Dermatopathology

Case Report

A 63-year-old woman was referred to our clinic for evaluation of multiple papules and nodules on the neck and trunk that had been present for 2 years. Three years prior to presentation she had been diagnosed with systemic sclerosis (SSc) after developing progressive diffuse cutaneous sclerosis, Raynaud phenomenon with digital pitted scarring, esophageal dysmotility, myositis, pericardial effusion, and interstitial lung disease. Serologic test results were positive for anti-Scl-70 antibodies. Antinuclear antibody test results were negative for anti–double-stranded DNA, anti-nRNP, anti-Ro/La, anti-Sm, and anti-Jo-1 antibodies. The patient was treated with prednisolone 7.5 mg daily, nifedipine 15 mg daily, valsartan 80 mg daily, manidipine 20 mg daily, omeprazole 20 mg daily, and beraprost 80 mg daily. One year later, numerous asymptomatic flesh-colored papules and nodules developed on the neck, chest, abdomen, and back. There was no history of trauma or surgery at any of the affected sites.

On further investigation, anti–hepatitis C virus (HCV) antibodies were identified and confirmed by HCV ribonucleic acid polymerase chain reaction at the same time that the diagnosis of SSc was established. Hepatitis C virus genotype 3a was noted, and the patient’s viral load was 378,000 IU/mL. Therefore, a diagnosis of chronic HCV infection was established. The patient was initially unable to receive medical treatment due to lack of finances. A year and a half following the diagnosis of HCV infection, with worsening liver function tests and increasing viral load (1,369,113 IU/mL), the patient began therapy with peginterferon alfa-2b 80 mg weekly and ribavirin 800 mg daily. However, the medications were discontinued after 2 months when she developed severe hemolytic anemia related to ribavirin.

On physical examination, the patient was noted to have a masklike facies with a pinched nose and constricted opening of the mouth. Her skin was tightened and stiff extending from the fingers to the proximal extremities. Numerous well-circumscribed, flesh-colored, firm papules and nodules ranging from 2 to 20 mm in diameter were present on the neck (Figure 1), chest, abdomen (Figure 2), and back.

Figure 1. Numerous flesh-colored firm papules and nodules on the posterior aspect of the neck.

Figure 2. Multiple well-defined sclerotic papules and nodules on the abdomen.

Two 4-mm punch biopsy samples obtained from a papule on the neck and a nodule on the abdomen revealed homogenized collagen bundles with scattered plump fibroblasts in the lower reticular dermis. Clinicopathologic correlation of the biopsy findings with the cutaneous examination resulted in a diagnosis of nodular scleroderma (Figures 3 and 4).

Figure 3. The collagen bundles in the reticular dermis appeared thickened and closely packed. They stained more deeply eosinophilic than in the upper dermis. The overlying epidermis was normal (H&E, original magnification ×4). Figure 4. Thick, pale, hyalinized collagen bundles with scattered fibroblasts were seen in the lower reticular dermis. The eccrine glands were surrounded by sclerotic collagen and only a few adipocytes (H&E, original magnification ×20).

The patient began treatment with intralesional injections of triamcinolone 5 to 10 mg/mL for nodules as well as an ultrapotent corticosteroid cream, clobetasol propionate 0.05%, for small papules. Injections were performed at 4- to 8-week intervals and resulted in modest clinical improvement.

Comment

Scleroderma may be present only in the skin (morphea) or as a systemic disease (systemic scleroderma). Rarely, cutaneous involvement can exhibit a nodular or hypertrophic morphology, which has been described in the literature as nodular or keloidal scleroderma in a patient with known SSc^1-10 and as nodular or keloidal morphea in localized cutaneous scleroderma.^3,11-13

Histopathology

The distinction between the terms nodular scleroderma and keloidal scleroderma is not clear, and they are not necessarily interchangeable. To provide clarity, we find it useful to delineate specific histologic findings associated with the diagnoses of keloid, scleroderma, and the uncommon keloid/scleroderma overlap. The histopathologic findings of keloids include a fibrotic dermis and broad dispersed bundles of eosinophilic hyalinized collagen. The histopathologic findings of scleroderma include broad sclerotic bands of collagen throughout the dermis with loss of perieccrine fat. In the overlapping keloid/scleroderma condition, which is a variant of scleroderma, hyalinized collagen fibers and keloidal collagen appear in the same specimen.^3,4

To distinguish these conditions, Barzilai et al⁵ proposed that only cases showing both clinical and histologic characteristics of a keloid should be referred to as keloidal morphea/scleroderma. They further stated that the terms nodular morphea or nodular scleroderma ought to be used only for cases that are indistinguishable histologically from scleroderma. The term morphea is appropriate  when only a limited amount of skin disease is present, while scleroderma implies association with systemic disease.⁵ Likely, there is a histologic continuum in this variant of scleroderma, in which  nodular morphea/scleroderma exists at one end  and keloidal morphea/scleroderma exists at the other end.^5,13

In the case of our patient, papulonodular lesions developed 1 year after the diagnosis of SSc was made, and the histopathologic examination revealed classic findings of scleroderma. As a result, our patient is most appropriately classified as having nodular scleroderma.

Clinical Features

Nodular scleroderma mostly affects young and middle-aged women and is clinically characterized by solitary or multiple firm,  long-lasting papules or nodules on the upper trunk and chest, neck, and proximal extremities.^1-4,6

Etiology and Pathogenesis

The triggers and cellular mechanisms of nodular scleroderma are unclear. Some authors have implicated matricellular protein and growth factors such as tenascin, connective tissue growth factor, and epidermal growth factor in nodule formation.^7,8,11 Yamamoto et al⁹ cited chemical exposure to a silica-containing abrasive as the cause of nodular scleroderma in a worker.

Possible HCV Association

Some reports have indicated an association between nodular scleroderma and pathogens such as acid-fast bacteria¹⁰ and HCV.⁶ Of note, many extrahepatic conditions have been associated with HCV infection, such as membranoproliferative glomerulonephritis, cutaneous vasculitis, lichen planus, and porphyria cutanea tarda.¹⁴

The association of HCV infection with systemic autoimmune disease (SAD) has been described in a number of instances; cryoglobulinemia has most commonly been linked to HCV.¹⁵ Although the association between HCV and other SADs is less clear, there is growing interest in a possible relationship between them. To that end, physicians of the HISPAMEC (Hispanoamerican Study Group of Autoimmune Manifestations Associated With Hepatitis C Virus) study group described the clinical and immunologic characteristics of 1020 patients with SAD and associated chronic HCV infection. The  3 most frequent SADs (>90% of cases) were Sjögren syndrome, rheumatoid arthritis, and systemic lupus erythematosus.¹⁶ However, the strength of association differs for each SAD based on existing descriptions.^16,17 Less commonly, there may be a causal relationship between HCV infection and SSc. It should be noted that most of these data are based on small series and case reports.^6,16-19

The role of HCV in the pathogenesis of systemic scleroderma and other autoimmune diseases is unknown. It is also possible that the replication of HCV outside the liver, particularly in mononuclear cells, may suppress immune tolerance in genetically predisposed individuals.²⁰

Conclusion

Nodular scleroderma associated with HCV infection is a rare entity. At present, it cannot be determined whether there is an etiopathologic association between HCV infection and SSc or whether the simultaneous diagnosis may be coincidental. Routine determination of HCV serology in scleroderma patients may help to clarify this issue.

Case Report

A 63-year-old woman was referred to our clinic for evaluation of multiple papules and nodules on the neck and trunk that had been present for 2 years. Three years prior to presentation she had been diagnosed with systemic sclerosis (SSc) after developing progressive diffuse cutaneous sclerosis, Raynaud phenomenon with digital pitted scarring, esophageal dysmotility, myositis, pericardial effusion, and interstitial lung disease. Serologic test results were positive for anti-Scl-70 antibodies. Antinuclear antibody test results were negative for anti–double-stranded DNA, anti-nRNP, anti-Ro/La, anti-Sm, and anti-Jo-1 antibodies. The patient was treated with prednisolone 7.5 mg daily, nifedipine 15 mg daily, valsartan 80 mg daily, manidipine 20 mg daily, omeprazole 20 mg daily, and beraprost 80 mg daily. One year later, numerous asymptomatic flesh-colored papules and nodules developed on the neck, chest, abdomen, and back. There was no history of trauma or surgery at any of the affected sites.

On further investigation, anti–hepatitis C virus (HCV) antibodies were identified and confirmed by HCV ribonucleic acid polymerase chain reaction at the same time that the diagnosis of SSc was established. Hepatitis C virus genotype 3a was noted, and the patient’s viral load was 378,000 IU/mL. Therefore, a diagnosis of chronic HCV infection was established. The patient was initially unable to receive medical treatment due to lack of finances. A year and a half following the diagnosis of HCV infection, with worsening liver function tests and increasing viral load (1,369,113 IU/mL), the patient began therapy with peginterferon alfa-2b 80 mg weekly and ribavirin 800 mg daily. However, the medications were discontinued after 2 months when she developed severe hemolytic anemia related to ribavirin.

On physical examination, the patient was noted to have a masklike facies with a pinched nose and constricted opening of the mouth. Her skin was tightened and stiff extending from the fingers to the proximal extremities. Numerous well-circumscribed, flesh-colored, firm papules and nodules ranging from 2 to 20 mm in diameter were present on the neck (Figure 1), chest, abdomen (Figure 2), and back.

Figure 1. Numerous flesh-colored firm papules and nodules on the posterior aspect of the neck.

Figure 2. Multiple well-defined sclerotic papules and nodules on the abdomen.

Two 4-mm punch biopsy samples obtained from a papule on the neck and a nodule on the abdomen revealed homogenized collagen bundles with scattered plump fibroblasts in the lower reticular dermis. Clinicopathologic correlation of the biopsy findings with the cutaneous examination resulted in a diagnosis of nodular scleroderma (Figures 3 and 4).

Figure 3. The collagen bundles in the reticular dermis appeared thickened and closely packed. They stained more deeply eosinophilic than in the upper dermis. The overlying epidermis was normal (H&E, original magnification ×4). Figure 4. Thick, pale, hyalinized collagen bundles with scattered fibroblasts were seen in the lower reticular dermis. The eccrine glands were surrounded by sclerotic collagen and only a few adipocytes (H&E, original magnification ×20).

The patient began treatment with intralesional injections of triamcinolone 5 to 10 mg/mL for nodules as well as an ultrapotent corticosteroid cream, clobetasol propionate 0.05%, for small papules. Injections were performed at 4- to 8-week intervals and resulted in modest clinical improvement.

Comment

Scleroderma may be present only in the skin (morphea) or as a systemic disease (systemic scleroderma). Rarely, cutaneous involvement can exhibit a nodular or hypertrophic morphology, which has been described in the literature as nodular or keloidal scleroderma in a patient with known SSc^1-10 and as nodular or keloidal morphea in localized cutaneous scleroderma.^3,11-13

Histopathology

The distinction between the terms nodular scleroderma and keloidal scleroderma is not clear, and they are not necessarily interchangeable. To provide clarity, we find it useful to delineate specific histologic findings associated with the diagnoses of keloid, scleroderma, and the uncommon keloid/scleroderma overlap. The histopathologic findings of keloids include a fibrotic dermis and broad dispersed bundles of eosinophilic hyalinized collagen. The histopathologic findings of scleroderma include broad sclerotic bands of collagen throughout the dermis with loss of perieccrine fat. In the overlapping keloid/scleroderma condition, which is a variant of scleroderma, hyalinized collagen fibers and keloidal collagen appear in the same specimen.^3,4

To distinguish these conditions, Barzilai et al⁵ proposed that only cases showing both clinical and histologic characteristics of a keloid should be referred to as keloidal morphea/scleroderma. They further stated that the terms nodular morphea or nodular scleroderma ought to be used only for cases that are indistinguishable histologically from scleroderma. The term morphea is appropriate  when only a limited amount of skin disease is present, while scleroderma implies association with systemic disease.⁵ Likely, there is a histologic continuum in this variant of scleroderma, in which  nodular morphea/scleroderma exists at one end  and keloidal morphea/scleroderma exists at the other end.^5,13

In the case of our patient, papulonodular lesions developed 1 year after the diagnosis of SSc was made, and the histopathologic examination revealed classic findings of scleroderma. As a result, our patient is most appropriately classified as having nodular scleroderma.

Clinical Features

Nodular scleroderma mostly affects young and middle-aged women and is clinically characterized by solitary or multiple firm,  long-lasting papules or nodules on the upper trunk and chest, neck, and proximal extremities.^1-4,6

Etiology and Pathogenesis

The triggers and cellular mechanisms of nodular scleroderma are unclear. Some authors have implicated matricellular protein and growth factors such as tenascin, connective tissue growth factor, and epidermal growth factor in nodule formation.^7,8,11 Yamamoto et al⁹ cited chemical exposure to a silica-containing abrasive as the cause of nodular scleroderma in a worker.

Possible HCV Association

Some reports have indicated an association between nodular scleroderma and pathogens such as acid-fast bacteria¹⁰ and HCV.⁶ Of note, many extrahepatic conditions have been associated with HCV infection, such as membranoproliferative glomerulonephritis, cutaneous vasculitis, lichen planus, and porphyria cutanea tarda.¹⁴

The association of HCV infection with systemic autoimmune disease (SAD) has been described in a number of instances; cryoglobulinemia has most commonly been linked to HCV.¹⁵ Although the association between HCV and other SADs is less clear, there is growing interest in a possible relationship between them. To that end, physicians of the HISPAMEC (Hispanoamerican Study Group of Autoimmune Manifestations Associated With Hepatitis C Virus) study group described the clinical and immunologic characteristics of 1020 patients with SAD and associated chronic HCV infection. The  3 most frequent SADs (>90% of cases) were Sjögren syndrome, rheumatoid arthritis, and systemic lupus erythematosus.¹⁶ However, the strength of association differs for each SAD based on existing descriptions.^16,17 Less commonly, there may be a causal relationship between HCV infection and SSc. It should be noted that most of these data are based on small series and case reports.^6,16-19

The role of HCV in the pathogenesis of systemic scleroderma and other autoimmune diseases is unknown. It is also possible that the replication of HCV outside the liver, particularly in mononuclear cells, may suppress immune tolerance in genetically predisposed individuals.²⁰

Conclusion

Nodular scleroderma associated with HCV infection is a rare entity. At present, it cannot be determined whether there is an etiopathologic association between HCV infection and SSc or whether the simultaneous diagnosis may be coincidental. Routine determination of HCV serology in scleroderma patients may help to clarify this issue.

Case Report

A 63-year-old woman was referred to our clinic for evaluation of multiple papules and nodules on the neck and trunk that had been present for 2 years. Three years prior to presentation she had been diagnosed with systemic sclerosis (SSc) after developing progressive diffuse cutaneous sclerosis, Raynaud phenomenon with digital pitted scarring, esophageal dysmotility, myositis, pericardial effusion, and interstitial lung disease. Serologic test results were positive for anti-Scl-70 antibodies. Antinuclear antibody test results were negative for anti–double-stranded DNA, anti-nRNP, anti-Ro/La, anti-Sm, and anti-Jo-1 antibodies. The patient was treated with prednisolone 7.5 mg daily, nifedipine 15 mg daily, valsartan 80 mg daily, manidipine 20 mg daily, omeprazole 20 mg daily, and beraprost 80 mg daily. One year later, numerous asymptomatic flesh-colored papules and nodules developed on the neck, chest, abdomen, and back. There was no history of trauma or surgery at any of the affected sites.

On further investigation, anti–hepatitis C virus (HCV) antibodies were identified and confirmed by HCV ribonucleic acid polymerase chain reaction at the same time that the diagnosis of SSc was established. Hepatitis C virus genotype 3a was noted, and the patient’s viral load was 378,000 IU/mL. Therefore, a diagnosis of chronic HCV infection was established. The patient was initially unable to receive medical treatment due to lack of finances. A year and a half following the diagnosis of HCV infection, with worsening liver function tests and increasing viral load (1,369,113 IU/mL), the patient began therapy with peginterferon alfa-2b 80 mg weekly and ribavirin 800 mg daily. However, the medications were discontinued after 2 months when she developed severe hemolytic anemia related to ribavirin.

On physical examination, the patient was noted to have a masklike facies with a pinched nose and constricted opening of the mouth. Her skin was tightened and stiff extending from the fingers to the proximal extremities. Numerous well-circumscribed, flesh-colored, firm papules and nodules ranging from 2 to 20 mm in diameter were present on the neck (Figure 1), chest, abdomen (Figure 2), and back.

Figure 1. Numerous flesh-colored firm papules and nodules on the posterior aspect of the neck.

Figure 2. Multiple well-defined sclerotic papules and nodules on the abdomen.

Two 4-mm punch biopsy samples obtained from a papule on the neck and a nodule on the abdomen revealed homogenized collagen bundles with scattered plump fibroblasts in the lower reticular dermis. Clinicopathologic correlation of the biopsy findings with the cutaneous examination resulted in a diagnosis of nodular scleroderma (Figures 3 and 4).

Figure 3. The collagen bundles in the reticular dermis appeared thickened and closely packed. They stained more deeply eosinophilic than in the upper dermis. The overlying epidermis was normal (H&E, original magnification ×4). Figure 4. Thick, pale, hyalinized collagen bundles with scattered fibroblasts were seen in the lower reticular dermis. The eccrine glands were surrounded by sclerotic collagen and only a few adipocytes (H&E, original magnification ×20).

The patient began treatment with intralesional injections of triamcinolone 5 to 10 mg/mL for nodules as well as an ultrapotent corticosteroid cream, clobetasol propionate 0.05%, for small papules. Injections were performed at 4- to 8-week intervals and resulted in modest clinical improvement.

Comment

Scleroderma may be present only in the skin (morphea) or as a systemic disease (systemic scleroderma). Rarely, cutaneous involvement can exhibit a nodular or hypertrophic morphology, which has been described in the literature as nodular or keloidal scleroderma in a patient with known SSc^1-10 and as nodular or keloidal morphea in localized cutaneous scleroderma.^3,11-13

Histopathology

The distinction between the terms nodular scleroderma and keloidal scleroderma is not clear, and they are not necessarily interchangeable. To provide clarity, we find it useful to delineate specific histologic findings associated with the diagnoses of keloid, scleroderma, and the uncommon keloid/scleroderma overlap. The histopathologic findings of keloids include a fibrotic dermis and broad dispersed bundles of eosinophilic hyalinized collagen. The histopathologic findings of scleroderma include broad sclerotic bands of collagen throughout the dermis with loss of perieccrine fat. In the overlapping keloid/scleroderma condition, which is a variant of scleroderma, hyalinized collagen fibers and keloidal collagen appear in the same specimen.^3,4

To distinguish these conditions, Barzilai et al⁵ proposed that only cases showing both clinical and histologic characteristics of a keloid should be referred to as keloidal morphea/scleroderma. They further stated that the terms nodular morphea or nodular scleroderma ought to be used only for cases that are indistinguishable histologically from scleroderma. The term morphea is appropriate  when only a limited amount of skin disease is present, while scleroderma implies association with systemic disease.⁵ Likely, there is a histologic continuum in this variant of scleroderma, in which  nodular morphea/scleroderma exists at one end  and keloidal morphea/scleroderma exists at the other end.^5,13

In the case of our patient, papulonodular lesions developed 1 year after the diagnosis of SSc was made, and the histopathologic examination revealed classic findings of scleroderma. As a result, our patient is most appropriately classified as having nodular scleroderma.

Clinical Features

Nodular scleroderma mostly affects young and middle-aged women and is clinically characterized by solitary or multiple firm,  long-lasting papules or nodules on the upper trunk and chest, neck, and proximal extremities.^1-4,6

Etiology and Pathogenesis

The triggers and cellular mechanisms of nodular scleroderma are unclear. Some authors have implicated matricellular protein and growth factors such as tenascin, connective tissue growth factor, and epidermal growth factor in nodule formation.^7,8,11 Yamamoto et al⁹ cited chemical exposure to a silica-containing abrasive as the cause of nodular scleroderma in a worker.

Possible HCV Association

Some reports have indicated an association between nodular scleroderma and pathogens such as acid-fast bacteria¹⁰ and HCV.⁶ Of note, many extrahepatic conditions have been associated with HCV infection, such as membranoproliferative glomerulonephritis, cutaneous vasculitis, lichen planus, and porphyria cutanea tarda.¹⁴

The association of HCV infection with systemic autoimmune disease (SAD) has been described in a number of instances; cryoglobulinemia has most commonly been linked to HCV.¹⁵ Although the association between HCV and other SADs is less clear, there is growing interest in a possible relationship between them. To that end, physicians of the HISPAMEC (Hispanoamerican Study Group of Autoimmune Manifestations Associated With Hepatitis C Virus) study group described the clinical and immunologic characteristics of 1020 patients with SAD and associated chronic HCV infection. The  3 most frequent SADs (>90% of cases) were Sjögren syndrome, rheumatoid arthritis, and systemic lupus erythematosus.¹⁶ However, the strength of association differs for each SAD based on existing descriptions.^16,17 Less commonly, there may be a causal relationship between HCV infection and SSc. It should be noted that most of these data are based on small series and case reports.^6,16-19

The role of HCV in the pathogenesis of systemic scleroderma and other autoimmune diseases is unknown. It is also possible that the replication of HCV outside the liver, particularly in mononuclear cells, may suppress immune tolerance in genetically predisposed individuals.²⁰

Conclusion

Nodular scleroderma associated with HCV infection is a rare entity. At present, it cannot be determined whether there is an etiopathologic association between HCV infection and SSc or whether the simultaneous diagnosis may be coincidental. Routine determination of HCV serology in scleroderma patients may help to clarify this issue.

The traditional approach for confirming the diagnosis of subepidermal blistering diseases such as bullous pemphigoid (BP), epidermolysis bullosa acquisita (EBA), dermatitis herpetiformis (DH), linear IgA bullous dermatosis (LABD) requires 2 punch biopsies: one from perilesional skin for direct immunofluorescence (DIF) and one from lesional skin for light microscopy using hematoxylin and eosin (H&E) stain.1-4 These conditions are distinguished by a combination of features appreciated on H&E-stained sections, DIF, and indirect immunofluorescence for a subset of disorders. Additional information may be provided by DIF or indirect immunofluorescence utilizing the salt-split skin technique to differentiate BP (in which linear IgG deposition is identified by immunofluorescence on the roof of salt-split skin) from EBA and 
antiepiligrin cicatricial BP (in which linear IgG deposition is identified by immunofluorescence along the floor of the salt-split skin), which is more rare.4 One bisected punch biopsy of a subepidermal blister yields salt-split skin–like information through standard DIF and supersedes the need for the more cumbersome salt-split skin technique.

Serologic tests for the presence of circulating antibodies to BP180 and BP230 represent an emerging technology that can confirm the diagnosis of BP, but it has been difficult to identify clinically useful autoantibodies to confirm diagnoses of EBA and LABD.^5-7 Serologic tests for tissue transglutaminase IgA antibodies may be useful in the diagnosis of DH.⁸ We present a cost-effective approach to biopsy in the diagnosis of subepidermal blistering diseases that provides the necessary diagnostic information to distinguish relevant disease processes.

Subepidermal Blistering Diseases

Bullous pemphigoid commonly presents with widespread tense bullae of varying sizes on an erythematous base or on otherwise normal skin.⁹ Some cases of BP present not with bullae but with pruritic, urticarial, plaquelike, or papular lesions. Bullous pemphigoid commonly involves flexural surfaces and the trunk but can appear anywhere on the skin. The induction of blisters by shearing with mechanical pressure on perilesional skin (Nikolsky sign) is not characteristically present in BP as it is in pemphigus vulgaris.¹⁰ Epidermolysis bullosa acquisita can mimic BP in the development of widespread tense bullae, but blisters typically appear on areas of the skin that are prone to trauma (eg, toes, knees, elbows, hands). Crusted erosions, scarring, and milia also are clinical manifestations of EBA.¹¹ Dermatitis herpetiformis presents with grouped vesicles, papulovesicles, plaques, and excoriations that are symmetrically distributed on extensor surfaces of the skin but also can occur on the buttocks, scalp, and other areas of the skin.^12,13 Although it may mimic both BP and DH, LABD frequently is less pruritic than these other conditions.^14,15 Linear IgA bullous dermatosis also demonstrates the characteristic finding of multiple bullae that form concentrically around a crusted area of skin. This physical finding is known as a string of pearls. Linear IgA bullous dermatosis typically occurs in childhood and may resolve without treatment in months to years.¹⁶

Traditional Biopsy Approach

A review of several articles from the literature and multiple dermatology and dermatopathology textbooks revealed uniform recommendations for biopsy of subepidermal blistering conditions that manifest as tense blisters.^1-4,9-23 A biopsy of early lesional skin or of a blister for light microscopy with H&E stain and biopsy of perilesional skin for DIF is recommended.^1-4,9-23 Three review articles specifically suggested biopsy of “perilesional skin” for DIF.^1-3 The majority of textbooks we reviewed also suggested that perilesional skin, or skin adjacent to a zone of erythema in the case of DH, should be sampled for DIF to assist in the diagnosis of BP, EBA, DH, and LABD.^4,9-21 Biopsy of adjacent or nonlesional skin or skin around the lesion for DIF also was recommended by other textbooks for diagnosis of subepidermal blistering diseases.^22,23 Perilesional skin is chosen because it is critical that the epidermis be included for adequate immunofluorescence studies.^5,20 Biopsy of healed and crusted lesions should be avoided.²⁴

Recommended Alternative Approach

A single punch biopsy produces the best possible specimen for H&E and DIF if it is obtained via one of 2 methods.

The first method involves choosing a small, 1- to 2-mm tense blister.²⁵ Use an 8-mm punch centered on the blister that includes at least 3 mm of circumferential perilesional skin (Figures 1 
and 2).²⁰ Holding the specimen with forceps, use a no. 15 scalpel blade to bisect the blister with a sawing motion. Place half of the specimen in formalin for H&E staining and the other half in Zeus 
(or Michel) medium for DIF (Figure 3).

The second method is to choose any intact tense blister^20,24 and, utilizing a surgical marker, draw a line from the roof of the blister onto the adjacent perilesional skin (Figure 1). After blotting with an alcohol pad so as not to remove the mark, anesthetize the site with lidocaine 1% with epinephrine,²⁴ then take an 8-mm punch biopsy encompassing 75% perilesional skin and 25% of the blister centered on the line (Figure 2). After separating the punch specimen from the subcutaneous tissue with surgical scissors, hold the tissue with forceps and bisect the specimen with a no. 15 scalpel blade. Use a sawing motion along the line drawn in the prior steps (Figure 3). Submit half of the biopsy for H&E staining in formalin and the other half for DIF in Zeus medium.

Advantages

This approach offers several advantages. First, the technique requires only 1 invasive procedure, not 
2 separate biopsies, so that the procedure can be done quickly and efficiently with the least morbidity and scarring. Secondly, because the patient is billed for 1 biopsy instead of 2, the single punch biopsy technique is more cost effective.

The bisected specimen resulting from complete excision of a small blister or from biopsy of a larger blister that includes 75% perilesional skin and 25% from the blister cavity also provides the best tissue specimen for interpretation of the subepidermal blistering processes via H&E staining.^4,20,24 When traditional unmarked punch specimens of a blister margin are sent to the laboratory in formalin for H&E staining, the technician that grosses the specimen may or may not bisect the specimen showing the “take-off” point of the blister.

Finally, when the DIF specimen is prepared using either of these 2 approaches, the immunoprecipitants can be seen at the dermoepidermal junction or in the papillary dermis in the perilesional portion of the specimen.^2,4 Additionally, the immunoprecipitant may be identified on the roof or floor of the blister. Although this approach has not been studied in a systematic fashion, we believe this technique provides “bonus” information to help differentiate BP and EBA correlating with salt-split skin blisters produced for indirect immunofluorescence.^5,6

Limitations

It is critical for the pathologist or technician grossing these specimens to understand the techniques that are being employed and to ensure that the submitted half punch specimens are embedded so that the flat surface is cut so that the edge of the blister is properly sectioned for both H&E and DIF specimens. Additionally, with either recommended technique, if the portion of perilesional skin is not sufficient and the epidermis completely separates from the dermis, interpretation of both the H&E staining and DIF sections is substantially compromised.²⁰ Therefore, an 8-mm disposable punch is recommended to avoid mangling the specimens when they are bisected and to insure that the epithelium is not lost. This technique is less suitable for blistering processes with a positive Nikolsky sign, such as pemphigus and toxic epidermal necrolysis, because the small area of perilesional skin adjacent to the blister may detach completely, requiring the epidermis and dermis to be evaluated separately or, in the worst-case scenario, the epidermis may be lost in processing.

Conclusion

Bisecting a single punch biopsy on subepidermal blisters provides the best specimen for H&E staining and DIF. The single punch biopsy technique 
also differentiates BP and EBA without utilizing salt-split skin immunofluorescence studies. This technique is more efficient and cost effective than the traditional approach of multiple biopsies on 
subepidermal blisters.

The traditional approach for confirming the diagnosis of subepidermal blistering diseases such as bullous pemphigoid (BP), epidermolysis bullosa acquisita (EBA), dermatitis herpetiformis (DH), linear IgA bullous dermatosis (LABD) requires 2 punch biopsies: one from perilesional skin for direct immunofluorescence (DIF) and one from lesional skin for light microscopy using hematoxylin and eosin (H&E) stain.1-4 These conditions are distinguished by a combination of features appreciated on H&E-stained sections, DIF, and indirect immunofluorescence for a subset of disorders. Additional information may be provided by DIF or indirect immunofluorescence utilizing the salt-split skin technique to differentiate BP (in which linear IgG deposition is identified by immunofluorescence on the roof of salt-split skin) from EBA and 
antiepiligrin cicatricial BP (in which linear IgG deposition is identified by immunofluorescence along the floor of the salt-split skin), which is more rare.4 One bisected punch biopsy of a subepidermal blister yields salt-split skin–like information through standard DIF and supersedes the need for the more cumbersome salt-split skin technique.

Serologic tests for the presence of circulating antibodies to BP180 and BP230 represent an emerging technology that can confirm the diagnosis of BP, but it has been difficult to identify clinically useful autoantibodies to confirm diagnoses of EBA and LABD.^5-7 Serologic tests for tissue transglutaminase IgA antibodies may be useful in the diagnosis of DH.⁸ We present a cost-effective approach to biopsy in the diagnosis of subepidermal blistering diseases that provides the necessary diagnostic information to distinguish relevant disease processes.

Subepidermal Blistering Diseases

Bullous pemphigoid commonly presents with widespread tense bullae of varying sizes on an erythematous base or on otherwise normal skin.⁹ Some cases of BP present not with bullae but with pruritic, urticarial, plaquelike, or papular lesions. Bullous pemphigoid commonly involves flexural surfaces and the trunk but can appear anywhere on the skin. The induction of blisters by shearing with mechanical pressure on perilesional skin (Nikolsky sign) is not characteristically present in BP as it is in pemphigus vulgaris.¹⁰ Epidermolysis bullosa acquisita can mimic BP in the development of widespread tense bullae, but blisters typically appear on areas of the skin that are prone to trauma (eg, toes, knees, elbows, hands). Crusted erosions, scarring, and milia also are clinical manifestations of EBA.¹¹ Dermatitis herpetiformis presents with grouped vesicles, papulovesicles, plaques, and excoriations that are symmetrically distributed on extensor surfaces of the skin but also can occur on the buttocks, scalp, and other areas of the skin.^12,13 Although it may mimic both BP and DH, LABD frequently is less pruritic than these other conditions.^14,15 Linear IgA bullous dermatosis also demonstrates the characteristic finding of multiple bullae that form concentrically around a crusted area of skin. This physical finding is known as a string of pearls. Linear IgA bullous dermatosis typically occurs in childhood and may resolve without treatment in months to years.¹⁶

Traditional Biopsy Approach

A review of several articles from the literature and multiple dermatology and dermatopathology textbooks revealed uniform recommendations for biopsy of subepidermal blistering conditions that manifest as tense blisters.^1-4,9-23 A biopsy of early lesional skin or of a blister for light microscopy with H&E stain and biopsy of perilesional skin for DIF is recommended.^1-4,9-23 Three review articles specifically suggested biopsy of “perilesional skin” for DIF.^1-3 The majority of textbooks we reviewed also suggested that perilesional skin, or skin adjacent to a zone of erythema in the case of DH, should be sampled for DIF to assist in the diagnosis of BP, EBA, DH, and LABD.^4,9-21 Biopsy of adjacent or nonlesional skin or skin around the lesion for DIF also was recommended by other textbooks for diagnosis of subepidermal blistering diseases.^22,23 Perilesional skin is chosen because it is critical that the epidermis be included for adequate immunofluorescence studies.^5,20 Biopsy of healed and crusted lesions should be avoided.²⁴

Recommended Alternative Approach

A single punch biopsy produces the best possible specimen for H&E and DIF if it is obtained via one of 2 methods.

The first method involves choosing a small, 1- to 2-mm tense blister.²⁵ Use an 8-mm punch centered on the blister that includes at least 3 mm of circumferential perilesional skin (Figures 1 
and 2).²⁰ Holding the specimen with forceps, use a no. 15 scalpel blade to bisect the blister with a sawing motion. Place half of the specimen in formalin for H&E staining and the other half in Zeus 
(or Michel) medium for DIF (Figure 3).

The second method is to choose any intact tense blister^20,24 and, utilizing a surgical marker, draw a line from the roof of the blister onto the adjacent perilesional skin (Figure 1). After blotting with an alcohol pad so as not to remove the mark, anesthetize the site with lidocaine 1% with epinephrine,²⁴ then take an 8-mm punch biopsy encompassing 75% perilesional skin and 25% of the blister centered on the line (Figure 2). After separating the punch specimen from the subcutaneous tissue with surgical scissors, hold the tissue with forceps and bisect the specimen with a no. 15 scalpel blade. Use a sawing motion along the line drawn in the prior steps (Figure 3). Submit half of the biopsy for H&E staining in formalin and the other half for DIF in Zeus medium.

Advantages

This approach offers several advantages. First, the technique requires only 1 invasive procedure, not 
2 separate biopsies, so that the procedure can be done quickly and efficiently with the least morbidity and scarring. Secondly, because the patient is billed for 1 biopsy instead of 2, the single punch biopsy technique is more cost effective.

The bisected specimen resulting from complete excision of a small blister or from biopsy of a larger blister that includes 75% perilesional skin and 25% from the blister cavity also provides the best tissue specimen for interpretation of the subepidermal blistering processes via H&E staining.^4,20,24 When traditional unmarked punch specimens of a blister margin are sent to the laboratory in formalin for H&E staining, the technician that grosses the specimen may or may not bisect the specimen showing the “take-off” point of the blister.

Finally, when the DIF specimen is prepared using either of these 2 approaches, the immunoprecipitants can be seen at the dermoepidermal junction or in the papillary dermis in the perilesional portion of the specimen.^2,4 Additionally, the immunoprecipitant may be identified on the roof or floor of the blister. Although this approach has not been studied in a systematic fashion, we believe this technique provides “bonus” information to help differentiate BP and EBA correlating with salt-split skin blisters produced for indirect immunofluorescence.^5,6

Limitations

It is critical for the pathologist or technician grossing these specimens to understand the techniques that are being employed and to ensure that the submitted half punch specimens are embedded so that the flat surface is cut so that the edge of the blister is properly sectioned for both H&E and DIF specimens. Additionally, with either recommended technique, if the portion of perilesional skin is not sufficient and the epidermis completely separates from the dermis, interpretation of both the H&E staining and DIF sections is substantially compromised.²⁰ Therefore, an 8-mm disposable punch is recommended to avoid mangling the specimens when they are bisected and to insure that the epithelium is not lost. This technique is less suitable for blistering processes with a positive Nikolsky sign, such as pemphigus and toxic epidermal necrolysis, because the small area of perilesional skin adjacent to the blister may detach completely, requiring the epidermis and dermis to be evaluated separately or, in the worst-case scenario, the epidermis may be lost in processing.

Conclusion

Bisecting a single punch biopsy on subepidermal blisters provides the best specimen for H&E staining and DIF. The single punch biopsy technique 
also differentiates BP and EBA without utilizing salt-split skin immunofluorescence studies. This technique is more efficient and cost effective than the traditional approach of multiple biopsies on 
subepidermal blisters.

The traditional approach for confirming the diagnosis of subepidermal blistering diseases such as bullous pemphigoid (BP), epidermolysis bullosa acquisita (EBA), dermatitis herpetiformis (DH), linear IgA bullous dermatosis (LABD) requires 2 punch biopsies: one from perilesional skin for direct immunofluorescence (DIF) and one from lesional skin for light microscopy using hematoxylin and eosin (H&E) stain.1-4 These conditions are distinguished by a combination of features appreciated on H&E-stained sections, DIF, and indirect immunofluorescence for a subset of disorders. Additional information may be provided by DIF or indirect immunofluorescence utilizing the salt-split skin technique to differentiate BP (in which linear IgG deposition is identified by immunofluorescence on the roof of salt-split skin) from EBA and 
antiepiligrin cicatricial BP (in which linear IgG deposition is identified by immunofluorescence along the floor of the salt-split skin), which is more rare.4 One bisected punch biopsy of a subepidermal blister yields salt-split skin–like information through standard DIF and supersedes the need for the more cumbersome salt-split skin technique.

Serologic tests for the presence of circulating antibodies to BP180 and BP230 represent an emerging technology that can confirm the diagnosis of BP, but it has been difficult to identify clinically useful autoantibodies to confirm diagnoses of EBA and LABD.^5-7 Serologic tests for tissue transglutaminase IgA antibodies may be useful in the diagnosis of DH.⁸ We present a cost-effective approach to biopsy in the diagnosis of subepidermal blistering diseases that provides the necessary diagnostic information to distinguish relevant disease processes.

Subepidermal Blistering Diseases

Bullous pemphigoid commonly presents with widespread tense bullae of varying sizes on an erythematous base or on otherwise normal skin.⁹ Some cases of BP present not with bullae but with pruritic, urticarial, plaquelike, or papular lesions. Bullous pemphigoid commonly involves flexural surfaces and the trunk but can appear anywhere on the skin. The induction of blisters by shearing with mechanical pressure on perilesional skin (Nikolsky sign) is not characteristically present in BP as it is in pemphigus vulgaris.¹⁰ Epidermolysis bullosa acquisita can mimic BP in the development of widespread tense bullae, but blisters typically appear on areas of the skin that are prone to trauma (eg, toes, knees, elbows, hands). Crusted erosions, scarring, and milia also are clinical manifestations of EBA.¹¹ Dermatitis herpetiformis presents with grouped vesicles, papulovesicles, plaques, and excoriations that are symmetrically distributed on extensor surfaces of the skin but also can occur on the buttocks, scalp, and other areas of the skin.^12,13 Although it may mimic both BP and DH, LABD frequently is less pruritic than these other conditions.^14,15 Linear IgA bullous dermatosis also demonstrates the characteristic finding of multiple bullae that form concentrically around a crusted area of skin. This physical finding is known as a string of pearls. Linear IgA bullous dermatosis typically occurs in childhood and may resolve without treatment in months to years.¹⁶

Traditional Biopsy Approach

A review of several articles from the literature and multiple dermatology and dermatopathology textbooks revealed uniform recommendations for biopsy of subepidermal blistering conditions that manifest as tense blisters.^1-4,9-23 A biopsy of early lesional skin or of a blister for light microscopy with H&E stain and biopsy of perilesional skin for DIF is recommended.^1-4,9-23 Three review articles specifically suggested biopsy of “perilesional skin” for DIF.^1-3 The majority of textbooks we reviewed also suggested that perilesional skin, or skin adjacent to a zone of erythema in the case of DH, should be sampled for DIF to assist in the diagnosis of BP, EBA, DH, and LABD.^4,9-21 Biopsy of adjacent or nonlesional skin or skin around the lesion for DIF also was recommended by other textbooks for diagnosis of subepidermal blistering diseases.^22,23 Perilesional skin is chosen because it is critical that the epidermis be included for adequate immunofluorescence studies.^5,20 Biopsy of healed and crusted lesions should be avoided.²⁴

Recommended Alternative Approach

A single punch biopsy produces the best possible specimen for H&E and DIF if it is obtained via one of 2 methods.

The first method involves choosing a small, 1- to 2-mm tense blister.²⁵ Use an 8-mm punch centered on the blister that includes at least 3 mm of circumferential perilesional skin (Figures 1 
and 2).²⁰ Holding the specimen with forceps, use a no. 15 scalpel blade to bisect the blister with a sawing motion. Place half of the specimen in formalin for H&E staining and the other half in Zeus 
(or Michel) medium for DIF (Figure 3).

The second method is to choose any intact tense blister^20,24 and, utilizing a surgical marker, draw a line from the roof of the blister onto the adjacent perilesional skin (Figure 1). After blotting with an alcohol pad so as not to remove the mark, anesthetize the site with lidocaine 1% with epinephrine,²⁴ then take an 8-mm punch biopsy encompassing 75% perilesional skin and 25% of the blister centered on the line (Figure 2). After separating the punch specimen from the subcutaneous tissue with surgical scissors, hold the tissue with forceps and bisect the specimen with a no. 15 scalpel blade. Use a sawing motion along the line drawn in the prior steps (Figure 3). Submit half of the biopsy for H&E staining in formalin and the other half for DIF in Zeus medium.

Advantages

This approach offers several advantages. First, the technique requires only 1 invasive procedure, not 
2 separate biopsies, so that the procedure can be done quickly and efficiently with the least morbidity and scarring. Secondly, because the patient is billed for 1 biopsy instead of 2, the single punch biopsy technique is more cost effective.

The bisected specimen resulting from complete excision of a small blister or from biopsy of a larger blister that includes 75% perilesional skin and 25% from the blister cavity also provides the best tissue specimen for interpretation of the subepidermal blistering processes via H&E staining.^4,20,24 When traditional unmarked punch specimens of a blister margin are sent to the laboratory in formalin for H&E staining, the technician that grosses the specimen may or may not bisect the specimen showing the “take-off” point of the blister.

Finally, when the DIF specimen is prepared using either of these 2 approaches, the immunoprecipitants can be seen at the dermoepidermal junction or in the papillary dermis in the perilesional portion of the specimen.^2,4 Additionally, the immunoprecipitant may be identified on the roof or floor of the blister. Although this approach has not been studied in a systematic fashion, we believe this technique provides “bonus” information to help differentiate BP and EBA correlating with salt-split skin blisters produced for indirect immunofluorescence.^5,6

Limitations

It is critical for the pathologist or technician grossing these specimens to understand the techniques that are being employed and to ensure that the submitted half punch specimens are embedded so that the flat surface is cut so that the edge of the blister is properly sectioned for both H&E and DIF specimens. Additionally, with either recommended technique, if the portion of perilesional skin is not sufficient and the epidermis completely separates from the dermis, interpretation of both the H&E staining and DIF sections is substantially compromised.²⁰ Therefore, an 8-mm disposable punch is recommended to avoid mangling the specimens when they are bisected and to insure that the epithelium is not lost. This technique is less suitable for blistering processes with a positive Nikolsky sign, such as pemphigus and toxic epidermal necrolysis, because the small area of perilesional skin adjacent to the blister may detach completely, requiring the epidermis and dermis to be evaluated separately or, in the worst-case scenario, the epidermis may be lost in processing.

Conclusion

Bisecting a single punch biopsy on subepidermal blisters provides the best specimen for H&E staining and DIF. The single punch biopsy technique 
also differentiates BP and EBA without utilizing salt-split skin immunofluorescence studies. This technique is more efficient and cost effective than the traditional approach of multiple biopsies on 
subepidermal blisters.

The Diagnosis: Nodular Hidradenoma

Nodular hidradenomas (NHs) are rare benign cutaneous adnexal neoplasms first described in 1949 as clear cell papillary carcinomas.¹ Since then, various terms have been used to describe this entity, such as eccrine acrospiroma, solid-cystic hidradenoma, and clear cell hidradenoma.² Review of the literature revealed a female predominance (2:1 ratio) and a mean age at presentation of 37.2 years.^3,4 Nodular hidradenoma presents as an asymptomatic, solitary, mobile, firm nodule with intact overlying skin. Rarely, multiple nodules may occur.³ Some tumors display ulceration and serous fluid leakage.⁵ They occur most commonly on the scalp, face, and upper extremities with an average size of 2 cm.³ Rapid growth of the tumor may signal a malignant change.⁶

Histopathology reveals a lobulated, circumscribed, symmetrical tumor with dermal nests of epithelial cells that are polygonal with eosinophilic cytoplasm forming ductlike spaces (Figure). However, clear cell changes and squamous differentiation may be prominent features. Cystic spaces may result from tumor cell degeneration. Most tumors are encased by collagenous fibrous tissue and rarely have epidermal attachments.³

Anastomosing aggregates of squamous cells forming ductlike spaces were viewed on low-power magnification (A)(H&E, original magnification ×10). On higher power there were ductlike spaces and eosinophilic hyalinized stroma entrapped by the bland-appearing squamous proliferation (B)(H&E, original magnification ×20).

Nodular hidradenoma traditionally has been considered to be of eccrine origin, but more recent literature indicates that the majority of NHs are of apocrine origin. Histologically, apocrine tumors display eosinophilic secretion, mucinous epithelium, squamous or sebaceous differentiation, and decapitation secretion, whereas eccrine tumors are identified by their lack of specific features.³

Nodular hidradenoma may recur after excision. Malignant transformation is rare. In one review, 6.7% (6/89) of NHs were malignant, characterized by abnormal mitoses, nuclear atypia, and necrosis.⁴ Malignant NH or nodular hidradenocarcinoma behaves aggressively with up to an 86% local recurrence and 60% rate of metastasis within 2 years.⁶ Survival time is inversely proportional to the size of the tumor and is generally poor, with a 5-year disease-free survival of less than 30%.^6,7

Treatment of NH is achieved through primary excision or Mohs micrographic surgery; however, treatment of nodular hidradenocarcinoma is controversial and typically begins with wide local excision but may involve lymph node dissection if necessary. Use of adjuvant chemotherapy and radiation therapy for metastases warrants more clinical studies, as it is a rare occurrence.⁶ Our patient planned to undergo a total excision of the benign nodule once she healed from the biopsy; however, she was lost to follow-up, as she moved out of state.

The Diagnosis: Nodular Hidradenoma

Nodular hidradenomas (NHs) are rare benign cutaneous adnexal neoplasms first described in 1949 as clear cell papillary carcinomas.¹ Since then, various terms have been used to describe this entity, such as eccrine acrospiroma, solid-cystic hidradenoma, and clear cell hidradenoma.² Review of the literature revealed a female predominance (2:1 ratio) and a mean age at presentation of 37.2 years.^3,4 Nodular hidradenoma presents as an asymptomatic, solitary, mobile, firm nodule with intact overlying skin. Rarely, multiple nodules may occur.³ Some tumors display ulceration and serous fluid leakage.⁵ They occur most commonly on the scalp, face, and upper extremities with an average size of 2 cm.³ Rapid growth of the tumor may signal a malignant change.⁶

Histopathology reveals a lobulated, circumscribed, symmetrical tumor with dermal nests of epithelial cells that are polygonal with eosinophilic cytoplasm forming ductlike spaces (Figure). However, clear cell changes and squamous differentiation may be prominent features. Cystic spaces may result from tumor cell degeneration. Most tumors are encased by collagenous fibrous tissue and rarely have epidermal attachments.³

Anastomosing aggregates of squamous cells forming ductlike spaces were viewed on low-power magnification (A)(H&E, original magnification ×10). On higher power there were ductlike spaces and eosinophilic hyalinized stroma entrapped by the bland-appearing squamous proliferation (B)(H&E, original magnification ×20).

Nodular hidradenoma traditionally has been considered to be of eccrine origin, but more recent literature indicates that the majority of NHs are of apocrine origin. Histologically, apocrine tumors display eosinophilic secretion, mucinous epithelium, squamous or sebaceous differentiation, and decapitation secretion, whereas eccrine tumors are identified by their lack of specific features.³

Nodular hidradenoma may recur after excision. Malignant transformation is rare. In one review, 6.7% (6/89) of NHs were malignant, characterized by abnormal mitoses, nuclear atypia, and necrosis.⁴ Malignant NH or nodular hidradenocarcinoma behaves aggressively with up to an 86% local recurrence and 60% rate of metastasis within 2 years.⁶ Survival time is inversely proportional to the size of the tumor and is generally poor, with a 5-year disease-free survival of less than 30%.^6,7

Treatment of NH is achieved through primary excision or Mohs micrographic surgery; however, treatment of nodular hidradenocarcinoma is controversial and typically begins with wide local excision but may involve lymph node dissection if necessary. Use of adjuvant chemotherapy and radiation therapy for metastases warrants more clinical studies, as it is a rare occurrence.⁶ Our patient planned to undergo a total excision of the benign nodule once she healed from the biopsy; however, she was lost to follow-up, as she moved out of state.

The Diagnosis: Nodular Hidradenoma

Nodular hidradenomas (NHs) are rare benign cutaneous adnexal neoplasms first described in 1949 as clear cell papillary carcinomas.¹ Since then, various terms have been used to describe this entity, such as eccrine acrospiroma, solid-cystic hidradenoma, and clear cell hidradenoma.² Review of the literature revealed a female predominance (2:1 ratio) and a mean age at presentation of 37.2 years.^3,4 Nodular hidradenoma presents as an asymptomatic, solitary, mobile, firm nodule with intact overlying skin. Rarely, multiple nodules may occur.³ Some tumors display ulceration and serous fluid leakage.⁵ They occur most commonly on the scalp, face, and upper extremities with an average size of 2 cm.³ Rapid growth of the tumor may signal a malignant change.⁶

Histopathology reveals a lobulated, circumscribed, symmetrical tumor with dermal nests of epithelial cells that are polygonal with eosinophilic cytoplasm forming ductlike spaces (Figure). However, clear cell changes and squamous differentiation may be prominent features. Cystic spaces may result from tumor cell degeneration. Most tumors are encased by collagenous fibrous tissue and rarely have epidermal attachments.³

Anastomosing aggregates of squamous cells forming ductlike spaces were viewed on low-power magnification (A)(H&E, original magnification ×10). On higher power there were ductlike spaces and eosinophilic hyalinized stroma entrapped by the bland-appearing squamous proliferation (B)(H&E, original magnification ×20).

Nodular hidradenoma traditionally has been considered to be of eccrine origin, but more recent literature indicates that the majority of NHs are of apocrine origin. Histologically, apocrine tumors display eosinophilic secretion, mucinous epithelium, squamous or sebaceous differentiation, and decapitation secretion, whereas eccrine tumors are identified by their lack of specific features.³

Nodular hidradenoma may recur after excision. Malignant transformation is rare. In one review, 6.7% (6/89) of NHs were malignant, characterized by abnormal mitoses, nuclear atypia, and necrosis.⁴ Malignant NH or nodular hidradenocarcinoma behaves aggressively with up to an 86% local recurrence and 60% rate of metastasis within 2 years.⁶ Survival time is inversely proportional to the size of the tumor and is generally poor, with a 5-year disease-free survival of less than 30%.^6,7

Treatment of NH is achieved through primary excision or Mohs micrographic surgery; however, treatment of nodular hidradenocarcinoma is controversial and typically begins with wide local excision but may involve lymph node dissection if necessary. Use of adjuvant chemotherapy and radiation therapy for metastases warrants more clinical studies, as it is a rare occurrence.⁶ Our patient planned to undergo a total excision of the benign nodule once she healed from the biopsy; however, she was lost to follow-up, as she moved out of state.

Kaposi sarcoma (KS) is a vascular neoplasm associated with human herpesvirus 8 (HHV-8) infection that is conventionally divided into 4 clinical variants: classic, African, transplant associated, and AIDS related. In the United States, classic KS predominantly is observed in elderly white men of Ashkenazi Jewish or Mediterranean descent.¹

The clinical and histological changes seen in KS can be confused with those from chronic venous insufficiency. Both conditions tend to present with purple-colored patches, plaques, or nodules on the lower extremities. Histologically, both KS and chronic venous insufficiency are characterized by blood vessel and endothelial cell proliferation in the papillary dermis, red blood cell extravasation, and hemosiderin deposition.² Nevertheless, KS can be diagnosed based on the presence of neoplastic spindle-shaped cells and positive immunostaining for HHV-8 antigen.³

We describe the cases of 2 elderly Hispanic patients in the United States with no history of human immunodeficiency virus (HIV), immunosuppression, or travel to the Mediterranean region who presented with erythematous to violaceous papules, plaques, and nodules on the distal lower extremities in the setting of chronic venous insufficiency. We review the relationship between KS and chronic venous insufficiency and suggest that these presentations may represent a distinct clinical variant of KS.

Case Reports

Patient 1

An 83-year-old Hispanic woman with a history of hypertension, atrial fibrillation, and chronic venous insufficiency presented with a chronic painful violaceous eruption on the lower legs of 3 years’ duration. The patient reported that the erythematous patches, which she described as bruiselike, originally developed 3 years prior after starting warfarin therapy for atrial fibrillation. At that time, a biopsy indicated findings of pigmented purpuric dermatosis and negative immunostaining for HHV-8. Her condition had worsened over the last 6 months with the development of tender eroded plaques on the dorsal aspects of the feet (Figure 1) and purple-brown patches and plaques on the legs. Prior treatment with topical corticosteroids and a short course of prednisone was unsuccessful. Of note, the patient had no history of immunosuppression or HIV and was not of Mediterranean or African descent.

Punch biopsies from the left dorsal foot and left lower leg revealed dermal fibrosis, a proliferation of small blood vessels with plump endothelial cells, and foci of spindled endothelial cells with narrow slitlike spaces containing erythrocytes (Figure 2). There also were extravasated erythrocytes and a sparse inflammatory cell infiltrate comprised of lymphocytes, eosinophils, neutrophils, and plasma cells. Perls Prussian blue stain highlighted numerous siderophages scattered in the dermis. Based on these findings, immunostaining for HHV-8 was performed and highlighted reactivity of the spindled cells (Figure 3). The patient was diagnosed with KS in the setting of chronic venous insufficiency.

Figure 2. Dermal fibrosis, proliferation of small blood vessels, and spindled endothelial cells with narrow slitlike spaces were observed (H&E, original magnification ×100).   Figure 3. Spindled cells reactive to human herpesvirus 8 immunostaining (original magnification ×100).

Patient 2

A 67-year-old Hispanic man with a history of diabetes mellitus presented with 10 asymptomatic purple papules and hyperkeratotic and hyperpigmented plaques on the distal aspect of the legs of 1 year’s duration in the setting of chronic venous insufficiency (Figure 4). The patient had no history of immunosuppression or HIV and was not of Mediterranean or African descent. An excisional biopsy from the left fourth toe revealed a cellular dermal vascular proliferation associated with numerous small slitlike vessels and scattered dilated blood vessels with prominent hemorrhage and surrounding dermal fibrosis (Figure 5). The lesion was markedly cellular with nuclear atypia. Many cells showed enlarged oval- to spindle-shaped hyperchromatic nuclei, some with prominent nucleoli and scant amounts of eosinophilic cytoplasm. Although the differential diagnosis included an unusual cellular pyogenic granuloma with atypia in the setting of chronic venous insufficiency, the degree of cellularity and presence of spindled cells associated with slitlike vessels were more consistent with a pyogenic granulomalike variant of KS. This variant is rare but has previously been reported.⁴ Many of the tumor nucleoli stained strongly for HHV-8, which is a diagnostic finding of KS (Figure 6). The patient subsequently was diagnosed with KS.

Comment

These 2 cases represent unusual clinical presentations of KS in Hispanic patients with no known risk factors for KS. In patient 1, an initial skin biopsy prompted HHV-8 testing due to suspicion for KS. At that time, HHV-8 was negative, perhaps because of technical deficiencies in the staining protocol; alternatively, the patient may have subsequently developed KS. Both patients had known chronic venous insufficiency. However, biopsies revealed spindle-shaped cells forming clefts and positivity for HHV-8. We propose that these cases may represent an additional clinical variant of KS, chronic venous insufficiency–associated KS.

If similar presentations of KS are identified, studies will need to be done to uncover the specific risk factors involved. Human herpesvirus 8 is not sufficient for the development of KS on its own, as oncogenesis of KS requires immunodeficiency or an additional environmental factor such as diabetes mellitus.5 Through impaired microvascular circulation and the release of hypoxia-inducible factor 1a, diabetes can promote KS-herpesvirus replication. Therefore, the risk for KS is increased in individuals with diabetes regardless of a negative history of immunodeficiency, which may have been the case in patient 2.

Our cases suggest that chronic venous insufficiency may be another factor that predisposes immunocompetent individuals to KS. Chronic venous insufficiency can cause hypoxia, promoting the release of cytokines and angiogenic factors responsible for the formation of vascular tumors such as KS.⁶ Once present, KS can worsen preexisting stasis dermatitis by compressing the external lymphatics and exacerbating lymphedema.⁷ Stasis dermatitis and KS may be part of a self-perpetuating cycle that involves obstruction due to secondary lymphadenopathy, the development of lymphedema, and the release of cytokines and growth factors that lead to further vascular proliferation.⁸

Figure 5. A cellular dermal vascular proliferation associated with slitlike vessels, dermal fibrosis, and marked cellularity with nuclear atypia (H&E, original magnification ×200).

Figure 6. Spindled cells reactive to human herpesvirus 8 immunostain (original magnification ×400).

In summary, we present 2 cases of non–HIV-related KS that may represent an additional clinical variant of KS that mimics and/or arises in chronic venous insufficiency and appears as papules and plaques in elderly patients who are Hispanic, immunocompetent, and HIV negative. We suggest including KS in the differential diagnosis for chronic venous insufficiency, especially in cases with an unusual clinical appearance or course. In these cases, skin biopsy with HHV-8 testing may be warranted.

Acknowledgment

The authors would like to acknowledge William Putnam, BFA, New York, New York, for his assistance with the figures.

Kaposi sarcoma (KS) is a vascular neoplasm associated with human herpesvirus 8 (HHV-8) infection that is conventionally divided into 4 clinical variants: classic, African, transplant associated, and AIDS related. In the United States, classic KS predominantly is observed in elderly white men of Ashkenazi Jewish or Mediterranean descent.¹

The clinical and histological changes seen in KS can be confused with those from chronic venous insufficiency. Both conditions tend to present with purple-colored patches, plaques, or nodules on the lower extremities. Histologically, both KS and chronic venous insufficiency are characterized by blood vessel and endothelial cell proliferation in the papillary dermis, red blood cell extravasation, and hemosiderin deposition.² Nevertheless, KS can be diagnosed based on the presence of neoplastic spindle-shaped cells and positive immunostaining for HHV-8 antigen.³

We describe the cases of 2 elderly Hispanic patients in the United States with no history of human immunodeficiency virus (HIV), immunosuppression, or travel to the Mediterranean region who presented with erythematous to violaceous papules, plaques, and nodules on the distal lower extremities in the setting of chronic venous insufficiency. We review the relationship between KS and chronic venous insufficiency and suggest that these presentations may represent a distinct clinical variant of KS.

Case Reports

Patient 1

An 83-year-old Hispanic woman with a history of hypertension, atrial fibrillation, and chronic venous insufficiency presented with a chronic painful violaceous eruption on the lower legs of 3 years’ duration. The patient reported that the erythematous patches, which she described as bruiselike, originally developed 3 years prior after starting warfarin therapy for atrial fibrillation. At that time, a biopsy indicated findings of pigmented purpuric dermatosis and negative immunostaining for HHV-8. Her condition had worsened over the last 6 months with the development of tender eroded plaques on the dorsal aspects of the feet (Figure 1) and purple-brown patches and plaques on the legs. Prior treatment with topical corticosteroids and a short course of prednisone was unsuccessful. Of note, the patient had no history of immunosuppression or HIV and was not of Mediterranean or African descent.

Punch biopsies from the left dorsal foot and left lower leg revealed dermal fibrosis, a proliferation of small blood vessels with plump endothelial cells, and foci of spindled endothelial cells with narrow slitlike spaces containing erythrocytes (Figure 2). There also were extravasated erythrocytes and a sparse inflammatory cell infiltrate comprised of lymphocytes, eosinophils, neutrophils, and plasma cells. Perls Prussian blue stain highlighted numerous siderophages scattered in the dermis. Based on these findings, immunostaining for HHV-8 was performed and highlighted reactivity of the spindled cells (Figure 3). The patient was diagnosed with KS in the setting of chronic venous insufficiency.

Figure 2. Dermal fibrosis, proliferation of small blood vessels, and spindled endothelial cells with narrow slitlike spaces were observed (H&E, original magnification ×100).   Figure 3. Spindled cells reactive to human herpesvirus 8 immunostaining (original magnification ×100).

Patient 2

A 67-year-old Hispanic man with a history of diabetes mellitus presented with 10 asymptomatic purple papules and hyperkeratotic and hyperpigmented plaques on the distal aspect of the legs of 1 year’s duration in the setting of chronic venous insufficiency (Figure 4). The patient had no history of immunosuppression or HIV and was not of Mediterranean or African descent. An excisional biopsy from the left fourth toe revealed a cellular dermal vascular proliferation associated with numerous small slitlike vessels and scattered dilated blood vessels with prominent hemorrhage and surrounding dermal fibrosis (Figure 5). The lesion was markedly cellular with nuclear atypia. Many cells showed enlarged oval- to spindle-shaped hyperchromatic nuclei, some with prominent nucleoli and scant amounts of eosinophilic cytoplasm. Although the differential diagnosis included an unusual cellular pyogenic granuloma with atypia in the setting of chronic venous insufficiency, the degree of cellularity and presence of spindled cells associated with slitlike vessels were more consistent with a pyogenic granulomalike variant of KS. This variant is rare but has previously been reported.⁴ Many of the tumor nucleoli stained strongly for HHV-8, which is a diagnostic finding of KS (Figure 6). The patient subsequently was diagnosed with KS.

Comment

These 2 cases represent unusual clinical presentations of KS in Hispanic patients with no known risk factors for KS. In patient 1, an initial skin biopsy prompted HHV-8 testing due to suspicion for KS. At that time, HHV-8 was negative, perhaps because of technical deficiencies in the staining protocol; alternatively, the patient may have subsequently developed KS. Both patients had known chronic venous insufficiency. However, biopsies revealed spindle-shaped cells forming clefts and positivity for HHV-8. We propose that these cases may represent an additional clinical variant of KS, chronic venous insufficiency–associated KS.

If similar presentations of KS are identified, studies will need to be done to uncover the specific risk factors involved. Human herpesvirus 8 is not sufficient for the development of KS on its own, as oncogenesis of KS requires immunodeficiency or an additional environmental factor such as diabetes mellitus.5 Through impaired microvascular circulation and the release of hypoxia-inducible factor 1a, diabetes can promote KS-herpesvirus replication. Therefore, the risk for KS is increased in individuals with diabetes regardless of a negative history of immunodeficiency, which may have been the case in patient 2.

Our cases suggest that chronic venous insufficiency may be another factor that predisposes immunocompetent individuals to KS. Chronic venous insufficiency can cause hypoxia, promoting the release of cytokines and angiogenic factors responsible for the formation of vascular tumors such as KS.⁶ Once present, KS can worsen preexisting stasis dermatitis by compressing the external lymphatics and exacerbating lymphedema.⁷ Stasis dermatitis and KS may be part of a self-perpetuating cycle that involves obstruction due to secondary lymphadenopathy, the development of lymphedema, and the release of cytokines and growth factors that lead to further vascular proliferation.⁸

Figure 5. A cellular dermal vascular proliferation associated with slitlike vessels, dermal fibrosis, and marked cellularity with nuclear atypia (H&E, original magnification ×200).

Figure 6. Spindled cells reactive to human herpesvirus 8 immunostain (original magnification ×400).

In summary, we present 2 cases of non–HIV-related KS that may represent an additional clinical variant of KS that mimics and/or arises in chronic venous insufficiency and appears as papules and plaques in elderly patients who are Hispanic, immunocompetent, and HIV negative. We suggest including KS in the differential diagnosis for chronic venous insufficiency, especially in cases with an unusual clinical appearance or course. In these cases, skin biopsy with HHV-8 testing may be warranted.

Acknowledgment

The authors would like to acknowledge William Putnam, BFA, New York, New York, for his assistance with the figures.

Kaposi sarcoma (KS) is a vascular neoplasm associated with human herpesvirus 8 (HHV-8) infection that is conventionally divided into 4 clinical variants: classic, African, transplant associated, and AIDS related. In the United States, classic KS predominantly is observed in elderly white men of Ashkenazi Jewish or Mediterranean descent.¹

The clinical and histological changes seen in KS can be confused with those from chronic venous insufficiency. Both conditions tend to present with purple-colored patches, plaques, or nodules on the lower extremities. Histologically, both KS and chronic venous insufficiency are characterized by blood vessel and endothelial cell proliferation in the papillary dermis, red blood cell extravasation, and hemosiderin deposition.² Nevertheless, KS can be diagnosed based on the presence of neoplastic spindle-shaped cells and positive immunostaining for HHV-8 antigen.³

We describe the cases of 2 elderly Hispanic patients in the United States with no history of human immunodeficiency virus (HIV), immunosuppression, or travel to the Mediterranean region who presented with erythematous to violaceous papules, plaques, and nodules on the distal lower extremities in the setting of chronic venous insufficiency. We review the relationship between KS and chronic venous insufficiency and suggest that these presentations may represent a distinct clinical variant of KS.

Case Reports

Patient 1

An 83-year-old Hispanic woman with a history of hypertension, atrial fibrillation, and chronic venous insufficiency presented with a chronic painful violaceous eruption on the lower legs of 3 years’ duration. The patient reported that the erythematous patches, which she described as bruiselike, originally developed 3 years prior after starting warfarin therapy for atrial fibrillation. At that time, a biopsy indicated findings of pigmented purpuric dermatosis and negative immunostaining for HHV-8. Her condition had worsened over the last 6 months with the development of tender eroded plaques on the dorsal aspects of the feet (Figure 1) and purple-brown patches and plaques on the legs. Prior treatment with topical corticosteroids and a short course of prednisone was unsuccessful. Of note, the patient had no history of immunosuppression or HIV and was not of Mediterranean or African descent.

Punch biopsies from the left dorsal foot and left lower leg revealed dermal fibrosis, a proliferation of small blood vessels with plump endothelial cells, and foci of spindled endothelial cells with narrow slitlike spaces containing erythrocytes (Figure 2). There also were extravasated erythrocytes and a sparse inflammatory cell infiltrate comprised of lymphocytes, eosinophils, neutrophils, and plasma cells. Perls Prussian blue stain highlighted numerous siderophages scattered in the dermis. Based on these findings, immunostaining for HHV-8 was performed and highlighted reactivity of the spindled cells (Figure 3). The patient was diagnosed with KS in the setting of chronic venous insufficiency.

Figure 2. Dermal fibrosis, proliferation of small blood vessels, and spindled endothelial cells with narrow slitlike spaces were observed (H&E, original magnification ×100).   Figure 3. Spindled cells reactive to human herpesvirus 8 immunostaining (original magnification ×100).

Patient 2

A 67-year-old Hispanic man with a history of diabetes mellitus presented with 10 asymptomatic purple papules and hyperkeratotic and hyperpigmented plaques on the distal aspect of the legs of 1 year’s duration in the setting of chronic venous insufficiency (Figure 4). The patient had no history of immunosuppression or HIV and was not of Mediterranean or African descent. An excisional biopsy from the left fourth toe revealed a cellular dermal vascular proliferation associated with numerous small slitlike vessels and scattered dilated blood vessels with prominent hemorrhage and surrounding dermal fibrosis (Figure 5). The lesion was markedly cellular with nuclear atypia. Many cells showed enlarged oval- to spindle-shaped hyperchromatic nuclei, some with prominent nucleoli and scant amounts of eosinophilic cytoplasm. Although the differential diagnosis included an unusual cellular pyogenic granuloma with atypia in the setting of chronic venous insufficiency, the degree of cellularity and presence of spindled cells associated with slitlike vessels were more consistent with a pyogenic granulomalike variant of KS. This variant is rare but has previously been reported.⁴ Many of the tumor nucleoli stained strongly for HHV-8, which is a diagnostic finding of KS (Figure 6). The patient subsequently was diagnosed with KS.

Comment

These 2 cases represent unusual clinical presentations of KS in Hispanic patients with no known risk factors for KS. In patient 1, an initial skin biopsy prompted HHV-8 testing due to suspicion for KS. At that time, HHV-8 was negative, perhaps because of technical deficiencies in the staining protocol; alternatively, the patient may have subsequently developed KS. Both patients had known chronic venous insufficiency. However, biopsies revealed spindle-shaped cells forming clefts and positivity for HHV-8. We propose that these cases may represent an additional clinical variant of KS, chronic venous insufficiency–associated KS.

If similar presentations of KS are identified, studies will need to be done to uncover the specific risk factors involved. Human herpesvirus 8 is not sufficient for the development of KS on its own, as oncogenesis of KS requires immunodeficiency or an additional environmental factor such as diabetes mellitus.5 Through impaired microvascular circulation and the release of hypoxia-inducible factor 1a, diabetes can promote KS-herpesvirus replication. Therefore, the risk for KS is increased in individuals with diabetes regardless of a negative history of immunodeficiency, which may have been the case in patient 2.

Our cases suggest that chronic venous insufficiency may be another factor that predisposes immunocompetent individuals to KS. Chronic venous insufficiency can cause hypoxia, promoting the release of cytokines and angiogenic factors responsible for the formation of vascular tumors such as KS.⁶ Once present, KS can worsen preexisting stasis dermatitis by compressing the external lymphatics and exacerbating lymphedema.⁷ Stasis dermatitis and KS may be part of a self-perpetuating cycle that involves obstruction due to secondary lymphadenopathy, the development of lymphedema, and the release of cytokines and growth factors that lead to further vascular proliferation.⁸

Figure 5. A cellular dermal vascular proliferation associated with slitlike vessels, dermal fibrosis, and marked cellularity with nuclear atypia (H&E, original magnification ×200).

Figure 6. Spindled cells reactive to human herpesvirus 8 immunostain (original magnification ×400).

In summary, we present 2 cases of non–HIV-related KS that may represent an additional clinical variant of KS that mimics and/or arises in chronic venous insufficiency and appears as papules and plaques in elderly patients who are Hispanic, immunocompetent, and HIV negative. We suggest including KS in the differential diagnosis for chronic venous insufficiency, especially in cases with an unusual clinical appearance or course. In these cases, skin biopsy with HHV-8 testing may be warranted.

Acknowledgment

The authors would like to acknowledge William Putnam, BFA, New York, New York, for his assistance with the figures.

The Diagnosis: Pancreatic Panniculitis

The biopsy specimen revealed necrosis of the panniculus with “ghost” cells (Figure). Calcification was encountered. Changes of vasculitis were not identified and fungal organisms were not noted. The histopathologic findings supported a diagnosis of pancreatic panniculitis.

Punch biopsy revealed necrosis of the panniculus with “ghost” cells, and calcification was encountered (H&E, original magnification ×20).

Pancreatic panniculitis has been associated with pancreatitis, pancreatic carcinoma, pancreatic pseudocysts, congenital abnormalities of the pancreas, and drug-induced pancreatitis.¹ Skin lesions may herald a diagnosis of pancreatic disease in an outpatient and should prompt thorough clinical evaluation when encountered in an outpatient setting. Our patient first developed tender nodules on the left shin 2 to 3 weeks prior to presentation. She reported that her initial nodules were flesh colored but then became erythematous and tender over 1 week’s time. The patient’s history was remarkable for ovarian cancer. She had been hospitalized 2 weeks prior to presentation for abdominal pain and ascites. Imaging studies revealed a cystic lesion in the head of the pancreas. The pancreas was traumatized during a peritoneal tap. Her nodules developed shortly thereafter and were distributed on the arms, legs, back, and abdomen.

Pancreatic tumors or inflammation are thought to trigger pancreatic panniculitis by releasing enzymes. Pancreatic enzymes such as lipase are thought to play a role in the development of pancreatic panniculitis by entering the vascular system and leading to fat necrosis.^2,3 Biopsy reveals necrosis of adipocytes in the center of fat lobules.⁴ Ghost cells result from hydrolytic activity of enzymes on the fat cells followed by calcium deposition. A report indicates that fungal infection or gout also can cause changes that mimic pancreatic panniculitis.⁵

Other entities in the differential diagnosis can be excluded by biopsy. Polyarteritis nodosa is a vasculitis. Although panniculitis may be seen in polyarteritis as a secondary phenomenon, lesions are centered around blood vessels and often eventuate in ulceration.⁶ Subcutaneous fungal infection typically reveals organisms on periodic acid–Schiff stain.⁷ Pyoderma gangrenosum is associated with ulceration and a neutrophilic infiltrate that is often centered around a central pilosebaceous unit in developing lesions.⁸ Erythema nodosum is a panniculitis in which septal inflammation predominates.⁹ These differential diagnoses of pancreatic panniculitis are summarized in the Table.

Pancreatic panniculitis can be associated with acute arthritis and inflammation of periarticular fat.¹⁰ Treatment of pancreatic panniculitis is usually focused on the underlying pancreatic disease.^11,12 Our patient benefited from analgesic therapy and her lesions improved on follow-up. Clinicians encountering a patient with new tender nodules should be prompted to perform a biopsy. When histopathologic evaluation reveals ghosted adipocytes, pancreatic panniculitis should be suspected and clinical evaluation undertaken.

The Diagnosis: Pancreatic Panniculitis

The biopsy specimen revealed necrosis of the panniculus with “ghost” cells (Figure). Calcification was encountered. Changes of vasculitis were not identified and fungal organisms were not noted. The histopathologic findings supported a diagnosis of pancreatic panniculitis.

Punch biopsy revealed necrosis of the panniculus with “ghost” cells, and calcification was encountered (H&E, original magnification ×20).

Pancreatic panniculitis has been associated with pancreatitis, pancreatic carcinoma, pancreatic pseudocysts, congenital abnormalities of the pancreas, and drug-induced pancreatitis.¹ Skin lesions may herald a diagnosis of pancreatic disease in an outpatient and should prompt thorough clinical evaluation when encountered in an outpatient setting. Our patient first developed tender nodules on the left shin 2 to 3 weeks prior to presentation. She reported that her initial nodules were flesh colored but then became erythematous and tender over 1 week’s time. The patient’s history was remarkable for ovarian cancer. She had been hospitalized 2 weeks prior to presentation for abdominal pain and ascites. Imaging studies revealed a cystic lesion in the head of the pancreas. The pancreas was traumatized during a peritoneal tap. Her nodules developed shortly thereafter and were distributed on the arms, legs, back, and abdomen.

Pancreatic tumors or inflammation are thought to trigger pancreatic panniculitis by releasing enzymes. Pancreatic enzymes such as lipase are thought to play a role in the development of pancreatic panniculitis by entering the vascular system and leading to fat necrosis.^2,3 Biopsy reveals necrosis of adipocytes in the center of fat lobules.⁴ Ghost cells result from hydrolytic activity of enzymes on the fat cells followed by calcium deposition. A report indicates that fungal infection or gout also can cause changes that mimic pancreatic panniculitis.⁵

Other entities in the differential diagnosis can be excluded by biopsy. Polyarteritis nodosa is a vasculitis. Although panniculitis may be seen in polyarteritis as a secondary phenomenon, lesions are centered around blood vessels and often eventuate in ulceration.⁶ Subcutaneous fungal infection typically reveals organisms on periodic acid–Schiff stain.⁷ Pyoderma gangrenosum is associated with ulceration and a neutrophilic infiltrate that is often centered around a central pilosebaceous unit in developing lesions.⁸ Erythema nodosum is a panniculitis in which septal inflammation predominates.⁹ These differential diagnoses of pancreatic panniculitis are summarized in the Table.

Pancreatic panniculitis can be associated with acute arthritis and inflammation of periarticular fat.¹⁰ Treatment of pancreatic panniculitis is usually focused on the underlying pancreatic disease.^11,12 Our patient benefited from analgesic therapy and her lesions improved on follow-up. Clinicians encountering a patient with new tender nodules should be prompted to perform a biopsy. When histopathologic evaluation reveals ghosted adipocytes, pancreatic panniculitis should be suspected and clinical evaluation undertaken.

The Diagnosis: Pancreatic Panniculitis

The biopsy specimen revealed necrosis of the panniculus with “ghost” cells (Figure). Calcification was encountered. Changes of vasculitis were not identified and fungal organisms were not noted. The histopathologic findings supported a diagnosis of pancreatic panniculitis.

Punch biopsy revealed necrosis of the panniculus with “ghost” cells, and calcification was encountered (H&E, original magnification ×20).

Pancreatic panniculitis has been associated with pancreatitis, pancreatic carcinoma, pancreatic pseudocysts, congenital abnormalities of the pancreas, and drug-induced pancreatitis.¹ Skin lesions may herald a diagnosis of pancreatic disease in an outpatient and should prompt thorough clinical evaluation when encountered in an outpatient setting. Our patient first developed tender nodules on the left shin 2 to 3 weeks prior to presentation. She reported that her initial nodules were flesh colored but then became erythematous and tender over 1 week’s time. The patient’s history was remarkable for ovarian cancer. She had been hospitalized 2 weeks prior to presentation for abdominal pain and ascites. Imaging studies revealed a cystic lesion in the head of the pancreas. The pancreas was traumatized during a peritoneal tap. Her nodules developed shortly thereafter and were distributed on the arms, legs, back, and abdomen.

Pancreatic tumors or inflammation are thought to trigger pancreatic panniculitis by releasing enzymes. Pancreatic enzymes such as lipase are thought to play a role in the development of pancreatic panniculitis by entering the vascular system and leading to fat necrosis.^2,3 Biopsy reveals necrosis of adipocytes in the center of fat lobules.⁴ Ghost cells result from hydrolytic activity of enzymes on the fat cells followed by calcium deposition. A report indicates that fungal infection or gout also can cause changes that mimic pancreatic panniculitis.⁵

Other entities in the differential diagnosis can be excluded by biopsy. Polyarteritis nodosa is a vasculitis. Although panniculitis may be seen in polyarteritis as a secondary phenomenon, lesions are centered around blood vessels and often eventuate in ulceration.⁶ Subcutaneous fungal infection typically reveals organisms on periodic acid–Schiff stain.⁷ Pyoderma gangrenosum is associated with ulceration and a neutrophilic infiltrate that is often centered around a central pilosebaceous unit in developing lesions.⁸ Erythema nodosum is a panniculitis in which septal inflammation predominates.⁹ These differential diagnoses of pancreatic panniculitis are summarized in the Table.

Pancreatic panniculitis can be associated with acute arthritis and inflammation of periarticular fat.¹⁰ Treatment of pancreatic panniculitis is usually focused on the underlying pancreatic disease.^11,12 Our patient benefited from analgesic therapy and her lesions improved on follow-up. Clinicians encountering a patient with new tender nodules should be prompted to perform a biopsy. When histopathologic evaluation reveals ghosted adipocytes, pancreatic panniculitis should be suspected and clinical evaluation undertaken.