Dermatopathology

Case Report

A 71-year-old woman presented with pink to violaceous, flat-topped, polygonal papules consistent with lichen planus (LP) on the volar wrists, extensor elbows, and bilateral lower legs of 3 years’ duration. She also had erythematous, violaceous, infiltrated plaques with microvesiculation on the bilateral thighs of several months’ duration (Figure 1). She reported pruritus, burning, and discomfort. Her medical history included type 2 diabetes mellitus, hypertension, and asthma with no history of skin rashes. A complete physical examination was performed. Age-appropriate screening for malignancy was negative. Hepatitis B and C antibody serologies were negative. Her medications at the time included risedronate and atenolol, which she had been taking for several years.

Punch biopsies from perilesional skin were submitted for hematoxylin and eosin staining and direct immunofluorescence (DIF). Histopathology showed a subepidermal blistering disease with tissue eosinophilia consistent with lichen planus pemphigoides (LPP)(Figure 2); direct immunofluorescence was positive for IgG, C3, and type IV collagen at the dermoepidermal junction. Serum BP180 was positive at 51 U/mL (reference range, <14 U/mL) and BP230 was negative. She was then started on tetracycline (500 mg twice daily), nicotinamide (500 mg twice daily), prednisone (5 mg daily), and dapsone (100 mg daily).

After 3 months without improvement, tetracycline and nicotinamide were discontinued, prednisone was increased to 10 mg daily, and dapsone was continued. A repeat biopsy was taken from a new area of involvement on the left lower leg, which revealed a psoriasiform dermatitis with interface changes. The DIF was positive for IgG and C3 along the basement membrane. A serum indirect immunofluorescence for BP180 also was positive.

The patient developed mild hemolytic anemia on dapsone; the medication was eventually discontinued. Subsequent treatments included adequate trials of azathioprine, mycophenolate mofetil, and hydroxychloroquine. Azathioprine (150 mg daily) and hydroxychloroquine (400 mg daily) treatment failed. She initially improved on mycophenolate mofetil (500 mg in the morning and 1000 mg in the evening) with flattening of the papules on the arms and legs and decreased erythema. However, mycophenolate mofetil eventually lost its efficacy and was discontinued.

Because several medications failed (ie, tetracycline, nicotinamide, prednisone, dapsone, azathioprine, mycophenolate mofetil, hydroxychloroquine), she was started on ustekinumab (45 mg) initial loading dose by subcutaneous injection (patient’s weight, 63 kg). At 4 weeks, the patient was given the second subcutaneous injection of ustekinumab (45 mg). She experienced marked improvement with no new lesions. The prior lesions also had decreased in size and were only slightly pink. The prednisone dose was tapered to 5 mg daily.

She had near-complete resolution of the skin lesions 12 weeks after the second dose of ustekinumab. Since then, she has had some recrudescence of the papulosquamous lesions but no vesicles or bullae. With the exception of occasional scattered pink papules on the forearms, her condition greatly improved on ustekinumab. She is no longer taking any of the other medications with the exception of prednisone (down to 1 mg daily) with a plan to gradually taper completely off of it.

Comment

Clinical Presentation
Lichen planus pemphigoides is a rare autoimmune subepidermal blistering disease with few cases reported in the literature. It is considered a clinical variation of bullous pemphigoid (BP) or a coexistence of LP and BP.^1,2 It is characterized by bullous lesions developing on LP papules as well as on clinically uninvolved areas of the skin. It has been reported that LPP is provoked by several medications including cinnarizine, captopril, ramipril, simvastatin, psoralen plus UVA, and antituberculous medications (eg, isoniazid, rifampin, ethambutol, pyrazinamide).¹ Risedronate or atenolol have not been reported to cause LPP, LP, or BP; however, according to Litt,³ a lichenoid drug eruption has been associated with atenolol. Furthermore, some cases of LPP demonstrate overlapping characteristics with paraneoplastic pemphigus and have been associated with internal malignancy. Hamada et al⁴ described a case of LPP coupled with colon adenocarcinoma and numerous keratoacanthomas. The earliest depiction of the coexistence of a case of mainstream LP complicated by an extensive bullous eruption was by Kaposi⁵ in 1892. He coined the term lichen ruber pemphigoides.⁵

Compared to BP, LPP is believed to affect a younger age group and have a less serious clinical course. The mean age of onset of LPP is in the third to fourth decades of life, while BP typically presents in the sixth decade. When comparing the location of bullae in LPP versus BP, the lesions of LPP tend to occur on the limbs, while BP tends to occur on the trunk.⁶

Clinically, LPP is distinguished by the existence of bullous lesions developing atop of the lesions of LP as well as on normal skin, with the latter being more commonplace. A classic example of LPP is characterized by an initial episode of traditional LP lesions often having severe pruritus, with or without patches of erythema, with the sudden eruption of tense bullae. These bullae commonly appear on the extremities and can appear over the normal skin, erythematous patches, or preexisting papules.⁷ In the atypical clinical presentations of this dubious skin condition, the bullae may only be seen on the lesions of LP.⁸ There also could be a lichenoid erythrodermic manifestation of a bullous eruption.⁹

Oral lesions of LPP have been described but had not been studied immunopathologically until Allen et al¹⁰ portrayed a 59-year-old man with cutaneous and oral lesions of LPP. They performed biopsies on the oral lesions and examined them by routine light microscopy and immunofluorescent techniques. The fine keratotic striae on the anterior buccal mucosal lesions were clinically consistent with oral LP. Perilesional tissue in conjunction with ulceration of the posterior buccal mucosa demonstrated histologic and immunopathologic alterations consistent with BP.¹⁰

Histopathology
Histopathologically, the lesions of LP show a bandlike lymphohistiocytic infiltrate, colloid bodies in the dermis, irregular acanthosis with saw-toothed rete ridges, orthokeratosis, wedge-shaped hypergranulosis, and liquefaction degeneration of the basal layer. Direct immunofluorescence shows mainly IgM and C3 deposited on colloid bodies, fibrin, and fibrinogen.¹¹ The histopathology of the bullous lesion of LPP depicts a subepidermal bulla with variable diffuse or sparse lymphohistiocytic infiltrate and frequent eosinophils with or without neutrophils in the upper dermis. The existence of C3 alone or with IgG along the dermoepidermal junction gives confirmation on DIF.⁷

Autoantibodies
The expression of IgG autoantibodies directed against the basement membrane zone distinguishes LPP from bullous LP.² IgG autoantibodies to either one or both the 230-kDa and 180-kDa BP (type XVII collagen) antigens has been demonstrated with LPP.^4,12-14 Hamada et al⁴ described a histologic pattern more consistent with paraneoplastic pemphigus. It has been suggested that injury to the basal cells in LP or damage due to other courses of therapy such as psoralen plus UVA unveil suppressed antigenic determinants or produce new antigens, leading to antibody development and production of BP.^12,15

Zillikens et al² performed a study to identify the target antigen of LPP autoantibodies. They used sera from patients with LPP (n=4) and stained the epidermal side of salt-split human skin in a configuration identical to BP sera. In BP, the autoimmune response is directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein. They demonstrated that sera from BP patients largely reacted with a set of 4 epitopes (MCW-0 through MCW-3) grouped within a 45 amino acid stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By immunoblotting and enzyme-linked immunosorbent assay, LPP sera also were compellingly reactive with recombinant BP180 NC16A. Lichen planus pemphigoides epitopes were additionally mapped using a series of overlapping recombinant segments of the NC16A domain. The authors demonstrated that all LPP sera reacted with amino acids 46 through 59 of domain NC16A, a protein portion that was previously shown to be unreactive with BP sera. In addition, they showed that 2 LPP sera reacted with the immunodominant antigenic region related to BP. Furthermore, they identified a unique epitope within the BP180 NC16A domain—MCW-4—which was distinctively recognized by sera from patients with LPP.²

Pathogenesis
The pathogenesis of both LP and BP has been linked to multiple cytokines that induce apoptosis in basal keratinocytes. Implicated cytokines include IFN-γ, tumor necrosis factor α (TNF-α), IL-1, IL-6, and IL-8, as well as other apoptosis-related molecules, such as Fas/Apo-1 and Bcl-2 in LP.^16-18 Soluble E-selectin, vascular endothelial growth factor, IL-1β, IL-8, IL-5, transforming growth factor β1, and TNF-α were found to be elevated in either blister fluid or sera of BP patients.^15-17

Management
Lichen planus pemphigoides usually responds well to traditional therapies, with systemic steroids being the most efficacious treatment of extensive disease.^12,13 Other options include tetracycline and nicotinamide, isotretinoin, dapsone, and immunosuppressive drugs such as systemic cortico-steroids.¹² Demirçay et al¹² described a patient with skin lesions that rapidly cleared after the administration of oral methylprednisolone (48 mg/d) and oral dapsone (100 mg/d). The methylprednisolone and dapsone were withdrawn after 12 and 16 weeks, respectively. There was no recurrence during the 1-year follow-up period.¹²Kolb-Mäurer et al¹⁹ described a patient who was treated with pulsed intravenous corticosteroids and continued to develop new papular and vesicular skin lesions. However, when oral acitretin was added to the patient’s regimen, the skin lesions cleared.¹⁹ There are several case reports of the successful use of hydroxychloroquine in LP.^20,21

Cutaneous, nail, and oral LP also can be treated with TNF-α inhibitors (eg, adalimumab, etanercept) with resolution of lesions.^22-25 However, we have not been able to find any reports of treating LPP with biologic medications in a search of PubMed articles indexed for MEDLINE using the terms lichen planus pemphigoides and biologic treatments/therapies. Given the fact that TNF-α and other inflammatory cytokines are involved in the pathogenesis of BP and LP, it is feasible that they also may be involved in the pathogenesis of LPP.

In our patient with cutaneous LPP, we chose to use ustekinumab instead of a primary TNF-α inhibitor because ustekinumab indirectly blocks TNF-α, as well as other proinflammatory cytokines such as IFN-γ, IL-17, and IL-22, which also could have played a role in the patient’s disease. Our goal was to use ustekinumab as a potential corticosteroid-sparing agent. Ustekinumab greatly improved her skin condition and allowed us to discontinue other medications.

Case Report

A 71-year-old woman presented with pink to violaceous, flat-topped, polygonal papules consistent with lichen planus (LP) on the volar wrists, extensor elbows, and bilateral lower legs of 3 years’ duration. She also had erythematous, violaceous, infiltrated plaques with microvesiculation on the bilateral thighs of several months’ duration (Figure 1). She reported pruritus, burning, and discomfort. Her medical history included type 2 diabetes mellitus, hypertension, and asthma with no history of skin rashes. A complete physical examination was performed. Age-appropriate screening for malignancy was negative. Hepatitis B and C antibody serologies were negative. Her medications at the time included risedronate and atenolol, which she had been taking for several years.

Punch biopsies from perilesional skin were submitted for hematoxylin and eosin staining and direct immunofluorescence (DIF). Histopathology showed a subepidermal blistering disease with tissue eosinophilia consistent with lichen planus pemphigoides (LPP)(Figure 2); direct immunofluorescence was positive for IgG, C3, and type IV collagen at the dermoepidermal junction. Serum BP180 was positive at 51 U/mL (reference range, <14 U/mL) and BP230 was negative. She was then started on tetracycline (500 mg twice daily), nicotinamide (500 mg twice daily), prednisone (5 mg daily), and dapsone (100 mg daily).

After 3 months without improvement, tetracycline and nicotinamide were discontinued, prednisone was increased to 10 mg daily, and dapsone was continued. A repeat biopsy was taken from a new area of involvement on the left lower leg, which revealed a psoriasiform dermatitis with interface changes. The DIF was positive for IgG and C3 along the basement membrane. A serum indirect immunofluorescence for BP180 also was positive.

The patient developed mild hemolytic anemia on dapsone; the medication was eventually discontinued. Subsequent treatments included adequate trials of azathioprine, mycophenolate mofetil, and hydroxychloroquine. Azathioprine (150 mg daily) and hydroxychloroquine (400 mg daily) treatment failed. She initially improved on mycophenolate mofetil (500 mg in the morning and 1000 mg in the evening) with flattening of the papules on the arms and legs and decreased erythema. However, mycophenolate mofetil eventually lost its efficacy and was discontinued.

Because several medications failed (ie, tetracycline, nicotinamide, prednisone, dapsone, azathioprine, mycophenolate mofetil, hydroxychloroquine), she was started on ustekinumab (45 mg) initial loading dose by subcutaneous injection (patient’s weight, 63 kg). At 4 weeks, the patient was given the second subcutaneous injection of ustekinumab (45 mg). She experienced marked improvement with no new lesions. The prior lesions also had decreased in size and were only slightly pink. The prednisone dose was tapered to 5 mg daily.

She had near-complete resolution of the skin lesions 12 weeks after the second dose of ustekinumab. Since then, she has had some recrudescence of the papulosquamous lesions but no vesicles or bullae. With the exception of occasional scattered pink papules on the forearms, her condition greatly improved on ustekinumab. She is no longer taking any of the other medications with the exception of prednisone (down to 1 mg daily) with a plan to gradually taper completely off of it.

Comment

Clinical Presentation
Lichen planus pemphigoides is a rare autoimmune subepidermal blistering disease with few cases reported in the literature. It is considered a clinical variation of bullous pemphigoid (BP) or a coexistence of LP and BP.^1,2 It is characterized by bullous lesions developing on LP papules as well as on clinically uninvolved areas of the skin. It has been reported that LPP is provoked by several medications including cinnarizine, captopril, ramipril, simvastatin, psoralen plus UVA, and antituberculous medications (eg, isoniazid, rifampin, ethambutol, pyrazinamide).¹ Risedronate or atenolol have not been reported to cause LPP, LP, or BP; however, according to Litt,³ a lichenoid drug eruption has been associated with atenolol. Furthermore, some cases of LPP demonstrate overlapping characteristics with paraneoplastic pemphigus and have been associated with internal malignancy. Hamada et al⁴ described a case of LPP coupled with colon adenocarcinoma and numerous keratoacanthomas. The earliest depiction of the coexistence of a case of mainstream LP complicated by an extensive bullous eruption was by Kaposi⁵ in 1892. He coined the term lichen ruber pemphigoides.⁵

Compared to BP, LPP is believed to affect a younger age group and have a less serious clinical course. The mean age of onset of LPP is in the third to fourth decades of life, while BP typically presents in the sixth decade. When comparing the location of bullae in LPP versus BP, the lesions of LPP tend to occur on the limbs, while BP tends to occur on the trunk.⁶

Clinically, LPP is distinguished by the existence of bullous lesions developing atop of the lesions of LP as well as on normal skin, with the latter being more commonplace. A classic example of LPP is characterized by an initial episode of traditional LP lesions often having severe pruritus, with or without patches of erythema, with the sudden eruption of tense bullae. These bullae commonly appear on the extremities and can appear over the normal skin, erythematous patches, or preexisting papules.⁷ In the atypical clinical presentations of this dubious skin condition, the bullae may only be seen on the lesions of LP.⁸ There also could be a lichenoid erythrodermic manifestation of a bullous eruption.⁹

Oral lesions of LPP have been described but had not been studied immunopathologically until Allen et al¹⁰ portrayed a 59-year-old man with cutaneous and oral lesions of LPP. They performed biopsies on the oral lesions and examined them by routine light microscopy and immunofluorescent techniques. The fine keratotic striae on the anterior buccal mucosal lesions were clinically consistent with oral LP. Perilesional tissue in conjunction with ulceration of the posterior buccal mucosa demonstrated histologic and immunopathologic alterations consistent with BP.¹⁰

Histopathology
Histopathologically, the lesions of LP show a bandlike lymphohistiocytic infiltrate, colloid bodies in the dermis, irregular acanthosis with saw-toothed rete ridges, orthokeratosis, wedge-shaped hypergranulosis, and liquefaction degeneration of the basal layer. Direct immunofluorescence shows mainly IgM and C3 deposited on colloid bodies, fibrin, and fibrinogen.¹¹ The histopathology of the bullous lesion of LPP depicts a subepidermal bulla with variable diffuse or sparse lymphohistiocytic infiltrate and frequent eosinophils with or without neutrophils in the upper dermis. The existence of C3 alone or with IgG along the dermoepidermal junction gives confirmation on DIF.⁷

Autoantibodies
The expression of IgG autoantibodies directed against the basement membrane zone distinguishes LPP from bullous LP.² IgG autoantibodies to either one or both the 230-kDa and 180-kDa BP (type XVII collagen) antigens has been demonstrated with LPP.^4,12-14 Hamada et al⁴ described a histologic pattern more consistent with paraneoplastic pemphigus. It has been suggested that injury to the basal cells in LP or damage due to other courses of therapy such as psoralen plus UVA unveil suppressed antigenic determinants or produce new antigens, leading to antibody development and production of BP.^12,15

Zillikens et al² performed a study to identify the target antigen of LPP autoantibodies. They used sera from patients with LPP (n=4) and stained the epidermal side of salt-split human skin in a configuration identical to BP sera. In BP, the autoimmune response is directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein. They demonstrated that sera from BP patients largely reacted with a set of 4 epitopes (MCW-0 through MCW-3) grouped within a 45 amino acid stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By immunoblotting and enzyme-linked immunosorbent assay, LPP sera also were compellingly reactive with recombinant BP180 NC16A. Lichen planus pemphigoides epitopes were additionally mapped using a series of overlapping recombinant segments of the NC16A domain. The authors demonstrated that all LPP sera reacted with amino acids 46 through 59 of domain NC16A, a protein portion that was previously shown to be unreactive with BP sera. In addition, they showed that 2 LPP sera reacted with the immunodominant antigenic region related to BP. Furthermore, they identified a unique epitope within the BP180 NC16A domain—MCW-4—which was distinctively recognized by sera from patients with LPP.²

Pathogenesis
The pathogenesis of both LP and BP has been linked to multiple cytokines that induce apoptosis in basal keratinocytes. Implicated cytokines include IFN-γ, tumor necrosis factor α (TNF-α), IL-1, IL-6, and IL-8, as well as other apoptosis-related molecules, such as Fas/Apo-1 and Bcl-2 in LP.^16-18 Soluble E-selectin, vascular endothelial growth factor, IL-1β, IL-8, IL-5, transforming growth factor β1, and TNF-α were found to be elevated in either blister fluid or sera of BP patients.^15-17

Management
Lichen planus pemphigoides usually responds well to traditional therapies, with systemic steroids being the most efficacious treatment of extensive disease.^12,13 Other options include tetracycline and nicotinamide, isotretinoin, dapsone, and immunosuppressive drugs such as systemic cortico-steroids.¹² Demirçay et al¹² described a patient with skin lesions that rapidly cleared after the administration of oral methylprednisolone (48 mg/d) and oral dapsone (100 mg/d). The methylprednisolone and dapsone were withdrawn after 12 and 16 weeks, respectively. There was no recurrence during the 1-year follow-up period.¹²Kolb-Mäurer et al¹⁹ described a patient who was treated with pulsed intravenous corticosteroids and continued to develop new papular and vesicular skin lesions. However, when oral acitretin was added to the patient’s regimen, the skin lesions cleared.¹⁹ There are several case reports of the successful use of hydroxychloroquine in LP.^20,21

Cutaneous, nail, and oral LP also can be treated with TNF-α inhibitors (eg, adalimumab, etanercept) with resolution of lesions.^22-25 However, we have not been able to find any reports of treating LPP with biologic medications in a search of PubMed articles indexed for MEDLINE using the terms lichen planus pemphigoides and biologic treatments/therapies. Given the fact that TNF-α and other inflammatory cytokines are involved in the pathogenesis of BP and LP, it is feasible that they also may be involved in the pathogenesis of LPP.

In our patient with cutaneous LPP, we chose to use ustekinumab instead of a primary TNF-α inhibitor because ustekinumab indirectly blocks TNF-α, as well as other proinflammatory cytokines such as IFN-γ, IL-17, and IL-22, which also could have played a role in the patient’s disease. Our goal was to use ustekinumab as a potential corticosteroid-sparing agent. Ustekinumab greatly improved her skin condition and allowed us to discontinue other medications.

Case Report

A 71-year-old woman presented with pink to violaceous, flat-topped, polygonal papules consistent with lichen planus (LP) on the volar wrists, extensor elbows, and bilateral lower legs of 3 years’ duration. She also had erythematous, violaceous, infiltrated plaques with microvesiculation on the bilateral thighs of several months’ duration (Figure 1). She reported pruritus, burning, and discomfort. Her medical history included type 2 diabetes mellitus, hypertension, and asthma with no history of skin rashes. A complete physical examination was performed. Age-appropriate screening for malignancy was negative. Hepatitis B and C antibody serologies were negative. Her medications at the time included risedronate and atenolol, which she had been taking for several years.

Punch biopsies from perilesional skin were submitted for hematoxylin and eosin staining and direct immunofluorescence (DIF). Histopathology showed a subepidermal blistering disease with tissue eosinophilia consistent with lichen planus pemphigoides (LPP)(Figure 2); direct immunofluorescence was positive for IgG, C3, and type IV collagen at the dermoepidermal junction. Serum BP180 was positive at 51 U/mL (reference range, <14 U/mL) and BP230 was negative. She was then started on tetracycline (500 mg twice daily), nicotinamide (500 mg twice daily), prednisone (5 mg daily), and dapsone (100 mg daily).

After 3 months without improvement, tetracycline and nicotinamide were discontinued, prednisone was increased to 10 mg daily, and dapsone was continued. A repeat biopsy was taken from a new area of involvement on the left lower leg, which revealed a psoriasiform dermatitis with interface changes. The DIF was positive for IgG and C3 along the basement membrane. A serum indirect immunofluorescence for BP180 also was positive.

The patient developed mild hemolytic anemia on dapsone; the medication was eventually discontinued. Subsequent treatments included adequate trials of azathioprine, mycophenolate mofetil, and hydroxychloroquine. Azathioprine (150 mg daily) and hydroxychloroquine (400 mg daily) treatment failed. She initially improved on mycophenolate mofetil (500 mg in the morning and 1000 mg in the evening) with flattening of the papules on the arms and legs and decreased erythema. However, mycophenolate mofetil eventually lost its efficacy and was discontinued.

Because several medications failed (ie, tetracycline, nicotinamide, prednisone, dapsone, azathioprine, mycophenolate mofetil, hydroxychloroquine), she was started on ustekinumab (45 mg) initial loading dose by subcutaneous injection (patient’s weight, 63 kg). At 4 weeks, the patient was given the second subcutaneous injection of ustekinumab (45 mg). She experienced marked improvement with no new lesions. The prior lesions also had decreased in size and were only slightly pink. The prednisone dose was tapered to 5 mg daily.

She had near-complete resolution of the skin lesions 12 weeks after the second dose of ustekinumab. Since then, she has had some recrudescence of the papulosquamous lesions but no vesicles or bullae. With the exception of occasional scattered pink papules on the forearms, her condition greatly improved on ustekinumab. She is no longer taking any of the other medications with the exception of prednisone (down to 1 mg daily) with a plan to gradually taper completely off of it.

Comment

Clinical Presentation
Lichen planus pemphigoides is a rare autoimmune subepidermal blistering disease with few cases reported in the literature. It is considered a clinical variation of bullous pemphigoid (BP) or a coexistence of LP and BP.^1,2 It is characterized by bullous lesions developing on LP papules as well as on clinically uninvolved areas of the skin. It has been reported that LPP is provoked by several medications including cinnarizine, captopril, ramipril, simvastatin, psoralen plus UVA, and antituberculous medications (eg, isoniazid, rifampin, ethambutol, pyrazinamide).¹ Risedronate or atenolol have not been reported to cause LPP, LP, or BP; however, according to Litt,³ a lichenoid drug eruption has been associated with atenolol. Furthermore, some cases of LPP demonstrate overlapping characteristics with paraneoplastic pemphigus and have been associated with internal malignancy. Hamada et al⁴ described a case of LPP coupled with colon adenocarcinoma and numerous keratoacanthomas. The earliest depiction of the coexistence of a case of mainstream LP complicated by an extensive bullous eruption was by Kaposi⁵ in 1892. He coined the term lichen ruber pemphigoides.⁵

Compared to BP, LPP is believed to affect a younger age group and have a less serious clinical course. The mean age of onset of LPP is in the third to fourth decades of life, while BP typically presents in the sixth decade. When comparing the location of bullae in LPP versus BP, the lesions of LPP tend to occur on the limbs, while BP tends to occur on the trunk.⁶

Clinically, LPP is distinguished by the existence of bullous lesions developing atop of the lesions of LP as well as on normal skin, with the latter being more commonplace. A classic example of LPP is characterized by an initial episode of traditional LP lesions often having severe pruritus, with or without patches of erythema, with the sudden eruption of tense bullae. These bullae commonly appear on the extremities and can appear over the normal skin, erythematous patches, or preexisting papules.⁷ In the atypical clinical presentations of this dubious skin condition, the bullae may only be seen on the lesions of LP.⁸ There also could be a lichenoid erythrodermic manifestation of a bullous eruption.⁹

Oral lesions of LPP have been described but had not been studied immunopathologically until Allen et al¹⁰ portrayed a 59-year-old man with cutaneous and oral lesions of LPP. They performed biopsies on the oral lesions and examined them by routine light microscopy and immunofluorescent techniques. The fine keratotic striae on the anterior buccal mucosal lesions were clinically consistent with oral LP. Perilesional tissue in conjunction with ulceration of the posterior buccal mucosa demonstrated histologic and immunopathologic alterations consistent with BP.¹⁰

Histopathology
Histopathologically, the lesions of LP show a bandlike lymphohistiocytic infiltrate, colloid bodies in the dermis, irregular acanthosis with saw-toothed rete ridges, orthokeratosis, wedge-shaped hypergranulosis, and liquefaction degeneration of the basal layer. Direct immunofluorescence shows mainly IgM and C3 deposited on colloid bodies, fibrin, and fibrinogen.¹¹ The histopathology of the bullous lesion of LPP depicts a subepidermal bulla with variable diffuse or sparse lymphohistiocytic infiltrate and frequent eosinophils with or without neutrophils in the upper dermis. The existence of C3 alone or with IgG along the dermoepidermal junction gives confirmation on DIF.⁷

Autoantibodies
The expression of IgG autoantibodies directed against the basement membrane zone distinguishes LPP from bullous LP.² IgG autoantibodies to either one or both the 230-kDa and 180-kDa BP (type XVII collagen) antigens has been demonstrated with LPP.^4,12-14 Hamada et al⁴ described a histologic pattern more consistent with paraneoplastic pemphigus. It has been suggested that injury to the basal cells in LP or damage due to other courses of therapy such as psoralen plus UVA unveil suppressed antigenic determinants or produce new antigens, leading to antibody development and production of BP.^12,15

Zillikens et al² performed a study to identify the target antigen of LPP autoantibodies. They used sera from patients with LPP (n=4) and stained the epidermal side of salt-split human skin in a configuration identical to BP sera. In BP, the autoimmune response is directed against BP180, a hemidesmosomal transmembrane collagenous glycoprotein. They demonstrated that sera from BP patients largely reacted with a set of 4 epitopes (MCW-0 through MCW-3) grouped within a 45 amino acid stretch of the major noncollagenous extracellular domain (NC16A) of BP180. By immunoblotting and enzyme-linked immunosorbent assay, LPP sera also were compellingly reactive with recombinant BP180 NC16A. Lichen planus pemphigoides epitopes were additionally mapped using a series of overlapping recombinant segments of the NC16A domain. The authors demonstrated that all LPP sera reacted with amino acids 46 through 59 of domain NC16A, a protein portion that was previously shown to be unreactive with BP sera. In addition, they showed that 2 LPP sera reacted with the immunodominant antigenic region related to BP. Furthermore, they identified a unique epitope within the BP180 NC16A domain—MCW-4—which was distinctively recognized by sera from patients with LPP.²

Pathogenesis
The pathogenesis of both LP and BP has been linked to multiple cytokines that induce apoptosis in basal keratinocytes. Implicated cytokines include IFN-γ, tumor necrosis factor α (TNF-α), IL-1, IL-6, and IL-8, as well as other apoptosis-related molecules, such as Fas/Apo-1 and Bcl-2 in LP.^16-18 Soluble E-selectin, vascular endothelial growth factor, IL-1β, IL-8, IL-5, transforming growth factor β1, and TNF-α were found to be elevated in either blister fluid or sera of BP patients.^15-17

Management
Lichen planus pemphigoides usually responds well to traditional therapies, with systemic steroids being the most efficacious treatment of extensive disease.^12,13 Other options include tetracycline and nicotinamide, isotretinoin, dapsone, and immunosuppressive drugs such as systemic cortico-steroids.¹² Demirçay et al¹² described a patient with skin lesions that rapidly cleared after the administration of oral methylprednisolone (48 mg/d) and oral dapsone (100 mg/d). The methylprednisolone and dapsone were withdrawn after 12 and 16 weeks, respectively. There was no recurrence during the 1-year follow-up period.¹²Kolb-Mäurer et al¹⁹ described a patient who was treated with pulsed intravenous corticosteroids and continued to develop new papular and vesicular skin lesions. However, when oral acitretin was added to the patient’s regimen, the skin lesions cleared.¹⁹ There are several case reports of the successful use of hydroxychloroquine in LP.^20,21

Cutaneous, nail, and oral LP also can be treated with TNF-α inhibitors (eg, adalimumab, etanercept) with resolution of lesions.^22-25 However, we have not been able to find any reports of treating LPP with biologic medications in a search of PubMed articles indexed for MEDLINE using the terms lichen planus pemphigoides and biologic treatments/therapies. Given the fact that TNF-α and other inflammatory cytokines are involved in the pathogenesis of BP and LP, it is feasible that they also may be involved in the pathogenesis of LPP.

In our patient with cutaneous LPP, we chose to use ustekinumab instead of a primary TNF-α inhibitor because ustekinumab indirectly blocks TNF-α, as well as other proinflammatory cytokines such as IFN-γ, IL-17, and IL-22, which also could have played a role in the patient’s disease. Our goal was to use ustekinumab as a potential corticosteroid-sparing agent. Ustekinumab greatly improved her skin condition and allowed us to discontinue other medications.

Multinucleate cell angiohistiocytoma (MCAH) is a rare benign, soft-tissue tumor first described in 1985 by Smith and Jones¹ that presents clinically as erythematous to violaceous papules most commonly affecting females on the dorsal aspect of the hands and face.² Multinucleate cell angiohistiocytoma is histologically characterized by vascular and histiocytic proliferations with dermal fibrosis. Few cases have been reported of lesions affecting the lower extremities. We report a case of MCAH affecting the legs.

Case Report

An 83-year-old white man with a history of basal cell carcinoma presented for evaluation of grouped, well-circumscribed, soft, red-violet, painless papules on the right anterior thigh that had been present for 8 months (Figure 1A). A review of symptoms was negative for immunologic, respiratory, and hematologic changes. The patient’s medical history also was remarkable for prostate cancer treated with radiation 18 years prior as well as right hip and left knee implants. The initial clinical impression was Kaposi sarcoma or a granulomatous disorder.

Histopathologic evaluation of a deep shave biopsy initially determined the lesion to be scar tissue without other pathologic findings. The patient returned to the clinic 12 months later for a complete skin examination given his history of skin cancer. Compared to clinical photographs taken a year prior, new violaceous papules were noted on the right thigh (Figure 1B) and left calf. Furthermore, there was no recurrence of the lesion at the prior biopsy site. Shave biopsies of the papules on the right thigh and left calf demonstrated similar histologic findings to each other. There was a mild increase in the number of small blood vessels in the superficial dermis (Figure 2A). A mild perivascular lymphocytic infiltrate surrounded some of these blood vessels. The endothelial cells had small nuclei with no evidence of nuclear pleomorphism. Careful examination of the interstitial dermis revealed scattered multinucleate cells with angulated cytoplasm (Figure 2B). Immunostaining for CD31 and human herpesvirus 8 were negative, excluding an infiltrative vascular tumor and Kaposi sarcoma, respectively. The diagnosis of MCAH was made based on the histopathologic findings.

At 1-year follow-up, the condition was stable with no gross changes in the lesions based on prior photographs. Once again, there was no recurrence of the excised lesions at both biopsy sites.

Comment

Presentation
A systematic review of published reports determined that 79% of MCAH cases occur in females, with an average age of onset of 50.1 years.² However, MCAH likely is underreported due to the overall lack of knowledge regarding this condition by physicians and pathologists. The hands and face are the most commonly affected areas, though other sites of involvement have been reported, including the lower extremities,^3,4 oral mucosa and upper lip,^5,6 and trunk,^7,8 as well as generalized distribution.^9-12 Additionally, 1 case presented as a single plaque on the trunk rather than having papular or nodular morphology.⁸ Multinucleate cell angiohistiocytoma lesions generally are asymptomatic, though pruritus may be present.¹³ The condition is regarded as benign, though a minority of cases have exhibited spontaneous resolution.^14-16

Histopathology
Multinucleate cell angiohistiocytoma histology demonstrates full-thickness dermal microvessel proliferation and fibrosis with characteristic multinucleate giant cells.^2,3 Vascular endothelial cells stained positive for CD68 in 60% of cases² as well as the normal endothelial markers (ie, factor VIII, CD31, CD34). The multinucleate giant cells exhibit immunoreactivity for macrophage/histiocytic markers factor XIIIa and CD68.

Etiology
The pathogenesis of MCAH is not yet fully understood, but it is considered to be a benign vascular or fibrohistiocytic neoplasm.¹⁷ Calderaro et al¹⁸ described a series of 8 patients who developed MCAH either within a cutaneous neoplastic process or in conjunction with various cutaneous reactive conditions, including hidradenitis suppurativa and chronic radiation dermatitis, as well as overlying a bone prosthesis placed due to degenerative arthritis. These cases suggest that MCAH, or possibly a subset of the disease, is a reactive process. Suggested inciting events include cancer with stromal inflammatory reaction, chronic inflammation (as seen in hidradenitis suppurativa), chronic radiation dermatitis, scarring, and vascular injury.¹⁸ Retrospective immunohistochemical evaluation of a series of MCAH cases demonstrated intralesional spindle cells to strongly express estrogen receptor alpha and factor XIIIa. Additionally, these cells sparsely expressed progesterone receptor and demonstrated no vascular endothelial growth factor immunoreactivity.¹⁹ This immunohistochemical profile supports MCAH as a distinct entity from dermatofibromas. These findings also suggest a role of hormone signaling, namely estrogen receptor alpha, in MCAH tumor biology and may offer an explanation for the predilection of MCAH in females. Furthermore, estrogen receptor positivity offers a possible mechanism for the highly vascular nature of the lesions, considering the angiogenic properties of estrogen signaling.²⁰ In a systematic review of 142 published cases of MCAH, CD68 positivity on multinucleate cells in MCAH lesions suggested a fibrohistiocytic origin.² However, a number of these cases exhibited CD34 positivity, thus a macrophage origin may not be excluded.

Differential Diagnosis
The differential diagnosis for MCAH includes Kaposi sarcoma clinically and dermatofibroma and fibrous papules histologically. Sass et al²¹ determined the in vitro behavior of cultured MCAH cells to contrast markedly with Kaposi sarcoma–derived cells. Although Kaposi sarcoma–derived cells exhibited invasive behavior, cells isolated from MCAH lesions were less elongated and were unable to traverse basement membranes.

Treatment
Surgical excision or cryotherapy appear to be definitive treatments of MCAH; however, a number of cases have reported light and laser modalities as successful alternatives to excision. One case of MCAH affecting the face was treated with pulsed dye laser monotherapy.²² This modality allowed selective coagulation of the vascular structures in MCAH. At 8-month follow-up, the initial lesion was noted to be completely cleared, though similar lesions had recently appeared elsewhere on the face.²² Another case of MCAH affecting the leg was treated with pulsed dye laser and both topical and intralesional corticosteroid combination therapy. In this case, the lesion failed to respond to treatment, which may suggest that facial localization could influence response in pulsed dye laser treatment.³

Intense pulsed light also has been reported as a definitive treatment in 2 cases.^2,13 Slight erythema and transient pruritus have been reported immediately following treatment. In this case, complete resolution with only residual hyperpigmentation was reported at 2-month follow-up, with no recurrence during 12 months of follow-up.¹³

Argon laser therapy has been used in 2 cases. After a single session, lesions were no longer palpable, with no scarring noted at 8 weeks follow-up.²³ Lastly, 2 cases of MCAH have been successfully treated with the CO₂ laser, with no relapse noted at 2.5- or 5-month follow-up, respectively.²⁴

Conclusion

Multinucleate cell angiohistiocytoma is a rare and likely underdiagnosed dermatologic condition that is believed to be a reactive process. Characteristic histology of MCAH demonstrates microvascular proliferations of the dermis with multinucleate giant cells amidst a fibrous background. Although surgical excision is curative, there are reports in which laser and light therapies were used to effectively treat MCAH.

Multinucleate cell angiohistiocytoma (MCAH) is a rare benign, soft-tissue tumor first described in 1985 by Smith and Jones¹ that presents clinically as erythematous to violaceous papules most commonly affecting females on the dorsal aspect of the hands and face.² Multinucleate cell angiohistiocytoma is histologically characterized by vascular and histiocytic proliferations with dermal fibrosis. Few cases have been reported of lesions affecting the lower extremities. We report a case of MCAH affecting the legs.

Case Report

An 83-year-old white man with a history of basal cell carcinoma presented for evaluation of grouped, well-circumscribed, soft, red-violet, painless papules on the right anterior thigh that had been present for 8 months (Figure 1A). A review of symptoms was negative for immunologic, respiratory, and hematologic changes. The patient’s medical history also was remarkable for prostate cancer treated with radiation 18 years prior as well as right hip and left knee implants. The initial clinical impression was Kaposi sarcoma or a granulomatous disorder.

Histopathologic evaluation of a deep shave biopsy initially determined the lesion to be scar tissue without other pathologic findings. The patient returned to the clinic 12 months later for a complete skin examination given his history of skin cancer. Compared to clinical photographs taken a year prior, new violaceous papules were noted on the right thigh (Figure 1B) and left calf. Furthermore, there was no recurrence of the lesion at the prior biopsy site. Shave biopsies of the papules on the right thigh and left calf demonstrated similar histologic findings to each other. There was a mild increase in the number of small blood vessels in the superficial dermis (Figure 2A). A mild perivascular lymphocytic infiltrate surrounded some of these blood vessels. The endothelial cells had small nuclei with no evidence of nuclear pleomorphism. Careful examination of the interstitial dermis revealed scattered multinucleate cells with angulated cytoplasm (Figure 2B). Immunostaining for CD31 and human herpesvirus 8 were negative, excluding an infiltrative vascular tumor and Kaposi sarcoma, respectively. The diagnosis of MCAH was made based on the histopathologic findings.

At 1-year follow-up, the condition was stable with no gross changes in the lesions based on prior photographs. Once again, there was no recurrence of the excised lesions at both biopsy sites.

Comment

Presentation
A systematic review of published reports determined that 79% of MCAH cases occur in females, with an average age of onset of 50.1 years.² However, MCAH likely is underreported due to the overall lack of knowledge regarding this condition by physicians and pathologists. The hands and face are the most commonly affected areas, though other sites of involvement have been reported, including the lower extremities,^3,4 oral mucosa and upper lip,^5,6 and trunk,^7,8 as well as generalized distribution.^9-12 Additionally, 1 case presented as a single plaque on the trunk rather than having papular or nodular morphology.⁸ Multinucleate cell angiohistiocytoma lesions generally are asymptomatic, though pruritus may be present.¹³ The condition is regarded as benign, though a minority of cases have exhibited spontaneous resolution.^14-16

Histopathology
Multinucleate cell angiohistiocytoma histology demonstrates full-thickness dermal microvessel proliferation and fibrosis with characteristic multinucleate giant cells.^2,3 Vascular endothelial cells stained positive for CD68 in 60% of cases² as well as the normal endothelial markers (ie, factor VIII, CD31, CD34). The multinucleate giant cells exhibit immunoreactivity for macrophage/histiocytic markers factor XIIIa and CD68.

Etiology
The pathogenesis of MCAH is not yet fully understood, but it is considered to be a benign vascular or fibrohistiocytic neoplasm.¹⁷ Calderaro et al¹⁸ described a series of 8 patients who developed MCAH either within a cutaneous neoplastic process or in conjunction with various cutaneous reactive conditions, including hidradenitis suppurativa and chronic radiation dermatitis, as well as overlying a bone prosthesis placed due to degenerative arthritis. These cases suggest that MCAH, or possibly a subset of the disease, is a reactive process. Suggested inciting events include cancer with stromal inflammatory reaction, chronic inflammation (as seen in hidradenitis suppurativa), chronic radiation dermatitis, scarring, and vascular injury.¹⁸ Retrospective immunohistochemical evaluation of a series of MCAH cases demonstrated intralesional spindle cells to strongly express estrogen receptor alpha and factor XIIIa. Additionally, these cells sparsely expressed progesterone receptor and demonstrated no vascular endothelial growth factor immunoreactivity.¹⁹ This immunohistochemical profile supports MCAH as a distinct entity from dermatofibromas. These findings also suggest a role of hormone signaling, namely estrogen receptor alpha, in MCAH tumor biology and may offer an explanation for the predilection of MCAH in females. Furthermore, estrogen receptor positivity offers a possible mechanism for the highly vascular nature of the lesions, considering the angiogenic properties of estrogen signaling.²⁰ In a systematic review of 142 published cases of MCAH, CD68 positivity on multinucleate cells in MCAH lesions suggested a fibrohistiocytic origin.² However, a number of these cases exhibited CD34 positivity, thus a macrophage origin may not be excluded.

Differential Diagnosis
The differential diagnosis for MCAH includes Kaposi sarcoma clinically and dermatofibroma and fibrous papules histologically. Sass et al²¹ determined the in vitro behavior of cultured MCAH cells to contrast markedly with Kaposi sarcoma–derived cells. Although Kaposi sarcoma–derived cells exhibited invasive behavior, cells isolated from MCAH lesions were less elongated and were unable to traverse basement membranes.

Treatment
Surgical excision or cryotherapy appear to be definitive treatments of MCAH; however, a number of cases have reported light and laser modalities as successful alternatives to excision. One case of MCAH affecting the face was treated with pulsed dye laser monotherapy.²² This modality allowed selective coagulation of the vascular structures in MCAH. At 8-month follow-up, the initial lesion was noted to be completely cleared, though similar lesions had recently appeared elsewhere on the face.²² Another case of MCAH affecting the leg was treated with pulsed dye laser and both topical and intralesional corticosteroid combination therapy. In this case, the lesion failed to respond to treatment, which may suggest that facial localization could influence response in pulsed dye laser treatment.³

Intense pulsed light also has been reported as a definitive treatment in 2 cases.^2,13 Slight erythema and transient pruritus have been reported immediately following treatment. In this case, complete resolution with only residual hyperpigmentation was reported at 2-month follow-up, with no recurrence during 12 months of follow-up.¹³

Argon laser therapy has been used in 2 cases. After a single session, lesions were no longer palpable, with no scarring noted at 8 weeks follow-up.²³ Lastly, 2 cases of MCAH have been successfully treated with the CO₂ laser, with no relapse noted at 2.5- or 5-month follow-up, respectively.²⁴

Conclusion

Multinucleate cell angiohistiocytoma is a rare and likely underdiagnosed dermatologic condition that is believed to be a reactive process. Characteristic histology of MCAH demonstrates microvascular proliferations of the dermis with multinucleate giant cells amidst a fibrous background. Although surgical excision is curative, there are reports in which laser and light therapies were used to effectively treat MCAH.

Multinucleate cell angiohistiocytoma (MCAH) is a rare benign, soft-tissue tumor first described in 1985 by Smith and Jones¹ that presents clinically as erythematous to violaceous papules most commonly affecting females on the dorsal aspect of the hands and face.² Multinucleate cell angiohistiocytoma is histologically characterized by vascular and histiocytic proliferations with dermal fibrosis. Few cases have been reported of lesions affecting the lower extremities. We report a case of MCAH affecting the legs.

Case Report

An 83-year-old white man with a history of basal cell carcinoma presented for evaluation of grouped, well-circumscribed, soft, red-violet, painless papules on the right anterior thigh that had been present for 8 months (Figure 1A). A review of symptoms was negative for immunologic, respiratory, and hematologic changes. The patient’s medical history also was remarkable for prostate cancer treated with radiation 18 years prior as well as right hip and left knee implants. The initial clinical impression was Kaposi sarcoma or a granulomatous disorder.

Histopathologic evaluation of a deep shave biopsy initially determined the lesion to be scar tissue without other pathologic findings. The patient returned to the clinic 12 months later for a complete skin examination given his history of skin cancer. Compared to clinical photographs taken a year prior, new violaceous papules were noted on the right thigh (Figure 1B) and left calf. Furthermore, there was no recurrence of the lesion at the prior biopsy site. Shave biopsies of the papules on the right thigh and left calf demonstrated similar histologic findings to each other. There was a mild increase in the number of small blood vessels in the superficial dermis (Figure 2A). A mild perivascular lymphocytic infiltrate surrounded some of these blood vessels. The endothelial cells had small nuclei with no evidence of nuclear pleomorphism. Careful examination of the interstitial dermis revealed scattered multinucleate cells with angulated cytoplasm (Figure 2B). Immunostaining for CD31 and human herpesvirus 8 were negative, excluding an infiltrative vascular tumor and Kaposi sarcoma, respectively. The diagnosis of MCAH was made based on the histopathologic findings.

At 1-year follow-up, the condition was stable with no gross changes in the lesions based on prior photographs. Once again, there was no recurrence of the excised lesions at both biopsy sites.

Comment

Presentation
A systematic review of published reports determined that 79% of MCAH cases occur in females, with an average age of onset of 50.1 years.² However, MCAH likely is underreported due to the overall lack of knowledge regarding this condition by physicians and pathologists. The hands and face are the most commonly affected areas, though other sites of involvement have been reported, including the lower extremities,^3,4 oral mucosa and upper lip,^5,6 and trunk,^7,8 as well as generalized distribution.^9-12 Additionally, 1 case presented as a single plaque on the trunk rather than having papular or nodular morphology.⁸ Multinucleate cell angiohistiocytoma lesions generally are asymptomatic, though pruritus may be present.¹³ The condition is regarded as benign, though a minority of cases have exhibited spontaneous resolution.^14-16

Histopathology
Multinucleate cell angiohistiocytoma histology demonstrates full-thickness dermal microvessel proliferation and fibrosis with characteristic multinucleate giant cells.^2,3 Vascular endothelial cells stained positive for CD68 in 60% of cases² as well as the normal endothelial markers (ie, factor VIII, CD31, CD34). The multinucleate giant cells exhibit immunoreactivity for macrophage/histiocytic markers factor XIIIa and CD68.

Etiology
The pathogenesis of MCAH is not yet fully understood, but it is considered to be a benign vascular or fibrohistiocytic neoplasm.¹⁷ Calderaro et al¹⁸ described a series of 8 patients who developed MCAH either within a cutaneous neoplastic process or in conjunction with various cutaneous reactive conditions, including hidradenitis suppurativa and chronic radiation dermatitis, as well as overlying a bone prosthesis placed due to degenerative arthritis. These cases suggest that MCAH, or possibly a subset of the disease, is a reactive process. Suggested inciting events include cancer with stromal inflammatory reaction, chronic inflammation (as seen in hidradenitis suppurativa), chronic radiation dermatitis, scarring, and vascular injury.¹⁸ Retrospective immunohistochemical evaluation of a series of MCAH cases demonstrated intralesional spindle cells to strongly express estrogen receptor alpha and factor XIIIa. Additionally, these cells sparsely expressed progesterone receptor and demonstrated no vascular endothelial growth factor immunoreactivity.¹⁹ This immunohistochemical profile supports MCAH as a distinct entity from dermatofibromas. These findings also suggest a role of hormone signaling, namely estrogen receptor alpha, in MCAH tumor biology and may offer an explanation for the predilection of MCAH in females. Furthermore, estrogen receptor positivity offers a possible mechanism for the highly vascular nature of the lesions, considering the angiogenic properties of estrogen signaling.²⁰ In a systematic review of 142 published cases of MCAH, CD68 positivity on multinucleate cells in MCAH lesions suggested a fibrohistiocytic origin.² However, a number of these cases exhibited CD34 positivity, thus a macrophage origin may not be excluded.

Differential Diagnosis
The differential diagnosis for MCAH includes Kaposi sarcoma clinically and dermatofibroma and fibrous papules histologically. Sass et al²¹ determined the in vitro behavior of cultured MCAH cells to contrast markedly with Kaposi sarcoma–derived cells. Although Kaposi sarcoma–derived cells exhibited invasive behavior, cells isolated from MCAH lesions were less elongated and were unable to traverse basement membranes.

Treatment
Surgical excision or cryotherapy appear to be definitive treatments of MCAH; however, a number of cases have reported light and laser modalities as successful alternatives to excision. One case of MCAH affecting the face was treated with pulsed dye laser monotherapy.²² This modality allowed selective coagulation of the vascular structures in MCAH. At 8-month follow-up, the initial lesion was noted to be completely cleared, though similar lesions had recently appeared elsewhere on the face.²² Another case of MCAH affecting the leg was treated with pulsed dye laser and both topical and intralesional corticosteroid combination therapy. In this case, the lesion failed to respond to treatment, which may suggest that facial localization could influence response in pulsed dye laser treatment.³

Intense pulsed light also has been reported as a definitive treatment in 2 cases.^2,13 Slight erythema and transient pruritus have been reported immediately following treatment. In this case, complete resolution with only residual hyperpigmentation was reported at 2-month follow-up, with no recurrence during 12 months of follow-up.¹³

Argon laser therapy has been used in 2 cases. After a single session, lesions were no longer palpable, with no scarring noted at 8 weeks follow-up.²³ Lastly, 2 cases of MCAH have been successfully treated with the CO₂ laser, with no relapse noted at 2.5- or 5-month follow-up, respectively.²⁴

Conclusion

Multinucleate cell angiohistiocytoma is a rare and likely underdiagnosed dermatologic condition that is believed to be a reactive process. Characteristic histology of MCAH demonstrates microvascular proliferations of the dermis with multinucleate giant cells amidst a fibrous background. Although surgical excision is curative, there are reports in which laser and light therapies were used to effectively treat MCAH.

The Diagnosis: Fibroblastic Rheumatism

Routine histologic sections stained with hematoxylin and eosin demonstrated a noncircumscribed dermal proliferation of fibroblasts and myofibroblasts with thickened collagen bundles (Figure, A and B). Focally fragmented elastin fibers were noted with Verhoeff elastic tissue stain. Alcian blue stain did not show increased dermal mucin. With the clinical presentation and histologic findings described, we diagnosed the patient with fibroblastic rheumatism (FR). To date, the patient's condition has stabilized overall with skin lesions fading and minimal to no joint pain. Current therapies include adalimumab, mycophenolate mofetil 500 mg 3 times daily, and low-dose prednisone.

Fibroblastic rheumatism is a rare arthropathy with cutaneous findings initially described by Chaouat et al¹ in 1980. Age of onset varies, and the condition also has been observed in pediatric patients.² Fibroblastic rheumatism is characterized by sudden onset of firm, flesh-colored, subcutaneous nodules on periungual and periarticular surfaces.² Neck lesions rarely are described,^2-4 and cordlike plaques previously have not been reported in FR. Typically, patients develop diffusely swollen fingers, palmar thickening, sclerodactyly, and contractures. The eruption may be accompanied by Raynaud phenomenon as well as a progressive symmetric erosive arthropathy.^2,5

The clinical course in FR is variable. The cutaneous findings spontaneously may regress in months to years.^3,4 However, polyarthropathy often is destructive and progresses to disability.³ Response to therapy has been unpredictable, and the following treatments have been tried, generally with poor efficacy: aspirin, nonsteroidal anti-inflammatory drugs, hydroxychloroquine, colchicine, methotrexate, prednisone, infliximab, D-penicillamine, interferon alfa, and intensive physical therapy.^2-4,6 Histologic characteristics may include thickened collagen bundles along with a fibroblastic and myofibroblastic proliferation. Elastic fibers may be decreased or absent.^2,3,5

Clinical and histologic features in FR may mimic other entities; thus, clinical pathological correlation is essential in determining the correct diagnosis. Considerations in the differential diagnoses include multicentric reticulohistiocytosis (MRH), palisaded neutrophilic and granulomatous dermatitis, and scleroderma.

In MRH, a symmetric erosive arthritis of mainly distal interphalangeal joints typically precedes the cutaneous disease. Occurrence of arthritis mutilans is reported in approximately half of patients.⁴ Cutaneous manifestations typically include the presence of coral bead-like papules and nodules over the dorsal aspect of the hands, face, and neck. Unlike FR, MRH has a concomitant autoimmune disease in up to 20% of cases and an associated malignancy in up to 31% of cases, with breast and ovarian carcinomas most common. On histology, MRH is characterized by a nodular infiltrate of histiocytes and multinucleated giant cells with eosinophilic ground-glass cytoplasm.⁴ No notable collagen changes or fibroblastic proliferations typically are present.

Palisaded neutrophilic and granulomatous dermatitis, usually associated with rheumatoid arthritis or connective tissue disease, classically presents as annular plaques and indurated linear bands over the trunk and extremities. However, its clinical presentation is quite variable and may include pink to violaceous urticarialike; livedoid-appearing; or nonspecific papules, plaques, or nodules. Histology in palisaded neutrophilic and granulomatous dermatitis shows a dense dermal neutrophilic infiltrate associated with interstitial histiocytes having a palisading arrangement around degenerated collagen.⁷ No fibroblastic proliferation typically is present.

Scleroderma can be distinguished based on additional clinical and laboratory findings as well as histology showing thickened collagen bundles without fibroblastic proliferation.2 The histologic findings also may suggest inclusion of dermatofibroma or a scar in the differential diagnosis, though the clinical presentation of these entities would not support these diagnoses.  
 
Acknowledgments
We thank the patient for granting permission to share this information. We also thank Sheng Chen, MD, PhD (Lake Success, New York), for his dermatopathological contributions to the case.

The Diagnosis: Fibroblastic Rheumatism

Routine histologic sections stained with hematoxylin and eosin demonstrated a noncircumscribed dermal proliferation of fibroblasts and myofibroblasts with thickened collagen bundles (Figure, A and B). Focally fragmented elastin fibers were noted with Verhoeff elastic tissue stain. Alcian blue stain did not show increased dermal mucin. With the clinical presentation and histologic findings described, we diagnosed the patient with fibroblastic rheumatism (FR). To date, the patient's condition has stabilized overall with skin lesions fading and minimal to no joint pain. Current therapies include adalimumab, mycophenolate mofetil 500 mg 3 times daily, and low-dose prednisone.

Fibroblastic rheumatism is a rare arthropathy with cutaneous findings initially described by Chaouat et al¹ in 1980. Age of onset varies, and the condition also has been observed in pediatric patients.² Fibroblastic rheumatism is characterized by sudden onset of firm, flesh-colored, subcutaneous nodules on periungual and periarticular surfaces.² Neck lesions rarely are described,^2-4 and cordlike plaques previously have not been reported in FR. Typically, patients develop diffusely swollen fingers, palmar thickening, sclerodactyly, and contractures. The eruption may be accompanied by Raynaud phenomenon as well as a progressive symmetric erosive arthropathy.^2,5

The clinical course in FR is variable. The cutaneous findings spontaneously may regress in months to years.^3,4 However, polyarthropathy often is destructive and progresses to disability.³ Response to therapy has been unpredictable, and the following treatments have been tried, generally with poor efficacy: aspirin, nonsteroidal anti-inflammatory drugs, hydroxychloroquine, colchicine, methotrexate, prednisone, infliximab, D-penicillamine, interferon alfa, and intensive physical therapy.^2-4,6 Histologic characteristics may include thickened collagen bundles along with a fibroblastic and myofibroblastic proliferation. Elastic fibers may be decreased or absent.^2,3,5

Clinical and histologic features in FR may mimic other entities; thus, clinical pathological correlation is essential in determining the correct diagnosis. Considerations in the differential diagnoses include multicentric reticulohistiocytosis (MRH), palisaded neutrophilic and granulomatous dermatitis, and scleroderma.

In MRH, a symmetric erosive arthritis of mainly distal interphalangeal joints typically precedes the cutaneous disease. Occurrence of arthritis mutilans is reported in approximately half of patients.⁴ Cutaneous manifestations typically include the presence of coral bead-like papules and nodules over the dorsal aspect of the hands, face, and neck. Unlike FR, MRH has a concomitant autoimmune disease in up to 20% of cases and an associated malignancy in up to 31% of cases, with breast and ovarian carcinomas most common. On histology, MRH is characterized by a nodular infiltrate of histiocytes and multinucleated giant cells with eosinophilic ground-glass cytoplasm.⁴ No notable collagen changes or fibroblastic proliferations typically are present.

Palisaded neutrophilic and granulomatous dermatitis, usually associated with rheumatoid arthritis or connective tissue disease, classically presents as annular plaques and indurated linear bands over the trunk and extremities. However, its clinical presentation is quite variable and may include pink to violaceous urticarialike; livedoid-appearing; or nonspecific papules, plaques, or nodules. Histology in palisaded neutrophilic and granulomatous dermatitis shows a dense dermal neutrophilic infiltrate associated with interstitial histiocytes having a palisading arrangement around degenerated collagen.⁷ No fibroblastic proliferation typically is present.

Scleroderma can be distinguished based on additional clinical and laboratory findings as well as histology showing thickened collagen bundles without fibroblastic proliferation.2 The histologic findings also may suggest inclusion of dermatofibroma or a scar in the differential diagnosis, though the clinical presentation of these entities would not support these diagnoses.  
 
Acknowledgments
We thank the patient for granting permission to share this information. We also thank Sheng Chen, MD, PhD (Lake Success, New York), for his dermatopathological contributions to the case.

The Diagnosis: Fibroblastic Rheumatism

Routine histologic sections stained with hematoxylin and eosin demonstrated a noncircumscribed dermal proliferation of fibroblasts and myofibroblasts with thickened collagen bundles (Figure, A and B). Focally fragmented elastin fibers were noted with Verhoeff elastic tissue stain. Alcian blue stain did not show increased dermal mucin. With the clinical presentation and histologic findings described, we diagnosed the patient with fibroblastic rheumatism (FR). To date, the patient's condition has stabilized overall with skin lesions fading and minimal to no joint pain. Current therapies include adalimumab, mycophenolate mofetil 500 mg 3 times daily, and low-dose prednisone.

Fibroblastic rheumatism is a rare arthropathy with cutaneous findings initially described by Chaouat et al¹ in 1980. Age of onset varies, and the condition also has been observed in pediatric patients.² Fibroblastic rheumatism is characterized by sudden onset of firm, flesh-colored, subcutaneous nodules on periungual and periarticular surfaces.² Neck lesions rarely are described,^2-4 and cordlike plaques previously have not been reported in FR. Typically, patients develop diffusely swollen fingers, palmar thickening, sclerodactyly, and contractures. The eruption may be accompanied by Raynaud phenomenon as well as a progressive symmetric erosive arthropathy.^2,5

The clinical course in FR is variable. The cutaneous findings spontaneously may regress in months to years.^3,4 However, polyarthropathy often is destructive and progresses to disability.³ Response to therapy has been unpredictable, and the following treatments have been tried, generally with poor efficacy: aspirin, nonsteroidal anti-inflammatory drugs, hydroxychloroquine, colchicine, methotrexate, prednisone, infliximab, D-penicillamine, interferon alfa, and intensive physical therapy.^2-4,6 Histologic characteristics may include thickened collagen bundles along with a fibroblastic and myofibroblastic proliferation. Elastic fibers may be decreased or absent.^2,3,5

Clinical and histologic features in FR may mimic other entities; thus, clinical pathological correlation is essential in determining the correct diagnosis. Considerations in the differential diagnoses include multicentric reticulohistiocytosis (MRH), palisaded neutrophilic and granulomatous dermatitis, and scleroderma.

In MRH, a symmetric erosive arthritis of mainly distal interphalangeal joints typically precedes the cutaneous disease. Occurrence of arthritis mutilans is reported in approximately half of patients.⁴ Cutaneous manifestations typically include the presence of coral bead-like papules and nodules over the dorsal aspect of the hands, face, and neck. Unlike FR, MRH has a concomitant autoimmune disease in up to 20% of cases and an associated malignancy in up to 31% of cases, with breast and ovarian carcinomas most common. On histology, MRH is characterized by a nodular infiltrate of histiocytes and multinucleated giant cells with eosinophilic ground-glass cytoplasm.⁴ No notable collagen changes or fibroblastic proliferations typically are present.

Palisaded neutrophilic and granulomatous dermatitis, usually associated with rheumatoid arthritis or connective tissue disease, classically presents as annular plaques and indurated linear bands over the trunk and extremities. However, its clinical presentation is quite variable and may include pink to violaceous urticarialike; livedoid-appearing; or nonspecific papules, plaques, or nodules. Histology in palisaded neutrophilic and granulomatous dermatitis shows a dense dermal neutrophilic infiltrate associated with interstitial histiocytes having a palisading arrangement around degenerated collagen.⁷ No fibroblastic proliferation typically is present.

Scleroderma can be distinguished based on additional clinical and laboratory findings as well as histology showing thickened collagen bundles without fibroblastic proliferation.2 The histologic findings also may suggest inclusion of dermatofibroma or a scar in the differential diagnosis, though the clinical presentation of these entities would not support these diagnoses.  
 
Acknowledgments
We thank the patient for granting permission to share this information. We also thank Sheng Chen, MD, PhD (Lake Success, New York), for his dermatopathological contributions to the case.

The Diagnosis: Microcystic Adnexal Carcinoma

Microcystic adnexal carcinoma (MAC) is a rare, low-grade adnexal carcinoma consisting of both ductal and pilar differentiation.¹ It typically presents in young to middle-aged adults as a flesh-colored or yellow indurated plaque on the upper lip, medial cheek, or chin. Histologically, MACs exhibit a biphasic pattern consisting of epithelial islands of cords and lumina creating tadpolelike ducts intermixed with basaloid nests (quiz image). Keratin horn cysts are common superficially. A dense red sclerotic stroma is seen interspersed between the ducts and epithelial islands creating a "paisley tie" appearance. The lesion displays an infiltrative pattern and can be deeply invasive, extending down to the fat and muscle (quiz image, inset). Perineural invasion is common. Atypia, when present, is minimal or mild and mitoses are rare. Although this tumor's histologic pattern appears aggressive in nature, it lacks immunohistochemical staining such as p53, Ki-67, bcl-2, and c-erbB-2 that correlate with malignant behavior.² A common diagnostic pitfall is examination of a superficial biopsy in which an MAC may be mistakenly identified as another entity.

Syringomas are benign adnexal neoplasms with ductal differentiation.³ They are more common in women, especially those of Asian descent, and in patients with Down syndrome. They typically present as multiple small, firm, flesh-colored papules in the periorbital area or upper trunk. Histologically, syringomas also display comma-shaped tubules and ducts with a tadpolelike appearance and a dense red stroma creating a paisley tie-like pattern. Ductal cells have an abundant pink cytoplasm. Syringomas are well-circumscribed and more superficial than MACs without an infiltrative pattern. They lack mitotic activity or perineural invasion (Figure 1).

Desmoplastic trichoepithelioma (DTE) is a benign follicular neoplasm.⁴ It presents in adulthood with a female predominance. Clinically, it appears as a solitary flesh-colored to yellow annular plaque with raised borders and a depressed central area, often on the medial cheek. Histologically, DTEs are well-circumscribed with narrow branching cords lined with polygonal cells. A dense red stroma in combination with the epithelioid aggregates also creates the paisley tie-like pattern in this lesion. Retraction between collagen bundles within the stroma can be seen, helping distinguish this lesion from a morpheaform basal cell carcinoma (BCC), which has retraction between the epithelium and stroma. Immunohistochemistry also can be a useful tool to help differentiate DTEs from morpheaform BCCs in that sparse cytokeratin 20-positive Merkel cells can be seen within the basaloid islands of DTE but not BCC.⁵ Also seen with DTEs are numerous keratin horn cysts that commonly are filled with dystrophic calcifications. Cellular atypia and mitoses are not seen (Figure 2). Compared to MACs, DTEs lack abundant ductal structures and also contain papillary mesenchymal bodies and a more fibroblast-rich stroma.

Morpheaform BCC is an aggressive subtype of BCC. It presents as a scarlike plaque that gradually expands. Thin infiltrating strands of basaloid cells are seen haphazardly throughout a pink sclerotic stroma. Tadpolelike basaloid islands and rarely horn cysts can be seen scattered superficially, creating the paisley tie-like pattern. This lesion is more infiltrating than a syringoma or a DTE, and perineural invasion is common. Retraction is uncommon, but when present, it is seen between the epithelial cords and adjacent stroma (Figure 3).

Trichoadenoma is another benign neoplasm of follicular differentiation.⁶ It typically presents as a dome-shaped papule or plaque on the head or neck. Histologically it displays numerous dilated cystic spaces that reflect its origin from isthmic and infundibular differentiation. There is no attachment to the overlying epidermis. It can be distinguished from MAC, DTE, and syringoma due to a lack of basaloid aggregates and only a small number of non-cyst-forming epithelial cells (Figure 4).

The Diagnosis: Microcystic Adnexal Carcinoma

Microcystic adnexal carcinoma (MAC) is a rare, low-grade adnexal carcinoma consisting of both ductal and pilar differentiation.¹ It typically presents in young to middle-aged adults as a flesh-colored or yellow indurated plaque on the upper lip, medial cheek, or chin. Histologically, MACs exhibit a biphasic pattern consisting of epithelial islands of cords and lumina creating tadpolelike ducts intermixed with basaloid nests (quiz image). Keratin horn cysts are common superficially. A dense red sclerotic stroma is seen interspersed between the ducts and epithelial islands creating a "paisley tie" appearance. The lesion displays an infiltrative pattern and can be deeply invasive, extending down to the fat and muscle (quiz image, inset). Perineural invasion is common. Atypia, when present, is minimal or mild and mitoses are rare. Although this tumor's histologic pattern appears aggressive in nature, it lacks immunohistochemical staining such as p53, Ki-67, bcl-2, and c-erbB-2 that correlate with malignant behavior.² A common diagnostic pitfall is examination of a superficial biopsy in which an MAC may be mistakenly identified as another entity.

Syringomas are benign adnexal neoplasms with ductal differentiation.³ They are more common in women, especially those of Asian descent, and in patients with Down syndrome. They typically present as multiple small, firm, flesh-colored papules in the periorbital area or upper trunk. Histologically, syringomas also display comma-shaped tubules and ducts with a tadpolelike appearance and a dense red stroma creating a paisley tie-like pattern. Ductal cells have an abundant pink cytoplasm. Syringomas are well-circumscribed and more superficial than MACs without an infiltrative pattern. They lack mitotic activity or perineural invasion (Figure 1).

Desmoplastic trichoepithelioma (DTE) is a benign follicular neoplasm.⁴ It presents in adulthood with a female predominance. Clinically, it appears as a solitary flesh-colored to yellow annular plaque with raised borders and a depressed central area, often on the medial cheek. Histologically, DTEs are well-circumscribed with narrow branching cords lined with polygonal cells. A dense red stroma in combination with the epithelioid aggregates also creates the paisley tie-like pattern in this lesion. Retraction between collagen bundles within the stroma can be seen, helping distinguish this lesion from a morpheaform basal cell carcinoma (BCC), which has retraction between the epithelium and stroma. Immunohistochemistry also can be a useful tool to help differentiate DTEs from morpheaform BCCs in that sparse cytokeratin 20-positive Merkel cells can be seen within the basaloid islands of DTE but not BCC.⁵ Also seen with DTEs are numerous keratin horn cysts that commonly are filled with dystrophic calcifications. Cellular atypia and mitoses are not seen (Figure 2). Compared to MACs, DTEs lack abundant ductal structures and also contain papillary mesenchymal bodies and a more fibroblast-rich stroma.

Morpheaform BCC is an aggressive subtype of BCC. It presents as a scarlike plaque that gradually expands. Thin infiltrating strands of basaloid cells are seen haphazardly throughout a pink sclerotic stroma. Tadpolelike basaloid islands and rarely horn cysts can be seen scattered superficially, creating the paisley tie-like pattern. This lesion is more infiltrating than a syringoma or a DTE, and perineural invasion is common. Retraction is uncommon, but when present, it is seen between the epithelial cords and adjacent stroma (Figure 3).

Trichoadenoma is another benign neoplasm of follicular differentiation.⁶ It typically presents as a dome-shaped papule or plaque on the head or neck. Histologically it displays numerous dilated cystic spaces that reflect its origin from isthmic and infundibular differentiation. There is no attachment to the overlying epidermis. It can be distinguished from MAC, DTE, and syringoma due to a lack of basaloid aggregates and only a small number of non-cyst-forming epithelial cells (Figure 4).

The Diagnosis: Microcystic Adnexal Carcinoma

Microcystic adnexal carcinoma (MAC) is a rare, low-grade adnexal carcinoma consisting of both ductal and pilar differentiation.¹ It typically presents in young to middle-aged adults as a flesh-colored or yellow indurated plaque on the upper lip, medial cheek, or chin. Histologically, MACs exhibit a biphasic pattern consisting of epithelial islands of cords and lumina creating tadpolelike ducts intermixed with basaloid nests (quiz image). Keratin horn cysts are common superficially. A dense red sclerotic stroma is seen interspersed between the ducts and epithelial islands creating a "paisley tie" appearance. The lesion displays an infiltrative pattern and can be deeply invasive, extending down to the fat and muscle (quiz image, inset). Perineural invasion is common. Atypia, when present, is minimal or mild and mitoses are rare. Although this tumor's histologic pattern appears aggressive in nature, it lacks immunohistochemical staining such as p53, Ki-67, bcl-2, and c-erbB-2 that correlate with malignant behavior.² A common diagnostic pitfall is examination of a superficial biopsy in which an MAC may be mistakenly identified as another entity.

Syringomas are benign adnexal neoplasms with ductal differentiation.³ They are more common in women, especially those of Asian descent, and in patients with Down syndrome. They typically present as multiple small, firm, flesh-colored papules in the periorbital area or upper trunk. Histologically, syringomas also display comma-shaped tubules and ducts with a tadpolelike appearance and a dense red stroma creating a paisley tie-like pattern. Ductal cells have an abundant pink cytoplasm. Syringomas are well-circumscribed and more superficial than MACs without an infiltrative pattern. They lack mitotic activity or perineural invasion (Figure 1).

Desmoplastic trichoepithelioma (DTE) is a benign follicular neoplasm.⁴ It presents in adulthood with a female predominance. Clinically, it appears as a solitary flesh-colored to yellow annular plaque with raised borders and a depressed central area, often on the medial cheek. Histologically, DTEs are well-circumscribed with narrow branching cords lined with polygonal cells. A dense red stroma in combination with the epithelioid aggregates also creates the paisley tie-like pattern in this lesion. Retraction between collagen bundles within the stroma can be seen, helping distinguish this lesion from a morpheaform basal cell carcinoma (BCC), which has retraction between the epithelium and stroma. Immunohistochemistry also can be a useful tool to help differentiate DTEs from morpheaform BCCs in that sparse cytokeratin 20-positive Merkel cells can be seen within the basaloid islands of DTE but not BCC.⁵ Also seen with DTEs are numerous keratin horn cysts that commonly are filled with dystrophic calcifications. Cellular atypia and mitoses are not seen (Figure 2). Compared to MACs, DTEs lack abundant ductal structures and also contain papillary mesenchymal bodies and a more fibroblast-rich stroma.

Morpheaform BCC is an aggressive subtype of BCC. It presents as a scarlike plaque that gradually expands. Thin infiltrating strands of basaloid cells are seen haphazardly throughout a pink sclerotic stroma. Tadpolelike basaloid islands and rarely horn cysts can be seen scattered superficially, creating the paisley tie-like pattern. This lesion is more infiltrating than a syringoma or a DTE, and perineural invasion is common. Retraction is uncommon, but when present, it is seen between the epithelial cords and adjacent stroma (Figure 3).

Trichoadenoma is another benign neoplasm of follicular differentiation.⁶ It typically presents as a dome-shaped papule or plaque on the head or neck. Histologically it displays numerous dilated cystic spaces that reflect its origin from isthmic and infundibular differentiation. There is no attachment to the overlying epidermis. It can be distinguished from MAC, DTE, and syringoma due to a lack of basaloid aggregates and only a small number of non-cyst-forming epithelial cells (Figure 4).

The Diagnosis: Primary Cutaneous Follicle Center Lymphoma

Immunohistochemistry revealed a nodular infiltrate consisting of small to large atypical lymphocytes forming an irregular germinal center with notably thinned mantle zones and lack of polarization (Figure, A). Atypical cells stained positively with Bcl-6, and CD20 was diffusely positive (Figure, B-D). Bcl-2 and CD3 colocalized to the reactive T-cell infiltrate, and CD10 was largely negative. Further workup with bone marrow biopsy and full-body positron emission tomography-computed tomography was unremarkable. Given these findings, a diagnosis of primary cutaneous follicle center lymphoma (FCL) was made. At 1 month following radiation therapy, complete clinical clearance of the lymphoma was achieved.

Follicle center lymphoma, also known as cutaneous follicular lymphoma, is the most common subtype of primary cutaneous B-cell lymphomas, representing approximately 57% of cases.¹ Follicle center lymphoma typically affects older, non-Hispanic white adults with a median age of onset of 60 years. It has a predilection for the head, neck, and trunk.² Lesions present as solitary erythematous to violaceous papules, plaques, or nodules, but they can more rarely be multifocal.³ Clinical diagnosis of FCL can be difficult, with papular lesions resembling acne, rosacea, folliculitis, or arthropod assault.^4,5 As such, diagnosis of FCL typically relies on histopathologic analysis.

Histologically, FCL can present in several different patterns including follicular, nodular, diffuse, or a pleomorphic mix of these.^2,6 The cells are comprised of germinal center B cells, staining positively for Bcl-6, CD20, and CD79a.⁷ Tumor cells do not exhibit the t(14;18) translocation seen in nodal follicular lymphomas.^2,8 Unlike marginal zone lymphoma, FCL stains negatively for Bcl-2 and multiple myeloma 1/interferon regulatory factor 4 (MUM1/IRF-4).^2,9 Forkhead box P1 (FOXP1) also is usually negative, but its presence can indicate a poorer prognosis.² It is important to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphoma with secondary cutaneous involvement, as they have a different clinical prognosis and management course. Further workup includes bone marrow biopsy, serum analysis for clonal involvement, and positron emission tomography-computed tomography imaging. Follicle center lymphoma generally has an indolent disease course with a favorable 5-year survival rate of approximately 95%.^6,8

Untreated lesions may enlarge slowly or even spontaneously involute.¹⁰ The histologic growth pattern and number of lesions do not affect prognosis, but presence on the legs has a 5-year survival rate of 41%.² Extracutaneous dissemination can occur in 5% to 10% of cases.² Given the slow progression of FCL, conservative management with observation is an option. However, curative treatment can be reasonably attempted for solitary lesions by excision or radiation. Treatment of FCL often can be complicated by its predilection for the head and neck. Other treatment modalities include topical steroids, imiquimod, nitrogen mustard, and bexarotene.¹⁰ More generalized involvement may require systemic therapy with rituximab or chemotherapy. Recurrence after therapy is common, reported in 46.5% of patients, but does not affect prognosis.²

The Diagnosis: Primary Cutaneous Follicle Center Lymphoma

Immunohistochemistry revealed a nodular infiltrate consisting of small to large atypical lymphocytes forming an irregular germinal center with notably thinned mantle zones and lack of polarization (Figure, A). Atypical cells stained positively with Bcl-6, and CD20 was diffusely positive (Figure, B-D). Bcl-2 and CD3 colocalized to the reactive T-cell infiltrate, and CD10 was largely negative. Further workup with bone marrow biopsy and full-body positron emission tomography-computed tomography was unremarkable. Given these findings, a diagnosis of primary cutaneous follicle center lymphoma (FCL) was made. At 1 month following radiation therapy, complete clinical clearance of the lymphoma was achieved.

Follicle center lymphoma, also known as cutaneous follicular lymphoma, is the most common subtype of primary cutaneous B-cell lymphomas, representing approximately 57% of cases.¹ Follicle center lymphoma typically affects older, non-Hispanic white adults with a median age of onset of 60 years. It has a predilection for the head, neck, and trunk.² Lesions present as solitary erythematous to violaceous papules, plaques, or nodules, but they can more rarely be multifocal.³ Clinical diagnosis of FCL can be difficult, with papular lesions resembling acne, rosacea, folliculitis, or arthropod assault.^4,5 As such, diagnosis of FCL typically relies on histopathologic analysis.

Histologically, FCL can present in several different patterns including follicular, nodular, diffuse, or a pleomorphic mix of these.^2,6 The cells are comprised of germinal center B cells, staining positively for Bcl-6, CD20, and CD79a.⁷ Tumor cells do not exhibit the t(14;18) translocation seen in nodal follicular lymphomas.^2,8 Unlike marginal zone lymphoma, FCL stains negatively for Bcl-2 and multiple myeloma 1/interferon regulatory factor 4 (MUM1/IRF-4).^2,9 Forkhead box P1 (FOXP1) also is usually negative, but its presence can indicate a poorer prognosis.² It is important to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphoma with secondary cutaneous involvement, as they have a different clinical prognosis and management course. Further workup includes bone marrow biopsy, serum analysis for clonal involvement, and positron emission tomography-computed tomography imaging. Follicle center lymphoma generally has an indolent disease course with a favorable 5-year survival rate of approximately 95%.^6,8

Untreated lesions may enlarge slowly or even spontaneously involute.¹⁰ The histologic growth pattern and number of lesions do not affect prognosis, but presence on the legs has a 5-year survival rate of 41%.² Extracutaneous dissemination can occur in 5% to 10% of cases.² Given the slow progression of FCL, conservative management with observation is an option. However, curative treatment can be reasonably attempted for solitary lesions by excision or radiation. Treatment of FCL often can be complicated by its predilection for the head and neck. Other treatment modalities include topical steroids, imiquimod, nitrogen mustard, and bexarotene.¹⁰ More generalized involvement may require systemic therapy with rituximab or chemotherapy. Recurrence after therapy is common, reported in 46.5% of patients, but does not affect prognosis.²

The Diagnosis: Primary Cutaneous Follicle Center Lymphoma

Immunohistochemistry revealed a nodular infiltrate consisting of small to large atypical lymphocytes forming an irregular germinal center with notably thinned mantle zones and lack of polarization (Figure, A). Atypical cells stained positively with Bcl-6, and CD20 was diffusely positive (Figure, B-D). Bcl-2 and CD3 colocalized to the reactive T-cell infiltrate, and CD10 was largely negative. Further workup with bone marrow biopsy and full-body positron emission tomography-computed tomography was unremarkable. Given these findings, a diagnosis of primary cutaneous follicle center lymphoma (FCL) was made. At 1 month following radiation therapy, complete clinical clearance of the lymphoma was achieved.

Follicle center lymphoma, also known as cutaneous follicular lymphoma, is the most common subtype of primary cutaneous B-cell lymphomas, representing approximately 57% of cases.¹ Follicle center lymphoma typically affects older, non-Hispanic white adults with a median age of onset of 60 years. It has a predilection for the head, neck, and trunk.² Lesions present as solitary erythematous to violaceous papules, plaques, or nodules, but they can more rarely be multifocal.³ Clinical diagnosis of FCL can be difficult, with papular lesions resembling acne, rosacea, folliculitis, or arthropod assault.^4,5 As such, diagnosis of FCL typically relies on histopathologic analysis.

Histologically, FCL can present in several different patterns including follicular, nodular, diffuse, or a pleomorphic mix of these.^2,6 The cells are comprised of germinal center B cells, staining positively for Bcl-6, CD20, and CD79a.⁷ Tumor cells do not exhibit the t(14;18) translocation seen in nodal follicular lymphomas.^2,8 Unlike marginal zone lymphoma, FCL stains negatively for Bcl-2 and multiple myeloma 1/interferon regulatory factor 4 (MUM1/IRF-4).^2,9 Forkhead box P1 (FOXP1) also is usually negative, but its presence can indicate a poorer prognosis.² It is important to distinguish primary cutaneous B-cell lymphomas from systemic B-cell lymphoma with secondary cutaneous involvement, as they have a different clinical prognosis and management course. Further workup includes bone marrow biopsy, serum analysis for clonal involvement, and positron emission tomography-computed tomography imaging. Follicle center lymphoma generally has an indolent disease course with a favorable 5-year survival rate of approximately 95%.^6,8

Untreated lesions may enlarge slowly or even spontaneously involute.¹⁰ The histologic growth pattern and number of lesions do not affect prognosis, but presence on the legs has a 5-year survival rate of 41%.² Extracutaneous dissemination can occur in 5% to 10% of cases.² Given the slow progression of FCL, conservative management with observation is an option. However, curative treatment can be reasonably attempted for solitary lesions by excision or radiation. Treatment of FCL often can be complicated by its predilection for the head and neck. Other treatment modalities include topical steroids, imiquimod, nitrogen mustard, and bexarotene.¹⁰ More generalized involvement may require systemic therapy with rituximab or chemotherapy. Recurrence after therapy is common, reported in 46.5% of patients, but does not affect prognosis.²

To the Editor:

Primary mucinous carcinoma (PMC) is an exceedingly rare adnexal tumor with an incidence of 0.07 cases per million individuals.^1,2 First described by Lennox et al³ in 1952, this entity often presents as slow-growing, solitary nodules that often are soft on palpation but may have an indurated quality and range in color from reddish blue to flesh colored to white.⁴ Primary mucinous carcinoma most commonly is found on the eyelid (38%) but may affect other sites on the face (20.3%), scalp (16%), and axilla (10%).⁵ Historically, it has been thought to be more common among men; however, a 2005 large case series by Kazakov et al⁵ found that women were twice as likely to be affected. Primary mucinous carcinoma most frequently is diagnosed in the fifth through seventh decades of life, with a median age at onset of 63 years.^6,7 Because of its rarity, PMC is most frequently confused clinically with basal cell carcinoma, keratoacanthoma, apocrine hidrocystoma, epidermoid cyst, Kaposi sarcoma, neuroma, lacrimal sac tumor, squamous cell carcinoma, granulomatous tumors, and metastatic adenocarcinoma.^1,8-10

Primary mucinous carcinoma is thought to be derived from sweat glands, and select features such as decapitation secretion are more suggestive of apocrine than eccrine differentiation.^5,8 On histopathology, PMC classically is described as nests of epithelial cells floating in lakes of extracellular mucin, primarily in the dermis and subcutis. The nests are composed of basaloid cells in solid to cribriform arrangements, usually with a low mitotic count and little nuclear atypia. These nests are suspended within periodic acid–Schiff positive mucinous pools partitioned by delicate fibrous septa. The mucin produced by PMC is sialomucin, and as such it is hyaluronidase resistant and sialidase labile.⁶ At least 1 report has been made of the presence of psammoma bodies in PMC.¹¹

The neoplasm is characterized by an indolent course with frequent recurrence but rare metastasis.^5,12 Treatment is primarily surgical, with Mohs micrographic surgery (MMS) offering improved tissue conservation and reduced recurrence rates.¹² The diagnostic challenge lies in distinguishing PMC from a variety of metastatic mucinous internal malignancies that portend a notably greater morbidity and mortality to the patient. We describe a case of PMC, discuss the differentiation of PMC from metastatic mucinous carcinoma, and review the literature regarding treatment of this rare neoplasm.

A 65-year-old white woman was referred to our tertiary-care dermatologic surgery clinic for treatment of an incompletely excised mucinous carcinoma of the right lateral canthus (Figure 1). The clinically evident scar measured 0.5×0.5 cm. Although difficult to appreciate in Figure 1, a slight textural change of the surrounding skin, including the upper and lower eyelid, was apparent. Prior to her arrival to our clinic, the referring physician had completed a thorough review of systems and physical examination, which did not suggest an underlying malignancy. Computed tomography of the head, neck, chest, abdomen, and pelvis revealed a mass in the thyroid that was removed and found to be benign. The patient’s cutaneous lesion was therefore considered to be a PMC of the skin.

Given the prior incomplete excision of the lesion and its periocular location, we treated the patient with MMS. After 6 surgical stages, we continued to see evidence of the neoplasm as it tracked medially along the orbicularis oculi muscle (Figure 2). Due to the patient’s physical and emotional exhaustion at this point, we discontinued MMS and referred her to a colleague in plastic surgery for further excision of the remaining focus of positivity as well as repair. The final Mohs defect measured 4.2×4.0 cm (Figure 3). Approximately 2.3×1.0 cm of tissue in the area of remaining tumor was excised by plastic surgery, and the defect was repaired with a cervicofacial advancement flap closure of the right cheek and lower eyelid and full-thickness skin graft of the left upper eyelid. Histopathologic investigation found the additional tissue resected to be free of residual tumor.

To diagnose a patient with PMC, one must first rule out cutaneous metastasis of various internal malignancies that may appear similar on histopathology. A full clinical investigation consisting of a thorough history, physical examination, and appropriate radiographic imaging is required. Cutaneous metastases most commonly arise from the breast or gastrointestinal tract (GIT) but also can originate from the prostate, lungs, ovaries, pancreas, and kidneys.⁵ Histologically, PMC may be identical to metastatic adenocarcinoma.¹³ Location on the body may be a clue to a lesion’s origin, as metastases from a mucinous adenocarcinoma of the breast typically occur on the chest, breast, or axilla,⁵ whereas PMC primarily is found on the head and neck.

Certain histopathologic features may be suggestive of either a primary or metastatic etiology. Lesions arising in the skin may reveal an in situ component representing ductal hyperplasia, atypical ductal hyperplasia, or ductal carcinoma in situ. Identification of an in situ component defines a cutaneous primary neoplasm, but its absence does not exclude PMC.⁵ Additionally, metastatic lesions from the GIT typically have greater pleomorphism and “dirty” necrosis defined as eosinophilic foci containing nuclear debris.⁵

The expression pattern of cytokeratins (CKs) also can be suggestive. Primary mucinous carcinoma and metastatic breast adenocarcinoma are both CK7⁺ and CK20⁻. By contrast, mucinous adenocarcinoma of the GIT stains CK20⁺ and CK7⁻.¹⁴ Another marker that stains PMC is CK5 and CK6, though infrequently present. Levy et al¹⁵ reported positive staining for CK5 and CK6 in only 1 of 5 PMC cases. Positive staining for CK5 and CK6 has not been reported in any metastatic mucinous carcinoma.

The role of p63 immunostaining in the setting of mucinous carcinoma is controversial.^16-18 Some practi-tioners have reported using p63 immunostaining to assist in establishing the diagnosis of PMC but only after performing a clinical workup to search for any primary sites of mucinous carcinoma in other organs.¹¹ Other studies, however, have found select metastatic lesions from the breast^17,18 and GIT¹⁸ to stain positively with p63. It is important to remember that these clinical and pathologic features are only suggestive of the primary etiology and are not replacement for a full clinical investigation.

Primary mucinous carcinoma is considered an indolent tumor with the majority of patient morbidity attributable to local recurrence and regional metastasis. Although uncommon, regional and distant metastasis rates have been reported to be 11% and 3%, respectively.¹⁹ Direct lymphatic invasion has been reported and indicates a more aggressive tumor with shorter recurrence-free intervals and predicts nodal metastases. Paradela et al²⁰ recommended the use of D2-40, a monoclonal antibody and specific marker for lymphatic endothelium, to detect lymphatic invasion, particularly in node-negative primary tumors.

In one case of PMC on the jaw of a 39-year-old Japanese man, no recurrence or metastases were discovered until the 11th year of follow-up. At that time, he was found to have lung and bone metastases and died after 3 years.²¹ Other investigators report death occurring 4 to 24 months following diagnosis of distant metastases.^7,22 Direct extension of the tumor into skeletal muscle, periosteum, bone, and dura also has been documented.⁷

Treatment principally is surgical, with PMC known to be resistant to both chemotherapy and radiation therapy.^19,22 The recommended margins for simple excision range from 1 to 2 cm, but this method of treatment yields recurrence rates upward of 30% to 40%, especially for lesions located on the eyelid.^12,13 First utilized in PMC of the eyelid to conserve tissue, MMS is rapidly becoming the treatment of choice because of its notably improved recurrence rate. A case series of 4 PMCs of the eyelid treated via MMS or frozen section control found the recurrence rate to be 7%.²³ Another report of 2 cases of PMC treated by MMS reported no recurrence after 42 and 26 months.¹³ Ortiz et al⁷ reported an additional case of a patient treated by MMS that was recurrence free for 30 months at the time of publication. Further investigation is required to definitively recommend MMS on the basis of improved recurrence rate but should now be considered standard of care in recurrent, sizeable, or eyelid PMC.

Despite its ascension as treatment of choice in many cases of PMC, MMS is not without its risk of metastasis and recurrence. Tam et al²⁴ reported a case of PMC with multiple recurrences and metastases following 3 simple excisions and 2 excisions via MMS. Although the lesion’s previously recurrent nature increased the likelihood of failure of MMS, this case demonstrates that all patients should be followed periodically after the treatment of PMC.

We presented a case of PMC in which standard surgical margins would have been insufficient to clear the lesion. Mohs micrographic surgery was used to remove the majority of the tumor. As is common in PMC, the lesion was indolent and periocular in location. It also was incompletely excised due to notable subclinical extension, which is common for PMC. The distinction of PMC from metastatic mucinous carcinoma is paramount but sometimes difficult. Randomized controlled trials are lacking with regards to preferred method of treatment, but MMS has shown benefit and should be considered for recurrent lesions and lesions in cosmetically sensitive areas.

To the Editor:

Primary mucinous carcinoma (PMC) is an exceedingly rare adnexal tumor with an incidence of 0.07 cases per million individuals.^1,2 First described by Lennox et al³ in 1952, this entity often presents as slow-growing, solitary nodules that often are soft on palpation but may have an indurated quality and range in color from reddish blue to flesh colored to white.⁴ Primary mucinous carcinoma most commonly is found on the eyelid (38%) but may affect other sites on the face (20.3%), scalp (16%), and axilla (10%).⁵ Historically, it has been thought to be more common among men; however, a 2005 large case series by Kazakov et al⁵ found that women were twice as likely to be affected. Primary mucinous carcinoma most frequently is diagnosed in the fifth through seventh decades of life, with a median age at onset of 63 years.^6,7 Because of its rarity, PMC is most frequently confused clinically with basal cell carcinoma, keratoacanthoma, apocrine hidrocystoma, epidermoid cyst, Kaposi sarcoma, neuroma, lacrimal sac tumor, squamous cell carcinoma, granulomatous tumors, and metastatic adenocarcinoma.^1,8-10

Primary mucinous carcinoma is thought to be derived from sweat glands, and select features such as decapitation secretion are more suggestive of apocrine than eccrine differentiation.^5,8 On histopathology, PMC classically is described as nests of epithelial cells floating in lakes of extracellular mucin, primarily in the dermis and subcutis. The nests are composed of basaloid cells in solid to cribriform arrangements, usually with a low mitotic count and little nuclear atypia. These nests are suspended within periodic acid–Schiff positive mucinous pools partitioned by delicate fibrous septa. The mucin produced by PMC is sialomucin, and as such it is hyaluronidase resistant and sialidase labile.⁶ At least 1 report has been made of the presence of psammoma bodies in PMC.¹¹

The neoplasm is characterized by an indolent course with frequent recurrence but rare metastasis.^5,12 Treatment is primarily surgical, with Mohs micrographic surgery (MMS) offering improved tissue conservation and reduced recurrence rates.¹² The diagnostic challenge lies in distinguishing PMC from a variety of metastatic mucinous internal malignancies that portend a notably greater morbidity and mortality to the patient. We describe a case of PMC, discuss the differentiation of PMC from metastatic mucinous carcinoma, and review the literature regarding treatment of this rare neoplasm.

A 65-year-old white woman was referred to our tertiary-care dermatologic surgery clinic for treatment of an incompletely excised mucinous carcinoma of the right lateral canthus (Figure 1). The clinically evident scar measured 0.5×0.5 cm. Although difficult to appreciate in Figure 1, a slight textural change of the surrounding skin, including the upper and lower eyelid, was apparent. Prior to her arrival to our clinic, the referring physician had completed a thorough review of systems and physical examination, which did not suggest an underlying malignancy. Computed tomography of the head, neck, chest, abdomen, and pelvis revealed a mass in the thyroid that was removed and found to be benign. The patient’s cutaneous lesion was therefore considered to be a PMC of the skin.

Given the prior incomplete excision of the lesion and its periocular location, we treated the patient with MMS. After 6 surgical stages, we continued to see evidence of the neoplasm as it tracked medially along the orbicularis oculi muscle (Figure 2). Due to the patient’s physical and emotional exhaustion at this point, we discontinued MMS and referred her to a colleague in plastic surgery for further excision of the remaining focus of positivity as well as repair. The final Mohs defect measured 4.2×4.0 cm (Figure 3). Approximately 2.3×1.0 cm of tissue in the area of remaining tumor was excised by plastic surgery, and the defect was repaired with a cervicofacial advancement flap closure of the right cheek and lower eyelid and full-thickness skin graft of the left upper eyelid. Histopathologic investigation found the additional tissue resected to be free of residual tumor.

To diagnose a patient with PMC, one must first rule out cutaneous metastasis of various internal malignancies that may appear similar on histopathology. A full clinical investigation consisting of a thorough history, physical examination, and appropriate radiographic imaging is required. Cutaneous metastases most commonly arise from the breast or gastrointestinal tract (GIT) but also can originate from the prostate, lungs, ovaries, pancreas, and kidneys.⁵ Histologically, PMC may be identical to metastatic adenocarcinoma.¹³ Location on the body may be a clue to a lesion’s origin, as metastases from a mucinous adenocarcinoma of the breast typically occur on the chest, breast, or axilla,⁵ whereas PMC primarily is found on the head and neck.

Certain histopathologic features may be suggestive of either a primary or metastatic etiology. Lesions arising in the skin may reveal an in situ component representing ductal hyperplasia, atypical ductal hyperplasia, or ductal carcinoma in situ. Identification of an in situ component defines a cutaneous primary neoplasm, but its absence does not exclude PMC.⁵ Additionally, metastatic lesions from the GIT typically have greater pleomorphism and “dirty” necrosis defined as eosinophilic foci containing nuclear debris.⁵

The expression pattern of cytokeratins (CKs) also can be suggestive. Primary mucinous carcinoma and metastatic breast adenocarcinoma are both CK7⁺ and CK20⁻. By contrast, mucinous adenocarcinoma of the GIT stains CK20⁺ and CK7⁻.¹⁴ Another marker that stains PMC is CK5 and CK6, though infrequently present. Levy et al¹⁵ reported positive staining for CK5 and CK6 in only 1 of 5 PMC cases. Positive staining for CK5 and CK6 has not been reported in any metastatic mucinous carcinoma.

The role of p63 immunostaining in the setting of mucinous carcinoma is controversial.^16-18 Some practi-tioners have reported using p63 immunostaining to assist in establishing the diagnosis of PMC but only after performing a clinical workup to search for any primary sites of mucinous carcinoma in other organs.¹¹ Other studies, however, have found select metastatic lesions from the breast^17,18 and GIT¹⁸ to stain positively with p63. It is important to remember that these clinical and pathologic features are only suggestive of the primary etiology and are not replacement for a full clinical investigation.

Primary mucinous carcinoma is considered an indolent tumor with the majority of patient morbidity attributable to local recurrence and regional metastasis. Although uncommon, regional and distant metastasis rates have been reported to be 11% and 3%, respectively.¹⁹ Direct lymphatic invasion has been reported and indicates a more aggressive tumor with shorter recurrence-free intervals and predicts nodal metastases. Paradela et al²⁰ recommended the use of D2-40, a monoclonal antibody and specific marker for lymphatic endothelium, to detect lymphatic invasion, particularly in node-negative primary tumors.

In one case of PMC on the jaw of a 39-year-old Japanese man, no recurrence or metastases were discovered until the 11th year of follow-up. At that time, he was found to have lung and bone metastases and died after 3 years.²¹ Other investigators report death occurring 4 to 24 months following diagnosis of distant metastases.^7,22 Direct extension of the tumor into skeletal muscle, periosteum, bone, and dura also has been documented.⁷

Treatment principally is surgical, with PMC known to be resistant to both chemotherapy and radiation therapy.^19,22 The recommended margins for simple excision range from 1 to 2 cm, but this method of treatment yields recurrence rates upward of 30% to 40%, especially for lesions located on the eyelid.^12,13 First utilized in PMC of the eyelid to conserve tissue, MMS is rapidly becoming the treatment of choice because of its notably improved recurrence rate. A case series of 4 PMCs of the eyelid treated via MMS or frozen section control found the recurrence rate to be 7%.²³ Another report of 2 cases of PMC treated by MMS reported no recurrence after 42 and 26 months.¹³ Ortiz et al⁷ reported an additional case of a patient treated by MMS that was recurrence free for 30 months at the time of publication. Further investigation is required to definitively recommend MMS on the basis of improved recurrence rate but should now be considered standard of care in recurrent, sizeable, or eyelid PMC.

Despite its ascension as treatment of choice in many cases of PMC, MMS is not without its risk of metastasis and recurrence. Tam et al²⁴ reported a case of PMC with multiple recurrences and metastases following 3 simple excisions and 2 excisions via MMS. Although the lesion’s previously recurrent nature increased the likelihood of failure of MMS, this case demonstrates that all patients should be followed periodically after the treatment of PMC.

We presented a case of PMC in which standard surgical margins would have been insufficient to clear the lesion. Mohs micrographic surgery was used to remove the majority of the tumor. As is common in PMC, the lesion was indolent and periocular in location. It also was incompletely excised due to notable subclinical extension, which is common for PMC. The distinction of PMC from metastatic mucinous carcinoma is paramount but sometimes difficult. Randomized controlled trials are lacking with regards to preferred method of treatment, but MMS has shown benefit and should be considered for recurrent lesions and lesions in cosmetically sensitive areas.

To the Editor:

Primary mucinous carcinoma (PMC) is an exceedingly rare adnexal tumor with an incidence of 0.07 cases per million individuals.^1,2 First described by Lennox et al³ in 1952, this entity often presents as slow-growing, solitary nodules that often are soft on palpation but may have an indurated quality and range in color from reddish blue to flesh colored to white.⁴ Primary mucinous carcinoma most commonly is found on the eyelid (38%) but may affect other sites on the face (20.3%), scalp (16%), and axilla (10%).⁵ Historically, it has been thought to be more common among men; however, a 2005 large case series by Kazakov et al⁵ found that women were twice as likely to be affected. Primary mucinous carcinoma most frequently is diagnosed in the fifth through seventh decades of life, with a median age at onset of 63 years.^6,7 Because of its rarity, PMC is most frequently confused clinically with basal cell carcinoma, keratoacanthoma, apocrine hidrocystoma, epidermoid cyst, Kaposi sarcoma, neuroma, lacrimal sac tumor, squamous cell carcinoma, granulomatous tumors, and metastatic adenocarcinoma.^1,8-10

Primary mucinous carcinoma is thought to be derived from sweat glands, and select features such as decapitation secretion are more suggestive of apocrine than eccrine differentiation.^5,8 On histopathology, PMC classically is described as nests of epithelial cells floating in lakes of extracellular mucin, primarily in the dermis and subcutis. The nests are composed of basaloid cells in solid to cribriform arrangements, usually with a low mitotic count and little nuclear atypia. These nests are suspended within periodic acid–Schiff positive mucinous pools partitioned by delicate fibrous septa. The mucin produced by PMC is sialomucin, and as such it is hyaluronidase resistant and sialidase labile.⁶ At least 1 report has been made of the presence of psammoma bodies in PMC.¹¹

The neoplasm is characterized by an indolent course with frequent recurrence but rare metastasis.^5,12 Treatment is primarily surgical, with Mohs micrographic surgery (MMS) offering improved tissue conservation and reduced recurrence rates.¹² The diagnostic challenge lies in distinguishing PMC from a variety of metastatic mucinous internal malignancies that portend a notably greater morbidity and mortality to the patient. We describe a case of PMC, discuss the differentiation of PMC from metastatic mucinous carcinoma, and review the literature regarding treatment of this rare neoplasm.

A 65-year-old white woman was referred to our tertiary-care dermatologic surgery clinic for treatment of an incompletely excised mucinous carcinoma of the right lateral canthus (Figure 1). The clinically evident scar measured 0.5×0.5 cm. Although difficult to appreciate in Figure 1, a slight textural change of the surrounding skin, including the upper and lower eyelid, was apparent. Prior to her arrival to our clinic, the referring physician had completed a thorough review of systems and physical examination, which did not suggest an underlying malignancy. Computed tomography of the head, neck, chest, abdomen, and pelvis revealed a mass in the thyroid that was removed and found to be benign. The patient’s cutaneous lesion was therefore considered to be a PMC of the skin.

Given the prior incomplete excision of the lesion and its periocular location, we treated the patient with MMS. After 6 surgical stages, we continued to see evidence of the neoplasm as it tracked medially along the orbicularis oculi muscle (Figure 2). Due to the patient’s physical and emotional exhaustion at this point, we discontinued MMS and referred her to a colleague in plastic surgery for further excision of the remaining focus of positivity as well as repair. The final Mohs defect measured 4.2×4.0 cm (Figure 3). Approximately 2.3×1.0 cm of tissue in the area of remaining tumor was excised by plastic surgery, and the defect was repaired with a cervicofacial advancement flap closure of the right cheek and lower eyelid and full-thickness skin graft of the left upper eyelid. Histopathologic investigation found the additional tissue resected to be free of residual tumor.

To diagnose a patient with PMC, one must first rule out cutaneous metastasis of various internal malignancies that may appear similar on histopathology. A full clinical investigation consisting of a thorough history, physical examination, and appropriate radiographic imaging is required. Cutaneous metastases most commonly arise from the breast or gastrointestinal tract (GIT) but also can originate from the prostate, lungs, ovaries, pancreas, and kidneys.⁵ Histologically, PMC may be identical to metastatic adenocarcinoma.¹³ Location on the body may be a clue to a lesion’s origin, as metastases from a mucinous adenocarcinoma of the breast typically occur on the chest, breast, or axilla,⁵ whereas PMC primarily is found on the head and neck.

Certain histopathologic features may be suggestive of either a primary or metastatic etiology. Lesions arising in the skin may reveal an in situ component representing ductal hyperplasia, atypical ductal hyperplasia, or ductal carcinoma in situ. Identification of an in situ component defines a cutaneous primary neoplasm, but its absence does not exclude PMC.⁵ Additionally, metastatic lesions from the GIT typically have greater pleomorphism and “dirty” necrosis defined as eosinophilic foci containing nuclear debris.⁵

The expression pattern of cytokeratins (CKs) also can be suggestive. Primary mucinous carcinoma and metastatic breast adenocarcinoma are both CK7⁺ and CK20⁻. By contrast, mucinous adenocarcinoma of the GIT stains CK20⁺ and CK7⁻.¹⁴ Another marker that stains PMC is CK5 and CK6, though infrequently present. Levy et al¹⁵ reported positive staining for CK5 and CK6 in only 1 of 5 PMC cases. Positive staining for CK5 and CK6 has not been reported in any metastatic mucinous carcinoma.

The role of p63 immunostaining in the setting of mucinous carcinoma is controversial.^16-18 Some practi-tioners have reported using p63 immunostaining to assist in establishing the diagnosis of PMC but only after performing a clinical workup to search for any primary sites of mucinous carcinoma in other organs.¹¹ Other studies, however, have found select metastatic lesions from the breast^17,18 and GIT¹⁸ to stain positively with p63. It is important to remember that these clinical and pathologic features are only suggestive of the primary etiology and are not replacement for a full clinical investigation.

Primary mucinous carcinoma is considered an indolent tumor with the majority of patient morbidity attributable to local recurrence and regional metastasis. Although uncommon, regional and distant metastasis rates have been reported to be 11% and 3%, respectively.¹⁹ Direct lymphatic invasion has been reported and indicates a more aggressive tumor with shorter recurrence-free intervals and predicts nodal metastases. Paradela et al²⁰ recommended the use of D2-40, a monoclonal antibody and specific marker for lymphatic endothelium, to detect lymphatic invasion, particularly in node-negative primary tumors.

In one case of PMC on the jaw of a 39-year-old Japanese man, no recurrence or metastases were discovered until the 11th year of follow-up. At that time, he was found to have lung and bone metastases and died after 3 years.²¹ Other investigators report death occurring 4 to 24 months following diagnosis of distant metastases.^7,22 Direct extension of the tumor into skeletal muscle, periosteum, bone, and dura also has been documented.⁷

Treatment principally is surgical, with PMC known to be resistant to both chemotherapy and radiation therapy.^19,22 The recommended margins for simple excision range from 1 to 2 cm, but this method of treatment yields recurrence rates upward of 30% to 40%, especially for lesions located on the eyelid.^12,13 First utilized in PMC of the eyelid to conserve tissue, MMS is rapidly becoming the treatment of choice because of its notably improved recurrence rate. A case series of 4 PMCs of the eyelid treated via MMS or frozen section control found the recurrence rate to be 7%.²³ Another report of 2 cases of PMC treated by MMS reported no recurrence after 42 and 26 months.¹³ Ortiz et al⁷ reported an additional case of a patient treated by MMS that was recurrence free for 30 months at the time of publication. Further investigation is required to definitively recommend MMS on the basis of improved recurrence rate but should now be considered standard of care in recurrent, sizeable, or eyelid PMC.

Despite its ascension as treatment of choice in many cases of PMC, MMS is not without its risk of metastasis and recurrence. Tam et al²⁴ reported a case of PMC with multiple recurrences and metastases following 3 simple excisions and 2 excisions via MMS. Although the lesion’s previously recurrent nature increased the likelihood of failure of MMS, this case demonstrates that all patients should be followed periodically after the treatment of PMC.

We presented a case of PMC in which standard surgical margins would have been insufficient to clear the lesion. Mohs micrographic surgery was used to remove the majority of the tumor. As is common in PMC, the lesion was indolent and periocular in location. It also was incompletely excised due to notable subclinical extension, which is common for PMC. The distinction of PMC from metastatic mucinous carcinoma is paramount but sometimes difficult. Randomized controlled trials are lacking with regards to preferred method of treatment, but MMS has shown benefit and should be considered for recurrent lesions and lesions in cosmetically sensitive areas.

To the Editor:

Acrodermatitis enteropathica (AE) is an inherited defect in zinc absorption that leads to hypozincemia. Its clinical presentation can vary based on serum zinc level and ranges from periorificial erosive dermatitis to psoriasiform dermatitis.¹ Recognition of the cutaneous manifestations of zinc deficiency can lead to early intervention with zinc supplementation and prevention of long-term morbidity and even mortality. In our case, the coexistence of a bullous acral dermatosis with the additional feature of extensor digital dermatitis with fissuring suggests a diagnosis of AE and can alert the astute clinician to the need for testing of serum zinc levels and/or treatment with zinc supplementation. Causes of acquired zinc deficiency that have been reported in the literature include eating disorders such as anorexia nervosa and bulimia nervosa, Crohn disease, food allergy, intestinal parasitic infestations, and an inborn error of metabolism known as nonketotic hyperglycemia (Table).^2-4

RELATED ARTICLE: Acquired Acrodermatitis Enteropathica Secondary to Alcoholism

A 42-year-old woman with a medical history of rheumatoid arthritis and short bowel syndrome due to multiple small bowel obstructions with subsequent bowel resections who was on chronic total parenteral nutrition (TPN) presented with bullae on the hands, shins, and feet. The patient initially noticed small erythematous macules on the hands and feet months prior to presentation. Three weeks prior to presentation, bullae started to form on the hands, mostly between the web spaces; dorsal aspects of the feet; and anterior aspects of the shins. The patient denied any oral ulcers. One day prior to presentation the patient was seen at an outside hospital and was started on prednisone 5 mg daily, oral clindamycin, mupirocin ointment, and nystatin-triamcinolone cream. These medications failed to improve her condition. On review of systems, the patient denied any fever, chills, eye pain, or dysuria.

Upon initial presentation the patient appeared weak and fatigued, though vital signs were normal. Physical examination revealed multiple flaccid bullae in the web spaces of the hands and shallow erosions with hemorrhagic crusts on the bilateral wrists. She also had violaceous patches in the extensor creases of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints, which were strikingly symmetric (Figure 1). Prominent flaccid bullae and shallow erosions with hemorrhagic crusts also were present on the bilateral shins and dorsal aspects of the feet (Figure 2). No oral ulcers were present. A punch biopsy from the dorsal aspect of the left foot revealed psoriasiform hyperplasia of the epidermis with prominent ballooning degeneration and hyperkeratosis/parakeratosis (Figure 3); a periodic acid–Schiff stain was negative for fungal organisms.

Given the biopsy results and clinical presentation, a nutritional deficiency was suspected and serum levels of zinc, vitamin B₁, vitamin B₂, and vitamin B₃ were assessed. Vitamins B₁, B₂, and B₃ all were within reference range, but the patient’s serum zinc level was found to be low at 11 μg/mL (reference range, 55–150 μg/mL). The alkaline phosphatase level also was measured to be low at 22 U/L (reference range, 31–103 U/L). Additionally, a hepatitis panel was drawn and glucagon levels were checked, which were found to be within reference range. These findings were consistent with a diagnosis of acquired AE. Prednisone and clindamycin were stopped and the patient was started on zinc supplementation in her TPN therapy. Mupirocin ointment was continued on the existing bullae. Upon discharge 10 days later, there were no new bullae and the existing bullae had sloughed off, revealing healthy skin underneath.

Zinc is an essential trace element and can be found in high concentration in foods such as shellfish, green vegetables, legumes, nuts, and whole grains.⁶ The majority of zinc is absorbed in the jejunum; as such, many cases of acquired zinc deficiency leading to AE are dueto disorders that affect the small intestine.² Conditions that may lead to poor gastrointestinal zinc absorption include alcoholism, eating disorders, TPN, burns, surgery, and malignancies.^2,7

Diagnosis typically is made based on characteristic clinical features, biopsy results, and a measurement of the serum zinc concentration. Although a low serum zinc level supports the diagnosis, serum zinc concentration is not a reliable indicator of body zinc stores and a normal serum zinc concentration does not rule out AE. The gold standard for diagnosis is the resolution of lesions after zinc supplementation.¹ Notably, because the production of alkaline phosphatase is dependent on zinc, levels of this enzyme also may be low in cases of AE,⁶ as in our patient.

The clinical manifestations of AE can vary greatly; patients may initially present with eczematous pink scaly plaques, which may subsequently become vesicular, bullous, pustular, or desquamative. The lesions may develop over the arms and legs as well as the anogenital and periorificial areas.⁵ Other notable manifestations that may present early in the course of AE include angular cheilitis followed by paronychia. In patients who are not promptly treated, long-term zinc deficiency may lead to growth delay, mental slowing, poor wound healing, anemia, and anorexia.⁵ Of note, deficiencies of branched-chain amino acids and essential fatty acids may appear clinically similar to AE.²

Zinc replacement is the treatment of choice for patients with AE due to dietary deficiency, and replacement therapy should begin with 0.5 to 1 mg/kg daily of elemental zinc.⁵ Response to acquired AE with zinc supplementation often is rapid. Lesions tend to resolve within days to weeks depending on the degree of deficiency.²

Although AE is an uncommon dermatosis in the United States, it is an important diagnosis to make because its clinical features are fairly specific and early zinc supplementation allows for full resolution of the disease without permanent sequelae. The diagnosis of AE should be strongly considered when features of an acral bullous dermatosis are combined with a fissured dermatitis of extensor joints of the hands or elbows. It is particularly important to recognize that alcoholics, burn victims, postsurgical patients, and those with malignancies and eating disorders are at an increased risk for developing this nutritional deficiency.

To the Editor:

Acrodermatitis enteropathica (AE) is an inherited defect in zinc absorption that leads to hypozincemia. Its clinical presentation can vary based on serum zinc level and ranges from periorificial erosive dermatitis to psoriasiform dermatitis.¹ Recognition of the cutaneous manifestations of zinc deficiency can lead to early intervention with zinc supplementation and prevention of long-term morbidity and even mortality. In our case, the coexistence of a bullous acral dermatosis with the additional feature of extensor digital dermatitis with fissuring suggests a diagnosis of AE and can alert the astute clinician to the need for testing of serum zinc levels and/or treatment with zinc supplementation. Causes of acquired zinc deficiency that have been reported in the literature include eating disorders such as anorexia nervosa and bulimia nervosa, Crohn disease, food allergy, intestinal parasitic infestations, and an inborn error of metabolism known as nonketotic hyperglycemia (Table).^2-4

RELATED ARTICLE: Acquired Acrodermatitis Enteropathica Secondary to Alcoholism

A 42-year-old woman with a medical history of rheumatoid arthritis and short bowel syndrome due to multiple small bowel obstructions with subsequent bowel resections who was on chronic total parenteral nutrition (TPN) presented with bullae on the hands, shins, and feet. The patient initially noticed small erythematous macules on the hands and feet months prior to presentation. Three weeks prior to presentation, bullae started to form on the hands, mostly between the web spaces; dorsal aspects of the feet; and anterior aspects of the shins. The patient denied any oral ulcers. One day prior to presentation the patient was seen at an outside hospital and was started on prednisone 5 mg daily, oral clindamycin, mupirocin ointment, and nystatin-triamcinolone cream. These medications failed to improve her condition. On review of systems, the patient denied any fever, chills, eye pain, or dysuria.

Upon initial presentation the patient appeared weak and fatigued, though vital signs were normal. Physical examination revealed multiple flaccid bullae in the web spaces of the hands and shallow erosions with hemorrhagic crusts on the bilateral wrists. She also had violaceous patches in the extensor creases of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints, which were strikingly symmetric (Figure 1). Prominent flaccid bullae and shallow erosions with hemorrhagic crusts also were present on the bilateral shins and dorsal aspects of the feet (Figure 2). No oral ulcers were present. A punch biopsy from the dorsal aspect of the left foot revealed psoriasiform hyperplasia of the epidermis with prominent ballooning degeneration and hyperkeratosis/parakeratosis (Figure 3); a periodic acid–Schiff stain was negative for fungal organisms.

Given the biopsy results and clinical presentation, a nutritional deficiency was suspected and serum levels of zinc, vitamin B₁, vitamin B₂, and vitamin B₃ were assessed. Vitamins B₁, B₂, and B₃ all were within reference range, but the patient’s serum zinc level was found to be low at 11 μg/mL (reference range, 55–150 μg/mL). The alkaline phosphatase level also was measured to be low at 22 U/L (reference range, 31–103 U/L). Additionally, a hepatitis panel was drawn and glucagon levels were checked, which were found to be within reference range. These findings were consistent with a diagnosis of acquired AE. Prednisone and clindamycin were stopped and the patient was started on zinc supplementation in her TPN therapy. Mupirocin ointment was continued on the existing bullae. Upon discharge 10 days later, there were no new bullae and the existing bullae had sloughed off, revealing healthy skin underneath.

Zinc is an essential trace element and can be found in high concentration in foods such as shellfish, green vegetables, legumes, nuts, and whole grains.⁶ The majority of zinc is absorbed in the jejunum; as such, many cases of acquired zinc deficiency leading to AE are dueto disorders that affect the small intestine.² Conditions that may lead to poor gastrointestinal zinc absorption include alcoholism, eating disorders, TPN, burns, surgery, and malignancies.^2,7

Diagnosis typically is made based on characteristic clinical features, biopsy results, and a measurement of the serum zinc concentration. Although a low serum zinc level supports the diagnosis, serum zinc concentration is not a reliable indicator of body zinc stores and a normal serum zinc concentration does not rule out AE. The gold standard for diagnosis is the resolution of lesions after zinc supplementation.¹ Notably, because the production of alkaline phosphatase is dependent on zinc, levels of this enzyme also may be low in cases of AE,⁶ as in our patient.

The clinical manifestations of AE can vary greatly; patients may initially present with eczematous pink scaly plaques, which may subsequently become vesicular, bullous, pustular, or desquamative. The lesions may develop over the arms and legs as well as the anogenital and periorificial areas.⁵ Other notable manifestations that may present early in the course of AE include angular cheilitis followed by paronychia. In patients who are not promptly treated, long-term zinc deficiency may lead to growth delay, mental slowing, poor wound healing, anemia, and anorexia.⁵ Of note, deficiencies of branched-chain amino acids and essential fatty acids may appear clinically similar to AE.²

Zinc replacement is the treatment of choice for patients with AE due to dietary deficiency, and replacement therapy should begin with 0.5 to 1 mg/kg daily of elemental zinc.⁵ Response to acquired AE with zinc supplementation often is rapid. Lesions tend to resolve within days to weeks depending on the degree of deficiency.²

Although AE is an uncommon dermatosis in the United States, it is an important diagnosis to make because its clinical features are fairly specific and early zinc supplementation allows for full resolution of the disease without permanent sequelae. The diagnosis of AE should be strongly considered when features of an acral bullous dermatosis are combined with a fissured dermatitis of extensor joints of the hands or elbows. It is particularly important to recognize that alcoholics, burn victims, postsurgical patients, and those with malignancies and eating disorders are at an increased risk for developing this nutritional deficiency.

To the Editor:

Acrodermatitis enteropathica (AE) is an inherited defect in zinc absorption that leads to hypozincemia. Its clinical presentation can vary based on serum zinc level and ranges from periorificial erosive dermatitis to psoriasiform dermatitis.¹ Recognition of the cutaneous manifestations of zinc deficiency can lead to early intervention with zinc supplementation and prevention of long-term morbidity and even mortality. In our case, the coexistence of a bullous acral dermatosis with the additional feature of extensor digital dermatitis with fissuring suggests a diagnosis of AE and can alert the astute clinician to the need for testing of serum zinc levels and/or treatment with zinc supplementation. Causes of acquired zinc deficiency that have been reported in the literature include eating disorders such as anorexia nervosa and bulimia nervosa, Crohn disease, food allergy, intestinal parasitic infestations, and an inborn error of metabolism known as nonketotic hyperglycemia (Table).^2-4

RELATED ARTICLE: Acquired Acrodermatitis Enteropathica Secondary to Alcoholism

A 42-year-old woman with a medical history of rheumatoid arthritis and short bowel syndrome due to multiple small bowel obstructions with subsequent bowel resections who was on chronic total parenteral nutrition (TPN) presented with bullae on the hands, shins, and feet. The patient initially noticed small erythematous macules on the hands and feet months prior to presentation. Three weeks prior to presentation, bullae started to form on the hands, mostly between the web spaces; dorsal aspects of the feet; and anterior aspects of the shins. The patient denied any oral ulcers. One day prior to presentation the patient was seen at an outside hospital and was started on prednisone 5 mg daily, oral clindamycin, mupirocin ointment, and nystatin-triamcinolone cream. These medications failed to improve her condition. On review of systems, the patient denied any fever, chills, eye pain, or dysuria.

Upon initial presentation the patient appeared weak and fatigued, though vital signs were normal. Physical examination revealed multiple flaccid bullae in the web spaces of the hands and shallow erosions with hemorrhagic crusts on the bilateral wrists. She also had violaceous patches in the extensor creases of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints, which were strikingly symmetric (Figure 1). Prominent flaccid bullae and shallow erosions with hemorrhagic crusts also were present on the bilateral shins and dorsal aspects of the feet (Figure 2). No oral ulcers were present. A punch biopsy from the dorsal aspect of the left foot revealed psoriasiform hyperplasia of the epidermis with prominent ballooning degeneration and hyperkeratosis/parakeratosis (Figure 3); a periodic acid–Schiff stain was negative for fungal organisms.

Given the biopsy results and clinical presentation, a nutritional deficiency was suspected and serum levels of zinc, vitamin B₁, vitamin B₂, and vitamin B₃ were assessed. Vitamins B₁, B₂, and B₃ all were within reference range, but the patient’s serum zinc level was found to be low at 11 μg/mL (reference range, 55–150 μg/mL). The alkaline phosphatase level also was measured to be low at 22 U/L (reference range, 31–103 U/L). Additionally, a hepatitis panel was drawn and glucagon levels were checked, which were found to be within reference range. These findings were consistent with a diagnosis of acquired AE. Prednisone and clindamycin were stopped and the patient was started on zinc supplementation in her TPN therapy. Mupirocin ointment was continued on the existing bullae. Upon discharge 10 days later, there were no new bullae and the existing bullae had sloughed off, revealing healthy skin underneath.

Zinc is an essential trace element and can be found in high concentration in foods such as shellfish, green vegetables, legumes, nuts, and whole grains.⁶ The majority of zinc is absorbed in the jejunum; as such, many cases of acquired zinc deficiency leading to AE are dueto disorders that affect the small intestine.² Conditions that may lead to poor gastrointestinal zinc absorption include alcoholism, eating disorders, TPN, burns, surgery, and malignancies.^2,7

Diagnosis typically is made based on characteristic clinical features, biopsy results, and a measurement of the serum zinc concentration. Although a low serum zinc level supports the diagnosis, serum zinc concentration is not a reliable indicator of body zinc stores and a normal serum zinc concentration does not rule out AE. The gold standard for diagnosis is the resolution of lesions after zinc supplementation.¹ Notably, because the production of alkaline phosphatase is dependent on zinc, levels of this enzyme also may be low in cases of AE,⁶ as in our patient.

The clinical manifestations of AE can vary greatly; patients may initially present with eczematous pink scaly plaques, which may subsequently become vesicular, bullous, pustular, or desquamative. The lesions may develop over the arms and legs as well as the anogenital and periorificial areas.⁵ Other notable manifestations that may present early in the course of AE include angular cheilitis followed by paronychia. In patients who are not promptly treated, long-term zinc deficiency may lead to growth delay, mental slowing, poor wound healing, anemia, and anorexia.⁵ Of note, deficiencies of branched-chain amino acids and essential fatty acids may appear clinically similar to AE.²

Zinc replacement is the treatment of choice for patients with AE due to dietary deficiency, and replacement therapy should begin with 0.5 to 1 mg/kg daily of elemental zinc.⁵ Response to acquired AE with zinc supplementation often is rapid. Lesions tend to resolve within days to weeks depending on the degree of deficiency.²

Although AE is an uncommon dermatosis in the United States, it is an important diagnosis to make because its clinical features are fairly specific and early zinc supplementation allows for full resolution of the disease without permanent sequelae. The diagnosis of AE should be strongly considered when features of an acral bullous dermatosis are combined with a fissured dermatitis of extensor joints of the hands or elbows. It is particularly important to recognize that alcoholics, burn victims, postsurgical patients, and those with malignancies and eating disorders are at an increased risk for developing this nutritional deficiency.

The Diagnosis: Solitary Fibrous Tumor

Solitary fibrous tumors (SFTs), as first described by Klemperer and Rabin1 in 1931, are relatively uncommon mesenchymal neoplasms that occur primarily in the pleura. This lesion is now known to affect many other extrathoracic sites, such as the liver, kidney, adrenal glands, thyroid, central nervous system, and soft tissue, with rare examples originating from the skin.² Okamura et al³ reported the first known case of cutaneous SFT in 1997, with most of the literature limited to case reports. Erdag et al² described one of the largest case series of primary cutaneous SFTs. These lesions can occur across a wide age range but tend to primarily affect middle-aged adults. Solitary fibrous tumors have been known to have no sex predilection; however, Erdag et al² found a male predominance with a male to female ratio of 4 to 1. 

Histopathologically, a cutaneous SFT is known to appear as a well-circumscribed nodular spindle cell proliferation arranged in interlacing fascicles with an abundant hyalinized collagen stroma (quiz image). Alternating hypocellular and hypercellular areas can be seen. Supporting vasculature often is relatively prominent, represented by angulated and branching staghorn blood vessels (Figure 1).² A common histopathologic finding of SFTs is a patternless pattern, which suggests that the tumor can have a variety of morphologic appearances (eg, storiform, fascicular, neural, herringbone growth patterns), making histologic diagnosis difficult (quiz image).⁴ Therefore, immunohistochemistry plays a large role in the diagnosis of this tumor. The most important positive markers include CD34, CD99, B-cell lymphoma 2 (BCL-2), and signal transducer and activator of transcription 6 (STAT6).⁵ Nuclear STAT6 staining is an immunomarker for NGFI-A binding protein 2 (NAB2)-STAT6 gene fusion, which is specific for SFT.^5,6 Vivero et al⁷ also reported glutamate receptor, inotropic, AMPA 2 (GRIA2) as a useful immunostain in SFT, though it is also expressed in dermatofibrosarcoma protuberans (DFSP). In this case, the clinical and histopathologic findings best supported a diagnosis of SFT. Some consider hemangiopericytomas to be examples of SFTs; however, true hemangiopericytomas lack the thick hyalinized collagen and hypercellular areas seen in SFT.

A cellular dermatofibroma generally presents as a single round, reddish brown papule or nodule approximately 0.5 to 1 cm in diameter that is firm to palpation with a central depression or dimple created over the lesion from the lateral pressure. Cellular dermatofibromas mostly occur in middle-aged adults, with the most common locations on the legs and on the sides of the trunk. They are thought to arise after injuries to the skin. On histopathologic examination, cellular dermatofibromas typically exhibit a proliferation of fibrohistiocytic cells with collagen trapping, often at the periphery of the tumor (Figure 2). Although cellular dermatofibromas appear clinically different than SFTs, they often mimic SFTs histopathologically. Immunostaining also can be helpful in differentiating cellular dermatofibromas in which cells stain positive for factor XIIIa. CD34 staining is negative.

Dermatofibrosarcoma protuberans usually appears as one or multiple firm, red to violaceous nodules or plaques. They most often occur on the trunk in middle-aged adults. Histopathologically, DFSP presents with a dense, hypercellular, spindle cell proliferation that demonstrates a typical storiform pattern. The tumor generally infiltrates into the deep dermis and subcutaneous adipose layer with characteristic adipocyte entrapment (Figure 3). Positive CD34 and negative factor XIIIa staining helps to differentiate DFSP from a cellular dermatofibroma. Immunohistochemically, it is more difficult to distinguish DFSP from SFT, as both are CD34⁺ spindle cell neoplasms that also stain positive for CD99 and BCL-2.² GRIA2 positivity also is seen in both SFT and DFSP.⁷ However, differentiation can be made on morphologic grounds alone, as DFSP has ill-defined tumor borders with adnexal and fat entrapment and SFT tends to be more circumscribed with prominent arborizing hyalinized vessels.⁸

Spindle cell lipoma (SCL) is an asymptomatic subcutaneous tumor commonly located on the back, neck, and shoulders in older patients, typically men. It often presents as a solitary lesion, though multiple lesions may occur. It is a well-circumscribed tumor of mature adipose tissue with areas of spindle cell proliferation and ropey collagen bundles (Figure 4). In early lesions, the spindle cell areas are myxoid with the presence of many mast cells.⁹ The spindle cells stain positive for CD34. Although spindle cell lipoma would be included in both the clinical and histopathologic differential diagnosis for SFT, its histopathologic features often are enough to differentiate SCL, which is highlighted by the aforementioned features as well as a relatively low cellularity and lack of ectatic vessels.⁸ However, discerning tumor variants, such as low-fat pseudoangiomatous SCL and lipomatous or myxoid SFT, might prove more challenging.

Nodular fasciitis typically presents as a rapidly growing subcutaneous nodule that may be tender. It is a benign reactive process usually affecting the arms and trunk of young to middle-aged adults, though it commonly involves the head and neck region in children.¹⁰ The tumor histopathologically appears as a well-circumscribed subcutaneous or fascial nodule with an angulated appearance. Spindle-shaped and stellate fibroblasts are loosely arranged in an edematous myxomatous stroma with a feathered appearance (Figure 5). Extravasated erythrocytes often are present. With time, collagen bundles become thicker and hyalinized. Immunohistochemical studies demonstrate positivity for vimentin, calponin, muscle-specific actin, and smooth muscle actin. Desmin, CD34, cytokeratin, and S-100 typically are negative.^10-12 Therefore, CD34 staining is one of the main differentiating factors between nodular fasciitis and SFTs.

The Diagnosis: Solitary Fibrous Tumor

Solitary fibrous tumors (SFTs), as first described by Klemperer and Rabin1 in 1931, are relatively uncommon mesenchymal neoplasms that occur primarily in the pleura. This lesion is now known to affect many other extrathoracic sites, such as the liver, kidney, adrenal glands, thyroid, central nervous system, and soft tissue, with rare examples originating from the skin.² Okamura et al³ reported the first known case of cutaneous SFT in 1997, with most of the literature limited to case reports. Erdag et al² described one of the largest case series of primary cutaneous SFTs. These lesions can occur across a wide age range but tend to primarily affect middle-aged adults. Solitary fibrous tumors have been known to have no sex predilection; however, Erdag et al² found a male predominance with a male to female ratio of 4 to 1. 

Histopathologically, a cutaneous SFT is known to appear as a well-circumscribed nodular spindle cell proliferation arranged in interlacing fascicles with an abundant hyalinized collagen stroma (quiz image). Alternating hypocellular and hypercellular areas can be seen. Supporting vasculature often is relatively prominent, represented by angulated and branching staghorn blood vessels (Figure 1).² A common histopathologic finding of SFTs is a patternless pattern, which suggests that the tumor can have a variety of morphologic appearances (eg, storiform, fascicular, neural, herringbone growth patterns), making histologic diagnosis difficult (quiz image).⁴ Therefore, immunohistochemistry plays a large role in the diagnosis of this tumor. The most important positive markers include CD34, CD99, B-cell lymphoma 2 (BCL-2), and signal transducer and activator of transcription 6 (STAT6).⁵ Nuclear STAT6 staining is an immunomarker for NGFI-A binding protein 2 (NAB2)-STAT6 gene fusion, which is specific for SFT.^5,6 Vivero et al⁷ also reported glutamate receptor, inotropic, AMPA 2 (GRIA2) as a useful immunostain in SFT, though it is also expressed in dermatofibrosarcoma protuberans (DFSP). In this case, the clinical and histopathologic findings best supported a diagnosis of SFT. Some consider hemangiopericytomas to be examples of SFTs; however, true hemangiopericytomas lack the thick hyalinized collagen and hypercellular areas seen in SFT.

A cellular dermatofibroma generally presents as a single round, reddish brown papule or nodule approximately 0.5 to 1 cm in diameter that is firm to palpation with a central depression or dimple created over the lesion from the lateral pressure. Cellular dermatofibromas mostly occur in middle-aged adults, with the most common locations on the legs and on the sides of the trunk. They are thought to arise after injuries to the skin. On histopathologic examination, cellular dermatofibromas typically exhibit a proliferation of fibrohistiocytic cells with collagen trapping, often at the periphery of the tumor (Figure 2). Although cellular dermatofibromas appear clinically different than SFTs, they often mimic SFTs histopathologically. Immunostaining also can be helpful in differentiating cellular dermatofibromas in which cells stain positive for factor XIIIa. CD34 staining is negative.

Dermatofibrosarcoma protuberans usually appears as one or multiple firm, red to violaceous nodules or plaques. They most often occur on the trunk in middle-aged adults. Histopathologically, DFSP presents with a dense, hypercellular, spindle cell proliferation that demonstrates a typical storiform pattern. The tumor generally infiltrates into the deep dermis and subcutaneous adipose layer with characteristic adipocyte entrapment (Figure 3). Positive CD34 and negative factor XIIIa staining helps to differentiate DFSP from a cellular dermatofibroma. Immunohistochemically, it is more difficult to distinguish DFSP from SFT, as both are CD34⁺ spindle cell neoplasms that also stain positive for CD99 and BCL-2.² GRIA2 positivity also is seen in both SFT and DFSP.⁷ However, differentiation can be made on morphologic grounds alone, as DFSP has ill-defined tumor borders with adnexal and fat entrapment and SFT tends to be more circumscribed with prominent arborizing hyalinized vessels.⁸

Spindle cell lipoma (SCL) is an asymptomatic subcutaneous tumor commonly located on the back, neck, and shoulders in older patients, typically men. It often presents as a solitary lesion, though multiple lesions may occur. It is a well-circumscribed tumor of mature adipose tissue with areas of spindle cell proliferation and ropey collagen bundles (Figure 4). In early lesions, the spindle cell areas are myxoid with the presence of many mast cells.⁹ The spindle cells stain positive for CD34. Although spindle cell lipoma would be included in both the clinical and histopathologic differential diagnosis for SFT, its histopathologic features often are enough to differentiate SCL, which is highlighted by the aforementioned features as well as a relatively low cellularity and lack of ectatic vessels.⁸ However, discerning tumor variants, such as low-fat pseudoangiomatous SCL and lipomatous or myxoid SFT, might prove more challenging.

Nodular fasciitis typically presents as a rapidly growing subcutaneous nodule that may be tender. It is a benign reactive process usually affecting the arms and trunk of young to middle-aged adults, though it commonly involves the head and neck region in children.¹⁰ The tumor histopathologically appears as a well-circumscribed subcutaneous or fascial nodule with an angulated appearance. Spindle-shaped and stellate fibroblasts are loosely arranged in an edematous myxomatous stroma with a feathered appearance (Figure 5). Extravasated erythrocytes often are present. With time, collagen bundles become thicker and hyalinized. Immunohistochemical studies demonstrate positivity for vimentin, calponin, muscle-specific actin, and smooth muscle actin. Desmin, CD34, cytokeratin, and S-100 typically are negative.^10-12 Therefore, CD34 staining is one of the main differentiating factors between nodular fasciitis and SFTs.

The Diagnosis: Solitary Fibrous Tumor

Solitary fibrous tumors (SFTs), as first described by Klemperer and Rabin1 in 1931, are relatively uncommon mesenchymal neoplasms that occur primarily in the pleura. This lesion is now known to affect many other extrathoracic sites, such as the liver, kidney, adrenal glands, thyroid, central nervous system, and soft tissue, with rare examples originating from the skin.² Okamura et al³ reported the first known case of cutaneous SFT in 1997, with most of the literature limited to case reports. Erdag et al² described one of the largest case series of primary cutaneous SFTs. These lesions can occur across a wide age range but tend to primarily affect middle-aged adults. Solitary fibrous tumors have been known to have no sex predilection; however, Erdag et al² found a male predominance with a male to female ratio of 4 to 1. 

Histopathologically, a cutaneous SFT is known to appear as a well-circumscribed nodular spindle cell proliferation arranged in interlacing fascicles with an abundant hyalinized collagen stroma (quiz image). Alternating hypocellular and hypercellular areas can be seen. Supporting vasculature often is relatively prominent, represented by angulated and branching staghorn blood vessels (Figure 1).² A common histopathologic finding of SFTs is a patternless pattern, which suggests that the tumor can have a variety of morphologic appearances (eg, storiform, fascicular, neural, herringbone growth patterns), making histologic diagnosis difficult (quiz image).⁴ Therefore, immunohistochemistry plays a large role in the diagnosis of this tumor. The most important positive markers include CD34, CD99, B-cell lymphoma 2 (BCL-2), and signal transducer and activator of transcription 6 (STAT6).⁵ Nuclear STAT6 staining is an immunomarker for NGFI-A binding protein 2 (NAB2)-STAT6 gene fusion, which is specific for SFT.^5,6 Vivero et al⁷ also reported glutamate receptor, inotropic, AMPA 2 (GRIA2) as a useful immunostain in SFT, though it is also expressed in dermatofibrosarcoma protuberans (DFSP). In this case, the clinical and histopathologic findings best supported a diagnosis of SFT. Some consider hemangiopericytomas to be examples of SFTs; however, true hemangiopericytomas lack the thick hyalinized collagen and hypercellular areas seen in SFT.

A cellular dermatofibroma generally presents as a single round, reddish brown papule or nodule approximately 0.5 to 1 cm in diameter that is firm to palpation with a central depression or dimple created over the lesion from the lateral pressure. Cellular dermatofibromas mostly occur in middle-aged adults, with the most common locations on the legs and on the sides of the trunk. They are thought to arise after injuries to the skin. On histopathologic examination, cellular dermatofibromas typically exhibit a proliferation of fibrohistiocytic cells with collagen trapping, often at the periphery of the tumor (Figure 2). Although cellular dermatofibromas appear clinically different than SFTs, they often mimic SFTs histopathologically. Immunostaining also can be helpful in differentiating cellular dermatofibromas in which cells stain positive for factor XIIIa. CD34 staining is negative.

Dermatofibrosarcoma protuberans usually appears as one or multiple firm, red to violaceous nodules or plaques. They most often occur on the trunk in middle-aged adults. Histopathologically, DFSP presents with a dense, hypercellular, spindle cell proliferation that demonstrates a typical storiform pattern. The tumor generally infiltrates into the deep dermis and subcutaneous adipose layer with characteristic adipocyte entrapment (Figure 3). Positive CD34 and negative factor XIIIa staining helps to differentiate DFSP from a cellular dermatofibroma. Immunohistochemically, it is more difficult to distinguish DFSP from SFT, as both are CD34⁺ spindle cell neoplasms that also stain positive for CD99 and BCL-2.² GRIA2 positivity also is seen in both SFT and DFSP.⁷ However, differentiation can be made on morphologic grounds alone, as DFSP has ill-defined tumor borders with adnexal and fat entrapment and SFT tends to be more circumscribed with prominent arborizing hyalinized vessels.⁸

Spindle cell lipoma (SCL) is an asymptomatic subcutaneous tumor commonly located on the back, neck, and shoulders in older patients, typically men. It often presents as a solitary lesion, though multiple lesions may occur. It is a well-circumscribed tumor of mature adipose tissue with areas of spindle cell proliferation and ropey collagen bundles (Figure 4). In early lesions, the spindle cell areas are myxoid with the presence of many mast cells.⁹ The spindle cells stain positive for CD34. Although spindle cell lipoma would be included in both the clinical and histopathologic differential diagnosis for SFT, its histopathologic features often are enough to differentiate SCL, which is highlighted by the aforementioned features as well as a relatively low cellularity and lack of ectatic vessels.⁸ However, discerning tumor variants, such as low-fat pseudoangiomatous SCL and lipomatous or myxoid SFT, might prove more challenging.

Nodular fasciitis typically presents as a rapidly growing subcutaneous nodule that may be tender. It is a benign reactive process usually affecting the arms and trunk of young to middle-aged adults, though it commonly involves the head and neck region in children.¹⁰ The tumor histopathologically appears as a well-circumscribed subcutaneous or fascial nodule with an angulated appearance. Spindle-shaped and stellate fibroblasts are loosely arranged in an edematous myxomatous stroma with a feathered appearance (Figure 5). Extravasated erythrocytes often are present. With time, collagen bundles become thicker and hyalinized. Immunohistochemical studies demonstrate positivity for vimentin, calponin, muscle-specific actin, and smooth muscle actin. Desmin, CD34, cytokeratin, and S-100 typically are negative.^10-12 Therefore, CD34 staining is one of the main differentiating factors between nodular fasciitis and SFTs.

The Diagnosis: Lymphomatoid Papulosis

Histopathologic and immunohistochemical examination of the ulcer revealed a dense nodular and diffuse infiltrate in the papillary and reticular dermis comprised predominantly of atypical, CD30⁺, small T cells and large lymphoid cells admixed with neutrophils and eosinophils (Figures 1 and 2). Tissue cultures and infectious stains were negative. The complete blood cell count, metabolic panel, serum lactate dehydrogenase level, and peripheral blood flow cytometry were normal. Correlation of the lesions' self-healing nature with the histopathologic and immunohistochemical findings led to a diagnosis of lymphomatoid papulosis (LyP). In light of this diagnosis, a shave biopsy was obtained of one of the patient's poikilodermatous patches and was found to be consistent with poikilodermatous mycosis fungoides (MF).

At 4-month follow-up, the patient reported that she continued to develop crops of 1 to 3 LyP lesions each month. She continued to deny systemic concerns, and the poikilodermatous MF appeared unchanged. As part of a hematologic workup, a positron emission tomography-computed tomography scan revealed glucose-avid lymph nodes in the axillary, supraclavicular, abdominal, and inguinal regions. These findings raised concern for possible lymphomatous involvement of the patient's MF. Systemic therapy may be required pending further surveillance.

Lymphomatoid papulosis is a chronic papulonecrotic disease characterized clinically by recurrent crops of self-healing papules. Histopathologically, LyP features a perivascular infiltrate with atypical dermal T cells. Macaulay¹ first described LyP in 1968 in a 41-year-old woman with a several-year history of continuously self-resolving crops of necrotic papules, noting the paradox between the patient's benign clinical course and malignant-seeming histology featuring "an alarming infiltrate of anaplastic cells." Since this report, LyP has continued to spur debate regarding its malignant potential but is now recognized as an indolent cutaneous T-cell lymphoma with an excellent prognosis.²

There are several histopathologic subtypes of LyP, the most common of which are type A, resembling Hodgkin lymphoma; type B, resembling MF; type C, resembling primary cutaneous anaplastic large cell lymphoma (C-ALCL); and type D, resembling aggressive epidermotropic CD8⁺ cutaneous T-cell lymphoma.² 

The multifocal ulcers and eschars of LyP may appropriately raise suspicion for an infectious process, as in the present case. Numerous reports show that LyP may be initially misdiagnosed as an infection, such as cellulitis,³ furunculosis,⁴ parapoxvirus Orf,⁵ and ecthyma.⁶ Furthermore, several cutaneous infections have histopathologic features indistinguishable from LyP.⁷ For example, herpes simplex virus infection, molluscum contagiosum, Milker nodule, syphilis, and leishmaniasis may contain an appreciable number of large CD30⁺ T cells, which is compatible with both LyP type C and C-ALCL.⁷ As in the present case, the final diagnosis rests on clinicopathologic correlation, with LyP often distinguished by its invariable self-resolution, unlike its numerous infectious mimickers. The self-regressing nature of LyP also helps differentiate LyP occurring in the setting of MF from MF that has underwent CD30⁺ large cell transformation. In addition, the diagnosis of MF-associated LyP is favored over transformed MF when, as in the present case, CD30⁺ lesions develop on skin distinct from MF-affected skin.

Although isolated LyP is benign, 18% (11/61) of patients will subsequently develop lymphoma. More commonly, lymphomas may precede or occur concomitantly with the onset of LyP. In a retrospective study of 84 LyP patients, for example, 40% (34/84) had prior or concomitant lymphoma.8 Owing to the well-established link between LyP and lymphoma, there is appropriate emphasis on close monitoring of these patients. In addition, a careful history and physical examination are necessary to evaluate for a preceding, previously undiagnosed lymphoma. In point of fact, our patient had undiagnosed poikilodermatous MF prior to developing LyP, which was proven by biopsy at the time of LyP diagnosis. A distinct clinical variant of MF, poikilodermatous MF is characterized by hyperpigmented and hypopigmented patches, atrophy, and telangiectasia. A study of 49 patients with poikilodermatous MF found that this variant had an earlier age of onset compared with other types of MF. The study also showed that 18% (9/49) of patients had coexistent LyP, suggesting that poikilodermatous MF and LyP may be more frequently associated than previously believed.⁹

Treatment of LyP is unnecessary beyond basic wound care to avoid bacterial superinfection.^2,10 Therapy for poikilodermatous MF, similar to other types of MF, is based on disease stage. Topical therapy may be utilized for localized disease, while systemic therapies are reserved for recalcitrant cases and internal involvement.⁹
 
Acknowledgments
We thank David L. Ramsay, MD, for obtaining aspects of the patient's history, and Shane A. Meehan, MD, and Adnan Mir, MD, PhD, as well as Cynthia M. Magro, MD, (all from New York, New York) for performing the histopathologic and immunohistochemical analyses.

The Diagnosis: Lymphomatoid Papulosis

Histopathologic and immunohistochemical examination of the ulcer revealed a dense nodular and diffuse infiltrate in the papillary and reticular dermis comprised predominantly of atypical, CD30⁺, small T cells and large lymphoid cells admixed with neutrophils and eosinophils (Figures 1 and 2). Tissue cultures and infectious stains were negative. The complete blood cell count, metabolic panel, serum lactate dehydrogenase level, and peripheral blood flow cytometry were normal. Correlation of the lesions' self-healing nature with the histopathologic and immunohistochemical findings led to a diagnosis of lymphomatoid papulosis (LyP). In light of this diagnosis, a shave biopsy was obtained of one of the patient's poikilodermatous patches and was found to be consistent with poikilodermatous mycosis fungoides (MF).

At 4-month follow-up, the patient reported that she continued to develop crops of 1 to 3 LyP lesions each month. She continued to deny systemic concerns, and the poikilodermatous MF appeared unchanged. As part of a hematologic workup, a positron emission tomography-computed tomography scan revealed glucose-avid lymph nodes in the axillary, supraclavicular, abdominal, and inguinal regions. These findings raised concern for possible lymphomatous involvement of the patient's MF. Systemic therapy may be required pending further surveillance.

Lymphomatoid papulosis is a chronic papulonecrotic disease characterized clinically by recurrent crops of self-healing papules. Histopathologically, LyP features a perivascular infiltrate with atypical dermal T cells. Macaulay¹ first described LyP in 1968 in a 41-year-old woman with a several-year history of continuously self-resolving crops of necrotic papules, noting the paradox between the patient's benign clinical course and malignant-seeming histology featuring "an alarming infiltrate of anaplastic cells." Since this report, LyP has continued to spur debate regarding its malignant potential but is now recognized as an indolent cutaneous T-cell lymphoma with an excellent prognosis.²

There are several histopathologic subtypes of LyP, the most common of which are type A, resembling Hodgkin lymphoma; type B, resembling MF; type C, resembling primary cutaneous anaplastic large cell lymphoma (C-ALCL); and type D, resembling aggressive epidermotropic CD8⁺ cutaneous T-cell lymphoma.² 

The multifocal ulcers and eschars of LyP may appropriately raise suspicion for an infectious process, as in the present case. Numerous reports show that LyP may be initially misdiagnosed as an infection, such as cellulitis,³ furunculosis,⁴ parapoxvirus Orf,⁵ and ecthyma.⁶ Furthermore, several cutaneous infections have histopathologic features indistinguishable from LyP.⁷ For example, herpes simplex virus infection, molluscum contagiosum, Milker nodule, syphilis, and leishmaniasis may contain an appreciable number of large CD30⁺ T cells, which is compatible with both LyP type C and C-ALCL.⁷ As in the present case, the final diagnosis rests on clinicopathologic correlation, with LyP often distinguished by its invariable self-resolution, unlike its numerous infectious mimickers. The self-regressing nature of LyP also helps differentiate LyP occurring in the setting of MF from MF that has underwent CD30⁺ large cell transformation. In addition, the diagnosis of MF-associated LyP is favored over transformed MF when, as in the present case, CD30⁺ lesions develop on skin distinct from MF-affected skin.

Although isolated LyP is benign, 18% (11/61) of patients will subsequently develop lymphoma. More commonly, lymphomas may precede or occur concomitantly with the onset of LyP. In a retrospective study of 84 LyP patients, for example, 40% (34/84) had prior or concomitant lymphoma.8 Owing to the well-established link between LyP and lymphoma, there is appropriate emphasis on close monitoring of these patients. In addition, a careful history and physical examination are necessary to evaluate for a preceding, previously undiagnosed lymphoma. In point of fact, our patient had undiagnosed poikilodermatous MF prior to developing LyP, which was proven by biopsy at the time of LyP diagnosis. A distinct clinical variant of MF, poikilodermatous MF is characterized by hyperpigmented and hypopigmented patches, atrophy, and telangiectasia. A study of 49 patients with poikilodermatous MF found that this variant had an earlier age of onset compared with other types of MF. The study also showed that 18% (9/49) of patients had coexistent LyP, suggesting that poikilodermatous MF and LyP may be more frequently associated than previously believed.⁹

Treatment of LyP is unnecessary beyond basic wound care to avoid bacterial superinfection.^2,10 Therapy for poikilodermatous MF, similar to other types of MF, is based on disease stage. Topical therapy may be utilized for localized disease, while systemic therapies are reserved for recalcitrant cases and internal involvement.⁹
 
Acknowledgments
We thank David L. Ramsay, MD, for obtaining aspects of the patient's history, and Shane A. Meehan, MD, and Adnan Mir, MD, PhD, as well as Cynthia M. Magro, MD, (all from New York, New York) for performing the histopathologic and immunohistochemical analyses.

The Diagnosis: Lymphomatoid Papulosis

Histopathologic and immunohistochemical examination of the ulcer revealed a dense nodular and diffuse infiltrate in the papillary and reticular dermis comprised predominantly of atypical, CD30⁺, small T cells and large lymphoid cells admixed with neutrophils and eosinophils (Figures 1 and 2). Tissue cultures and infectious stains were negative. The complete blood cell count, metabolic panel, serum lactate dehydrogenase level, and peripheral blood flow cytometry were normal. Correlation of the lesions' self-healing nature with the histopathologic and immunohistochemical findings led to a diagnosis of lymphomatoid papulosis (LyP). In light of this diagnosis, a shave biopsy was obtained of one of the patient's poikilodermatous patches and was found to be consistent with poikilodermatous mycosis fungoides (MF).

At 4-month follow-up, the patient reported that she continued to develop crops of 1 to 3 LyP lesions each month. She continued to deny systemic concerns, and the poikilodermatous MF appeared unchanged. As part of a hematologic workup, a positron emission tomography-computed tomography scan revealed glucose-avid lymph nodes in the axillary, supraclavicular, abdominal, and inguinal regions. These findings raised concern for possible lymphomatous involvement of the patient's MF. Systemic therapy may be required pending further surveillance.

Lymphomatoid papulosis is a chronic papulonecrotic disease characterized clinically by recurrent crops of self-healing papules. Histopathologically, LyP features a perivascular infiltrate with atypical dermal T cells. Macaulay¹ first described LyP in 1968 in a 41-year-old woman with a several-year history of continuously self-resolving crops of necrotic papules, noting the paradox between the patient's benign clinical course and malignant-seeming histology featuring "an alarming infiltrate of anaplastic cells." Since this report, LyP has continued to spur debate regarding its malignant potential but is now recognized as an indolent cutaneous T-cell lymphoma with an excellent prognosis.²

There are several histopathologic subtypes of LyP, the most common of which are type A, resembling Hodgkin lymphoma; type B, resembling MF; type C, resembling primary cutaneous anaplastic large cell lymphoma (C-ALCL); and type D, resembling aggressive epidermotropic CD8⁺ cutaneous T-cell lymphoma.² 

The multifocal ulcers and eschars of LyP may appropriately raise suspicion for an infectious process, as in the present case. Numerous reports show that LyP may be initially misdiagnosed as an infection, such as cellulitis,³ furunculosis,⁴ parapoxvirus Orf,⁵ and ecthyma.⁶ Furthermore, several cutaneous infections have histopathologic features indistinguishable from LyP.⁷ For example, herpes simplex virus infection, molluscum contagiosum, Milker nodule, syphilis, and leishmaniasis may contain an appreciable number of large CD30⁺ T cells, which is compatible with both LyP type C and C-ALCL.⁷ As in the present case, the final diagnosis rests on clinicopathologic correlation, with LyP often distinguished by its invariable self-resolution, unlike its numerous infectious mimickers. The self-regressing nature of LyP also helps differentiate LyP occurring in the setting of MF from MF that has underwent CD30⁺ large cell transformation. In addition, the diagnosis of MF-associated LyP is favored over transformed MF when, as in the present case, CD30⁺ lesions develop on skin distinct from MF-affected skin.

Although isolated LyP is benign, 18% (11/61) of patients will subsequently develop lymphoma. More commonly, lymphomas may precede or occur concomitantly with the onset of LyP. In a retrospective study of 84 LyP patients, for example, 40% (34/84) had prior or concomitant lymphoma.8 Owing to the well-established link between LyP and lymphoma, there is appropriate emphasis on close monitoring of these patients. In addition, a careful history and physical examination are necessary to evaluate for a preceding, previously undiagnosed lymphoma. In point of fact, our patient had undiagnosed poikilodermatous MF prior to developing LyP, which was proven by biopsy at the time of LyP diagnosis. A distinct clinical variant of MF, poikilodermatous MF is characterized by hyperpigmented and hypopigmented patches, atrophy, and telangiectasia. A study of 49 patients with poikilodermatous MF found that this variant had an earlier age of onset compared with other types of MF. The study also showed that 18% (9/49) of patients had coexistent LyP, suggesting that poikilodermatous MF and LyP may be more frequently associated than previously believed.⁹

Treatment of LyP is unnecessary beyond basic wound care to avoid bacterial superinfection.^2,10 Therapy for poikilodermatous MF, similar to other types of MF, is based on disease stage. Topical therapy may be utilized for localized disease, while systemic therapies are reserved for recalcitrant cases and internal involvement.⁹
 
Acknowledgments
We thank David L. Ramsay, MD, for obtaining aspects of the patient's history, and Shane A. Meehan, MD, and Adnan Mir, MD, PhD, as well as Cynthia M. Magro, MD, (all from New York, New York) for performing the histopathologic and immunohistochemical analyses.

To the Editor:

A 69-year-old woman with no history of immunodeficiency presented 1 month after a thorn from her locally grown Madagascar palm plant (Pachypodium lamerei) pierced the skin. The patient developed a painful nodule at the site on the left elbow (Figure 1). An excisional biopsy by an outside dermatologist was performed, which showed granulomatous inflammation within the dermis with epidermal hyperplasia and the presence of golden brown spherules (medlar bodies). The diagnosis was a dermal fungal infection consistent with chromoblastomycosis. A curative surgical excision was performed, and medlar bodies were seen adjacent to a polarizable foreign body consistent with plant material on histology (Figure 2). Because the lesion was localized, adjuvant medical treatment was not deemed necessary. The patient has not had any recurrence in the last 1.5 years since the resection.

The categorization of chromoblastomycosis includes a chronic fungal infection of the cutaneous and subcutaneous tissues by dematiaceous (pigmented) fungi. This definition is such that there are a multitude of organisms that can be the primary cause of this diagnosis. Generally, infection follows a traumatic permeation of the skin by a foreign body contaminated by the causative organism in agricultural workers. The most common dematiaceous pathogens are Fonsecaea pedrosoi, Phialophora verrucosa, and Cladosporium carrionii; however, the specific causative organism varies heavily on geographic location. With inoculation by a foreign body, a small papule develops at the site of the lesion. Several years after the primary infection, nodules and verrucous erythematous plaques develop in the same area, and patients present with concerns of pain and pruritus.¹ Lesions usually are localized to the initial area of inoculation, generally a break in the skin by the offending foreign body, on the legs, arms, or hands, but hematogenous or lymphatic dissemination with distant transmission due to scratching also can occur. Ulceration due to secondary bacterial infection is another possible manifestation, resulting in a foul odor and less commonly lymphedema. Rarely, squamous cell carcinoma is a complication.²

RELATED ARTICLE: Fungal Foes: Presentations of Chromoblastomycosis Post–Hurricane Ike

On histopathology, thick-walled sclerotic bodies termed medlar bodies or copper pennies are pathognomonic for chromoblastomycosis and represent the fungal elements. Grossly, black dots can be seen on the skin in the affected areas from the transepidermal elimination of the fungi.^1,2 However, there is no specificity for determining the causative organism in this manner, or even with culture, as it is difficult to differentiate the species morphologically. More advanced tests can help, such as polymerase chain reaction or enzyme-linked immunosorbent assay, where available.² Hematoxylin and eosin stain also shows epidermal hyperplasia and dermal mononuclear infiltrate.

Treatment modalities include surgical excision, cryotherapy, pharmacologic treatment, and combination therapy. Localized lesions often can be resected, but more severe infections can require pharmacologic treatment. Unfortunately, there tends to be a high risk for relapse with most antifungal modalities. The combination of itraconazole and terbinafine has been shown to offer the best medical therapy with lower risk for refractoriness to treatment by producing a synergistic effect between the 2 antifungals.^2,3 Many surgical treatments often are combined with oral antifungals to try to attain complete eradication in deep or extensive lesions, as seen in a case in which oral terbinafine was used prior to surgery to reduce the size of the lesion, followed by complete resection.⁴ With localized lesions that are resectable, a wide and deep incision often can be curative. Cryotherapy also may be coupled with surgical excision or pharmacologic therapy. Most literature suggests that cryotherapy or the use of antifungals prior to excision offers improved outcomes.^2,5 Prognosis tends to be good for chromoblastomycoses, particularly with smaller lesions. Complete eradication varies greatly on the size and depth of the lesion, independent of the causative pathogen.

Our patient’s presentation with chromoblastomycosis is unique because of the source of infection, which was a plant grown from seeds in a local nursery in South Florida and then sold to the patient. The majority of chromoblastomycosis infections occur in agricultural workers, typically in tropical climates such as South and Central America, the Caribbean, and Mexico.^1,2 Historically, infections in the United States have been uncommon, with the majority presenting in patients on prolonged corticosteroid therapy or with other immunosuppressive conditions.^6,7 This presentation of a chromoblastomycosis infection in a 69-year-old woman with no history of immunosuppression or chronic disease can serve as a teaching point about atypical presentations of the disease. The Madagascar palm plant that was responsible for the initial lesion in our case is a member of the Pachypodium species of plant that is endemic to Madagascar, one of the few regions outside of Latin America that has displayed numerous cases of chromoblastomycosis. In this fashion, a domestic gardener can now become exposed to dematiaceous pathogens that normally are not found in the continental United States, and knowledge of this possible exposure source can be crucial in the diagnosis and management of similar patients.

To the Editor:

A 69-year-old woman with no history of immunodeficiency presented 1 month after a thorn from her locally grown Madagascar palm plant (Pachypodium lamerei) pierced the skin. The patient developed a painful nodule at the site on the left elbow (Figure 1). An excisional biopsy by an outside dermatologist was performed, which showed granulomatous inflammation within the dermis with epidermal hyperplasia and the presence of golden brown spherules (medlar bodies). The diagnosis was a dermal fungal infection consistent with chromoblastomycosis. A curative surgical excision was performed, and medlar bodies were seen adjacent to a polarizable foreign body consistent with plant material on histology (Figure 2). Because the lesion was localized, adjuvant medical treatment was not deemed necessary. The patient has not had any recurrence in the last 1.5 years since the resection.

The categorization of chromoblastomycosis includes a chronic fungal infection of the cutaneous and subcutaneous tissues by dematiaceous (pigmented) fungi. This definition is such that there are a multitude of organisms that can be the primary cause of this diagnosis. Generally, infection follows a traumatic permeation of the skin by a foreign body contaminated by the causative organism in agricultural workers. The most common dematiaceous pathogens are Fonsecaea pedrosoi, Phialophora verrucosa, and Cladosporium carrionii; however, the specific causative organism varies heavily on geographic location. With inoculation by a foreign body, a small papule develops at the site of the lesion. Several years after the primary infection, nodules and verrucous erythematous plaques develop in the same area, and patients present with concerns of pain and pruritus.¹ Lesions usually are localized to the initial area of inoculation, generally a break in the skin by the offending foreign body, on the legs, arms, or hands, but hematogenous or lymphatic dissemination with distant transmission due to scratching also can occur. Ulceration due to secondary bacterial infection is another possible manifestation, resulting in a foul odor and less commonly lymphedema. Rarely, squamous cell carcinoma is a complication.²

RELATED ARTICLE: Fungal Foes: Presentations of Chromoblastomycosis Post–Hurricane Ike

On histopathology, thick-walled sclerotic bodies termed medlar bodies or copper pennies are pathognomonic for chromoblastomycosis and represent the fungal elements. Grossly, black dots can be seen on the skin in the affected areas from the transepidermal elimination of the fungi.^1,2 However, there is no specificity for determining the causative organism in this manner, or even with culture, as it is difficult to differentiate the species morphologically. More advanced tests can help, such as polymerase chain reaction or enzyme-linked immunosorbent assay, where available.² Hematoxylin and eosin stain also shows epidermal hyperplasia and dermal mononuclear infiltrate.

Treatment modalities include surgical excision, cryotherapy, pharmacologic treatment, and combination therapy. Localized lesions often can be resected, but more severe infections can require pharmacologic treatment. Unfortunately, there tends to be a high risk for relapse with most antifungal modalities. The combination of itraconazole and terbinafine has been shown to offer the best medical therapy with lower risk for refractoriness to treatment by producing a synergistic effect between the 2 antifungals.^2,3 Many surgical treatments often are combined with oral antifungals to try to attain complete eradication in deep or extensive lesions, as seen in a case in which oral terbinafine was used prior to surgery to reduce the size of the lesion, followed by complete resection.⁴ With localized lesions that are resectable, a wide and deep incision often can be curative. Cryotherapy also may be coupled with surgical excision or pharmacologic therapy. Most literature suggests that cryotherapy or the use of antifungals prior to excision offers improved outcomes.^2,5 Prognosis tends to be good for chromoblastomycoses, particularly with smaller lesions. Complete eradication varies greatly on the size and depth of the lesion, independent of the causative pathogen.

Our patient’s presentation with chromoblastomycosis is unique because of the source of infection, which was a plant grown from seeds in a local nursery in South Florida and then sold to the patient. The majority of chromoblastomycosis infections occur in agricultural workers, typically in tropical climates such as South and Central America, the Caribbean, and Mexico.^1,2 Historically, infections in the United States have been uncommon, with the majority presenting in patients on prolonged corticosteroid therapy or with other immunosuppressive conditions.^6,7 This presentation of a chromoblastomycosis infection in a 69-year-old woman with no history of immunosuppression or chronic disease can serve as a teaching point about atypical presentations of the disease. The Madagascar palm plant that was responsible for the initial lesion in our case is a member of the Pachypodium species of plant that is endemic to Madagascar, one of the few regions outside of Latin America that has displayed numerous cases of chromoblastomycosis. In this fashion, a domestic gardener can now become exposed to dematiaceous pathogens that normally are not found in the continental United States, and knowledge of this possible exposure source can be crucial in the diagnosis and management of similar patients.

To the Editor:

A 69-year-old woman with no history of immunodeficiency presented 1 month after a thorn from her locally grown Madagascar palm plant (Pachypodium lamerei) pierced the skin. The patient developed a painful nodule at the site on the left elbow (Figure 1). An excisional biopsy by an outside dermatologist was performed, which showed granulomatous inflammation within the dermis with epidermal hyperplasia and the presence of golden brown spherules (medlar bodies). The diagnosis was a dermal fungal infection consistent with chromoblastomycosis. A curative surgical excision was performed, and medlar bodies were seen adjacent to a polarizable foreign body consistent with plant material on histology (Figure 2). Because the lesion was localized, adjuvant medical treatment was not deemed necessary. The patient has not had any recurrence in the last 1.5 years since the resection.

The categorization of chromoblastomycosis includes a chronic fungal infection of the cutaneous and subcutaneous tissues by dematiaceous (pigmented) fungi. This definition is such that there are a multitude of organisms that can be the primary cause of this diagnosis. Generally, infection follows a traumatic permeation of the skin by a foreign body contaminated by the causative organism in agricultural workers. The most common dematiaceous pathogens are Fonsecaea pedrosoi, Phialophora verrucosa, and Cladosporium carrionii; however, the specific causative organism varies heavily on geographic location. With inoculation by a foreign body, a small papule develops at the site of the lesion. Several years after the primary infection, nodules and verrucous erythematous plaques develop in the same area, and patients present with concerns of pain and pruritus.¹ Lesions usually are localized to the initial area of inoculation, generally a break in the skin by the offending foreign body, on the legs, arms, or hands, but hematogenous or lymphatic dissemination with distant transmission due to scratching also can occur. Ulceration due to secondary bacterial infection is another possible manifestation, resulting in a foul odor and less commonly lymphedema. Rarely, squamous cell carcinoma is a complication.²

RELATED ARTICLE: Fungal Foes: Presentations of Chromoblastomycosis Post–Hurricane Ike

On histopathology, thick-walled sclerotic bodies termed medlar bodies or copper pennies are pathognomonic for chromoblastomycosis and represent the fungal elements. Grossly, black dots can be seen on the skin in the affected areas from the transepidermal elimination of the fungi.^1,2 However, there is no specificity for determining the causative organism in this manner, or even with culture, as it is difficult to differentiate the species morphologically. More advanced tests can help, such as polymerase chain reaction or enzyme-linked immunosorbent assay, where available.² Hematoxylin and eosin stain also shows epidermal hyperplasia and dermal mononuclear infiltrate.

Treatment modalities include surgical excision, cryotherapy, pharmacologic treatment, and combination therapy. Localized lesions often can be resected, but more severe infections can require pharmacologic treatment. Unfortunately, there tends to be a high risk for relapse with most antifungal modalities. The combination of itraconazole and terbinafine has been shown to offer the best medical therapy with lower risk for refractoriness to treatment by producing a synergistic effect between the 2 antifungals.^2,3 Many surgical treatments often are combined with oral antifungals to try to attain complete eradication in deep or extensive lesions, as seen in a case in which oral terbinafine was used prior to surgery to reduce the size of the lesion, followed by complete resection.⁴ With localized lesions that are resectable, a wide and deep incision often can be curative. Cryotherapy also may be coupled with surgical excision or pharmacologic therapy. Most literature suggests that cryotherapy or the use of antifungals prior to excision offers improved outcomes.^2,5 Prognosis tends to be good for chromoblastomycoses, particularly with smaller lesions. Complete eradication varies greatly on the size and depth of the lesion, independent of the causative pathogen.

Our patient’s presentation with chromoblastomycosis is unique because of the source of infection, which was a plant grown from seeds in a local nursery in South Florida and then sold to the patient. The majority of chromoblastomycosis infections occur in agricultural workers, typically in tropical climates such as South and Central America, the Caribbean, and Mexico.^1,2 Historically, infections in the United States have been uncommon, with the majority presenting in patients on prolonged corticosteroid therapy or with other immunosuppressive conditions.^6,7 This presentation of a chromoblastomycosis infection in a 69-year-old woman with no history of immunosuppression or chronic disease can serve as a teaching point about atypical presentations of the disease. The Madagascar palm plant that was responsible for the initial lesion in our case is a member of the Pachypodium species of plant that is endemic to Madagascar, one of the few regions outside of Latin America that has displayed numerous cases of chromoblastomycosis. In this fashion, a domestic gardener can now become exposed to dematiaceous pathogens that normally are not found in the continental United States, and knowledge of this possible exposure source can be crucial in the diagnosis and management of similar patients.