Dermatopathology

The Diagnosis: Linear IgA Bullous Dermatosis

A biopsy specimen from an intact vesicle was obtained. Histologic findings showed a basket weave stratum corneum suggestive of an acute process. There was subepidermal separation with an inflammatory infiltrate of neutrophils (Figure 1). Direct immunofluorescence yielded a pattern of IgA deposition along the dermoepidermal junction (Figure 2). A diagnosis of linear IgA bullous dermatosis (LABD) was made. The patient was started on 100 mg daily of dapsone. The dose was subsequently increased to 175 mg twice daily, resulting in complete clearance. He became dermatologically disease free after 10 months and the dapsone was successfully tapered.

Figure 1. Subepidermal separation with an inflammatory infiltrate composed of neutrophils (H&E, original magnification ×20). Figure 2. Direct immunofluorescence with linear deposition of IgA along the basement membrane zone (original magnification ×20).

Linear IgA bullous dermatosis is an autoimmune subepidermal blistering disease with linear IgA deposits found along the basement membrane of the skin. There are 3 major categories of LABD: drug induced, systemic disorder related, and idiopathic.¹ Patients with LABD present with a pruritic vesicobullous eruption that tends to favor the trunk, proximal extremities, and acral regions of the body. Mucous membrane lesions are present in less than 50% of patients.² Linear IgA bullous dermatosis may resemble bullous pemphigoid, erythema multiforme, dermatitis herpetiformis, or toxic epidermal necrolysis. The gold standard for diagnosis is immunofluorescence staining that shows linear IgA deposition along the skin’s basement membrane.¹ Prognosis for LABD is variable; there is risk for persistence and scarring.² The drug-induced form of LABD is associated with clearance with the removal of the inciting agent.¹

There are several autoimmune disorders that have been described in association with human immunodeficiency virus (HIV).³ Autoimmune bullous dermatoses, while described, are very uncommon in the setting of HIV infection. Previously reported cases include bullous pemphigoid, epidermolysis bullosa acquisita, pemphigus herpetiformis, pemphigus vegetans, pemphigus vulgaris, and cicatricial pemphigoid.^4-12 The presentation of LABD in an HIV-positive patient is extremely rare.

There are 3 proposed mechanisms by which HIV and autoimmune bullous dermatoses coexist: unregulated B-cell activation, loss of T-suppressor cell regulation, and molecular mimicry. In patients with HIV, infected macrophages increase production of IL-1 and IL-6, causing nonspecific stimulation of B cells. Further production of tumor necrosis factor and other lymphotoxins may kill CD8⁺ T-suppressor cells, which further reduces B-cell regulation and production of nonspecific antibodies. Unregulated B-cell activation could lead to proliferation of antiself-specific B cells and autoantibodies. Additionally, various autoantibodies may arise due to mimicry between HIV antigens and human proteins. Some of the antibodies produced may be cytotoxic antilymphocyte antibodies that further disrupt B-cell regulation.^13,14

Zandman-Goddard and Shoenfeld¹⁴ proposed a staging system of autoimmune disease and HIV with respect to CD4 count and viral load. Stage I is clinical latency of HIV, with a high CD4 count (>500 cells/mm³) and high viral load, which correlates with an acute infection of HIV and an intact immune system. Autoimmune disease can be seen in this stage. Stage II is cellular response, a quiescent period without overt manifestations of AIDS. The CD4 count is declining (200–499 cells/mm³), indicating immunosuppression, and the viral count is high. Autoimmune disease can occur and typically includes immune complex–mediated disease and vasculitis. Stage III is immune deficiency. The CD4 count is low (<200 cells/mm³), viral load is high, and AIDS develops. Autoimmune disease is not seen during this stage. Stage IV is the period of immune restoration following the advent of highly active antiretroviral therapy. There is a high CD4 count (>500 cells/mm³) and low viral load. There is a resurgence of autoimmune disease in this stage. Autoimmune disease can occur with an immune system capable of B- and T-cell interactions and a normal CD4 count. Autoimmunity is possible in stages I, II, and IV.¹⁴ Our patient developed bullous disease in stage II.

Although uncommon, autoimmune disease is possible in the setting of immune deficiency. The presence of autoimmune disease in a patient with HIV can only be seen during certain stages of infection. Knowledge of the possible scenarios of autoimmune disease can assist the clinician with monitoring status of the HIV infection or immune reconstitution.

The Diagnosis: Linear IgA Bullous Dermatosis

A biopsy specimen from an intact vesicle was obtained. Histologic findings showed a basket weave stratum corneum suggestive of an acute process. There was subepidermal separation with an inflammatory infiltrate of neutrophils (Figure 1). Direct immunofluorescence yielded a pattern of IgA deposition along the dermoepidermal junction (Figure 2). A diagnosis of linear IgA bullous dermatosis (LABD) was made. The patient was started on 100 mg daily of dapsone. The dose was subsequently increased to 175 mg twice daily, resulting in complete clearance. He became dermatologically disease free after 10 months and the dapsone was successfully tapered.

Figure 1. Subepidermal separation with an inflammatory infiltrate composed of neutrophils (H&E, original magnification ×20). Figure 2. Direct immunofluorescence with linear deposition of IgA along the basement membrane zone (original magnification ×20).

Linear IgA bullous dermatosis is an autoimmune subepidermal blistering disease with linear IgA deposits found along the basement membrane of the skin. There are 3 major categories of LABD: drug induced, systemic disorder related, and idiopathic.¹ Patients with LABD present with a pruritic vesicobullous eruption that tends to favor the trunk, proximal extremities, and acral regions of the body. Mucous membrane lesions are present in less than 50% of patients.² Linear IgA bullous dermatosis may resemble bullous pemphigoid, erythema multiforme, dermatitis herpetiformis, or toxic epidermal necrolysis. The gold standard for diagnosis is immunofluorescence staining that shows linear IgA deposition along the skin’s basement membrane.¹ Prognosis for LABD is variable; there is risk for persistence and scarring.² The drug-induced form of LABD is associated with clearance with the removal of the inciting agent.¹

There are several autoimmune disorders that have been described in association with human immunodeficiency virus (HIV).³ Autoimmune bullous dermatoses, while described, are very uncommon in the setting of HIV infection. Previously reported cases include bullous pemphigoid, epidermolysis bullosa acquisita, pemphigus herpetiformis, pemphigus vegetans, pemphigus vulgaris, and cicatricial pemphigoid.^4-12 The presentation of LABD in an HIV-positive patient is extremely rare.

There are 3 proposed mechanisms by which HIV and autoimmune bullous dermatoses coexist: unregulated B-cell activation, loss of T-suppressor cell regulation, and molecular mimicry. In patients with HIV, infected macrophages increase production of IL-1 and IL-6, causing nonspecific stimulation of B cells. Further production of tumor necrosis factor and other lymphotoxins may kill CD8⁺ T-suppressor cells, which further reduces B-cell regulation and production of nonspecific antibodies. Unregulated B-cell activation could lead to proliferation of antiself-specific B cells and autoantibodies. Additionally, various autoantibodies may arise due to mimicry between HIV antigens and human proteins. Some of the antibodies produced may be cytotoxic antilymphocyte antibodies that further disrupt B-cell regulation.^13,14

Zandman-Goddard and Shoenfeld¹⁴ proposed a staging system of autoimmune disease and HIV with respect to CD4 count and viral load. Stage I is clinical latency of HIV, with a high CD4 count (>500 cells/mm³) and high viral load, which correlates with an acute infection of HIV and an intact immune system. Autoimmune disease can be seen in this stage. Stage II is cellular response, a quiescent period without overt manifestations of AIDS. The CD4 count is declining (200–499 cells/mm³), indicating immunosuppression, and the viral count is high. Autoimmune disease can occur and typically includes immune complex–mediated disease and vasculitis. Stage III is immune deficiency. The CD4 count is low (<200 cells/mm³), viral load is high, and AIDS develops. Autoimmune disease is not seen during this stage. Stage IV is the period of immune restoration following the advent of highly active antiretroviral therapy. There is a high CD4 count (>500 cells/mm³) and low viral load. There is a resurgence of autoimmune disease in this stage. Autoimmune disease can occur with an immune system capable of B- and T-cell interactions and a normal CD4 count. Autoimmunity is possible in stages I, II, and IV.¹⁴ Our patient developed bullous disease in stage II.

Although uncommon, autoimmune disease is possible in the setting of immune deficiency. The presence of autoimmune disease in a patient with HIV can only be seen during certain stages of infection. Knowledge of the possible scenarios of autoimmune disease can assist the clinician with monitoring status of the HIV infection or immune reconstitution.

The Diagnosis: Linear IgA Bullous Dermatosis

A biopsy specimen from an intact vesicle was obtained. Histologic findings showed a basket weave stratum corneum suggestive of an acute process. There was subepidermal separation with an inflammatory infiltrate of neutrophils (Figure 1). Direct immunofluorescence yielded a pattern of IgA deposition along the dermoepidermal junction (Figure 2). A diagnosis of linear IgA bullous dermatosis (LABD) was made. The patient was started on 100 mg daily of dapsone. The dose was subsequently increased to 175 mg twice daily, resulting in complete clearance. He became dermatologically disease free after 10 months and the dapsone was successfully tapered.

Figure 1. Subepidermal separation with an inflammatory infiltrate composed of neutrophils (H&E, original magnification ×20). Figure 2. Direct immunofluorescence with linear deposition of IgA along the basement membrane zone (original magnification ×20).

Linear IgA bullous dermatosis is an autoimmune subepidermal blistering disease with linear IgA deposits found along the basement membrane of the skin. There are 3 major categories of LABD: drug induced, systemic disorder related, and idiopathic.¹ Patients with LABD present with a pruritic vesicobullous eruption that tends to favor the trunk, proximal extremities, and acral regions of the body. Mucous membrane lesions are present in less than 50% of patients.² Linear IgA bullous dermatosis may resemble bullous pemphigoid, erythema multiforme, dermatitis herpetiformis, or toxic epidermal necrolysis. The gold standard for diagnosis is immunofluorescence staining that shows linear IgA deposition along the skin’s basement membrane.¹ Prognosis for LABD is variable; there is risk for persistence and scarring.² The drug-induced form of LABD is associated with clearance with the removal of the inciting agent.¹

There are several autoimmune disorders that have been described in association with human immunodeficiency virus (HIV).³ Autoimmune bullous dermatoses, while described, are very uncommon in the setting of HIV infection. Previously reported cases include bullous pemphigoid, epidermolysis bullosa acquisita, pemphigus herpetiformis, pemphigus vegetans, pemphigus vulgaris, and cicatricial pemphigoid.^4-12 The presentation of LABD in an HIV-positive patient is extremely rare.

There are 3 proposed mechanisms by which HIV and autoimmune bullous dermatoses coexist: unregulated B-cell activation, loss of T-suppressor cell regulation, and molecular mimicry. In patients with HIV, infected macrophages increase production of IL-1 and IL-6, causing nonspecific stimulation of B cells. Further production of tumor necrosis factor and other lymphotoxins may kill CD8⁺ T-suppressor cells, which further reduces B-cell regulation and production of nonspecific antibodies. Unregulated B-cell activation could lead to proliferation of antiself-specific B cells and autoantibodies. Additionally, various autoantibodies may arise due to mimicry between HIV antigens and human proteins. Some of the antibodies produced may be cytotoxic antilymphocyte antibodies that further disrupt B-cell regulation.^13,14

Zandman-Goddard and Shoenfeld¹⁴ proposed a staging system of autoimmune disease and HIV with respect to CD4 count and viral load. Stage I is clinical latency of HIV, with a high CD4 count (>500 cells/mm³) and high viral load, which correlates with an acute infection of HIV and an intact immune system. Autoimmune disease can be seen in this stage. Stage II is cellular response, a quiescent period without overt manifestations of AIDS. The CD4 count is declining (200–499 cells/mm³), indicating immunosuppression, and the viral count is high. Autoimmune disease can occur and typically includes immune complex–mediated disease and vasculitis. Stage III is immune deficiency. The CD4 count is low (<200 cells/mm³), viral load is high, and AIDS develops. Autoimmune disease is not seen during this stage. Stage IV is the period of immune restoration following the advent of highly active antiretroviral therapy. There is a high CD4 count (>500 cells/mm³) and low viral load. There is a resurgence of autoimmune disease in this stage. Autoimmune disease can occur with an immune system capable of B- and T-cell interactions and a normal CD4 count. Autoimmunity is possible in stages I, II, and IV.¹⁴ Our patient developed bullous disease in stage II.

Although uncommon, autoimmune disease is possible in the setting of immune deficiency. The presence of autoimmune disease in a patient with HIV can only be seen during certain stages of infection. Knowledge of the possible scenarios of autoimmune disease can assist the clinician with monitoring status of the HIV infection or immune reconstitution.

The Diagnosis: Dermal Cylindroma

Microsopic evaluation of a tangential biopsy revealed findings of a dermal process consisting of well-circumscribed islands of pale and darker blue cells with little cytoplasm outlined by a hyaline basement membrane (Figure). These cellular islands were arranged in a jigsawlike configuration. These findings were thought to be consistent with a diagnosis of cylindroma.

Well-circumscribed dermal islands of both pale and darker blue cells outlined by a hyaline basement membrane. These cellular islands were arranged in a jigsawlike configuration (A and B)(both H&E, original magnifications ×20 and ×200).

Cylindromas are benign appendageal neoplasms with a somewhat controversial histogenesis. Munger and colleagues¹ investigated the pattern of acid mucopolysaccharide secretion by these tumors in association with prosecretory vacuoles in proximity to the Golgi apparatus, which led to their impression that cylindromas most resemble eccrine rather than apocrine sweat glands. Other researchers, however, have concluded that cylindromas are of apocrine derivation.²

Clinically, cylindromas appear most often in 2 settings: isolated or as a manifestation of one of several inherited familial syndromes. One such syndrome is familial cylindromatosis, a rare autosomal-dominant disorder in which affected individuals develop multiple cylindromas, usually on the head and neck. The merging of multiple lesions gives rise to the often-employed term turban tumor.³ This syndrome has been linked to mutations in the cylindromatosis gene, CYLD.⁴ Brooke-Spiegler syndrome also has been associated with the development of multiple cylindromas. Similar to familial cylindromatosis, it is inherited in an autosomal-dominant fashion. Brooke-Spiegler syndrome is typified by the appearance of multiple cylindromas, trichoepitheliomas, and less commonly spiradenomas. Mutations in the CYLD gene also have been linked to Brooke-Spiegler syndrome in some cases.⁵

Although considered a benign entity, in rare cases cylindromas have shown evidence of malignant transformation to cylindrocarcinoma. This more aggressive tumor may occur in the setting of isolated cylindromas or more commonly in individuals with numerous lesions, as with both familial cylindromatosis and Brooke-Spiegler syndrome. These lesions may appear to grow rapidly, ulcerate, or bleed, traits that are not associated with their benign counterparts.

Diagnosis of cylindromas rests on histopathologic confirmation, which demonstrates well-defined dermal islands of epithelial cells comprised of dark- and pale-staining nuclei. These tumor islands are surrounded by a hyaline basement membrane and often take on the appearance of a jigsaw puzzle. Cylindrocarcinomas exhibit greater cellular pleomorphism and higher mitotic rates.

Dermal cylindromas require no further treatment but can be electively excised, while treatment of cylindrocarcinoma with excision is curative.⁶ Definitive excision was offered to our patient, but she declined treatment.

The Diagnosis: Dermal Cylindroma

Microsopic evaluation of a tangential biopsy revealed findings of a dermal process consisting of well-circumscribed islands of pale and darker blue cells with little cytoplasm outlined by a hyaline basement membrane (Figure). These cellular islands were arranged in a jigsawlike configuration. These findings were thought to be consistent with a diagnosis of cylindroma.

Well-circumscribed dermal islands of both pale and darker blue cells outlined by a hyaline basement membrane. These cellular islands were arranged in a jigsawlike configuration (A and B)(both H&E, original magnifications ×20 and ×200).

Cylindromas are benign appendageal neoplasms with a somewhat controversial histogenesis. Munger and colleagues¹ investigated the pattern of acid mucopolysaccharide secretion by these tumors in association with prosecretory vacuoles in proximity to the Golgi apparatus, which led to their impression that cylindromas most resemble eccrine rather than apocrine sweat glands. Other researchers, however, have concluded that cylindromas are of apocrine derivation.²

Clinically, cylindromas appear most often in 2 settings: isolated or as a manifestation of one of several inherited familial syndromes. One such syndrome is familial cylindromatosis, a rare autosomal-dominant disorder in which affected individuals develop multiple cylindromas, usually on the head and neck. The merging of multiple lesions gives rise to the often-employed term turban tumor.³ This syndrome has been linked to mutations in the cylindromatosis gene, CYLD.⁴ Brooke-Spiegler syndrome also has been associated with the development of multiple cylindromas. Similar to familial cylindromatosis, it is inherited in an autosomal-dominant fashion. Brooke-Spiegler syndrome is typified by the appearance of multiple cylindromas, trichoepitheliomas, and less commonly spiradenomas. Mutations in the CYLD gene also have been linked to Brooke-Spiegler syndrome in some cases.⁵

Although considered a benign entity, in rare cases cylindromas have shown evidence of malignant transformation to cylindrocarcinoma. This more aggressive tumor may occur in the setting of isolated cylindromas or more commonly in individuals with numerous lesions, as with both familial cylindromatosis and Brooke-Spiegler syndrome. These lesions may appear to grow rapidly, ulcerate, or bleed, traits that are not associated with their benign counterparts.

Diagnosis of cylindromas rests on histopathologic confirmation, which demonstrates well-defined dermal islands of epithelial cells comprised of dark- and pale-staining nuclei. These tumor islands are surrounded by a hyaline basement membrane and often take on the appearance of a jigsaw puzzle. Cylindrocarcinomas exhibit greater cellular pleomorphism and higher mitotic rates.

Dermal cylindromas require no further treatment but can be electively excised, while treatment of cylindrocarcinoma with excision is curative.⁶ Definitive excision was offered to our patient, but she declined treatment.

The Diagnosis: Dermal Cylindroma

Microsopic evaluation of a tangential biopsy revealed findings of a dermal process consisting of well-circumscribed islands of pale and darker blue cells with little cytoplasm outlined by a hyaline basement membrane (Figure). These cellular islands were arranged in a jigsawlike configuration. These findings were thought to be consistent with a diagnosis of cylindroma.

Well-circumscribed dermal islands of both pale and darker blue cells outlined by a hyaline basement membrane. These cellular islands were arranged in a jigsawlike configuration (A and B)(both H&E, original magnifications ×20 and ×200).

Cylindromas are benign appendageal neoplasms with a somewhat controversial histogenesis. Munger and colleagues¹ investigated the pattern of acid mucopolysaccharide secretion by these tumors in association with prosecretory vacuoles in proximity to the Golgi apparatus, which led to their impression that cylindromas most resemble eccrine rather than apocrine sweat glands. Other researchers, however, have concluded that cylindromas are of apocrine derivation.²

Clinically, cylindromas appear most often in 2 settings: isolated or as a manifestation of one of several inherited familial syndromes. One such syndrome is familial cylindromatosis, a rare autosomal-dominant disorder in which affected individuals develop multiple cylindromas, usually on the head and neck. The merging of multiple lesions gives rise to the often-employed term turban tumor.³ This syndrome has been linked to mutations in the cylindromatosis gene, CYLD.⁴ Brooke-Spiegler syndrome also has been associated with the development of multiple cylindromas. Similar to familial cylindromatosis, it is inherited in an autosomal-dominant fashion. Brooke-Spiegler syndrome is typified by the appearance of multiple cylindromas, trichoepitheliomas, and less commonly spiradenomas. Mutations in the CYLD gene also have been linked to Brooke-Spiegler syndrome in some cases.⁵

Although considered a benign entity, in rare cases cylindromas have shown evidence of malignant transformation to cylindrocarcinoma. This more aggressive tumor may occur in the setting of isolated cylindromas or more commonly in individuals with numerous lesions, as with both familial cylindromatosis and Brooke-Spiegler syndrome. These lesions may appear to grow rapidly, ulcerate, or bleed, traits that are not associated with their benign counterparts.

Diagnosis of cylindromas rests on histopathologic confirmation, which demonstrates well-defined dermal islands of epithelial cells comprised of dark- and pale-staining nuclei. These tumor islands are surrounded by a hyaline basement membrane and often take on the appearance of a jigsaw puzzle. Cylindrocarcinomas exhibit greater cellular pleomorphism and higher mitotic rates.

Dermal cylindromas require no further treatment but can be electively excised, while treatment of cylindrocarcinoma with excision is curative.⁶ Definitive excision was offered to our patient, but she declined treatment.

Angiolipomas are benign subcutaneous tumors that usually present on the arms, legs, and trunk in young men. Angiolipomas typically range in size from 1 to 4 cm in diameter, and multiple lesions often are present. Tenderness or mild pain may be elicited with palpation, particularly during the initial growth period. Grossly they appear as yellow, firm, circumscribed tumors. Histologic examination generally is characterized by mature adipose tissue with an admixture of capillaries that often contain fibrin thrombi.

Angiolipomas most often occur sporadically, but in a minority of cases a family history can be identified. Although the exact incidence of familial cases has not been identified in the literature, it is estimated to be 5% to 10%.¹ This rare condition has been classified as familial angiolipomatosis, which may be inherited in either an autosomal-recessive or autosomal-dominant fashion, the former being far more prevalent.² We report the case of a 31-year-old man with multiple angiolipomas who served as a proband for an evaluation of familial angiolipomatosis transmitted in an autosomal-dominant fashion among several male family members.

Case Report

A 31-year-old man presented with a history of fatty tumors on the bilateral upper extremities. The patient’s medical history was remarkable for allergy to dogs and cats, as confirmed by positive skin testing, which was treated with hydroxyzine and albuterol. Physical examination was unremarkable, except for the subcutaneous nodules on both arms and forearms. Laboratory results from a complete blood cell count and a comprehensive metabolic panel including total cholesterol, triglycerides, and high-density lipoproteins were all within reference range. A family history revealed that the patient’s brother, father, and 3 paternal uncles had a history of similar fatty tumors, as well as 2 of his paternal grandmother’s brothers (Figure 1). At the time of presentation, clinical examination revealed multiple tumors distributed on the upper and lower left arm as well as on the posterior and anterior aspect of the right forearm and upper arm. The patient did not report antecedent trauma to these areas.

Figure 1. An autosomal-dominant inheritance pattern of familial angiolipomatosis with 8 affected individuals. Arrow indicates the proband.

During surgical evaluation several months later, the subcutaneous nodules were preliminarily diagnosed by the surgeon as lipomas. Following surgical excision of all 5 lesions, gross examination revealed tan-yellow, circumscribed, soft-tissue nodules measuring 0.6 to 2.1 cm. Histologic examination revealed circumscribed nodules surrounded by a thin fibrous capsule. The lesions were composed of mature fat cells and benign vessels arranged in lobules of various sizes divided by fibrous septa. The vascular component ranged from 10% to approximately 50% of the lesion and was predominantly composed of capillary-sized vessels with scattered intraluminal fibrin thrombi (Figure 2). The histologic findings were considered a classic presentation of angiolipoma. Unfortunately, the patient was not able to provide pathology results pertaining to the lesions of his relatives, which he referred to as fatty tumors. At follow-up 13 months after excision, the patient developed new lesions and was planning to return for further excisions.

Comment

Figure 2. Histologic examination showed an encapsulated tumor composed of adipose tissue and a vascular component more prominent in the subcapsular areas (A)(H&E, original magnification ×20). Histopathology of the lesion also showed mature fat cells admixed with a vascular component (B)(H&E original magnification ×100) and scattered fibrin thrombi (C)(H&E, original magnification ×200).

Angiolipomas are benign mesenchymal neoplasms composed of adipose tissue and blood vessels. They usually present subcutaneously but have been documented in other areas including the spinal region in rare instances.³ The most common locations include the forearms, upper arms, and trunk.⁴ Our case demonstrates a classic presentation of angiolipomatosis manifesting as multiple subcutaneous nodules on the upper arms of a young man. Although lipomas were clinically suspected, histologic examination revealed that the lesions were in fact angiolipomas.

Angiolipomas account for approximately 17% of all fatty tumors and are characterized by mature adipose tissue with an admixture of capillaries that often contain fibrin thrombi.⁴ Histologic variants of angiolipomas including cellular angiolipomas and angiomyxolipomas rarely are encountered.^5-7 Cellular angiolipomas are composed almost entirely of small vessels (>95% of the lesion).^5,6 In addition to the classic presentation, cellular angiolipomas also have been documented in unusual locations. Kahng et al⁸ reported a 73-year-old woman with abnormal mammographic findings who was found to have a cellular angiolipoma of the breast. Cellular angiolipoma with lymph node involvement was reported in a 67-year-old man with adenocarcinoma of the prostate who underwent a radical retropubic prostatectomy.⁹ Due to their prominent vascular component, cellular angiolipomas must be differentiated from spindle cell lipomas, Kaposi sarcoma, and other vascular tumors. Kaposi sarcomas usually have slitlike vascular spaces, contain globules in the cytoplasm of some cells that are positive on periodic acid–Schiff staining, display immunoreactivity for human herpesvirus 8, and lack microthrombi. Angiomyxolipomas also are rare. This variant of angiolipomas contains mature adipose tissue, extensive myxoid stroma, and numerous blood vessels.⁷ The differential diagnosis for angiomyxolipomas includes myxoid liposarcomas and other adipocytic lesions (eg, myxolipomas, myxoid spindle cell lipomas).

Angiolipomas most often occur sporadically; however, family history has been identified in a minority of cases. This rare finding has been classified as familial angiolipomatosis (Online Mendelian Inheritance in Man [OMIM] 206550), which can be inherited in either anautosomal-recessive or very rarely in an autosomal-dominant fashion.² Our patient had numerous relatives with a history of similar lesions, which supported the diagnosis of familial angiolipomatosis in an autosomal-dominant inheritance pattern (Figure 1). Patients with autosomal-dominant familial angiolipomatosis also have been described to have other coincidental medical conditions, such as polycystic kidney disease.¹⁰

The clinical presentation of familial angiolipomatosis includes multiple subcutaneous tumors and a family history of similar lesions that are not associated with malignant transformation. Subcutaneous tumors and a family history with autosomal-dominant inheritance also can be seen in neurofibromatosis type I, which is associated with various benign and malignant neoplasms (eg, meningiomas, gliomas, pheochromocytomas). Therefore, in familial cases of multiple subcutaneous tumors transmitted in an autosomal-dominant pattern, histologic examination is essential to establish the correct diagnosis. Goodman and Baskin¹¹ reported a patient with familial angiolipomatosis who initially was suspected to have neurofibromatosis. The patient also had a granular cell tumor, which occasionally can be seen in neurofibromatosis.¹¹ Another diagnostic problem between familial angiolipomatosis and neurofibromatosis was described by Cina et al² who documented a case of familial angiolipomatosis with Lisch nodules, which are common in neurofibromatosis but rarely are seen in patients without this condition.¹² These reported parallels have prompted some investigators to suggest that similar pathogenetic mechanisms might be involved in both familial angiolipomatosis with an autosomal-dominant inheritance and neurofibromatosis type I.¹¹ Karyotyping performed on angiolipomas has failed to reveal reproducible cytogenetic abnormalities,¹³ with the exception of 1 report that documented a patient in which 1 of 5 angiolipomas had a t(X;2) abnormality.¹⁴ Conversely, ordinary lipomas are associated with numerous karyotypic abnormalities.¹⁴

Angiolipomas are benign tumors, but patients with large or disfiguring angiolipomas may choose to undergo surgical excision. For neoplasms that deeply extend between muscles, tendons, and joint capsules, subtotal excision may be required to restore regular function; however, local recurrence with muscular hypotrophy and deformation of the bones near the affected joints may occur.¹⁵

Conclusion

We present the case of a 31-year-old man with a rare form of familial angiolipomatosis characterized by an autosomal-dominant inheritance pattern. Our case emphasizes the need to obtain a detailed family history to determine the inheritance pattern in patients with multiple lesions of angiolipoma. Pathology review is essential to differentiate other diseases such as neurofibromatosis, which may present in a similar fashion. We encourage reports of further cases of familial angiolipomatosis to document the inheritance patterns.

Angiolipomas are benign subcutaneous tumors that usually present on the arms, legs, and trunk in young men. Angiolipomas typically range in size from 1 to 4 cm in diameter, and multiple lesions often are present. Tenderness or mild pain may be elicited with palpation, particularly during the initial growth period. Grossly they appear as yellow, firm, circumscribed tumors. Histologic examination generally is characterized by mature adipose tissue with an admixture of capillaries that often contain fibrin thrombi.

Angiolipomas most often occur sporadically, but in a minority of cases a family history can be identified. Although the exact incidence of familial cases has not been identified in the literature, it is estimated to be 5% to 10%.¹ This rare condition has been classified as familial angiolipomatosis, which may be inherited in either an autosomal-recessive or autosomal-dominant fashion, the former being far more prevalent.² We report the case of a 31-year-old man with multiple angiolipomas who served as a proband for an evaluation of familial angiolipomatosis transmitted in an autosomal-dominant fashion among several male family members.

Case Report

A 31-year-old man presented with a history of fatty tumors on the bilateral upper extremities. The patient’s medical history was remarkable for allergy to dogs and cats, as confirmed by positive skin testing, which was treated with hydroxyzine and albuterol. Physical examination was unremarkable, except for the subcutaneous nodules on both arms and forearms. Laboratory results from a complete blood cell count and a comprehensive metabolic panel including total cholesterol, triglycerides, and high-density lipoproteins were all within reference range. A family history revealed that the patient’s brother, father, and 3 paternal uncles had a history of similar fatty tumors, as well as 2 of his paternal grandmother’s brothers (Figure 1). At the time of presentation, clinical examination revealed multiple tumors distributed on the upper and lower left arm as well as on the posterior and anterior aspect of the right forearm and upper arm. The patient did not report antecedent trauma to these areas.

Figure 1. An autosomal-dominant inheritance pattern of familial angiolipomatosis with 8 affected individuals. Arrow indicates the proband.

During surgical evaluation several months later, the subcutaneous nodules were preliminarily diagnosed by the surgeon as lipomas. Following surgical excision of all 5 lesions, gross examination revealed tan-yellow, circumscribed, soft-tissue nodules measuring 0.6 to 2.1 cm. Histologic examination revealed circumscribed nodules surrounded by a thin fibrous capsule. The lesions were composed of mature fat cells and benign vessels arranged in lobules of various sizes divided by fibrous septa. The vascular component ranged from 10% to approximately 50% of the lesion and was predominantly composed of capillary-sized vessels with scattered intraluminal fibrin thrombi (Figure 2). The histologic findings were considered a classic presentation of angiolipoma. Unfortunately, the patient was not able to provide pathology results pertaining to the lesions of his relatives, which he referred to as fatty tumors. At follow-up 13 months after excision, the patient developed new lesions and was planning to return for further excisions.

Comment

Figure 2. Histologic examination showed an encapsulated tumor composed of adipose tissue and a vascular component more prominent in the subcapsular areas (A)(H&E, original magnification ×20). Histopathology of the lesion also showed mature fat cells admixed with a vascular component (B)(H&E original magnification ×100) and scattered fibrin thrombi (C)(H&E, original magnification ×200).

Angiolipomas are benign mesenchymal neoplasms composed of adipose tissue and blood vessels. They usually present subcutaneously but have been documented in other areas including the spinal region in rare instances.³ The most common locations include the forearms, upper arms, and trunk.⁴ Our case demonstrates a classic presentation of angiolipomatosis manifesting as multiple subcutaneous nodules on the upper arms of a young man. Although lipomas were clinically suspected, histologic examination revealed that the lesions were in fact angiolipomas.

Angiolipomas account for approximately 17% of all fatty tumors and are characterized by mature adipose tissue with an admixture of capillaries that often contain fibrin thrombi.⁴ Histologic variants of angiolipomas including cellular angiolipomas and angiomyxolipomas rarely are encountered.^5-7 Cellular angiolipomas are composed almost entirely of small vessels (>95% of the lesion).^5,6 In addition to the classic presentation, cellular angiolipomas also have been documented in unusual locations. Kahng et al⁸ reported a 73-year-old woman with abnormal mammographic findings who was found to have a cellular angiolipoma of the breast. Cellular angiolipoma with lymph node involvement was reported in a 67-year-old man with adenocarcinoma of the prostate who underwent a radical retropubic prostatectomy.⁹ Due to their prominent vascular component, cellular angiolipomas must be differentiated from spindle cell lipomas, Kaposi sarcoma, and other vascular tumors. Kaposi sarcomas usually have slitlike vascular spaces, contain globules in the cytoplasm of some cells that are positive on periodic acid–Schiff staining, display immunoreactivity for human herpesvirus 8, and lack microthrombi. Angiomyxolipomas also are rare. This variant of angiolipomas contains mature adipose tissue, extensive myxoid stroma, and numerous blood vessels.⁷ The differential diagnosis for angiomyxolipomas includes myxoid liposarcomas and other adipocytic lesions (eg, myxolipomas, myxoid spindle cell lipomas).

Angiolipomas most often occur sporadically; however, family history has been identified in a minority of cases. This rare finding has been classified as familial angiolipomatosis (Online Mendelian Inheritance in Man [OMIM] 206550), which can be inherited in either anautosomal-recessive or very rarely in an autosomal-dominant fashion.² Our patient had numerous relatives with a history of similar lesions, which supported the diagnosis of familial angiolipomatosis in an autosomal-dominant inheritance pattern (Figure 1). Patients with autosomal-dominant familial angiolipomatosis also have been described to have other coincidental medical conditions, such as polycystic kidney disease.¹⁰

The clinical presentation of familial angiolipomatosis includes multiple subcutaneous tumors and a family history of similar lesions that are not associated with malignant transformation. Subcutaneous tumors and a family history with autosomal-dominant inheritance also can be seen in neurofibromatosis type I, which is associated with various benign and malignant neoplasms (eg, meningiomas, gliomas, pheochromocytomas). Therefore, in familial cases of multiple subcutaneous tumors transmitted in an autosomal-dominant pattern, histologic examination is essential to establish the correct diagnosis. Goodman and Baskin¹¹ reported a patient with familial angiolipomatosis who initially was suspected to have neurofibromatosis. The patient also had a granular cell tumor, which occasionally can be seen in neurofibromatosis.¹¹ Another diagnostic problem between familial angiolipomatosis and neurofibromatosis was described by Cina et al² who documented a case of familial angiolipomatosis with Lisch nodules, which are common in neurofibromatosis but rarely are seen in patients without this condition.¹² These reported parallels have prompted some investigators to suggest that similar pathogenetic mechanisms might be involved in both familial angiolipomatosis with an autosomal-dominant inheritance and neurofibromatosis type I.¹¹ Karyotyping performed on angiolipomas has failed to reveal reproducible cytogenetic abnormalities,¹³ with the exception of 1 report that documented a patient in which 1 of 5 angiolipomas had a t(X;2) abnormality.¹⁴ Conversely, ordinary lipomas are associated with numerous karyotypic abnormalities.¹⁴

Angiolipomas are benign tumors, but patients with large or disfiguring angiolipomas may choose to undergo surgical excision. For neoplasms that deeply extend between muscles, tendons, and joint capsules, subtotal excision may be required to restore regular function; however, local recurrence with muscular hypotrophy and deformation of the bones near the affected joints may occur.¹⁵

Conclusion

We present the case of a 31-year-old man with a rare form of familial angiolipomatosis characterized by an autosomal-dominant inheritance pattern. Our case emphasizes the need to obtain a detailed family history to determine the inheritance pattern in patients with multiple lesions of angiolipoma. Pathology review is essential to differentiate other diseases such as neurofibromatosis, which may present in a similar fashion. We encourage reports of further cases of familial angiolipomatosis to document the inheritance patterns.

Angiolipomas are benign subcutaneous tumors that usually present on the arms, legs, and trunk in young men. Angiolipomas typically range in size from 1 to 4 cm in diameter, and multiple lesions often are present. Tenderness or mild pain may be elicited with palpation, particularly during the initial growth period. Grossly they appear as yellow, firm, circumscribed tumors. Histologic examination generally is characterized by mature adipose tissue with an admixture of capillaries that often contain fibrin thrombi.

Angiolipomas most often occur sporadically, but in a minority of cases a family history can be identified. Although the exact incidence of familial cases has not been identified in the literature, it is estimated to be 5% to 10%.¹ This rare condition has been classified as familial angiolipomatosis, which may be inherited in either an autosomal-recessive or autosomal-dominant fashion, the former being far more prevalent.² We report the case of a 31-year-old man with multiple angiolipomas who served as a proband for an evaluation of familial angiolipomatosis transmitted in an autosomal-dominant fashion among several male family members.

Case Report

A 31-year-old man presented with a history of fatty tumors on the bilateral upper extremities. The patient’s medical history was remarkable for allergy to dogs and cats, as confirmed by positive skin testing, which was treated with hydroxyzine and albuterol. Physical examination was unremarkable, except for the subcutaneous nodules on both arms and forearms. Laboratory results from a complete blood cell count and a comprehensive metabolic panel including total cholesterol, triglycerides, and high-density lipoproteins were all within reference range. A family history revealed that the patient’s brother, father, and 3 paternal uncles had a history of similar fatty tumors, as well as 2 of his paternal grandmother’s brothers (Figure 1). At the time of presentation, clinical examination revealed multiple tumors distributed on the upper and lower left arm as well as on the posterior and anterior aspect of the right forearm and upper arm. The patient did not report antecedent trauma to these areas.

Figure 1. An autosomal-dominant inheritance pattern of familial angiolipomatosis with 8 affected individuals. Arrow indicates the proband.

During surgical evaluation several months later, the subcutaneous nodules were preliminarily diagnosed by the surgeon as lipomas. Following surgical excision of all 5 lesions, gross examination revealed tan-yellow, circumscribed, soft-tissue nodules measuring 0.6 to 2.1 cm. Histologic examination revealed circumscribed nodules surrounded by a thin fibrous capsule. The lesions were composed of mature fat cells and benign vessels arranged in lobules of various sizes divided by fibrous septa. The vascular component ranged from 10% to approximately 50% of the lesion and was predominantly composed of capillary-sized vessels with scattered intraluminal fibrin thrombi (Figure 2). The histologic findings were considered a classic presentation of angiolipoma. Unfortunately, the patient was not able to provide pathology results pertaining to the lesions of his relatives, which he referred to as fatty tumors. At follow-up 13 months after excision, the patient developed new lesions and was planning to return for further excisions.

Comment

Figure 2. Histologic examination showed an encapsulated tumor composed of adipose tissue and a vascular component more prominent in the subcapsular areas (A)(H&E, original magnification ×20). Histopathology of the lesion also showed mature fat cells admixed with a vascular component (B)(H&E original magnification ×100) and scattered fibrin thrombi (C)(H&E, original magnification ×200).

Angiolipomas are benign mesenchymal neoplasms composed of adipose tissue and blood vessels. They usually present subcutaneously but have been documented in other areas including the spinal region in rare instances.³ The most common locations include the forearms, upper arms, and trunk.⁴ Our case demonstrates a classic presentation of angiolipomatosis manifesting as multiple subcutaneous nodules on the upper arms of a young man. Although lipomas were clinically suspected, histologic examination revealed that the lesions were in fact angiolipomas.

Angiolipomas account for approximately 17% of all fatty tumors and are characterized by mature adipose tissue with an admixture of capillaries that often contain fibrin thrombi.⁴ Histologic variants of angiolipomas including cellular angiolipomas and angiomyxolipomas rarely are encountered.^5-7 Cellular angiolipomas are composed almost entirely of small vessels (>95% of the lesion).^5,6 In addition to the classic presentation, cellular angiolipomas also have been documented in unusual locations. Kahng et al⁸ reported a 73-year-old woman with abnormal mammographic findings who was found to have a cellular angiolipoma of the breast. Cellular angiolipoma with lymph node involvement was reported in a 67-year-old man with adenocarcinoma of the prostate who underwent a radical retropubic prostatectomy.⁹ Due to their prominent vascular component, cellular angiolipomas must be differentiated from spindle cell lipomas, Kaposi sarcoma, and other vascular tumors. Kaposi sarcomas usually have slitlike vascular spaces, contain globules in the cytoplasm of some cells that are positive on periodic acid–Schiff staining, display immunoreactivity for human herpesvirus 8, and lack microthrombi. Angiomyxolipomas also are rare. This variant of angiolipomas contains mature adipose tissue, extensive myxoid stroma, and numerous blood vessels.⁷ The differential diagnosis for angiomyxolipomas includes myxoid liposarcomas and other adipocytic lesions (eg, myxolipomas, myxoid spindle cell lipomas).

Angiolipomas most often occur sporadically; however, family history has been identified in a minority of cases. This rare finding has been classified as familial angiolipomatosis (Online Mendelian Inheritance in Man [OMIM] 206550), which can be inherited in either anautosomal-recessive or very rarely in an autosomal-dominant fashion.² Our patient had numerous relatives with a history of similar lesions, which supported the diagnosis of familial angiolipomatosis in an autosomal-dominant inheritance pattern (Figure 1). Patients with autosomal-dominant familial angiolipomatosis also have been described to have other coincidental medical conditions, such as polycystic kidney disease.¹⁰

The clinical presentation of familial angiolipomatosis includes multiple subcutaneous tumors and a family history of similar lesions that are not associated with malignant transformation. Subcutaneous tumors and a family history with autosomal-dominant inheritance also can be seen in neurofibromatosis type I, which is associated with various benign and malignant neoplasms (eg, meningiomas, gliomas, pheochromocytomas). Therefore, in familial cases of multiple subcutaneous tumors transmitted in an autosomal-dominant pattern, histologic examination is essential to establish the correct diagnosis. Goodman and Baskin¹¹ reported a patient with familial angiolipomatosis who initially was suspected to have neurofibromatosis. The patient also had a granular cell tumor, which occasionally can be seen in neurofibromatosis.¹¹ Another diagnostic problem between familial angiolipomatosis and neurofibromatosis was described by Cina et al² who documented a case of familial angiolipomatosis with Lisch nodules, which are common in neurofibromatosis but rarely are seen in patients without this condition.¹² These reported parallels have prompted some investigators to suggest that similar pathogenetic mechanisms might be involved in both familial angiolipomatosis with an autosomal-dominant inheritance and neurofibromatosis type I.¹¹ Karyotyping performed on angiolipomas has failed to reveal reproducible cytogenetic abnormalities,¹³ with the exception of 1 report that documented a patient in which 1 of 5 angiolipomas had a t(X;2) abnormality.¹⁴ Conversely, ordinary lipomas are associated with numerous karyotypic abnormalities.¹⁴

Angiolipomas are benign tumors, but patients with large or disfiguring angiolipomas may choose to undergo surgical excision. For neoplasms that deeply extend between muscles, tendons, and joint capsules, subtotal excision may be required to restore regular function; however, local recurrence with muscular hypotrophy and deformation of the bones near the affected joints may occur.¹⁵

Conclusion

We present the case of a 31-year-old man with a rare form of familial angiolipomatosis characterized by an autosomal-dominant inheritance pattern. Our case emphasizes the need to obtain a detailed family history to determine the inheritance pattern in patients with multiple lesions of angiolipoma. Pathology review is essential to differentiate other diseases such as neurofibromatosis, which may present in a similar fashion. We encourage reports of further cases of familial angiolipomatosis to document the inheritance patterns.

The Diagnosis: Myeloid Leukemia Cutis

Leukemia cutis represents the infiltration of leukemic cells into the skin. It has been described in the setting of both myeloid and lymphoid leukemia. In the setting of acute myeloid leukemia, it has been reported to occur in 2% to 13% of patients overall,^1,2 but it may occur in 31% of patients with the acute myelomonocytic or acute monocytic leukemia subtypes.³ Leukemia cutis is less common, with chronic myeloid leukemia occurring in 2.7% of patients in one study.⁴ In another study, 65% of patients with myeloid leukemia cutis had an acute myeloid leukemia.⁵

Myeloid leukemia cutis has been reported in patients aged 22 days to 90 years, with a median age of 62 years. There is a male predominance (1.4:1 ratio).^5,6 The diagnosis of leukemia cutis is made concurrently with the diagnosis of leukemia in approximately 30% of cases, subsequent to the diagnosis of leukemia in approximately 60% of cases, and prior to the diagnosis of leukemia in approximately 10% of cases.⁵

Clinically, myeloid leukemia cutis presents as an asymptomatic solitary lesion in 23% of cases or as multiple lesions in 77% of cases. Lesions consist of pink to red to violaceous papules, nodules, and macules that are occasionally purpuric and involve any cutaneous surface.⁵

Histologically, the epidermis is unremarkable. Beneath a grenz zone within the dermis and usually extending into the subcutis there is a diffuse or nodular proliferation of neoplastic cells, often with perivascular and periadnexal accentuation and sometimes single filing of cells between collagen bundles (Figure 1). The cells are immature myeloid cells with irregular nuclear contours that may be indented or reniform (Figure 2). Nuclei contain finely dispersed chromatin with variably prominent nucleoli.^5,6 Immunohistochemically, CD68 is positive in approximately 97% of cases, myeloperoxidase in 62%, and lysozyme in 85%. CD168, CD14, CD4, CD33, CD117, CD34, CD56, CD123, and CD303 are variably positive. CD3 and CD20, markers of lymphoid leukemia, are negative.^5-8

Leukemia cutis in the setting of a myeloid leukemia portends a grave prognosis. In a series of 18 patients, 16 had additional extramedullary leukemia, including meningeal leukemia in 6 patients.² Most patients with myeloid leukemia cutis die within an average of 1 to 8 months of diagnosis.⁹

The Diagnosis: Myeloid Leukemia Cutis

Leukemia cutis represents the infiltration of leukemic cells into the skin. It has been described in the setting of both myeloid and lymphoid leukemia. In the setting of acute myeloid leukemia, it has been reported to occur in 2% to 13% of patients overall,^1,2 but it may occur in 31% of patients with the acute myelomonocytic or acute monocytic leukemia subtypes.³ Leukemia cutis is less common, with chronic myeloid leukemia occurring in 2.7% of patients in one study.⁴ In another study, 65% of patients with myeloid leukemia cutis had an acute myeloid leukemia.⁵

Myeloid leukemia cutis has been reported in patients aged 22 days to 90 years, with a median age of 62 years. There is a male predominance (1.4:1 ratio).^5,6 The diagnosis of leukemia cutis is made concurrently with the diagnosis of leukemia in approximately 30% of cases, subsequent to the diagnosis of leukemia in approximately 60% of cases, and prior to the diagnosis of leukemia in approximately 10% of cases.⁵

Clinically, myeloid leukemia cutis presents as an asymptomatic solitary lesion in 23% of cases or as multiple lesions in 77% of cases. Lesions consist of pink to red to violaceous papules, nodules, and macules that are occasionally purpuric and involve any cutaneous surface.⁵

Histologically, the epidermis is unremarkable. Beneath a grenz zone within the dermis and usually extending into the subcutis there is a diffuse or nodular proliferation of neoplastic cells, often with perivascular and periadnexal accentuation and sometimes single filing of cells between collagen bundles (Figure 1). The cells are immature myeloid cells with irregular nuclear contours that may be indented or reniform (Figure 2). Nuclei contain finely dispersed chromatin with variably prominent nucleoli.^5,6 Immunohistochemically, CD68 is positive in approximately 97% of cases, myeloperoxidase in 62%, and lysozyme in 85%. CD168, CD14, CD4, CD33, CD117, CD34, CD56, CD123, and CD303 are variably positive. CD3 and CD20, markers of lymphoid leukemia, are negative.^5-8

Leukemia cutis in the setting of a myeloid leukemia portends a grave prognosis. In a series of 18 patients, 16 had additional extramedullary leukemia, including meningeal leukemia in 6 patients.² Most patients with myeloid leukemia cutis die within an average of 1 to 8 months of diagnosis.⁹

The Diagnosis: Myeloid Leukemia Cutis

Leukemia cutis represents the infiltration of leukemic cells into the skin. It has been described in the setting of both myeloid and lymphoid leukemia. In the setting of acute myeloid leukemia, it has been reported to occur in 2% to 13% of patients overall,^1,2 but it may occur in 31% of patients with the acute myelomonocytic or acute monocytic leukemia subtypes.³ Leukemia cutis is less common, with chronic myeloid leukemia occurring in 2.7% of patients in one study.⁴ In another study, 65% of patients with myeloid leukemia cutis had an acute myeloid leukemia.⁵

Myeloid leukemia cutis has been reported in patients aged 22 days to 90 years, with a median age of 62 years. There is a male predominance (1.4:1 ratio).^5,6 The diagnosis of leukemia cutis is made concurrently with the diagnosis of leukemia in approximately 30% of cases, subsequent to the diagnosis of leukemia in approximately 60% of cases, and prior to the diagnosis of leukemia in approximately 10% of cases.⁵

Clinically, myeloid leukemia cutis presents as an asymptomatic solitary lesion in 23% of cases or as multiple lesions in 77% of cases. Lesions consist of pink to red to violaceous papules, nodules, and macules that are occasionally purpuric and involve any cutaneous surface.⁵

Histologically, the epidermis is unremarkable. Beneath a grenz zone within the dermis and usually extending into the subcutis there is a diffuse or nodular proliferation of neoplastic cells, often with perivascular and periadnexal accentuation and sometimes single filing of cells between collagen bundles (Figure 1). The cells are immature myeloid cells with irregular nuclear contours that may be indented or reniform (Figure 2). Nuclei contain finely dispersed chromatin with variably prominent nucleoli.^5,6 Immunohistochemically, CD68 is positive in approximately 97% of cases, myeloperoxidase in 62%, and lysozyme in 85%. CD168, CD14, CD4, CD33, CD117, CD34, CD56, CD123, and CD303 are variably positive. CD3 and CD20, markers of lymphoid leukemia, are negative.^5-8

Leukemia cutis in the setting of a myeloid leukemia portends a grave prognosis. In a series of 18 patients, 16 had additional extramedullary leukemia, including meningeal leukemia in 6 patients.² Most patients with myeloid leukemia cutis die within an average of 1 to 8 months of diagnosis.⁹

Dermatologists are fortunate to specialize in the organ that is most accessible to evaluation. Although we use the physical examination to formulate the initial differential diagnosis, at times we must rely on ancillary tests to narrow down the diagnosis. Various bedside testing modalities—potassium hydroxide (KOH) preparation, Tzanck smear, mineral oil preparation, and Gram stain—are most useful in diagnosing infectious causes of cutaneous disease. This guide serves as a useful reference for residents on how to perform these tests and which conditions they can help diagnose. Several of these procedures have no standard protocol for performing them; the literature is littered with various methodologies, fixatives, and stains, and as such, this article will attempt to describe a technique that is convenient and quick to perform with readily available materials while still offering high diagnostic utility.

KOH Preparation

A standard in the armamentarium of a dermatologist, the KOH preparation is invaluable to diagnose fungal and yeast infections. Although there are many available preparations including varying concentrations of KOH, dimethyl sulfoxide, and various inks, the procedure is similar for all of them.¹ The first step involves collecting the specimen, which can be scale from an active border of suspected cutaneous dermatophyte or Malassezia infection, debris from suspected candidiasis, or hair shafts plucked from an area of alopecia of presumed tinea capitis. A no. 15 blade can be used to scrape the specimen onto a microscope slide, though a second microscope slide can be used in lieu of a blade in patients who will not remain still, and then a coverslip is placed. Two drops of the KOH solution of your choice are then placed on opposite ends of the coverslip, allowing capillary action to spread the stain evenly. A paper towel can be folded in half and pushed down on the surface of the coverslip to spread the stain and soak up any excess, and this pressure also can help the KOH solution digest the keratin in the specimen. Briefly heating the underside of the slide (below boiling point) will help digest the keratin; this step is not necessary when you are using a KOH preparation with dimethyl sulfoxide. Although many dermatologists view the slide almost immediately, ideally at least 5 minutes should pass before it is read. Particularly thick specimens may require additional digestion time, so setting them aside for later review may help visualize infectious agents. In a busy clinic where an immediate diagnosis may not be requisite and a prescription can be called in pending the result, waiting to review the slide may be feasible.

Tzanck Smear

The Tzanck smear is a useful cytopathologic test in the rapid diagnosis of herpetic lesions, though it cannot differentiate between herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus. It also has shown utility for rapid diagnosis of protean other dermatologic conditions including autoimmune blistering disorders, cutaneous malignancies, and other infectious processes, though it has been superseded by histopathology in most cases.² An ideal sample is collected by scraping the base of a fresh blister with a no. 15 blade or a second microscope slide. The scrapings then are smeared onto another microscope slide and allowed to air-dry briefly. Then, Wright-Giemsa stain is dispensed to cover the sample and allowed to sit for 15 minutes before being washed off with sterile water. After air-drying, the sample is examined for the presence of clumped multinucleated giant cells, a feature that confirms herpetic infection and allows rapid initiation of antiviral medication.³

Mineral Oil Preparation

A mineral oil preparation has utility in diagnosing ectoparasitic infestation. In the case of scabies, a positive microscopic examination is diagnostic and requires no further testing, allowing for rapid initiation of therapy. This technique also is useful in diagnosing rosacea related to Demodex, which requires a treatment algorithm that differs from the classic papulopustular rosacea which it mimics.⁴

Mineral oil preparations can be rapidly performed and interpreted. Several drops of mineral oil are placed onto a microscope slide and a no. 15 blade is dipped into this oil prior to scraping the sample lesion. For scabies, a burrow is scraped repeatedly with the blade, and the debris is collected in the mineral oil. Occasionally, the mite can be dermoscopically visualized as a jet plane or arrowhead at the leading edge of a burrow; scraping should be focused in the vicinity of the mite.⁵ A coverslip is applied to the microscope slide and examination for the mite, egg casings, and scybala can be performed with microscopy.⁶ For Demodex infestation, a facial pustule can be expressed or several eyelash hairs can be plucked and suspended in mineral oil. Examination of this specimen is identical to scabies.

Gram Stain

The Gram stain is invaluable in classifying bacteria, and a properly performed test can narrow the identification of a causative organism based on cellular morphology. Although it is more technically complex than other bedside diagnostic maneuvers, it can be rapidly performed once the sequence of stains is mastered. The collected sample is smeared onto a glass slide and then briefly passed over a flame several times to heat-fix the specimen. Caution should be taken to avoid direct or prolonged flame contact with the underside of the slide. After fixation, the staining can be performed. First, crystal violet is instilled onto the slide and remains on for 30 seconds before being rinsed off with sink water. Then, Gram iodine is used for 30 seconds, followed by another rinse in water. Next, pour the decolorizer solution over the slide until the runoff is clear, and then rinse in water. Finally, flood with safranin counterstain for 30 seconds and give the slide a final rinse. After air-drying, it is ready to be interpreted.⁷

Final Thoughts

Although the modern dermatologist has access to biopsies, cultures, and sophisticated diagnostic techniques, it is important to remember these useful bedside tests. The ability to rapidly pin a diagnosis is particularly useful on the consultative service where critically ill patients can benefit from identification of a causative pathogen sooner rather than later. Residents should master these stains in their training, as this knowledge may prove to be invaluable in their careers.

Dermatologists are fortunate to specialize in the organ that is most accessible to evaluation. Although we use the physical examination to formulate the initial differential diagnosis, at times we must rely on ancillary tests to narrow down the diagnosis. Various bedside testing modalities—potassium hydroxide (KOH) preparation, Tzanck smear, mineral oil preparation, and Gram stain—are most useful in diagnosing infectious causes of cutaneous disease. This guide serves as a useful reference for residents on how to perform these tests and which conditions they can help diagnose. Several of these procedures have no standard protocol for performing them; the literature is littered with various methodologies, fixatives, and stains, and as such, this article will attempt to describe a technique that is convenient and quick to perform with readily available materials while still offering high diagnostic utility.

KOH Preparation

A standard in the armamentarium of a dermatologist, the KOH preparation is invaluable to diagnose fungal and yeast infections. Although there are many available preparations including varying concentrations of KOH, dimethyl sulfoxide, and various inks, the procedure is similar for all of them.¹ The first step involves collecting the specimen, which can be scale from an active border of suspected cutaneous dermatophyte or Malassezia infection, debris from suspected candidiasis, or hair shafts plucked from an area of alopecia of presumed tinea capitis. A no. 15 blade can be used to scrape the specimen onto a microscope slide, though a second microscope slide can be used in lieu of a blade in patients who will not remain still, and then a coverslip is placed. Two drops of the KOH solution of your choice are then placed on opposite ends of the coverslip, allowing capillary action to spread the stain evenly. A paper towel can be folded in half and pushed down on the surface of the coverslip to spread the stain and soak up any excess, and this pressure also can help the KOH solution digest the keratin in the specimen. Briefly heating the underside of the slide (below boiling point) will help digest the keratin; this step is not necessary when you are using a KOH preparation with dimethyl sulfoxide. Although many dermatologists view the slide almost immediately, ideally at least 5 minutes should pass before it is read. Particularly thick specimens may require additional digestion time, so setting them aside for later review may help visualize infectious agents. In a busy clinic where an immediate diagnosis may not be requisite and a prescription can be called in pending the result, waiting to review the slide may be feasible.

Tzanck Smear

The Tzanck smear is a useful cytopathologic test in the rapid diagnosis of herpetic lesions, though it cannot differentiate between herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus. It also has shown utility for rapid diagnosis of protean other dermatologic conditions including autoimmune blistering disorders, cutaneous malignancies, and other infectious processes, though it has been superseded by histopathology in most cases.² An ideal sample is collected by scraping the base of a fresh blister with a no. 15 blade or a second microscope slide. The scrapings then are smeared onto another microscope slide and allowed to air-dry briefly. Then, Wright-Giemsa stain is dispensed to cover the sample and allowed to sit for 15 minutes before being washed off with sterile water. After air-drying, the sample is examined for the presence of clumped multinucleated giant cells, a feature that confirms herpetic infection and allows rapid initiation of antiviral medication.³

Mineral Oil Preparation

A mineral oil preparation has utility in diagnosing ectoparasitic infestation. In the case of scabies, a positive microscopic examination is diagnostic and requires no further testing, allowing for rapid initiation of therapy. This technique also is useful in diagnosing rosacea related to Demodex, which requires a treatment algorithm that differs from the classic papulopustular rosacea which it mimics.⁴

Mineral oil preparations can be rapidly performed and interpreted. Several drops of mineral oil are placed onto a microscope slide and a no. 15 blade is dipped into this oil prior to scraping the sample lesion. For scabies, a burrow is scraped repeatedly with the blade, and the debris is collected in the mineral oil. Occasionally, the mite can be dermoscopically visualized as a jet plane or arrowhead at the leading edge of a burrow; scraping should be focused in the vicinity of the mite.⁵ A coverslip is applied to the microscope slide and examination for the mite, egg casings, and scybala can be performed with microscopy.⁶ For Demodex infestation, a facial pustule can be expressed or several eyelash hairs can be plucked and suspended in mineral oil. Examination of this specimen is identical to scabies.

Gram Stain

The Gram stain is invaluable in classifying bacteria, and a properly performed test can narrow the identification of a causative organism based on cellular morphology. Although it is more technically complex than other bedside diagnostic maneuvers, it can be rapidly performed once the sequence of stains is mastered. The collected sample is smeared onto a glass slide and then briefly passed over a flame several times to heat-fix the specimen. Caution should be taken to avoid direct or prolonged flame contact with the underside of the slide. After fixation, the staining can be performed. First, crystal violet is instilled onto the slide and remains on for 30 seconds before being rinsed off with sink water. Then, Gram iodine is used for 30 seconds, followed by another rinse in water. Next, pour the decolorizer solution over the slide until the runoff is clear, and then rinse in water. Finally, flood with safranin counterstain for 30 seconds and give the slide a final rinse. After air-drying, it is ready to be interpreted.⁷

Final Thoughts

Although the modern dermatologist has access to biopsies, cultures, and sophisticated diagnostic techniques, it is important to remember these useful bedside tests. The ability to rapidly pin a diagnosis is particularly useful on the consultative service where critically ill patients can benefit from identification of a causative pathogen sooner rather than later. Residents should master these stains in their training, as this knowledge may prove to be invaluable in their careers.

Dermatologists are fortunate to specialize in the organ that is most accessible to evaluation. Although we use the physical examination to formulate the initial differential diagnosis, at times we must rely on ancillary tests to narrow down the diagnosis. Various bedside testing modalities—potassium hydroxide (KOH) preparation, Tzanck smear, mineral oil preparation, and Gram stain—are most useful in diagnosing infectious causes of cutaneous disease. This guide serves as a useful reference for residents on how to perform these tests and which conditions they can help diagnose. Several of these procedures have no standard protocol for performing them; the literature is littered with various methodologies, fixatives, and stains, and as such, this article will attempt to describe a technique that is convenient and quick to perform with readily available materials while still offering high diagnostic utility.

KOH Preparation

A standard in the armamentarium of a dermatologist, the KOH preparation is invaluable to diagnose fungal and yeast infections. Although there are many available preparations including varying concentrations of KOH, dimethyl sulfoxide, and various inks, the procedure is similar for all of them.¹ The first step involves collecting the specimen, which can be scale from an active border of suspected cutaneous dermatophyte or Malassezia infection, debris from suspected candidiasis, or hair shafts plucked from an area of alopecia of presumed tinea capitis. A no. 15 blade can be used to scrape the specimen onto a microscope slide, though a second microscope slide can be used in lieu of a blade in patients who will not remain still, and then a coverslip is placed. Two drops of the KOH solution of your choice are then placed on opposite ends of the coverslip, allowing capillary action to spread the stain evenly. A paper towel can be folded in half and pushed down on the surface of the coverslip to spread the stain and soak up any excess, and this pressure also can help the KOH solution digest the keratin in the specimen. Briefly heating the underside of the slide (below boiling point) will help digest the keratin; this step is not necessary when you are using a KOH preparation with dimethyl sulfoxide. Although many dermatologists view the slide almost immediately, ideally at least 5 minutes should pass before it is read. Particularly thick specimens may require additional digestion time, so setting them aside for later review may help visualize infectious agents. In a busy clinic where an immediate diagnosis may not be requisite and a prescription can be called in pending the result, waiting to review the slide may be feasible.

Tzanck Smear

The Tzanck smear is a useful cytopathologic test in the rapid diagnosis of herpetic lesions, though it cannot differentiate between herpes simplex virus type 1, herpes simplex virus type 2, and varicella-zoster virus. It also has shown utility for rapid diagnosis of protean other dermatologic conditions including autoimmune blistering disorders, cutaneous malignancies, and other infectious processes, though it has been superseded by histopathology in most cases.² An ideal sample is collected by scraping the base of a fresh blister with a no. 15 blade or a second microscope slide. The scrapings then are smeared onto another microscope slide and allowed to air-dry briefly. Then, Wright-Giemsa stain is dispensed to cover the sample and allowed to sit for 15 minutes before being washed off with sterile water. After air-drying, the sample is examined for the presence of clumped multinucleated giant cells, a feature that confirms herpetic infection and allows rapid initiation of antiviral medication.³

Mineral Oil Preparation

A mineral oil preparation has utility in diagnosing ectoparasitic infestation. In the case of scabies, a positive microscopic examination is diagnostic and requires no further testing, allowing for rapid initiation of therapy. This technique also is useful in diagnosing rosacea related to Demodex, which requires a treatment algorithm that differs from the classic papulopustular rosacea which it mimics.⁴

Mineral oil preparations can be rapidly performed and interpreted. Several drops of mineral oil are placed onto a microscope slide and a no. 15 blade is dipped into this oil prior to scraping the sample lesion. For scabies, a burrow is scraped repeatedly with the blade, and the debris is collected in the mineral oil. Occasionally, the mite can be dermoscopically visualized as a jet plane or arrowhead at the leading edge of a burrow; scraping should be focused in the vicinity of the mite.⁵ A coverslip is applied to the microscope slide and examination for the mite, egg casings, and scybala can be performed with microscopy.⁶ For Demodex infestation, a facial pustule can be expressed or several eyelash hairs can be plucked and suspended in mineral oil. Examination of this specimen is identical to scabies.

Gram Stain

The Gram stain is invaluable in classifying bacteria, and a properly performed test can narrow the identification of a causative organism based on cellular morphology. Although it is more technically complex than other bedside diagnostic maneuvers, it can be rapidly performed once the sequence of stains is mastered. The collected sample is smeared onto a glass slide and then briefly passed over a flame several times to heat-fix the specimen. Caution should be taken to avoid direct or prolonged flame contact with the underside of the slide. After fixation, the staining can be performed. First, crystal violet is instilled onto the slide and remains on for 30 seconds before being rinsed off with sink water. Then, Gram iodine is used for 30 seconds, followed by another rinse in water. Next, pour the decolorizer solution over the slide until the runoff is clear, and then rinse in water. Finally, flood with safranin counterstain for 30 seconds and give the slide a final rinse. After air-drying, it is ready to be interpreted.⁷

Final Thoughts

Although the modern dermatologist has access to biopsies, cultures, and sophisticated diagnostic techniques, it is important to remember these useful bedside tests. The ability to rapidly pin a diagnosis is particularly useful on the consultative service where critically ill patients can benefit from identification of a causative pathogen sooner rather than later. Residents should master these stains in their training, as this knowledge may prove to be invaluable in their careers.

Extramammary Paget disease (EMPD) is an uncommon neoplasm that most commonly occurs in the anogenital region but can arise in any area of the skin or mucosa.¹ On clinical examination, EMPD typically presents as a sharply demarcated, erythematous, eczematoid, weeping lesion with varying degrees of induration; it rarely presents as a palpable mass or evenly raised nodule.² Microscopically, it may be accompanied by varying degrees of epidermal hyperplasia.¹ In particular, fibroepitheliomatous hyperplasia contains lacy strands of squamous epithelium resembling fibroepithelioma of Pinkus.³ We report a case of EMPD in a 90-year-old man who presented with a verrucous nodule in the pubic area that histologically demonstrated fibroepitheliomatous hyperplasia with lacy strands of squamous epithelium.

Case Report

A 90-year-old man presented with asymptomatic, well-demarcated, erythematous plaques in the pubic area of 5 years’ duration, along with a 3.0×2.5-cm nodule on the left side of the pubic area (Figure 1). Laboratory test results including a complete blood cell count, blood chemistry, and routine urinalysis were within reference range. Punch biopsies were taken from each plaque and nodule, as marked with arrows in Figure 1. Histopathologically, the plaques were seen to contain a number of large round cells with abundant pale cytoplasm and pleomorphic hyperchromatic nuclei that were present at various levels of the epidermis where they formed nests and clusters but did not extend into the dermis (Figures 2A and 2B). The nodule contained lacy strands of squamous epithelium extending from the epidermis to the mid dermis as well as many glandular structures (Figures 2C and 2D). The cells in the epidermis stained positively with periodic acid–Schiff (PAS), carcinoembryonic antigen (CEA), and cytokeratin 7 (Figure 2E). We also tested for S-100 protein to rule out malignant melanoma, which was negative.

Figure 1. Well-demarcated erythematous plaques (red arrow) in the pubic area and a 3.0×2.5-cm verrucous erythematous nodule (black arrow) on the left side of the pubic area.

Based on both the clinical and histological features, a diagnosis of EMPD with fibroepitheliomatous hyperplasia was made. It was recommended that the patient undergo further evaluation and treatment; he declined due to his financial situation and was subsequently lost to follow-up.

Comment

Clinically, EMPD usually presents as a patch of macular erythema, an erythematous eruption, or erythematous papules and plaques.⁴ The palpable nodule seen in our patient is not a common presentation of EMPD. Pruritus is the most common symptom of EMPD, occurring in 70% of patients.⁵ Other symptoms include burning, irritation, pain, tenderness, bleeding, and swelling. Ten percent of EMPD cases are asymptomatic.⁵

Histologically, Paget cells primarily involve the epidermis where they usually form clusters or solid nests. In more than 90% of EMPD cases, the Paget cells contain cytoplasmic mucin that stains positively with mucicarmine and PAS. Immunohistochemical staining for cytokeratin 7, gross cystic disease fluid protein-15, S-100 protein, and CEA sometimes may be needed to differentiate from mimickers such as Bowen disease and superficial spreading melanoma.⁶ In our patient, the tumor cells stained positive for cytokeratin 7, CEA, and PAS. Malignant melanoma was ruled out with a test for S-100 protein.

Figure 2. Scanning power view demonstrated a plaque containing Pagetcells at various levels of the epidermis (A)(H&E, original magnification ×40). The lesion contained a number of large round cells with abundant pale cytoplasm and pleomorphic hyperchromatic nuclei (B)(H&E, original magnification ×100). The nodule contained lacy strands of squamous epithelium on scanning power view (C)(H&E, original magnification ×40). Tumor cells with numerous glandular structures were observed (D)(H&E, original magnification ×100). Paget cells stained positive with cytokeratin 7 (E)(original magnification ×40).

Extramammary Paget disease often is associated with epidermal hyperplasia, which can be classified as squamous, papillomatous, or fibroepitheliomatous.³ Microscopically, squamous hyperplasia is characterized by prominent thickening of the epidermis from diffuse plaquelike hyperplasia and is usually associated with hyperkeratosis. Papillomatous hyperplasia has an exophytic papillary or verrucous architecture and is associated with parakeratosis. Fibroepitheliomatous, or fibroepitheliomalike, hyperplasia generally consists of a discrete, broad, elevated plaque or nodule produced by hyperplasia of keratinocytes that form lacy strands of squamous epithelium.³ The biphasic pattern of proliferating epidermis and entrapped dermis simulates a so-called fibroepithelioma. Paget cells can be seen within the lacy strands of epidermal columns and in the acanthotic surface component.² The finding of fibroepitheliomatous hyperplasia in anogenital skin should prompt a search for the diagnostic Paget cells to eliminate a fibroepithelioma of Pinkus variant of basal cell carcinoma, though the latter is uncommon and rarely occurs at this site.⁷

Of the 3 types of epidermal hyperplasia, our case demonstrated the fibroepitheliomatous type. There may be some relationship between EMPD and fibroepitheliomatous hyperplasia because most reported cases of EMPD with fibroepitheliomatous hyperplasia have occurred in the anogenital region. Also, epidermal hyperplasia is more frequent in anogenital Paget disease than in axillary Paget disease.⁸

Conclusion

Our case showed the unique finding of a verrucous nodular EMPD lesion in which peculiar histological features presented as extensions of the tumor cells forming lacy strands of squamous epithelium from the epidermis to the mid dermis as well as many glandular structures.

Extramammary Paget disease (EMPD) is an uncommon neoplasm that most commonly occurs in the anogenital region but can arise in any area of the skin or mucosa.¹ On clinical examination, EMPD typically presents as a sharply demarcated, erythematous, eczematoid, weeping lesion with varying degrees of induration; it rarely presents as a palpable mass or evenly raised nodule.² Microscopically, it may be accompanied by varying degrees of epidermal hyperplasia.¹ In particular, fibroepitheliomatous hyperplasia contains lacy strands of squamous epithelium resembling fibroepithelioma of Pinkus.³ We report a case of EMPD in a 90-year-old man who presented with a verrucous nodule in the pubic area that histologically demonstrated fibroepitheliomatous hyperplasia with lacy strands of squamous epithelium.

Case Report

A 90-year-old man presented with asymptomatic, well-demarcated, erythematous plaques in the pubic area of 5 years’ duration, along with a 3.0×2.5-cm nodule on the left side of the pubic area (Figure 1). Laboratory test results including a complete blood cell count, blood chemistry, and routine urinalysis were within reference range. Punch biopsies were taken from each plaque and nodule, as marked with arrows in Figure 1. Histopathologically, the plaques were seen to contain a number of large round cells with abundant pale cytoplasm and pleomorphic hyperchromatic nuclei that were present at various levels of the epidermis where they formed nests and clusters but did not extend into the dermis (Figures 2A and 2B). The nodule contained lacy strands of squamous epithelium extending from the epidermis to the mid dermis as well as many glandular structures (Figures 2C and 2D). The cells in the epidermis stained positively with periodic acid–Schiff (PAS), carcinoembryonic antigen (CEA), and cytokeratin 7 (Figure 2E). We also tested for S-100 protein to rule out malignant melanoma, which was negative.

Figure 1. Well-demarcated erythematous plaques (red arrow) in the pubic area and a 3.0×2.5-cm verrucous erythematous nodule (black arrow) on the left side of the pubic area.

Based on both the clinical and histological features, a diagnosis of EMPD with fibroepitheliomatous hyperplasia was made. It was recommended that the patient undergo further evaluation and treatment; he declined due to his financial situation and was subsequently lost to follow-up.

Comment

Clinically, EMPD usually presents as a patch of macular erythema, an erythematous eruption, or erythematous papules and plaques.⁴ The palpable nodule seen in our patient is not a common presentation of EMPD. Pruritus is the most common symptom of EMPD, occurring in 70% of patients.⁵ Other symptoms include burning, irritation, pain, tenderness, bleeding, and swelling. Ten percent of EMPD cases are asymptomatic.⁵

Histologically, Paget cells primarily involve the epidermis where they usually form clusters or solid nests. In more than 90% of EMPD cases, the Paget cells contain cytoplasmic mucin that stains positively with mucicarmine and PAS. Immunohistochemical staining for cytokeratin 7, gross cystic disease fluid protein-15, S-100 protein, and CEA sometimes may be needed to differentiate from mimickers such as Bowen disease and superficial spreading melanoma.⁶ In our patient, the tumor cells stained positive for cytokeratin 7, CEA, and PAS. Malignant melanoma was ruled out with a test for S-100 protein.

Figure 2. Scanning power view demonstrated a plaque containing Pagetcells at various levels of the epidermis (A)(H&E, original magnification ×40). The lesion contained a number of large round cells with abundant pale cytoplasm and pleomorphic hyperchromatic nuclei (B)(H&E, original magnification ×100). The nodule contained lacy strands of squamous epithelium on scanning power view (C)(H&E, original magnification ×40). Tumor cells with numerous glandular structures were observed (D)(H&E, original magnification ×100). Paget cells stained positive with cytokeratin 7 (E)(original magnification ×40).

Extramammary Paget disease often is associated with epidermal hyperplasia, which can be classified as squamous, papillomatous, or fibroepitheliomatous.³ Microscopically, squamous hyperplasia is characterized by prominent thickening of the epidermis from diffuse plaquelike hyperplasia and is usually associated with hyperkeratosis. Papillomatous hyperplasia has an exophytic papillary or verrucous architecture and is associated with parakeratosis. Fibroepitheliomatous, or fibroepitheliomalike, hyperplasia generally consists of a discrete, broad, elevated plaque or nodule produced by hyperplasia of keratinocytes that form lacy strands of squamous epithelium.³ The biphasic pattern of proliferating epidermis and entrapped dermis simulates a so-called fibroepithelioma. Paget cells can be seen within the lacy strands of epidermal columns and in the acanthotic surface component.² The finding of fibroepitheliomatous hyperplasia in anogenital skin should prompt a search for the diagnostic Paget cells to eliminate a fibroepithelioma of Pinkus variant of basal cell carcinoma, though the latter is uncommon and rarely occurs at this site.⁷

Of the 3 types of epidermal hyperplasia, our case demonstrated the fibroepitheliomatous type. There may be some relationship between EMPD and fibroepitheliomatous hyperplasia because most reported cases of EMPD with fibroepitheliomatous hyperplasia have occurred in the anogenital region. Also, epidermal hyperplasia is more frequent in anogenital Paget disease than in axillary Paget disease.⁸

Conclusion

Our case showed the unique finding of a verrucous nodular EMPD lesion in which peculiar histological features presented as extensions of the tumor cells forming lacy strands of squamous epithelium from the epidermis to the mid dermis as well as many glandular structures.

Extramammary Paget disease (EMPD) is an uncommon neoplasm that most commonly occurs in the anogenital region but can arise in any area of the skin or mucosa.¹ On clinical examination, EMPD typically presents as a sharply demarcated, erythematous, eczematoid, weeping lesion with varying degrees of induration; it rarely presents as a palpable mass or evenly raised nodule.² Microscopically, it may be accompanied by varying degrees of epidermal hyperplasia.¹ In particular, fibroepitheliomatous hyperplasia contains lacy strands of squamous epithelium resembling fibroepithelioma of Pinkus.³ We report a case of EMPD in a 90-year-old man who presented with a verrucous nodule in the pubic area that histologically demonstrated fibroepitheliomatous hyperplasia with lacy strands of squamous epithelium.

Case Report

A 90-year-old man presented with asymptomatic, well-demarcated, erythematous plaques in the pubic area of 5 years’ duration, along with a 3.0×2.5-cm nodule on the left side of the pubic area (Figure 1). Laboratory test results including a complete blood cell count, blood chemistry, and routine urinalysis were within reference range. Punch biopsies were taken from each plaque and nodule, as marked with arrows in Figure 1. Histopathologically, the plaques were seen to contain a number of large round cells with abundant pale cytoplasm and pleomorphic hyperchromatic nuclei that were present at various levels of the epidermis where they formed nests and clusters but did not extend into the dermis (Figures 2A and 2B). The nodule contained lacy strands of squamous epithelium extending from the epidermis to the mid dermis as well as many glandular structures (Figures 2C and 2D). The cells in the epidermis stained positively with periodic acid–Schiff (PAS), carcinoembryonic antigen (CEA), and cytokeratin 7 (Figure 2E). We also tested for S-100 protein to rule out malignant melanoma, which was negative.

Figure 1. Well-demarcated erythematous plaques (red arrow) in the pubic area and a 3.0×2.5-cm verrucous erythematous nodule (black arrow) on the left side of the pubic area.

Based on both the clinical and histological features, a diagnosis of EMPD with fibroepitheliomatous hyperplasia was made. It was recommended that the patient undergo further evaluation and treatment; he declined due to his financial situation and was subsequently lost to follow-up.

Comment

Clinically, EMPD usually presents as a patch of macular erythema, an erythematous eruption, or erythematous papules and plaques.⁴ The palpable nodule seen in our patient is not a common presentation of EMPD. Pruritus is the most common symptom of EMPD, occurring in 70% of patients.⁵ Other symptoms include burning, irritation, pain, tenderness, bleeding, and swelling. Ten percent of EMPD cases are asymptomatic.⁵

Histologically, Paget cells primarily involve the epidermis where they usually form clusters or solid nests. In more than 90% of EMPD cases, the Paget cells contain cytoplasmic mucin that stains positively with mucicarmine and PAS. Immunohistochemical staining for cytokeratin 7, gross cystic disease fluid protein-15, S-100 protein, and CEA sometimes may be needed to differentiate from mimickers such as Bowen disease and superficial spreading melanoma.⁶ In our patient, the tumor cells stained positive for cytokeratin 7, CEA, and PAS. Malignant melanoma was ruled out with a test for S-100 protein.

Figure 2. Scanning power view demonstrated a plaque containing Pagetcells at various levels of the epidermis (A)(H&E, original magnification ×40). The lesion contained a number of large round cells with abundant pale cytoplasm and pleomorphic hyperchromatic nuclei (B)(H&E, original magnification ×100). The nodule contained lacy strands of squamous epithelium on scanning power view (C)(H&E, original magnification ×40). Tumor cells with numerous glandular structures were observed (D)(H&E, original magnification ×100). Paget cells stained positive with cytokeratin 7 (E)(original magnification ×40).

Extramammary Paget disease often is associated with epidermal hyperplasia, which can be classified as squamous, papillomatous, or fibroepitheliomatous.³ Microscopically, squamous hyperplasia is characterized by prominent thickening of the epidermis from diffuse plaquelike hyperplasia and is usually associated with hyperkeratosis. Papillomatous hyperplasia has an exophytic papillary or verrucous architecture and is associated with parakeratosis. Fibroepitheliomatous, or fibroepitheliomalike, hyperplasia generally consists of a discrete, broad, elevated plaque or nodule produced by hyperplasia of keratinocytes that form lacy strands of squamous epithelium.³ The biphasic pattern of proliferating epidermis and entrapped dermis simulates a so-called fibroepithelioma. Paget cells can be seen within the lacy strands of epidermal columns and in the acanthotic surface component.² The finding of fibroepitheliomatous hyperplasia in anogenital skin should prompt a search for the diagnostic Paget cells to eliminate a fibroepithelioma of Pinkus variant of basal cell carcinoma, though the latter is uncommon and rarely occurs at this site.⁷

Of the 3 types of epidermal hyperplasia, our case demonstrated the fibroepitheliomatous type. There may be some relationship between EMPD and fibroepitheliomatous hyperplasia because most reported cases of EMPD with fibroepitheliomatous hyperplasia have occurred in the anogenital region. Also, epidermal hyperplasia is more frequent in anogenital Paget disease than in axillary Paget disease.⁸

Conclusion

Our case showed the unique finding of a verrucous nodular EMPD lesion in which peculiar histological features presented as extensions of the tumor cells forming lacy strands of squamous epithelium from the epidermis to the mid dermis as well as many glandular structures.