform eruption develops 2 to 6 days after the onset of the fever, beginning on the trunk and spreading to the face and extremities.^1,7 The rash may become confluent with characteristic sparing of small round areas of normal skin described as white islands in a sea of red.² Verrucous papules on the ears also have been described and may resemble those seen in Cowden syndrome. In patients with prior infection with a different strain of the virus, hemorrhagic lesions may develop, including characteristic retiform purpura, a positive tourniquet test, and the appearance of petechiae on the lower legs. Pruritus and desquamation, especially on the palms and soles, may follow the termination of the eruption.⁷

The differential diagnosis of DF includes measles, rubella, enteroviruses, and influenza. Chikungunya and West Nile viruses in Asia and Africa and the O’nyong-nyong virus in Africa are also arboviruses that cause a clinical picture similar to DF but not DHF. Other diagnostic considerations include phases of scarlet fever, typhoid, malaria, leptospirosis, hepatitis A, and trypanosomal and rickettsial diseases.⁷ The differential diagnosis of DHF includes antineutrophil cytoplasmic antibody–associated vasculitis, rheumatoid vasculitis, and bacterial septic vasculitis.

Acute clinical diagnosis of DF can be challenging because of the nonspecific symptoms that can be seen in almost every infectious disease. Clinical presentation assessment should be confirmed with laboratory testing.⁶ Dengue virus infection usually is confirmed by the identification of viral genomic RNA, antigens, or the antibodies it elicits. Enzyme-linked immunosorbent assay–based serologic tests are cost-effective and easy to perform.⁵ IgM antibodies usually show cross-reactivity with platelets, but the antibody levels are not positively correlated with the severity of DF.⁸ Primary infection with the dengue virus is characterized by the elevation of specific IgM levels that usually occurs 3 to 5 days after symptom onset and persists during the postfebrile stage (up to 30 to 60 days). In secondary infections, the IgM levels usually rise more slowly and reach a lower level than in primary infections.⁹ For both primary and secondary infections, testing IgM levels after the febrile stage may be helpful with the laboratory diagnosis.

Currently, there is no antiviral drug available for dengue. Treatment of dengue infection is symptomatic and supportive.²

Dengue hemorrhagic fever is indicated by a rising hematocrit (≥20%) and a falling platelet count (>100,000/mm³) accompanying clinical signs of hemorrhage. Treatment includes intravenous fluid replacement and careful clinical monitoring of hematocrit levels, platelet count, vitals, urine output, and other signs of shock.⁵ For patients with a history of dengue infection, travel to areas with other serotypes is not recommended.

If any travel to a high-risk area is planned, countryspecific travel recommendations and warnings should be reviewed from the Centers for Disease Control and Prevention’s website (https://wwwnc.cdc.gov/travel/notices/level1/dengue-global). Use of an Environmental Protection Agency–registered insect repellent to avoid mosquito bites and acetaminophen for managing symptoms is advised. During travel, staying in places with window and door screens and using a bed net during sleep are suggested. Long-sleeved shirts and long pants also are preferred. Travelers should see a health care provider if they have symptoms of dengue.¹⁰

African tick bite fever (ATBF) is caused by Rickettsia africae transmitted by Amblyomma ticks. Skin findings in ATBF include erythematous, firm, tender papules with central eschars consistent with the feeding patterns of ticks.¹¹ Histopathology of ATBF usually includes fibrinoid necrosis of vessels in the dermis with a perivascular inflammatory infiltrate and coagulation necrosis of the surrounding dermis consistent with eschar formation.¹² The lack of an eschar weighs against this diagnosis.

African trypanosomiasis (also known as sleeping sickness) is caused by protozoa transmitted by the tsetse fly. A chancrelike, circumscribed, rubbery, indurated red or violaceous nodule measuring 2 to 5 cm in diameter often develops as the earliest cutaneous sign of the disease.¹³ Nonspecific histopathologic findings, such as infiltration of lymphocytes and macrophages and proliferation of endothelial cells and fibroblasts, may be observed.¹⁴ Extravascular parasites have been noted in skin biopsies.¹⁵ In later stages, skin lesions called trypanids may be observed as macular, papular, annular, targetoid, purpuric, and erythematous lesions, and histopathologic findings consistent with vasculitis also may be seen.¹³

Chikungunya virus infection is an acute-onset, mosquito-borne viral disease. Skin manifestations may start with nonspecific, generalized, morbilliform, maculopapular rashes coinciding with fever, which also may be seen initially with DHF. Skin hyperpigmentation, mostly centrofacial and involving the nose (chik sign); purpuric and ecchymotic lesions over the trunk and flexors of limbs in adults, often surmounted by subepidermal bullae and lesions resembling toxic epidermal necrolysis; and nonhealing ulcers in the genital and groin areas are common skin manifestations of chikungunya infection.¹⁶ Intraepithelial splitting with acantholysis and perivascular lymphohistiocytic infiltration may be observed in the histopathology of blistering lesions, which are not consistent with DHF.¹⁷

Zika virus infection is caused by an arbovirus within the Flaviviridae family, which also includes the dengue virus. Initial mucocutaneous findings of the Zika virus include nonspecific diffuse maculopapular eruptions. The eruption generally spares the palms and soles; however, various manifestations including involvement of the palms and soles have been reported.¹⁸ The morbilliform eruption begins on the face and extends to the trunk and extremities. Mild hemorrhagic manifestations, including petechiae and bleeding gums, may be observed. Distinguishing between dengue and Zika virus infection relies on the severity of symptoms and laboratory tests, including polymerase chain reaction or IgM antibody testing.¹⁹ The other conditions listed do not produce hemorrhagic fever.

To the Editor:

Histopathologic analysis of debulk specimens in Mohs micrographic surgery (MMS) may augment identification of high-risk factors in cutaneous squamous cell carcinoma (cSCC), which may warrant tumor upstaging.¹ Intratumor location has not been studied when looking at these high-risk factors. Herein, we report 4 cSCCs initially categorized as well differentiated that were reclassified as moderate to poorly differentiated on analysis of debulk specimens obtained via shave removal.

An 80-year-old man (patient 1) presented with a tender 2-cm erythematous plaque with dried hemorrhagic crusting on the frontal scalp. He had a history of nonmelanoma skin cancers. A biopsy revealed a ­well-differentiated cSCC, which was upgraded from a T2a tumor to T2b during MMS due to galea involvement. Debulk analysis revealed moderate to poorly differentiated cSCC, with the least-differentiated cells at the deep margin (Figure 1A). Given T2b staging, baseline imaging and radiation therapy were recommended.

To the Editor:

Histopathologic analysis of debulk specimens in Mohs micrographic surgery (MMS) may augment identification of high-risk factors in cutaneous squamous cell carcinoma (cSCC), which may warrant tumor upstaging.¹ Intratumor location has not been studied when looking at these high-risk factors. Herein, we report 4 cSCCs initially categorized as well differentiated that were reclassified as moderate to poorly differentiated on analysis of debulk specimens obtained via shave removal.

An 80-year-old man (patient 1) presented with a tender 2-cm erythematous plaque with dried hemorrhagic crusting on the frontal scalp. He had a history of nonmelanoma skin cancers. A biopsy revealed a ­well-differentiated cSCC, which was upgraded from a T2a tumor to T2b during MMS due to galea involvement. Debulk analysis revealed moderate to poorly differentiated cSCC, with the least-differentiated cells at the deep margin (Figure 1A). Given T2b staging, baseline imaging and radiation therapy were recommended.

To the Editor:

Histopathologic analysis of debulk specimens in Mohs micrographic surgery (MMS) may augment identification of high-risk factors in cutaneous squamous cell carcinoma (cSCC), which may warrant tumor upstaging.¹ Intratumor location has not been studied when looking at these high-risk factors. Herein, we report 4 cSCCs initially categorized as well differentiated that were reclassified as moderate to poorly differentiated on analysis of debulk specimens obtained via shave removal.

An 80-year-old man (patient 1) presented with a tender 2-cm erythematous plaque with dried hemorrhagic crusting on the frontal scalp. He had a history of nonmelanoma skin cancers. A biopsy revealed a ­well-differentiated cSCC, which was upgraded from a T2a tumor to T2b during MMS due to galea involvement. Debulk analysis revealed moderate to poorly differentiated cSCC, with the least-differentiated cells at the deep margin (Figure 1A). Given T2b staging, baseline imaging and radiation therapy were recommended.

To the Editor:

Mutations of the BRAF protein kinase gene are implicated in a variety of malignancies.¹BRAF mutations in malignancies cause the mitogen-activated protein kinase (MAPK) pathway to become constitutively active, which results in unchecked cellular proliferation,^2,3 making the BRAF mutation an attractive target for inhibition with pharmacologic agents to potentially halt cancer growth.⁴ Vemurafenib—the first selective BRAF inhibitor used in clinical practice—initially was approved by the US Food and Drug Administration in 2011. The approval of dabrafenib followed in 2013 and most recently encorafenib in 2018.⁵

Although targeted treatment of BRAF-mutated malignancies with BRAF inhibitors has become common, it often is associated with cutaneous adverse events (AEs), such as rash, pruritus, photosensitivity, actinic keratosis, and verrucous keratosis. Some reports demonstrate these events in up to 95% of patients undergoing BRAF inhibitor treatment.⁶ In several cases the eruption of verrucous keratoses is among the most common cutaneous AEs seen among patients receiving BRAF inhibitor treatment.^5-7

In general, lesions can appear days to months after therapy is initiated and may resolve after switching to dual therapy with a MEK inhibitor or with complete cessation of BRAF inhibitor therapy.^5,7,8 One case of spontaneous resolution of vemurafenib-associated panniculitis during ongoing BRAF inhibitor therapy has been reported⁹; however, spontaneous resolution of cutaneous AEs is uncommon. Herein, we describe verrucous keratoses in a patient undergoing treatment with encorafenib that resolved spontaneously despite ongoing BRAF inhibitor therapy.

A 61-year-old woman presented to the emergency department with pain in the right lower quadrant. Computed tomography (CT) of the abdomen and pelvis revealed a large ovarian mass. Subsequent bloodwork revealed elevated carcinoembryonic antigen levels. The patient underwent a hysterectomy, bilateral salpingo-oophorectomy, omentectomy, right hemicolectomy with ileotransverse side-to-side anastomosis, right pelvic lymph node reduction, and complete cytoreduction. Histopathology revealed an adenocarcinoma of the cecum with tumor invasion into the visceral peritoneum and metastases to the left ovary, fallopian tube, and omentum. A BRAF V600E mutation was detected.

Two months after the initial presentation, the patient started her first cycle of chemotherapy with a combination of folinic acid, fluorouracil, and oxaliplatin. She completed 11 cycles of this regimen, then was switched to capecitabine and oxaliplatin for an additional 2 cycles due to insurance concerns. At the end of treatment, there was no evidence of disease on CT, thus the patient was followed with observation. However, she presented 10 months later to the emergency department with abdominal pain, and CT revealed new lesions in the liver that were concerning for potential metastases. She started oral encorafenib 300 mg/d and intravenous cetuximab 500 mg weekly; after 1 week, encorafenib was reduced to 150 mg/d due to nausea and loss of appetite. Within 2 weeks of starting treatment, the patient reported the relatively abrupt appearance of more than 50 small papules across the shoulders and back (Figure 1A). She was referred to dermatology, and shave biopsies of 2 lesions—one from the left anterior thigh, the other from the right posterior shoulder—revealed verrucous keratosis pathology (Figure 2). At this time, encorafenib was increased again to 300 mg/d as the patient had been tolerating the reduced dose. She continued to report the appearance of new lesions for the next 3 months, after which the lesions were stable for approximately 2 months. By 2.5 months after initiation of therapy, the patient had ­undergone CT demonstrating resolution of the liver lesions. At 5 months of therapy, the patient reported a stable to slightly reduced number of skin lesions but had begun to experience worsening joint pain, and the dosage of encorafenib was reduced to 225 mg/d. At 7 months of therapy, the dosage was further reduced to 150 mg/d due to persistent arthralgia. A follow-up examination at 10 months of therapy showed improvement in the number and size of the verrucous keratoses, and near resolution was seen by 14 months after the initial onset of the lesions (Figure 1B). At 20 months after initial onset, only 1 remaining verrucous keratosis was identified on physical examination and biopsy. The patient had continued a regimen of encorafenib 150 mg/d and weekly intravenous 500 mg cetuximab up to this point. Over the entire time period that the patient was seen, up to 12 lesions located in high-friction areas had become irritated and were treated with cryotherapy, but this contributed only minorly to the patient’s overall presentation.

To the Editor:

Mutations of the BRAF protein kinase gene are implicated in a variety of malignancies.¹BRAF mutations in malignancies cause the mitogen-activated protein kinase (MAPK) pathway to become constitutively active, which results in unchecked cellular proliferation,^2,3 making the BRAF mutation an attractive target for inhibition with pharmacologic agents to potentially halt cancer growth.⁴ Vemurafenib—the first selective BRAF inhibitor used in clinical practice—initially was approved by the US Food and Drug Administration in 2011. The approval of dabrafenib followed in 2013 and most recently encorafenib in 2018.⁵

Although targeted treatment of BRAF-mutated malignancies with BRAF inhibitors has become common, it often is associated with cutaneous adverse events (AEs), such as rash, pruritus, photosensitivity, actinic keratosis, and verrucous keratosis. Some reports demonstrate these events in up to 95% of patients undergoing BRAF inhibitor treatment.⁶ In several cases the eruption of verrucous keratoses is among the most common cutaneous AEs seen among patients receiving BRAF inhibitor treatment.^5-7

In general, lesions can appear days to months after therapy is initiated and may resolve after switching to dual therapy with a MEK inhibitor or with complete cessation of BRAF inhibitor therapy.^5,7,8 One case of spontaneous resolution of vemurafenib-associated panniculitis during ongoing BRAF inhibitor therapy has been reported⁹; however, spontaneous resolution of cutaneous AEs is uncommon. Herein, we describe verrucous keratoses in a patient undergoing treatment with encorafenib that resolved spontaneously despite ongoing BRAF inhibitor therapy.

A 61-year-old woman presented to the emergency department with pain in the right lower quadrant. Computed tomography (CT) of the abdomen and pelvis revealed a large ovarian mass. Subsequent bloodwork revealed elevated carcinoembryonic antigen levels. The patient underwent a hysterectomy, bilateral salpingo-oophorectomy, omentectomy, right hemicolectomy with ileotransverse side-to-side anastomosis, right pelvic lymph node reduction, and complete cytoreduction. Histopathology revealed an adenocarcinoma of the cecum with tumor invasion into the visceral peritoneum and metastases to the left ovary, fallopian tube, and omentum. A BRAF V600E mutation was detected.

Two months after the initial presentation, the patient started her first cycle of chemotherapy with a combination of folinic acid, fluorouracil, and oxaliplatin. She completed 11 cycles of this regimen, then was switched to capecitabine and oxaliplatin for an additional 2 cycles due to insurance concerns. At the end of treatment, there was no evidence of disease on CT, thus the patient was followed with observation. However, she presented 10 months later to the emergency department with abdominal pain, and CT revealed new lesions in the liver that were concerning for potential metastases. She started oral encorafenib 300 mg/d and intravenous cetuximab 500 mg weekly; after 1 week, encorafenib was reduced to 150 mg/d due to nausea and loss of appetite. Within 2 weeks of starting treatment, the patient reported the relatively abrupt appearance of more than 50 small papules across the shoulders and back (Figure 1A). She was referred to dermatology, and shave biopsies of 2 lesions—one from the left anterior thigh, the other from the right posterior shoulder—revealed verrucous keratosis pathology (Figure 2). At this time, encorafenib was increased again to 300 mg/d as the patient had been tolerating the reduced dose. She continued to report the appearance of new lesions for the next 3 months, after which the lesions were stable for approximately 2 months. By 2.5 months after initiation of therapy, the patient had ­undergone CT demonstrating resolution of the liver lesions. At 5 months of therapy, the patient reported a stable to slightly reduced number of skin lesions but had begun to experience worsening joint pain, and the dosage of encorafenib was reduced to 225 mg/d. At 7 months of therapy, the dosage was further reduced to 150 mg/d due to persistent arthralgia. A follow-up examination at 10 months of therapy showed improvement in the number and size of the verrucous keratoses, and near resolution was seen by 14 months after the initial onset of the lesions (Figure 1B). At 20 months after initial onset, only 1 remaining verrucous keratosis was identified on physical examination and biopsy. The patient had continued a regimen of encorafenib 150 mg/d and weekly intravenous 500 mg cetuximab up to this point. Over the entire time period that the patient was seen, up to 12 lesions located in high-friction areas had become irritated and were treated with cryotherapy, but this contributed only minorly to the patient’s overall presentation.

To the Editor:

Mutations of the BRAF protein kinase gene are implicated in a variety of malignancies.¹BRAF mutations in malignancies cause the mitogen-activated protein kinase (MAPK) pathway to become constitutively active, which results in unchecked cellular proliferation,^2,3 making the BRAF mutation an attractive target for inhibition with pharmacologic agents to potentially halt cancer growth.⁴ Vemurafenib—the first selective BRAF inhibitor used in clinical practice—initially was approved by the US Food and Drug Administration in 2011. The approval of dabrafenib followed in 2013 and most recently encorafenib in 2018.⁵

Although targeted treatment of BRAF-mutated malignancies with BRAF inhibitors has become common, it often is associated with cutaneous adverse events (AEs), such as rash, pruritus, photosensitivity, actinic keratosis, and verrucous keratosis. Some reports demonstrate these events in up to 95% of patients undergoing BRAF inhibitor treatment.⁶ In several cases the eruption of verrucous keratoses is among the most common cutaneous AEs seen among patients receiving BRAF inhibitor treatment.^5-7

In general, lesions can appear days to months after therapy is initiated and may resolve after switching to dual therapy with a MEK inhibitor or with complete cessation of BRAF inhibitor therapy.^5,7,8 One case of spontaneous resolution of vemurafenib-associated panniculitis during ongoing BRAF inhibitor therapy has been reported⁹; however, spontaneous resolution of cutaneous AEs is uncommon. Herein, we describe verrucous keratoses in a patient undergoing treatment with encorafenib that resolved spontaneously despite ongoing BRAF inhibitor therapy.

A 61-year-old woman presented to the emergency department with pain in the right lower quadrant. Computed tomography (CT) of the abdomen and pelvis revealed a large ovarian mass. Subsequent bloodwork revealed elevated carcinoembryonic antigen levels. The patient underwent a hysterectomy, bilateral salpingo-oophorectomy, omentectomy, right hemicolectomy with ileotransverse side-to-side anastomosis, right pelvic lymph node reduction, and complete cytoreduction. Histopathology revealed an adenocarcinoma of the cecum with tumor invasion into the visceral peritoneum and metastases to the left ovary, fallopian tube, and omentum. A BRAF V600E mutation was detected.

Two months after the initial presentation, the patient started her first cycle of chemotherapy with a combination of folinic acid, fluorouracil, and oxaliplatin. She completed 11 cycles of this regimen, then was switched to capecitabine and oxaliplatin for an additional 2 cycles due to insurance concerns. At the end of treatment, there was no evidence of disease on CT, thus the patient was followed with observation. However, she presented 10 months later to the emergency department with abdominal pain, and CT revealed new lesions in the liver that were concerning for potential metastases. She started oral encorafenib 300 mg/d and intravenous cetuximab 500 mg weekly; after 1 week, encorafenib was reduced to 150 mg/d due to nausea and loss of appetite. Within 2 weeks of starting treatment, the patient reported the relatively abrupt appearance of more than 50 small papules across the shoulders and back (Figure 1A). She was referred to dermatology, and shave biopsies of 2 lesions—one from the left anterior thigh, the other from the right posterior shoulder—revealed verrucous keratosis pathology (Figure 2). At this time, encorafenib was increased again to 300 mg/d as the patient had been tolerating the reduced dose. She continued to report the appearance of new lesions for the next 3 months, after which the lesions were stable for approximately 2 months. By 2.5 months after initiation of therapy, the patient had ­undergone CT demonstrating resolution of the liver lesions. At 5 months of therapy, the patient reported a stable to slightly reduced number of skin lesions but had begun to experience worsening joint pain, and the dosage of encorafenib was reduced to 225 mg/d. At 7 months of therapy, the dosage was further reduced to 150 mg/d due to persistent arthralgia. A follow-up examination at 10 months of therapy showed improvement in the number and size of the verrucous keratoses, and near resolution was seen by 14 months after the initial onset of the lesions (Figure 1B). At 20 months after initial onset, only 1 remaining verrucous keratosis was identified on physical examination and biopsy. The patient had continued a regimen of encorafenib 150 mg/d and weekly intravenous 500 mg cetuximab up to this point. Over the entire time period that the patient was seen, up to 12 lesions located in high-friction areas had become irritated and were treated with cryotherapy, but this contributed only minorly to the patient’s overall presentation.

To the Editor:

Kratom (Mitragyna speciosa) is an evergreen tree native to Southeast Asia.¹ Its leaves contain psychoactive compounds including mitragynine and 7-­hydroxymitragynine, which exert dose-dependent effects on the central nervous system through opioid and monoaminergic receptors.^2,3 At low doses (1–5 g), kratom elicits mild stimulant effects such as increased sociability, alertness, and talkativeness. At high doses (5–15 g), kratom has depressant effects that can provide relief from pain and opioid-withdrawal symptoms.³

Traditionally, kratom has been used in Southeast Asia for recreational and ceremonial purposes, to ease opioid-withdrawal symptoms, and to reduce fatigue from manual labor.⁴ In the 21st century, availability of kratom expanded to Europe, Australia, and the United States, largely facilitated by widespread dissemination of deceitful ­marketing and unregulated sales on the internet.¹ Although large-scale epidemiologic studies evaluating kratom’s prevalence are scarce, available evidence indicates rising worldwide usage, with a notable increase in kratom-related poison center calls between 2011 and 2017 in the United States.⁵ In July 2023, kratom made headlines due to the death of a woman in Florida following use of the substance.⁶

A cross-sectional study revealed that in the United States, kratom typically is used by White individuals for self-treatment of anxiety, depression, pain, and opioid withdrawal.⁷ However, the potential for severe adverse effects and dependence on kratom can outweigh the benefits.^6,8 Reported adverse effects of kratom include tachycardia, hypercholesteremia, liver injury, hallucinations, respiratory depression, seizure, coma, and death.^9,10 We present a case of kratom-induced photodistributed hyperpigmentation.

A 63-year-old man presented to the dermatology clinic with diffuse tender, pruritic, hyperpigmented skin lesions that developed over the course of 1 year. The lesions were distributed on sun-exposed areas, including the face, neck, and forearms (Figure 1). The patient reported no other major symptoms, and his health was otherwise unremarkable. He had a medical history of psoriasiform and spongiotic dermatitis consistent with eczema, psoriasis, hypercholesteremia, and hyperlipidemia. The patient was not taking any medications at the time of presentation. He had a family history of plaque psoriasis in his father. Five years prior to the current presentation, the patient was treated with adalimumab for steroid-resistant psoriasis; however, despite initial improvement, he experienced recurrence of scaly erythematous plaques and had discontinued adalimumab the year prior to presentation.

To the Editor:

Kratom (Mitragyna speciosa) is an evergreen tree native to Southeast Asia.¹ Its leaves contain psychoactive compounds including mitragynine and 7-­hydroxymitragynine, which exert dose-dependent effects on the central nervous system through opioid and monoaminergic receptors.^2,3 At low doses (1–5 g), kratom elicits mild stimulant effects such as increased sociability, alertness, and talkativeness. At high doses (5–15 g), kratom has depressant effects that can provide relief from pain and opioid-withdrawal symptoms.³

Traditionally, kratom has been used in Southeast Asia for recreational and ceremonial purposes, to ease opioid-withdrawal symptoms, and to reduce fatigue from manual labor.⁴ In the 21st century, availability of kratom expanded to Europe, Australia, and the United States, largely facilitated by widespread dissemination of deceitful ­marketing and unregulated sales on the internet.¹ Although large-scale epidemiologic studies evaluating kratom’s prevalence are scarce, available evidence indicates rising worldwide usage, with a notable increase in kratom-related poison center calls between 2011 and 2017 in the United States.⁵ In July 2023, kratom made headlines due to the death of a woman in Florida following use of the substance.⁶

A cross-sectional study revealed that in the United States, kratom typically is used by White individuals for self-treatment of anxiety, depression, pain, and opioid withdrawal.⁷ However, the potential for severe adverse effects and dependence on kratom can outweigh the benefits.^6,8 Reported adverse effects of kratom include tachycardia, hypercholesteremia, liver injury, hallucinations, respiratory depression, seizure, coma, and death.^9,10 We present a case of kratom-induced photodistributed hyperpigmentation.

A 63-year-old man presented to the dermatology clinic with diffuse tender, pruritic, hyperpigmented skin lesions that developed over the course of 1 year. The lesions were distributed on sun-exposed areas, including the face, neck, and forearms (Figure 1). The patient reported no other major symptoms, and his health was otherwise unremarkable. He had a medical history of psoriasiform and spongiotic dermatitis consistent with eczema, psoriasis, hypercholesteremia, and hyperlipidemia. The patient was not taking any medications at the time of presentation. He had a family history of plaque psoriasis in his father. Five years prior to the current presentation, the patient was treated with adalimumab for steroid-resistant psoriasis; however, despite initial improvement, he experienced recurrence of scaly erythematous plaques and had discontinued adalimumab the year prior to presentation.

To the Editor:

Kratom (Mitragyna speciosa) is an evergreen tree native to Southeast Asia.¹ Its leaves contain psychoactive compounds including mitragynine and 7-­hydroxymitragynine, which exert dose-dependent effects on the central nervous system through opioid and monoaminergic receptors.^2,3 At low doses (1–5 g), kratom elicits mild stimulant effects such as increased sociability, alertness, and talkativeness. At high doses (5–15 g), kratom has depressant effects that can provide relief from pain and opioid-withdrawal symptoms.³

Traditionally, kratom has been used in Southeast Asia for recreational and ceremonial purposes, to ease opioid-withdrawal symptoms, and to reduce fatigue from manual labor.⁴ In the 21st century, availability of kratom expanded to Europe, Australia, and the United States, largely facilitated by widespread dissemination of deceitful ­marketing and unregulated sales on the internet.¹ Although large-scale epidemiologic studies evaluating kratom’s prevalence are scarce, available evidence indicates rising worldwide usage, with a notable increase in kratom-related poison center calls between 2011 and 2017 in the United States.⁵ In July 2023, kratom made headlines due to the death of a woman in Florida following use of the substance.⁶

A cross-sectional study revealed that in the United States, kratom typically is used by White individuals for self-treatment of anxiety, depression, pain, and opioid withdrawal.⁷ However, the potential for severe adverse effects and dependence on kratom can outweigh the benefits.^6,8 Reported adverse effects of kratom include tachycardia, hypercholesteremia, liver injury, hallucinations, respiratory depression, seizure, coma, and death.^9,10 We present a case of kratom-induced photodistributed hyperpigmentation.

A 63-year-old man presented to the dermatology clinic with diffuse tender, pruritic, hyperpigmented skin lesions that developed over the course of 1 year. The lesions were distributed on sun-exposed areas, including the face, neck, and forearms (Figure 1). The patient reported no other major symptoms, and his health was otherwise unremarkable. He had a medical history of psoriasiform and spongiotic dermatitis consistent with eczema, psoriasis, hypercholesteremia, and hyperlipidemia. The patient was not taking any medications at the time of presentation. He had a family history of plaque psoriasis in his father. Five years prior to the current presentation, the patient was treated with adalimumab for steroid-resistant psoriasis; however, despite initial improvement, he experienced recurrence of scaly erythematous plaques and had discontinued adalimumab the year prior to presentation.

The Diagnosis: Erythema Nodosum Leprosum

Erythema nodosum leprosum (ENL) is a type 2 reaction sometimes seen in patients infected with Mycobacterium leprae—primarily those with lepromatous or borderline lepromatous subtypes. Clinically, ENL manifests with abrupt onset of tender erythematous papules with associated fevers and general malaise. Studies have demonstrated a complex immune system reaction in ENL, but the detailed pathophysiology is not fully understood.¹ Biopsies conducted within 24 hours of lesion formation are most elucidating. Foamy histiocytes admixed with neutrophils are seen in the subcutis, often causing a lobular panniculitis (quiz image).² Neutrophils rarely are seen in other types of leprosy and thus are a useful diagnostic clue for ENL. Vasculitis of small- to medium-sized vessels can be seen but is not a necessary diagnostic criterion. Fite staining will highlight many acid-fast bacilli within the histiocytes (Figure 1).

Erythema nodosum leprosum is treated with a combination of immunosuppressants such as prednisone and thalidomide. Our patient was taking triple-antibiotic therapy—dapsone, rifampin, and clofazimine—for lepromatous leprosy when the erythematous papules developed on the arms and legs. After a skin biopsy confirmed the diagnosis of ENL, he was started on prednisone 20 mg daily with plans for close follow-up. Unfortunately, the patient was subsequently lost to follow-up.

Acute febrile neutrophilic dermatosis (also known as Sweet syndrome) is an acute inflammatory disease characterized by abrupt onset of painful erythematous papules, plaques, or nodules on the skin. It often is seen in association with preceding infections (especially those in the upper respiratory or gastrointestinal tracts), hematologic malignancies, inflammatory bowel disease, or exposure to certain classes of medications (eg, granulocyte colony-stimulating factor, tyrosine kinase inhibitors, various antibiotics).³ Histologically, acute febrile neutrophilic dermatosis is characterized by dense neutrophilic infiltrates, often with notable dermal edema (Figure 2).⁴ Many cases also show leukocytoclastic vasculitis; however, foamy histiocytes are not a notable component of the inflammatory infiltrate, though a histiocytoid form of acute febrile neutrophilic dermatosis has been described.⁵ Infections must be rigorously ruled out prior to diagnosing a patient with acute febrile neutrophilic dermatosis, making it a diagnosis of exclusion.

Cutaneous coccidioidomycosis is an infection caused by the dimorphic fungi Coccidioides immitis or Coccidioides posadasii. Cutaneous disease is rare but can occur from direct inoculation or dissemination from pulmonary disease in immunocompetent or immunocompromised patients. Papules, pustules, or plaques are seen clinically. Histologically, cutaneous coccidioidomycosis shows spherules that vary from 10 to 100 μm and are filled with multiple smaller endospores (Figure 3).⁶ Pseudoepitheliomatous hyperplasia with dense suppurative and granulomatous infiltrates also is seen.

Erythema induratum is characterized by tender nodules on the lower extremities and has a substantial female predominance. Many cases are associated with Mycobacterium tuberculosis infection. The bacteria are not seen directly in the skin but are instead detectable through DNA polymerase chain reaction testing or investigation of other organ systems.^7,8 Histologically, lesions show a lobular panniculitis with a mixed infiltrate. Vasculitis is seen in approximately 90% of erythema induratum cases vs approximately 25% of classic ENL cases (Figure 4),^2,9 which has led some to use the term nodular vasculitis to describe this disease entity. Nodular vasculitis is considered by others to be a distinct disease entity in which there are clinical and histologic features similar to erythema induratum but no evidence of M tuberculosis infection.⁹

Polyarteritis nodosa is a vasculitis that affects medium- sized vessels of various organ systems. The presenting signs and symptoms vary based on the affected organ systems. Palpable to retiform purpura, livedo racemosa, subcutaneous nodules, or ulcers are seen when the skin is involved. The histologic hallmark is necrotizing vasculitis of medium-sized arterioles (Figure 5), although leukocytoclastic vasculitis of small-caliber vessels also can be seen in biopsies of affected skin.¹⁰ The vascular changes are said to be segmental, with uninvolved segments interspersed with involved segments. Antineutrophil cytoplasmic antibody (ANCA)– associated vasculitis also must be considered when one sees leukocytoclastic vasculitis of small-caliber vessels in the skin, as it can be distinguished most readily by detecting circulating antibodies specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA).

The Diagnosis: Erythema Nodosum Leprosum

Erythema nodosum leprosum (ENL) is a type 2 reaction sometimes seen in patients infected with Mycobacterium leprae—primarily those with lepromatous or borderline lepromatous subtypes. Clinically, ENL manifests with abrupt onset of tender erythematous papules with associated fevers and general malaise. Studies have demonstrated a complex immune system reaction in ENL, but the detailed pathophysiology is not fully understood.¹ Biopsies conducted within 24 hours of lesion formation are most elucidating. Foamy histiocytes admixed with neutrophils are seen in the subcutis, often causing a lobular panniculitis (quiz image).² Neutrophils rarely are seen in other types of leprosy and thus are a useful diagnostic clue for ENL. Vasculitis of small- to medium-sized vessels can be seen but is not a necessary diagnostic criterion. Fite staining will highlight many acid-fast bacilli within the histiocytes (Figure 1).

Erythema nodosum leprosum is treated with a combination of immunosuppressants such as prednisone and thalidomide. Our patient was taking triple-antibiotic therapy—dapsone, rifampin, and clofazimine—for lepromatous leprosy when the erythematous papules developed on the arms and legs. After a skin biopsy confirmed the diagnosis of ENL, he was started on prednisone 20 mg daily with plans for close follow-up. Unfortunately, the patient was subsequently lost to follow-up.

Acute febrile neutrophilic dermatosis (also known as Sweet syndrome) is an acute inflammatory disease characterized by abrupt onset of painful erythematous papules, plaques, or nodules on the skin. It often is seen in association with preceding infections (especially those in the upper respiratory or gastrointestinal tracts), hematologic malignancies, inflammatory bowel disease, or exposure to certain classes of medications (eg, granulocyte colony-stimulating factor, tyrosine kinase inhibitors, various antibiotics).³ Histologically, acute febrile neutrophilic dermatosis is characterized by dense neutrophilic infiltrates, often with notable dermal edema (Figure 2).⁴ Many cases also show leukocytoclastic vasculitis; however, foamy histiocytes are not a notable component of the inflammatory infiltrate, though a histiocytoid form of acute febrile neutrophilic dermatosis has been described.⁵ Infections must be rigorously ruled out prior to diagnosing a patient with acute febrile neutrophilic dermatosis, making it a diagnosis of exclusion.

Cutaneous coccidioidomycosis is an infection caused by the dimorphic fungi Coccidioides immitis or Coccidioides posadasii. Cutaneous disease is rare but can occur from direct inoculation or dissemination from pulmonary disease in immunocompetent or immunocompromised patients. Papules, pustules, or plaques are seen clinically. Histologically, cutaneous coccidioidomycosis shows spherules that vary from 10 to 100 μm and are filled with multiple smaller endospores (Figure 3).⁶ Pseudoepitheliomatous hyperplasia with dense suppurative and granulomatous infiltrates also is seen.

Erythema induratum is characterized by tender nodules on the lower extremities and has a substantial female predominance. Many cases are associated with Mycobacterium tuberculosis infection. The bacteria are not seen directly in the skin but are instead detectable through DNA polymerase chain reaction testing or investigation of other organ systems.^7,8 Histologically, lesions show a lobular panniculitis with a mixed infiltrate. Vasculitis is seen in approximately 90% of erythema induratum cases vs approximately 25% of classic ENL cases (Figure 4),^2,9 which has led some to use the term nodular vasculitis to describe this disease entity. Nodular vasculitis is considered by others to be a distinct disease entity in which there are clinical and histologic features similar to erythema induratum but no evidence of M tuberculosis infection.⁹

Polyarteritis nodosa is a vasculitis that affects medium- sized vessels of various organ systems. The presenting signs and symptoms vary based on the affected organ systems. Palpable to retiform purpura, livedo racemosa, subcutaneous nodules, or ulcers are seen when the skin is involved. The histologic hallmark is necrotizing vasculitis of medium-sized arterioles (Figure 5), although leukocytoclastic vasculitis of small-caliber vessels also can be seen in biopsies of affected skin.¹⁰ The vascular changes are said to be segmental, with uninvolved segments interspersed with involved segments. Antineutrophil cytoplasmic antibody (ANCA)– associated vasculitis also must be considered when one sees leukocytoclastic vasculitis of small-caliber vessels in the skin, as it can be distinguished most readily by detecting circulating antibodies specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA).

The Diagnosis: Erythema Nodosum Leprosum

Erythema nodosum leprosum (ENL) is a type 2 reaction sometimes seen in patients infected with Mycobacterium leprae—primarily those with lepromatous or borderline lepromatous subtypes. Clinically, ENL manifests with abrupt onset of tender erythematous papules with associated fevers and general malaise. Studies have demonstrated a complex immune system reaction in ENL, but the detailed pathophysiology is not fully understood.¹ Biopsies conducted within 24 hours of lesion formation are most elucidating. Foamy histiocytes admixed with neutrophils are seen in the subcutis, often causing a lobular panniculitis (quiz image).² Neutrophils rarely are seen in other types of leprosy and thus are a useful diagnostic clue for ENL. Vasculitis of small- to medium-sized vessels can be seen but is not a necessary diagnostic criterion. Fite staining will highlight many acid-fast bacilli within the histiocytes (Figure 1).

Erythema nodosum leprosum is treated with a combination of immunosuppressants such as prednisone and thalidomide. Our patient was taking triple-antibiotic therapy—dapsone, rifampin, and clofazimine—for lepromatous leprosy when the erythematous papules developed on the arms and legs. After a skin biopsy confirmed the diagnosis of ENL, he was started on prednisone 20 mg daily with plans for close follow-up. Unfortunately, the patient was subsequently lost to follow-up.

Acute febrile neutrophilic dermatosis (also known as Sweet syndrome) is an acute inflammatory disease characterized by abrupt onset of painful erythematous papules, plaques, or nodules on the skin. It often is seen in association with preceding infections (especially those in the upper respiratory or gastrointestinal tracts), hematologic malignancies, inflammatory bowel disease, or exposure to certain classes of medications (eg, granulocyte colony-stimulating factor, tyrosine kinase inhibitors, various antibiotics).³ Histologically, acute febrile neutrophilic dermatosis is characterized by dense neutrophilic infiltrates, often with notable dermal edema (Figure 2).⁴ Many cases also show leukocytoclastic vasculitis; however, foamy histiocytes are not a notable component of the inflammatory infiltrate, though a histiocytoid form of acute febrile neutrophilic dermatosis has been described.⁵ Infections must be rigorously ruled out prior to diagnosing a patient with acute febrile neutrophilic dermatosis, making it a diagnosis of exclusion.

Cutaneous coccidioidomycosis is an infection caused by the dimorphic fungi Coccidioides immitis or Coccidioides posadasii. Cutaneous disease is rare but can occur from direct inoculation or dissemination from pulmonary disease in immunocompetent or immunocompromised patients. Papules, pustules, or plaques are seen clinically. Histologically, cutaneous coccidioidomycosis shows spherules that vary from 10 to 100 μm and are filled with multiple smaller endospores (Figure 3).⁶ Pseudoepitheliomatous hyperplasia with dense suppurative and granulomatous infiltrates also is seen.

Erythema induratum is characterized by tender nodules on the lower extremities and has a substantial female predominance. Many cases are associated with Mycobacterium tuberculosis infection. The bacteria are not seen directly in the skin but are instead detectable through DNA polymerase chain reaction testing or investigation of other organ systems.^7,8 Histologically, lesions show a lobular panniculitis with a mixed infiltrate. Vasculitis is seen in approximately 90% of erythema induratum cases vs approximately 25% of classic ENL cases (Figure 4),^2,9 which has led some to use the term nodular vasculitis to describe this disease entity. Nodular vasculitis is considered by others to be a distinct disease entity in which there are clinical and histologic features similar to erythema induratum but no evidence of M tuberculosis infection.⁹

Polyarteritis nodosa is a vasculitis that affects medium- sized vessels of various organ systems. The presenting signs and symptoms vary based on the affected organ systems. Palpable to retiform purpura, livedo racemosa, subcutaneous nodules, or ulcers are seen when the skin is involved. The histologic hallmark is necrotizing vasculitis of medium-sized arterioles (Figure 5), although leukocytoclastic vasculitis of small-caliber vessels also can be seen in biopsies of affected skin.¹⁰ The vascular changes are said to be segmental, with uninvolved segments interspersed with involved segments. Antineutrophil cytoplasmic antibody (ANCA)– associated vasculitis also must be considered when one sees leukocytoclastic vasculitis of small-caliber vessels in the skin, as it can be distinguished most readily by detecting circulating antibodies specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA).

The Diagnosis: Pityriasis Lichenoides et Varioliformis Acuta

Sectioned punch biopsies were performed on the patient’s right arm. Histopathology showed acanthosis and parakeratosis in the epidermis, with vacuolar degeneration and dyskeratosis in the basal layer. Dermal changes included extravasated red blood cells in the papillary dermis as well as perivascular lymphocytic infiltrates in both the papillary and reticular dermis (Figure). Direct immunofluorescence of a perilesional biopsy using anti–human IgG, IgM, IgA, C3, and fibrin conjugates showed no findings of immune deposition. Biopsy results were consistent with pityriasis lichenoides et varioliformis acuta (PLEVA), and the patient was treated with a 5-day course of oral azithromycin, triamcinolone ointment 0.1% twice daily, and phototherapy with narrowband UVB ³ times weekly. Rapid improvement was noted at 2-month follow-up.

Pityriasis lichenoides et varioliformis acuta is a form of pityriasis lichenoides, a group of inflammatory dermatoses that are characterized clinically by successive crops of morphologically diverse lesions. Epidemiologic studies have shown a slight male predominance. It primarily affects children and young adults, with peak ages of 8 and 32 years in pediatric and adult populations, respectively.¹

The pathogenesis of PLEVA remains unclear. An abnormal immune response to Toxoplasma, Epstein-Barr virus, HIV, and other pathogens has been suggested based on serologic evidence of concurrent disease activity with the onset of lesions as well as cutaneous improvement in some patients after treatment of the infection.¹ A T-cell lymphoproliferative etiology also has been considered based on histopathologic similarities between PLEVA and lymphomatoid papulosis (LyP) as well as findings of clonality in T-cell receptor gene rearrangement in many patients.^1,2 Some clinicians consider LyP and PLEVA as separate entities on one disease spectrum.

Eruptions of PLEVA tend to favor the trunk and proximal extremities. Lesions may begin as macules measuring 2 to 3 mm in diameter that quickly evolve into papules with fine scale that remains attached centrally. Ulcerations with hemorrhagic crusts also may be noted as the lesions progress in stage. The rash may persist for weeks to years, and overlapping crops of macules and papules at varying stages of development may be seen in the same patient.¹

Histopathologic findings of PLEVA include spongiosis, dyskeratosis, parakeratosis, and focal keratinocyte necrosis within the epidermis, as well as vacuolar degeneration of the basal layer. Lymphocyte and erythrocyte extravasation may extend into the epidermis. Dermal findings may include edema and wedge-shaped perivascular lymphocytic infiltrates extending into the reticular dermis.¹

Important differential diagnoses to consider include LyP, mycosis fungoides (MF), pemphigus foliaceus, and varicella. Lymphomatoid papulosis is a benign CD30+ lymphoproliferative disorder that is characterized by an indolent course of recurrent, often self-resolving papules that occur most frequently on the trunk, arms, and legs of older patients. There are several histologic subtypes of LyP, but the most common (type A) may manifest with wedge-shaped perivascular lymphocytic infiltrates in the dermis, similar to PLEVA. T-cell receptor gene rearrangement studies characteristically reveal clonality in LyP, and clonality has been reported in PLEVA. However, LyP demonstrates a higher cytologic grade and lacks the characteristic parakeratotic scale and superficial dermal microhemorrhage of PLEVA.³

Mycosis fungoides is a malignant lymphoproliferative disorder that is characterized by an indolent clinical course of persistent patches, plaques, or tumors of various sizes that often manifest in non–sun-exposed areas of the skin. Early stages of MF are difficult to detect histologically, but biopsies may show atypical lymphocytes with hyperchromatic, irregularly contoured nuclei arranged along the basal layer of the epidermis. Epidermal aggregates of atypical lymphocytes (also known as Pautrier microabscesses) are considered highly specific for MF. T-cell receptor and immunopathologic studies also are important adjuncts in the diagnosis of MF.⁴

Pemphigus foliaceus is an autoimmune blistering disease caused by antibodies directed against desmoglein 1, which is found in the granular layer of the epidermis. It manifests with a subtle onset of scattered crusted lesions in the seborrheic areas, such as the scalp, face, chest, and upper back. Histopathologic findings of early blisters may include acantholysis and dyskeratosis in the stratum granulosum as well as vacuolization of the granular layer. The blisters may coalesce into superficial bullae containing fibrin and neutrophils. Immunofluorescence studies that demonstrate intraepidermal C3 and IgG deposition are key to the diagnosis of pemphigus.⁵

Varicella (also known as chickenpox) manifests with crops of vesicles on an erythematous base in a centripetal distribution favoring the trunk and proximal extremities. It often is preceded by prodromal fever, malaise, and myalgia. Histopathologic evaluation of varicella is uncommon but may reveal acantholysis, multinucleation, and nuclear margination of keratinocytes. Viral culture or nucleic acid amplification testing of lesions can be used to verify the diagnosis.⁶

Most cases of PLEVA resolve without intervention.7 Treatment is directed at speeding recovery, providing symptomatic relief, and limiting permanent sequelae. Topical steroids often are used to alleviate inflammation and pruritus. Systemic antibiotics such as doxycycline, minocycline, and erythromycin have been used for their anti-inflammatory properties. Phototherapy of various wavelengths, including broadband and narrowband UVB as well as psoralen plus UVA, have led to improvements in affected patients. Refractory disease may warrant consideration of therapy with methotrexate, acitretin, dapsone, or cyclosporine.⁷

There have been rare reports of PLEVA evolving into its potentially lethal variant, febrile ulceronecrotic Mucha-Habermann disease, which is differentiated by the presence of systemic manifestations, including high fever, sore throat, diarrhea, central nervous system symptoms, abdominal pain, interstitial pneumonitis, splenomegaly, arthritis, sepsis, megaloblastic anemia, or conjunctival ulcers. The orogenital mucosa may be affected. Cutaneous lesions may rapidly progress to large, generalized, coalescent ulcers with necrotic crusts and vasculitic features on biopsy.8 Malignant transformation of PLEVA into LyP or MF rarely may occur and warrants continued follow-up of unresolved lesions.⁹

The Diagnosis: Pityriasis Lichenoides et Varioliformis Acuta

Sectioned punch biopsies were performed on the patient’s right arm. Histopathology showed acanthosis and parakeratosis in the epidermis, with vacuolar degeneration and dyskeratosis in the basal layer. Dermal changes included extravasated red blood cells in the papillary dermis as well as perivascular lymphocytic infiltrates in both the papillary and reticular dermis (Figure). Direct immunofluorescence of a perilesional biopsy using anti–human IgG, IgM, IgA, C3, and fibrin conjugates showed no findings of immune deposition. Biopsy results were consistent with pityriasis lichenoides et varioliformis acuta (PLEVA), and the patient was treated with a 5-day course of oral azithromycin, triamcinolone ointment 0.1% twice daily, and phototherapy with narrowband UVB ³ times weekly. Rapid improvement was noted at 2-month follow-up.

Pityriasis lichenoides et varioliformis acuta is a form of pityriasis lichenoides, a group of inflammatory dermatoses that are characterized clinically by successive crops of morphologically diverse lesions. Epidemiologic studies have shown a slight male predominance. It primarily affects children and young adults, with peak ages of 8 and 32 years in pediatric and adult populations, respectively.¹

The pathogenesis of PLEVA remains unclear. An abnormal immune response to Toxoplasma, Epstein-Barr virus, HIV, and other pathogens has been suggested based on serologic evidence of concurrent disease activity with the onset of lesions as well as cutaneous improvement in some patients after treatment of the infection.¹ A T-cell lymphoproliferative etiology also has been considered based on histopathologic similarities between PLEVA and lymphomatoid papulosis (LyP) as well as findings of clonality in T-cell receptor gene rearrangement in many patients.^1,2 Some clinicians consider LyP and PLEVA as separate entities on one disease spectrum.

Eruptions of PLEVA tend to favor the trunk and proximal extremities. Lesions may begin as macules measuring 2 to 3 mm in diameter that quickly evolve into papules with fine scale that remains attached centrally. Ulcerations with hemorrhagic crusts also may be noted as the lesions progress in stage. The rash may persist for weeks to years, and overlapping crops of macules and papules at varying stages of development may be seen in the same patient.¹

Histopathologic findings of PLEVA include spongiosis, dyskeratosis, parakeratosis, and focal keratinocyte necrosis within the epidermis, as well as vacuolar degeneration of the basal layer. Lymphocyte and erythrocyte extravasation may extend into the epidermis. Dermal findings may include edema and wedge-shaped perivascular lymphocytic infiltrates extending into the reticular dermis.¹

Important differential diagnoses to consider include LyP, mycosis fungoides (MF), pemphigus foliaceus, and varicella. Lymphomatoid papulosis is a benign CD30+ lymphoproliferative disorder that is characterized by an indolent course of recurrent, often self-resolving papules that occur most frequently on the trunk, arms, and legs of older patients. There are several histologic subtypes of LyP, but the most common (type A) may manifest with wedge-shaped perivascular lymphocytic infiltrates in the dermis, similar to PLEVA. T-cell receptor gene rearrangement studies characteristically reveal clonality in LyP, and clonality has been reported in PLEVA. However, LyP demonstrates a higher cytologic grade and lacks the characteristic parakeratotic scale and superficial dermal microhemorrhage of PLEVA.³

Mycosis fungoides is a malignant lymphoproliferative disorder that is characterized by an indolent clinical course of persistent patches, plaques, or tumors of various sizes that often manifest in non–sun-exposed areas of the skin. Early stages of MF are difficult to detect histologically, but biopsies may show atypical lymphocytes with hyperchromatic, irregularly contoured nuclei arranged along the basal layer of the epidermis. Epidermal aggregates of atypical lymphocytes (also known as Pautrier microabscesses) are considered highly specific for MF. T-cell receptor and immunopathologic studies also are important adjuncts in the diagnosis of MF.⁴

Pemphigus foliaceus is an autoimmune blistering disease caused by antibodies directed against desmoglein 1, which is found in the granular layer of the epidermis. It manifests with a subtle onset of scattered crusted lesions in the seborrheic areas, such as the scalp, face, chest, and upper back. Histopathologic findings of early blisters may include acantholysis and dyskeratosis in the stratum granulosum as well as vacuolization of the granular layer. The blisters may coalesce into superficial bullae containing fibrin and neutrophils. Immunofluorescence studies that demonstrate intraepidermal C3 and IgG deposition are key to the diagnosis of pemphigus.⁵

Varicella (also known as chickenpox) manifests with crops of vesicles on an erythematous base in a centripetal distribution favoring the trunk and proximal extremities. It often is preceded by prodromal fever, malaise, and myalgia. Histopathologic evaluation of varicella is uncommon but may reveal acantholysis, multinucleation, and nuclear margination of keratinocytes. Viral culture or nucleic acid amplification testing of lesions can be used to verify the diagnosis.⁶

Most cases of PLEVA resolve without intervention.7 Treatment is directed at speeding recovery, providing symptomatic relief, and limiting permanent sequelae. Topical steroids often are used to alleviate inflammation and pruritus. Systemic antibiotics such as doxycycline, minocycline, and erythromycin have been used for their anti-inflammatory properties. Phototherapy of various wavelengths, including broadband and narrowband UVB as well as psoralen plus UVA, have led to improvements in affected patients. Refractory disease may warrant consideration of therapy with methotrexate, acitretin, dapsone, or cyclosporine.⁷

There have been rare reports of PLEVA evolving into its potentially lethal variant, febrile ulceronecrotic Mucha-Habermann disease, which is differentiated by the presence of systemic manifestations, including high fever, sore throat, diarrhea, central nervous system symptoms, abdominal pain, interstitial pneumonitis, splenomegaly, arthritis, sepsis, megaloblastic anemia, or conjunctival ulcers. The orogenital mucosa may be affected. Cutaneous lesions may rapidly progress to large, generalized, coalescent ulcers with necrotic crusts and vasculitic features on biopsy.8 Malignant transformation of PLEVA into LyP or MF rarely may occur and warrants continued follow-up of unresolved lesions.⁹

The Diagnosis: Pityriasis Lichenoides et Varioliformis Acuta

Sectioned punch biopsies were performed on the patient’s right arm. Histopathology showed acanthosis and parakeratosis in the epidermis, with vacuolar degeneration and dyskeratosis in the basal layer. Dermal changes included extravasated red blood cells in the papillary dermis as well as perivascular lymphocytic infiltrates in both the papillary and reticular dermis (Figure). Direct immunofluorescence of a perilesional biopsy using anti–human IgG, IgM, IgA, C3, and fibrin conjugates showed no findings of immune deposition. Biopsy results were consistent with pityriasis lichenoides et varioliformis acuta (PLEVA), and the patient was treated with a 5-day course of oral azithromycin, triamcinolone ointment 0.1% twice daily, and phototherapy with narrowband UVB ³ times weekly. Rapid improvement was noted at 2-month follow-up.

Pityriasis lichenoides et varioliformis acuta is a form of pityriasis lichenoides, a group of inflammatory dermatoses that are characterized clinically by successive crops of morphologically diverse lesions. Epidemiologic studies have shown a slight male predominance. It primarily affects children and young adults, with peak ages of 8 and 32 years in pediatric and adult populations, respectively.¹

The pathogenesis of PLEVA remains unclear. An abnormal immune response to Toxoplasma, Epstein-Barr virus, HIV, and other pathogens has been suggested based on serologic evidence of concurrent disease activity with the onset of lesions as well as cutaneous improvement in some patients after treatment of the infection.¹ A T-cell lymphoproliferative etiology also has been considered based on histopathologic similarities between PLEVA and lymphomatoid papulosis (LyP) as well as findings of clonality in T-cell receptor gene rearrangement in many patients.^1,2 Some clinicians consider LyP and PLEVA as separate entities on one disease spectrum.

Eruptions of PLEVA tend to favor the trunk and proximal extremities. Lesions may begin as macules measuring 2 to 3 mm in diameter that quickly evolve into papules with fine scale that remains attached centrally. Ulcerations with hemorrhagic crusts also may be noted as the lesions progress in stage. The rash may persist for weeks to years, and overlapping crops of macules and papules at varying stages of development may be seen in the same patient.¹

Histopathologic findings of PLEVA include spongiosis, dyskeratosis, parakeratosis, and focal keratinocyte necrosis within the epidermis, as well as vacuolar degeneration of the basal layer. Lymphocyte and erythrocyte extravasation may extend into the epidermis. Dermal findings may include edema and wedge-shaped perivascular lymphocytic infiltrates extending into the reticular dermis.¹

Important differential diagnoses to consider include LyP, mycosis fungoides (MF), pemphigus foliaceus, and varicella. Lymphomatoid papulosis is a benign CD30+ lymphoproliferative disorder that is characterized by an indolent course of recurrent, often self-resolving papules that occur most frequently on the trunk, arms, and legs of older patients. There are several histologic subtypes of LyP, but the most common (type A) may manifest with wedge-shaped perivascular lymphocytic infiltrates in the dermis, similar to PLEVA. T-cell receptor gene rearrangement studies characteristically reveal clonality in LyP, and clonality has been reported in PLEVA. However, LyP demonstrates a higher cytologic grade and lacks the characteristic parakeratotic scale and superficial dermal microhemorrhage of PLEVA.³

Mycosis fungoides is a malignant lymphoproliferative disorder that is characterized by an indolent clinical course of persistent patches, plaques, or tumors of various sizes that often manifest in non–sun-exposed areas of the skin. Early stages of MF are difficult to detect histologically, but biopsies may show atypical lymphocytes with hyperchromatic, irregularly contoured nuclei arranged along the basal layer of the epidermis. Epidermal aggregates of atypical lymphocytes (also known as Pautrier microabscesses) are considered highly specific for MF. T-cell receptor and immunopathologic studies also are important adjuncts in the diagnosis of MF.⁴

Pemphigus foliaceus is an autoimmune blistering disease caused by antibodies directed against desmoglein 1, which is found in the granular layer of the epidermis. It manifests with a subtle onset of scattered crusted lesions in the seborrheic areas, such as the scalp, face, chest, and upper back. Histopathologic findings of early blisters may include acantholysis and dyskeratosis in the stratum granulosum as well as vacuolization of the granular layer. The blisters may coalesce into superficial bullae containing fibrin and neutrophils. Immunofluorescence studies that demonstrate intraepidermal C3 and IgG deposition are key to the diagnosis of pemphigus.⁵

Varicella (also known as chickenpox) manifests with crops of vesicles on an erythematous base in a centripetal distribution favoring the trunk and proximal extremities. It often is preceded by prodromal fever, malaise, and myalgia. Histopathologic evaluation of varicella is uncommon but may reveal acantholysis, multinucleation, and nuclear margination of keratinocytes. Viral culture or nucleic acid amplification testing of lesions can be used to verify the diagnosis.⁶

Most cases of PLEVA resolve without intervention.7 Treatment is directed at speeding recovery, providing symptomatic relief, and limiting permanent sequelae. Topical steroids often are used to alleviate inflammation and pruritus. Systemic antibiotics such as doxycycline, minocycline, and erythromycin have been used for their anti-inflammatory properties. Phototherapy of various wavelengths, including broadband and narrowband UVB as well as psoralen plus UVA, have led to improvements in affected patients. Refractory disease may warrant consideration of therapy with methotrexate, acitretin, dapsone, or cyclosporine.⁷

There have been rare reports of PLEVA evolving into its potentially lethal variant, febrile ulceronecrotic Mucha-Habermann disease, which is differentiated by the presence of systemic manifestations, including high fever, sore throat, diarrhea, central nervous system symptoms, abdominal pain, interstitial pneumonitis, splenomegaly, arthritis, sepsis, megaloblastic anemia, or conjunctival ulcers. The orogenital mucosa may be affected. Cutaneous lesions may rapidly progress to large, generalized, coalescent ulcers with necrotic crusts and vasculitic features on biopsy.8 Malignant transformation of PLEVA into LyP or MF rarely may occur and warrants continued follow-up of unresolved lesions.⁹

The Diagnosis: Brunsting-Perry Cicatricial Pemphigoid

Physical examination and histopathology are paramount in diagnosing Brunsting-Perry cicatricial pemphigoid (BPCP). In our patient, histopathology showed subepidermal blistering with a mixed superficial dermal inflammatory cell infiltrate. Direct immunofluorescence was positive for linear IgG and C3 antibodies along the basement membrane. The scarring erosions on the scalp combined with the autoantibody findings on direct immunofluorescence were consistent with BPCP. He was started on dapsone 100 mg daily and demonstrated complete resolution of symptoms after 10 months, with the exception of persistent scarring hair loss (Figure).

Brunsting-Perry cicatricial pemphigoid is a rare dermatologic condition. It was first defined in 1957 when Brunsting and Perry¹ examined 7 patients with cicatricial pemphigoid that predominantly affected the head and neck region, with occasional mucous membrane involvement but no mucosal scarring. Characteristically, BPCP manifests as scarring herpetiform plaques with varied blisters, erosions, crusts, and scarring.¹ It primarily affects middle-aged men.²

Historically, BPCP has been considered a variant of cicatricial pemphigoid (now known as mucous membrane pemphigoid), bullous pemphigoid, or epidermolysis bullosa acquisita.³ The antigen target has not been established clearly; however, autoantibodies against laminin 332, collagen VII, and BP180 and BP230 have been proposed.^2,4,5 Jacoby et al6 described BPCP on a spectrum with bullous pemphigoid and cicatricial pemphigoid, with primarily circulating autoantibodies on one end and tissue-fixed autoantibodies on the other.

The differential for BPCP also includes anti-p200 pemphigoid and anti–laminin 332 pemphigoid. Anti-p200 pemphigoid also is known as bullous pemphigoid with antibodies against the 200-kDa protein.⁷ It may clinically manifest similar to bullous pemphigoid and other subepidermal autoimmune blistering diseases; thus, immunopathologic differentiation can be helpful. Anti–laminin 332 pemphigoid (also known as anti–laminin gamma-1 pemphigoid) is characterized by autoantibodies targeting the laminin 332 protein in the basement membrane zone, resulting in blistering and erosions.⁸ Similar to BPCP and epidermolysis bullosa aquisita, anti–laminin 332 pemphigoid may affect cephalic regions and mucous membrane surfaces, resulting in scarring and cicatricial changes. Anti–laminin 332 pemphigoid also has been associated with internal malignancy.⁸ The use of the salt-split skin technique can be utilized to differentiate these entities based on their autoantibody-binding patterns in relation to the lamina densa.

Treatment options for mild BPCP include potent topical or intralesional steroids and dapsone, while more severe cases may require systemic therapy with rituximab, azathioprine, mycophenolate mofetil, or cyclophosphamide.⁴

This case highlights the importance of histopathologic examination of skin lesions with an unusual history or clinical presentation. Dermatologists should consider BPCP when presented with erosions, ulcerations, or blisters of the head and neck in middle-aged male patients.

The Diagnosis: Brunsting-Perry Cicatricial Pemphigoid

Physical examination and histopathology are paramount in diagnosing Brunsting-Perry cicatricial pemphigoid (BPCP). In our patient, histopathology showed subepidermal blistering with a mixed superficial dermal inflammatory cell infiltrate. Direct immunofluorescence was positive for linear IgG and C3 antibodies along the basement membrane. The scarring erosions on the scalp combined with the autoantibody findings on direct immunofluorescence were consistent with BPCP. He was started on dapsone 100 mg daily and demonstrated complete resolution of symptoms after 10 months, with the exception of persistent scarring hair loss (Figure).

Brunsting-Perry cicatricial pemphigoid is a rare dermatologic condition. It was first defined in 1957 when Brunsting and Perry¹ examined 7 patients with cicatricial pemphigoid that predominantly affected the head and neck region, with occasional mucous membrane involvement but no mucosal scarring. Characteristically, BPCP manifests as scarring herpetiform plaques with varied blisters, erosions, crusts, and scarring.¹ It primarily affects middle-aged men.²

Historically, BPCP has been considered a variant of cicatricial pemphigoid (now known as mucous membrane pemphigoid), bullous pemphigoid, or epidermolysis bullosa acquisita.³ The antigen target has not been established clearly; however, autoantibodies against laminin 332, collagen VII, and BP180 and BP230 have been proposed.^2,4,5 Jacoby et al6 described BPCP on a spectrum with bullous pemphigoid and cicatricial pemphigoid, with primarily circulating autoantibodies on one end and tissue-fixed autoantibodies on the other.

The differential for BPCP also includes anti-p200 pemphigoid and anti–laminin 332 pemphigoid. Anti-p200 pemphigoid also is known as bullous pemphigoid with antibodies against the 200-kDa protein.⁷ It may clinically manifest similar to bullous pemphigoid and other subepidermal autoimmune blistering diseases; thus, immunopathologic differentiation can be helpful. Anti–laminin 332 pemphigoid (also known as anti–laminin gamma-1 pemphigoid) is characterized by autoantibodies targeting the laminin 332 protein in the basement membrane zone, resulting in blistering and erosions.⁸ Similar to BPCP and epidermolysis bullosa aquisita, anti–laminin 332 pemphigoid may affect cephalic regions and mucous membrane surfaces, resulting in scarring and cicatricial changes. Anti–laminin 332 pemphigoid also has been associated with internal malignancy.⁸ The use of the salt-split skin technique can be utilized to differentiate these entities based on their autoantibody-binding patterns in relation to the lamina densa.

Treatment options for mild BPCP include potent topical or intralesional steroids and dapsone, while more severe cases may require systemic therapy with rituximab, azathioprine, mycophenolate mofetil, or cyclophosphamide.⁴

This case highlights the importance of histopathologic examination of skin lesions with an unusual history or clinical presentation. Dermatologists should consider BPCP when presented with erosions, ulcerations, or blisters of the head and neck in middle-aged male patients.

The Diagnosis: Brunsting-Perry Cicatricial Pemphigoid

Physical examination and histopathology are paramount in diagnosing Brunsting-Perry cicatricial pemphigoid (BPCP). In our patient, histopathology showed subepidermal blistering with a mixed superficial dermal inflammatory cell infiltrate. Direct immunofluorescence was positive for linear IgG and C3 antibodies along the basement membrane. The scarring erosions on the scalp combined with the autoantibody findings on direct immunofluorescence were consistent with BPCP. He was started on dapsone 100 mg daily and demonstrated complete resolution of symptoms after 10 months, with the exception of persistent scarring hair loss (Figure).

Brunsting-Perry cicatricial pemphigoid is a rare dermatologic condition. It was first defined in 1957 when Brunsting and Perry¹ examined 7 patients with cicatricial pemphigoid that predominantly affected the head and neck region, with occasional mucous membrane involvement but no mucosal scarring. Characteristically, BPCP manifests as scarring herpetiform plaques with varied blisters, erosions, crusts, and scarring.¹ It primarily affects middle-aged men.²

Historically, BPCP has been considered a variant of cicatricial pemphigoid (now known as mucous membrane pemphigoid), bullous pemphigoid, or epidermolysis bullosa acquisita.³ The antigen target has not been established clearly; however, autoantibodies against laminin 332, collagen VII, and BP180 and BP230 have been proposed.^2,4,5 Jacoby et al6 described BPCP on a spectrum with bullous pemphigoid and cicatricial pemphigoid, with primarily circulating autoantibodies on one end and tissue-fixed autoantibodies on the other.

The differential for BPCP also includes anti-p200 pemphigoid and anti–laminin 332 pemphigoid. Anti-p200 pemphigoid also is known as bullous pemphigoid with antibodies against the 200-kDa protein.⁷ It may clinically manifest similar to bullous pemphigoid and other subepidermal autoimmune blistering diseases; thus, immunopathologic differentiation can be helpful. Anti–laminin 332 pemphigoid (also known as anti–laminin gamma-1 pemphigoid) is characterized by autoantibodies targeting the laminin 332 protein in the basement membrane zone, resulting in blistering and erosions.⁸ Similar to BPCP and epidermolysis bullosa aquisita, anti–laminin 332 pemphigoid may affect cephalic regions and mucous membrane surfaces, resulting in scarring and cicatricial changes. Anti–laminin 332 pemphigoid also has been associated with internal malignancy.⁸ The use of the salt-split skin technique can be utilized to differentiate these entities based on their autoantibody-binding patterns in relation to the lamina densa.

Treatment options for mild BPCP include potent topical or intralesional steroids and dapsone, while more severe cases may require systemic therapy with rituximab, azathioprine, mycophenolate mofetil, or cyclophosphamide.⁴

This case highlights the importance of histopathologic examination of skin lesions with an unusual history or clinical presentation. Dermatologists should consider BPCP when presented with erosions, ulcerations, or blisters of the head and neck in middle-aged male patients.

The Diagnosis: Mycobacterium marinum Infection

A repeat excisional biopsy showed suppurative granulomatous dermatitis with negative stains for infectious organisms; however, tissue culture grew Mycobacterium marinum. The patient had a history of exposure to fish tanks, which are a potential habitat for nontuberculous mycobacteria. These bacteria can enter the body through a minor laceration or cut in the skin, which was likely due to her occupation and pet care activities.¹ Her fish tank exposure combined with the cutaneous findings of a long-standing indurated plaque with proximal nodular lymphangitis made M marinum infection the most likely diagnosis.²

Due to the limited specificity and sensitivity of patient symptoms, histologic staining, and direct microscopy, the gold standard for diagnosing acid-fast bacilli is tissue culture. ³ Tissue polymerase chain reaction testing is most useful in identifying the species of mycobacteria when histologic stains identify acid-fast bacilli but repeated tissue cultures are negative.⁴ With M marinum, a high clinical suspicion is needed to acquire a positive tissue culture because it needs to be grown for several weeks and at a temperature of 30 °C.⁵ Therefore, the physician should inform the laboratory if there is any suspicion for M marinum to increase the likelihood of obtaining a positive culture.

The differential diagnosis for M marinum infection includes other skin diseases that can cause nodular lymphangitis (also known as sporotrichoid spread) such as sporotrichosis, leishmaniasis, and certain bacterial and fungal infections. Although cat scratch disease, which is caused by Bartonella henselae, can appear similar to M marinum on histopathology, it clinically manifests with a single papulovesicular lesion at the site of inoculation that then forms a central eschar and resolves within a few weeks. Cat scratch disease typically causes painful lymphadenopathy, but it does not cause nodular lymphangitis or sporotrichoid spread.⁶ Sporotrichosis can have a similar clinical and histologic manifestation to M marinum infection, but the patient history typically includes exposure to Sporothrix schenckii through gardening or other contact with thorns, plants, or soil.² Cutaneous sarcoidosis can have a similar clinical appearance to M marinum infection, but nodular lymphangitis does not occur and histopathology would demonstrate noncaseating epithelioid cell granulomas.⁷ Lastly, although vegetative pyoderma gangrenosum can have some of the same histologic findings as M marinum, it typically also demonstrates sinus tract formation, which was not present in our case. Additionally, vegetative pyoderma gangrenosum manifests with a verrucous and pustular plaque that would not have lymphocutaneous spread.⁸

Treatment of cutaneous M marinum infection is guided by antibiotic susceptibility testing. One regimen is clarithromycin (500 mg twice daily⁹) plus ethambutol. ¹⁰ Treatment often entails a multidrug combination due to the high rates of antibiotic resistance. Other antibiotics that potentially can be used include rifampin, trimethoprim-sulfamethoxazole, minocycline, and quinolones. The treatment duration typically is more than 3 months, and therapy is continued for 4 to 6 weeks after the skin lesions resolve.¹¹ Excision of the lesion is reserved for patients with M marinum infection that fails to respond to antibiotic therapy.⁵

The Diagnosis: Mycobacterium marinum Infection

A repeat excisional biopsy showed suppurative granulomatous dermatitis with negative stains for infectious organisms; however, tissue culture grew Mycobacterium marinum. The patient had a history of exposure to fish tanks, which are a potential habitat for nontuberculous mycobacteria. These bacteria can enter the body through a minor laceration or cut in the skin, which was likely due to her occupation and pet care activities.¹ Her fish tank exposure combined with the cutaneous findings of a long-standing indurated plaque with proximal nodular lymphangitis made M marinum infection the most likely diagnosis.²

Due to the limited specificity and sensitivity of patient symptoms, histologic staining, and direct microscopy, the gold standard for diagnosing acid-fast bacilli is tissue culture. ³ Tissue polymerase chain reaction testing is most useful in identifying the species of mycobacteria when histologic stains identify acid-fast bacilli but repeated tissue cultures are negative.⁴ With M marinum, a high clinical suspicion is needed to acquire a positive tissue culture because it needs to be grown for several weeks and at a temperature of 30 °C.⁵ Therefore, the physician should inform the laboratory if there is any suspicion for M marinum to increase the likelihood of obtaining a positive culture.

The differential diagnosis for M marinum infection includes other skin diseases that can cause nodular lymphangitis (also known as sporotrichoid spread) such as sporotrichosis, leishmaniasis, and certain bacterial and fungal infections. Although cat scratch disease, which is caused by Bartonella henselae, can appear similar to M marinum on histopathology, it clinically manifests with a single papulovesicular lesion at the site of inoculation that then forms a central eschar and resolves within a few weeks. Cat scratch disease typically causes painful lymphadenopathy, but it does not cause nodular lymphangitis or sporotrichoid spread.⁶ Sporotrichosis can have a similar clinical and histologic manifestation to M marinum infection, but the patient history typically includes exposure to Sporothrix schenckii through gardening or other contact with thorns, plants, or soil.² Cutaneous sarcoidosis can have a similar clinical appearance to M marinum infection, but nodular lymphangitis does not occur and histopathology would demonstrate noncaseating epithelioid cell granulomas.⁷ Lastly, although vegetative pyoderma gangrenosum can have some of the same histologic findings as M marinum, it typically also demonstrates sinus tract formation, which was not present in our case. Additionally, vegetative pyoderma gangrenosum manifests with a verrucous and pustular plaque that would not have lymphocutaneous spread.⁸

Treatment of cutaneous M marinum infection is guided by antibiotic susceptibility testing. One regimen is clarithromycin (500 mg twice daily⁹) plus ethambutol. ¹⁰ Treatment often entails a multidrug combination due to the high rates of antibiotic resistance. Other antibiotics that potentially can be used include rifampin, trimethoprim-sulfamethoxazole, minocycline, and quinolones. The treatment duration typically is more than 3 months, and therapy is continued for 4 to 6 weeks after the skin lesions resolve.¹¹ Excision of the lesion is reserved for patients with M marinum infection that fails to respond to antibiotic therapy.⁵

The Diagnosis: Mycobacterium marinum Infection

A repeat excisional biopsy showed suppurative granulomatous dermatitis with negative stains for infectious organisms; however, tissue culture grew Mycobacterium marinum. The patient had a history of exposure to fish tanks, which are a potential habitat for nontuberculous mycobacteria. These bacteria can enter the body through a minor laceration or cut in the skin, which was likely due to her occupation and pet care activities.¹ Her fish tank exposure combined with the cutaneous findings of a long-standing indurated plaque with proximal nodular lymphangitis made M marinum infection the most likely diagnosis.²

Due to the limited specificity and sensitivity of patient symptoms, histologic staining, and direct microscopy, the gold standard for diagnosing acid-fast bacilli is tissue culture. ³ Tissue polymerase chain reaction testing is most useful in identifying the species of mycobacteria when histologic stains identify acid-fast bacilli but repeated tissue cultures are negative.⁴ With M marinum, a high clinical suspicion is needed to acquire a positive tissue culture because it needs to be grown for several weeks and at a temperature of 30 °C.⁵ Therefore, the physician should inform the laboratory if there is any suspicion for M marinum to increase the likelihood of obtaining a positive culture.

The differential diagnosis for M marinum infection includes other skin diseases that can cause nodular lymphangitis (also known as sporotrichoid spread) such as sporotrichosis, leishmaniasis, and certain bacterial and fungal infections. Although cat scratch disease, which is caused by Bartonella henselae, can appear similar to M marinum on histopathology, it clinically manifests with a single papulovesicular lesion at the site of inoculation that then forms a central eschar and resolves within a few weeks. Cat scratch disease typically causes painful lymphadenopathy, but it does not cause nodular lymphangitis or sporotrichoid spread.⁶ Sporotrichosis can have a similar clinical and histologic manifestation to M marinum infection, but the patient history typically includes exposure to Sporothrix schenckii through gardening or other contact with thorns, plants, or soil.² Cutaneous sarcoidosis can have a similar clinical appearance to M marinum infection, but nodular lymphangitis does not occur and histopathology would demonstrate noncaseating epithelioid cell granulomas.⁷ Lastly, although vegetative pyoderma gangrenosum can have some of the same histologic findings as M marinum, it typically also demonstrates sinus tract formation, which was not present in our case. Additionally, vegetative pyoderma gangrenosum manifests with a verrucous and pustular plaque that would not have lymphocutaneous spread.⁸

Treatment of cutaneous M marinum infection is guided by antibiotic susceptibility testing. One regimen is clarithromycin (500 mg twice daily⁹) plus ethambutol. ¹⁰ Treatment often entails a multidrug combination due to the high rates of antibiotic resistance. Other antibiotics that potentially can be used include rifampin, trimethoprim-sulfamethoxazole, minocycline, and quinolones. The treatment duration typically is more than 3 months, and therapy is continued for 4 to 6 weeks after the skin lesions resolve.¹¹ Excision of the lesion is reserved for patients with M marinum infection that fails to respond to antibiotic therapy.⁵