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The Diagnosis: Flagellate Hyperpigmentation

Physical examination of our patient revealed multiple linear, flagellate, and hyperpigmented plaques on the trunk. Similar lesions were seen on the upper and lower extremities. Given the patient's history of non-Hodgkin lymphoma and concurrent chemotherapy, the use of systemic steroids was avoided. Notable improvement in the symptoms was achieved with topical steroids (triamcinolone acetonide ointment) under occlusion and systemic gabapentin. The patient's chemotherapy is ongoing. This characteristic skin eruption often is seen after treatment with systemic bleomycin sulfate.

Flagellate hyperpigmentation following systemic bleomycin sulfate use as a chemotherapeutic agent is a well-known cutaneous reaction that occurs in approximately 10% of exposed individuals.¹ Bleomycin sul­fate, an antibiotic derived from Streptomyces verticillus, is a commonly used antitumor agent for both hema­tologic and solid-organ malignancies.² Many patients develop generalized pruritus within several days after initiating bleomycin sulfate, followed by the charac­teristic linear and hyperpigmented streaks. The exact mechanism of this characteristic rash is unknown. Suggested pathways include induction of neutrophilic eccrine hidradenitis, postinflammatory pigmentary incontinence, and altered levels of melanin due to a toxic effect of the medication. Other commonly re­ported adverse events to bleomycin sulfate include alopecia and stomatitis.³

Although a diffuse rash is the most commonly reported cutaneous reaction to systemic bleomycin sulfate, there have been reports of hyperpigmenta­tion only in areas of pressure and palmar creases. Tsuji and Sawabe⁴ reported a case of hyperpigmenta­tion limited to areas of striae distensae after systemic bleomycin sulfate. Flagellate hyperpigmentation also has been reported following intralesional bleomycin sulfate for the treatment of verruca plantaris. In that case, the patient had received 14 U of intralesional bleomycin sulfate injected at different sites of recal­citrant verruca and developed urticaria, generalized pruritus, and flagellate hyperpigmentation.⁵

Treatment of flagellate hyperpigmentation in­cludes cessation of the medication, which is not always possible due to the need for an effective che­motherapeutic regimen. Most cases are reversible following discontinuation of bleomycin sulfate, and care is directed at symptom relief with antipruritic agents, antihistamines, systemic steroids, or topical steroids.³

The Diagnosis: Flagellate Hyperpigmentation

Physical examination of our patient revealed multiple linear, flagellate, and hyperpigmented plaques on the trunk. Similar lesions were seen on the upper and lower extremities. Given the patient's history of non-Hodgkin lymphoma and concurrent chemotherapy, the use of systemic steroids was avoided. Notable improvement in the symptoms was achieved with topical steroids (triamcinolone acetonide ointment) under occlusion and systemic gabapentin. The patient's chemotherapy is ongoing. This characteristic skin eruption often is seen after treatment with systemic bleomycin sulfate.

Flagellate hyperpigmentation following systemic bleomycin sulfate use as a chemotherapeutic agent is a well-known cutaneous reaction that occurs in approximately 10% of exposed individuals.¹ Bleomycin sul­fate, an antibiotic derived from Streptomyces verticillus, is a commonly used antitumor agent for both hema­tologic and solid-organ malignancies.² Many patients develop generalized pruritus within several days after initiating bleomycin sulfate, followed by the charac­teristic linear and hyperpigmented streaks. The exact mechanism of this characteristic rash is unknown. Suggested pathways include induction of neutrophilic eccrine hidradenitis, postinflammatory pigmentary incontinence, and altered levels of melanin due to a toxic effect of the medication. Other commonly re­ported adverse events to bleomycin sulfate include alopecia and stomatitis.³

Although a diffuse rash is the most commonly reported cutaneous reaction to systemic bleomycin sulfate, there have been reports of hyperpigmenta­tion only in areas of pressure and palmar creases. Tsuji and Sawabe⁴ reported a case of hyperpigmenta­tion limited to areas of striae distensae after systemic bleomycin sulfate. Flagellate hyperpigmentation also has been reported following intralesional bleomycin sulfate for the treatment of verruca plantaris. In that case, the patient had received 14 U of intralesional bleomycin sulfate injected at different sites of recal­citrant verruca and developed urticaria, generalized pruritus, and flagellate hyperpigmentation.⁵

Treatment of flagellate hyperpigmentation in­cludes cessation of the medication, which is not always possible due to the need for an effective che­motherapeutic regimen. Most cases are reversible following discontinuation of bleomycin sulfate, and care is directed at symptom relief with antipruritic agents, antihistamines, systemic steroids, or topical steroids.³

The Diagnosis: Flagellate Hyperpigmentation

Physical examination of our patient revealed multiple linear, flagellate, and hyperpigmented plaques on the trunk. Similar lesions were seen on the upper and lower extremities. Given the patient's history of non-Hodgkin lymphoma and concurrent chemotherapy, the use of systemic steroids was avoided. Notable improvement in the symptoms was achieved with topical steroids (triamcinolone acetonide ointment) under occlusion and systemic gabapentin. The patient's chemotherapy is ongoing. This characteristic skin eruption often is seen after treatment with systemic bleomycin sulfate.

Flagellate hyperpigmentation following systemic bleomycin sulfate use as a chemotherapeutic agent is a well-known cutaneous reaction that occurs in approximately 10% of exposed individuals.¹ Bleomycin sul­fate, an antibiotic derived from Streptomyces verticillus, is a commonly used antitumor agent for both hema­tologic and solid-organ malignancies.² Many patients develop generalized pruritus within several days after initiating bleomycin sulfate, followed by the charac­teristic linear and hyperpigmented streaks. The exact mechanism of this characteristic rash is unknown. Suggested pathways include induction of neutrophilic eccrine hidradenitis, postinflammatory pigmentary incontinence, and altered levels of melanin due to a toxic effect of the medication. Other commonly re­ported adverse events to bleomycin sulfate include alopecia and stomatitis.³

Although a diffuse rash is the most commonly reported cutaneous reaction to systemic bleomycin sulfate, there have been reports of hyperpigmenta­tion only in areas of pressure and palmar creases. Tsuji and Sawabe⁴ reported a case of hyperpigmenta­tion limited to areas of striae distensae after systemic bleomycin sulfate. Flagellate hyperpigmentation also has been reported following intralesional bleomycin sulfate for the treatment of verruca plantaris. In that case, the patient had received 14 U of intralesional bleomycin sulfate injected at different sites of recal­citrant verruca and developed urticaria, generalized pruritus, and flagellate hyperpigmentation.⁵

Treatment of flagellate hyperpigmentation in­cludes cessation of the medication, which is not always possible due to the need for an effective che­motherapeutic regimen. Most cases are reversible following discontinuation of bleomycin sulfate, and care is directed at symptom relief with antipruritic agents, antihistamines, systemic steroids, or topical steroids.³

The Diagnosis: Recurrent Pyogenic Granuloma With Satellite Papules

Pyogenic granulomas, also known as lobular capil­lary hemangiomas, are common benign, friable, rapidly growing, erythematous and exophytic papules with a surrounding collarette of scale. Due to the friable nature of these lesions, they are often hemorrhagic and ulcerative on presentation; how­ever, disseminated pyogenic granulomas frequently are more sessile in appearance with a smooth surface. The pathogenesis of these lesions is largely unknown, but they exhibit a number of clinical features sugges­tive of reactive neovascularization.¹

Primary pyogenic granulomas occur most often on sites with high vascularity (eg, gingiva, lips, fingers, face, tongue), but no site on the skin is exempt.^2,3 They are found most commonly in children and young adults after minor trauma and also are associated with preg­nancy with a higher frequency of occurrence on the gingiva in that particular setting.²

The differential diagnosis of pyogenic granuloma includes warts or inflamed intradermal nevi as well as bacillary angiomatosis and Kaposi sarcoma in an immunosuppressed patient. Most importantly, pyogenic granulomas can be confused with amelanotic mela­noma; therefore, biopsy to rule out this condition is mandatory. On histopathology, pyogenic granuloma is characterized by a proliferation of capillaries arranged in a lobular pattern separated by a pale stroma (Figure).

The epidermis showed focal thinning. Within the dermis was a lobular proliferation of new blood vessel formation along vascular spaces lined by endothelial and perithelial cells. No cytologic atypia was noted (H&E, original magnification ×25).

Pyogenic granulomas usually are solitary lesions; however, recurrence after treatment is common. These benign growths have been reported to arise from certain systemic agents including epidermal growth factor receptor inhibitors, systemic retinoids, and indinavir.¹ Disseminated pyogenic granulomas are rare, but cases in children and adults have been reported, many associated with prior trauma. In ad­dition, congenital disseminated pyogenic granulomas have been described, which could be easily confused with infantile hemangiomatosis; however, the former are GLUT-1 (glucose transporter type 1) negative.⁴

Although recurrence of pyogenic granulomas is common, recurrence with satellite lesions is relatively rare. In documented cases, such as the Blickenstaff et al² report, recurrences occurred most commonly on the trunk, especially in the scapular area in adoles­cents and young adults. They often occur after prior irritation or treatment of the primary lesion but also may spontaneously develop. After initial therapy, sat­ellites may arise either with or without recurrence of the primary lesion. These satellite lesions usually are smaller than the original lesion, smooth, bright red, are not as friable, and lack a collarette.^2,3

Recurrence of pyogenic granulomas with satellite lesions has been reported to occur in association with almost all forms of treatment, including excision with cautery and CO₂ laser. These recurrences have been successfully treated with simple excision, cryotherapy, diathermy, and curettage; however, some physicians recommend a conservative approach to therapy, as a majority of these lesions tend to spontaneously resolve after 6 to 12 months.^2,3,5

Ezzell et al⁶ and others have reported successful treatment of pyogenic granulomas with imiquimod cream 5%. Imiquimod is thought to trigger resolution of pyogenic granulomas due to its antitumor and im­munoregulatory effects. As a topical agent, imiquimod would offer patients a safe and noninvasive therapy that would be especially beneficial for larger lesions with satellites, similar to the papules described in our patient.^6,7

After a repeat biopsy in our patient confirmed pyo­genic granuloma, she was started on imiquimod cream 5% applied nightly, which continued for 6 weeks. Follow-up after 6 weeks revealed no change in lesion size and the family opted to discontinue treatment at that time because of a lack of response. Although a continued conservative approach was recommended by our facility, the patient and guardians opted for surgical excision and were referred to a local pediatric surgeon for excision under general anesthesia.

The Diagnosis: Recurrent Pyogenic Granuloma With Satellite Papules

Pyogenic granulomas, also known as lobular capil­lary hemangiomas, are common benign, friable, rapidly growing, erythematous and exophytic papules with a surrounding collarette of scale. Due to the friable nature of these lesions, they are often hemorrhagic and ulcerative on presentation; how­ever, disseminated pyogenic granulomas frequently are more sessile in appearance with a smooth surface. The pathogenesis of these lesions is largely unknown, but they exhibit a number of clinical features sugges­tive of reactive neovascularization.¹

Primary pyogenic granulomas occur most often on sites with high vascularity (eg, gingiva, lips, fingers, face, tongue), but no site on the skin is exempt.^2,3 They are found most commonly in children and young adults after minor trauma and also are associated with preg­nancy with a higher frequency of occurrence on the gingiva in that particular setting.²

The differential diagnosis of pyogenic granuloma includes warts or inflamed intradermal nevi as well as bacillary angiomatosis and Kaposi sarcoma in an immunosuppressed patient. Most importantly, pyogenic granulomas can be confused with amelanotic mela­noma; therefore, biopsy to rule out this condition is mandatory. On histopathology, pyogenic granuloma is characterized by a proliferation of capillaries arranged in a lobular pattern separated by a pale stroma (Figure).

The epidermis showed focal thinning. Within the dermis was a lobular proliferation of new blood vessel formation along vascular spaces lined by endothelial and perithelial cells. No cytologic atypia was noted (H&E, original magnification ×25).

Pyogenic granulomas usually are solitary lesions; however, recurrence after treatment is common. These benign growths have been reported to arise from certain systemic agents including epidermal growth factor receptor inhibitors, systemic retinoids, and indinavir.¹ Disseminated pyogenic granulomas are rare, but cases in children and adults have been reported, many associated with prior trauma. In ad­dition, congenital disseminated pyogenic granulomas have been described, which could be easily confused with infantile hemangiomatosis; however, the former are GLUT-1 (glucose transporter type 1) negative.⁴

Although recurrence of pyogenic granulomas is common, recurrence with satellite lesions is relatively rare. In documented cases, such as the Blickenstaff et al² report, recurrences occurred most commonly on the trunk, especially in the scapular area in adoles­cents and young adults. They often occur after prior irritation or treatment of the primary lesion but also may spontaneously develop. After initial therapy, sat­ellites may arise either with or without recurrence of the primary lesion. These satellite lesions usually are smaller than the original lesion, smooth, bright red, are not as friable, and lack a collarette.^2,3

Recurrence of pyogenic granulomas with satellite lesions has been reported to occur in association with almost all forms of treatment, including excision with cautery and CO₂ laser. These recurrences have been successfully treated with simple excision, cryotherapy, diathermy, and curettage; however, some physicians recommend a conservative approach to therapy, as a majority of these lesions tend to spontaneously resolve after 6 to 12 months.^2,3,5

Ezzell et al⁶ and others have reported successful treatment of pyogenic granulomas with imiquimod cream 5%. Imiquimod is thought to trigger resolution of pyogenic granulomas due to its antitumor and im­munoregulatory effects. As a topical agent, imiquimod would offer patients a safe and noninvasive therapy that would be especially beneficial for larger lesions with satellites, similar to the papules described in our patient.^6,7

After a repeat biopsy in our patient confirmed pyo­genic granuloma, she was started on imiquimod cream 5% applied nightly, which continued for 6 weeks. Follow-up after 6 weeks revealed no change in lesion size and the family opted to discontinue treatment at that time because of a lack of response. Although a continued conservative approach was recommended by our facility, the patient and guardians opted for surgical excision and were referred to a local pediatric surgeon for excision under general anesthesia.

The Diagnosis: Recurrent Pyogenic Granuloma With Satellite Papules

Pyogenic granulomas, also known as lobular capil­lary hemangiomas, are common benign, friable, rapidly growing, erythematous and exophytic papules with a surrounding collarette of scale. Due to the friable nature of these lesions, they are often hemorrhagic and ulcerative on presentation; how­ever, disseminated pyogenic granulomas frequently are more sessile in appearance with a smooth surface. The pathogenesis of these lesions is largely unknown, but they exhibit a number of clinical features sugges­tive of reactive neovascularization.¹

Primary pyogenic granulomas occur most often on sites with high vascularity (eg, gingiva, lips, fingers, face, tongue), but no site on the skin is exempt.^2,3 They are found most commonly in children and young adults after minor trauma and also are associated with preg­nancy with a higher frequency of occurrence on the gingiva in that particular setting.²

The differential diagnosis of pyogenic granuloma includes warts or inflamed intradermal nevi as well as bacillary angiomatosis and Kaposi sarcoma in an immunosuppressed patient. Most importantly, pyogenic granulomas can be confused with amelanotic mela­noma; therefore, biopsy to rule out this condition is mandatory. On histopathology, pyogenic granuloma is characterized by a proliferation of capillaries arranged in a lobular pattern separated by a pale stroma (Figure).

The epidermis showed focal thinning. Within the dermis was a lobular proliferation of new blood vessel formation along vascular spaces lined by endothelial and perithelial cells. No cytologic atypia was noted (H&E, original magnification ×25).

Pyogenic granulomas usually are solitary lesions; however, recurrence after treatment is common. These benign growths have been reported to arise from certain systemic agents including epidermal growth factor receptor inhibitors, systemic retinoids, and indinavir.¹ Disseminated pyogenic granulomas are rare, but cases in children and adults have been reported, many associated with prior trauma. In ad­dition, congenital disseminated pyogenic granulomas have been described, which could be easily confused with infantile hemangiomatosis; however, the former are GLUT-1 (glucose transporter type 1) negative.⁴

Although recurrence of pyogenic granulomas is common, recurrence with satellite lesions is relatively rare. In documented cases, such as the Blickenstaff et al² report, recurrences occurred most commonly on the trunk, especially in the scapular area in adoles­cents and young adults. They often occur after prior irritation or treatment of the primary lesion but also may spontaneously develop. After initial therapy, sat­ellites may arise either with or without recurrence of the primary lesion. These satellite lesions usually are smaller than the original lesion, smooth, bright red, are not as friable, and lack a collarette.^2,3

Recurrence of pyogenic granulomas with satellite lesions has been reported to occur in association with almost all forms of treatment, including excision with cautery and CO₂ laser. These recurrences have been successfully treated with simple excision, cryotherapy, diathermy, and curettage; however, some physicians recommend a conservative approach to therapy, as a majority of these lesions tend to spontaneously resolve after 6 to 12 months.^2,3,5

Ezzell et al⁶ and others have reported successful treatment of pyogenic granulomas with imiquimod cream 5%. Imiquimod is thought to trigger resolution of pyogenic granulomas due to its antitumor and im­munoregulatory effects. As a topical agent, imiquimod would offer patients a safe and noninvasive therapy that would be especially beneficial for larger lesions with satellites, similar to the papules described in our patient.^6,7

After a repeat biopsy in our patient confirmed pyo­genic granuloma, she was started on imiquimod cream 5% applied nightly, which continued for 6 weeks. Follow-up after 6 weeks revealed no change in lesion size and the family opted to discontinue treatment at that time because of a lack of response. Although a continued conservative approach was recommended by our facility, the patient and guardians opted for surgical excision and were referred to a local pediatric surgeon for excision under general anesthesia.

The Diagnosis: Rosai-Dorfman Disease

Punch biopsies of the mass from the right thigh were obtained. Hematoxylin and eosin staining revealed a reactive fibroinflammatory process of the dermis and subcutaneous tissue with fibrosis and prominent lymphoplasmacytic and histiocytic infiltrate with emperipolesis (Figure 1). The histio­cytes stained positive for S-100 (Figure 2) and CD68. Markers for CD34, smooth muscle actin, and keratin were negative, as were acid-fast bacteria (Ziehl-Neelsen) and fungal (Gomori methenamine-silver) stains. The morphologic and immunohistochemical features of the biopsy specimens were consistent with Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy.

Rosai-Dorfman disease is a benign histiocytic pro­liferative disorder that usually involves the lymph nodes but may involve any organ system including the skin and soft tissue.^1,2 Systemic RDD usually presents in children or young adults as massive cervical lymphadenopathy, often with fever, polyclonal hyperglobulinemia, mild anemia, elevated erythrocyte sedimentation rate, and occasionally neutropenia.² Rosai-Dorfman disease was first described as a distinct clinicopathologic entity in 1969.³

Extranodal involvement occurs in approximately 40% of patients, with cutaneous disease in approxi­mately 10% of cases. Other sites that may be affected include the eyelid and orbit, salivary glands, lungs, central nervous system, and bone.² Purely cutane­ous RDD is rare and has a variable skin distribution. Compared to systemic RDD, cutaneous disease af­fects older patients with a predilection for females and white individuals.⁴

Histologic examination of cutaneous RDD reveals a dense dermal infiltrate of foamy histiocytes with scattered lymphocytes, plasma cells, and neutrophils.² Emperipolesis, consisting of intact lymphocytes and less commonly plasma cells in the cytoplasm of the his­tiocytes, is a characteristic feature of cutaneous RDD. Occasional findings include fibrosis, lymphoid aggre­gates, foamy histiocytes inside of dilated lymphatics, thick-walled venules with surrounding plasma cells, and multinucleate histiocytes.² Immunohistochemis­try is helpful in diagnosing RDD, as the histiocytes stain strongly positive for S-100, occasionally positive for CD68, and negative for CD1a.⁵

The pathogenesis of RDD remains unknown. Some cases of RDD have had positive serologies for human herpesvirus 6 and Epstein-Barr virus, though an infec­tious origin has not been proven.⁵ Clonality studies have shown the cellular infiltrate to be polyclonal, supporting a reactive rather than neoplastic process.⁶ The disease course of RDD varies from self-limited to protracted with remissions and exacerbations. Many cutaneous RDD lesions spontaneously heal and only require treatment when disseminated, destructive, or causing physical compromise.² Treatment modalities for cutaneous RDD have exhibited varying degrees of success and include surgical excision; thalidomide; isotretinoin; radiotherapy; alkylating agents; and oral, topical, and intralesional steroids.²

The mass in our patient was surgically excised, though surgical margins remained positive. He was followed by the hematology-oncology service and later reported the development of 2 additional masses in the right leg with intermittent tenderness. Mag­netic resonance imaging of the head was negative for intracranial abnormalities, though it did demon­strate prominent nasopharyngeal soft tissue and sinus disease. A complete skeletal radiograph survey and whole-body technetium bone scan did not show evidence of bone involvement. Chest computed tomography was negative for mass lesions. The patient deferred a bone marrow biopsy and was reportedly do­ing well at follow-up without further treatment.

The Diagnosis: Rosai-Dorfman Disease

Punch biopsies of the mass from the right thigh were obtained. Hematoxylin and eosin staining revealed a reactive fibroinflammatory process of the dermis and subcutaneous tissue with fibrosis and prominent lymphoplasmacytic and histiocytic infiltrate with emperipolesis (Figure 1). The histio­cytes stained positive for S-100 (Figure 2) and CD68. Markers for CD34, smooth muscle actin, and keratin were negative, as were acid-fast bacteria (Ziehl-Neelsen) and fungal (Gomori methenamine-silver) stains. The morphologic and immunohistochemical features of the biopsy specimens were consistent with Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy.

Rosai-Dorfman disease is a benign histiocytic pro­liferative disorder that usually involves the lymph nodes but may involve any organ system including the skin and soft tissue.^1,2 Systemic RDD usually presents in children or young adults as massive cervical lymphadenopathy, often with fever, polyclonal hyperglobulinemia, mild anemia, elevated erythrocyte sedimentation rate, and occasionally neutropenia.² Rosai-Dorfman disease was first described as a distinct clinicopathologic entity in 1969.³

Extranodal involvement occurs in approximately 40% of patients, with cutaneous disease in approxi­mately 10% of cases. Other sites that may be affected include the eyelid and orbit, salivary glands, lungs, central nervous system, and bone.² Purely cutane­ous RDD is rare and has a variable skin distribution. Compared to systemic RDD, cutaneous disease af­fects older patients with a predilection for females and white individuals.⁴

Histologic examination of cutaneous RDD reveals a dense dermal infiltrate of foamy histiocytes with scattered lymphocytes, plasma cells, and neutrophils.² Emperipolesis, consisting of intact lymphocytes and less commonly plasma cells in the cytoplasm of the his­tiocytes, is a characteristic feature of cutaneous RDD. Occasional findings include fibrosis, lymphoid aggre­gates, foamy histiocytes inside of dilated lymphatics, thick-walled venules with surrounding plasma cells, and multinucleate histiocytes.² Immunohistochemis­try is helpful in diagnosing RDD, as the histiocytes stain strongly positive for S-100, occasionally positive for CD68, and negative for CD1a.⁵

The pathogenesis of RDD remains unknown. Some cases of RDD have had positive serologies for human herpesvirus 6 and Epstein-Barr virus, though an infec­tious origin has not been proven.⁵ Clonality studies have shown the cellular infiltrate to be polyclonal, supporting a reactive rather than neoplastic process.⁶ The disease course of RDD varies from self-limited to protracted with remissions and exacerbations. Many cutaneous RDD lesions spontaneously heal and only require treatment when disseminated, destructive, or causing physical compromise.² Treatment modalities for cutaneous RDD have exhibited varying degrees of success and include surgical excision; thalidomide; isotretinoin; radiotherapy; alkylating agents; and oral, topical, and intralesional steroids.²

The mass in our patient was surgically excised, though surgical margins remained positive. He was followed by the hematology-oncology service and later reported the development of 2 additional masses in the right leg with intermittent tenderness. Mag­netic resonance imaging of the head was negative for intracranial abnormalities, though it did demon­strate prominent nasopharyngeal soft tissue and sinus disease. A complete skeletal radiograph survey and whole-body technetium bone scan did not show evidence of bone involvement. Chest computed tomography was negative for mass lesions. The patient deferred a bone marrow biopsy and was reportedly do­ing well at follow-up without further treatment.

The Diagnosis: Rosai-Dorfman Disease

Punch biopsies of the mass from the right thigh were obtained. Hematoxylin and eosin staining revealed a reactive fibroinflammatory process of the dermis and subcutaneous tissue with fibrosis and prominent lymphoplasmacytic and histiocytic infiltrate with emperipolesis (Figure 1). The histio­cytes stained positive for S-100 (Figure 2) and CD68. Markers for CD34, smooth muscle actin, and keratin were negative, as were acid-fast bacteria (Ziehl-Neelsen) and fungal (Gomori methenamine-silver) stains. The morphologic and immunohistochemical features of the biopsy specimens were consistent with Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy.

Rosai-Dorfman disease is a benign histiocytic pro­liferative disorder that usually involves the lymph nodes but may involve any organ system including the skin and soft tissue.^1,2 Systemic RDD usually presents in children or young adults as massive cervical lymphadenopathy, often with fever, polyclonal hyperglobulinemia, mild anemia, elevated erythrocyte sedimentation rate, and occasionally neutropenia.² Rosai-Dorfman disease was first described as a distinct clinicopathologic entity in 1969.³

Extranodal involvement occurs in approximately 40% of patients, with cutaneous disease in approxi­mately 10% of cases. Other sites that may be affected include the eyelid and orbit, salivary glands, lungs, central nervous system, and bone.² Purely cutane­ous RDD is rare and has a variable skin distribution. Compared to systemic RDD, cutaneous disease af­fects older patients with a predilection for females and white individuals.⁴

Histologic examination of cutaneous RDD reveals a dense dermal infiltrate of foamy histiocytes with scattered lymphocytes, plasma cells, and neutrophils.² Emperipolesis, consisting of intact lymphocytes and less commonly plasma cells in the cytoplasm of the his­tiocytes, is a characteristic feature of cutaneous RDD. Occasional findings include fibrosis, lymphoid aggre­gates, foamy histiocytes inside of dilated lymphatics, thick-walled venules with surrounding plasma cells, and multinucleate histiocytes.² Immunohistochemis­try is helpful in diagnosing RDD, as the histiocytes stain strongly positive for S-100, occasionally positive for CD68, and negative for CD1a.⁵

The pathogenesis of RDD remains unknown. Some cases of RDD have had positive serologies for human herpesvirus 6 and Epstein-Barr virus, though an infec­tious origin has not been proven.⁵ Clonality studies have shown the cellular infiltrate to be polyclonal, supporting a reactive rather than neoplastic process.⁶ The disease course of RDD varies from self-limited to protracted with remissions and exacerbations. Many cutaneous RDD lesions spontaneously heal and only require treatment when disseminated, destructive, or causing physical compromise.² Treatment modalities for cutaneous RDD have exhibited varying degrees of success and include surgical excision; thalidomide; isotretinoin; radiotherapy; alkylating agents; and oral, topical, and intralesional steroids.²

The mass in our patient was surgically excised, though surgical margins remained positive. He was followed by the hematology-oncology service and later reported the development of 2 additional masses in the right leg with intermittent tenderness. Mag­netic resonance imaging of the head was negative for intracranial abnormalities, though it did demon­strate prominent nasopharyngeal soft tissue and sinus disease. A complete skeletal radiograph survey and whole-body technetium bone scan did not show evidence of bone involvement. Chest computed tomography was negative for mass lesions. The patient deferred a bone marrow biopsy and was reportedly do­ing well at follow-up without further treatment.

The Diagnosis: Tripe Palms and Acanthosis Nigricans

A shave biopsy specimen from the left palm showed slight epidermal hyperplasia with substantial papillomatosis and compact orthokeratosis. The complete blood cell count, thy­rotropin level, uric acid level, liver function tests, mammogram, Papanicolaou test, and chest radio­graph were unremarkable. A basic metabolic panel showed mildly elevated blood glucose at 111 mg/dL (reference range, 70-99 mg/dL) and hemoglobin A_1c at 6.3% (reference range, <6.0%). Full-body com­puted tomography, endoscopy, and colonoscopy ini­tially were normal. One year later after presenting with tripe palms, the patient had a bowel obstruction secondary to omental carcinomatosis from a primary ovarian tumor.

The term tripe in tripe palms refers to the resem­blance to the edible lining of the bovine foregut. It originated in 1963 from a patient's own description of the rugose velvety texture of the palms.¹ In the lit­erature, tripe palms also is called acanthosis palmaris, acanthosis nigricans of the palms, palmar hyperkera­tosis, palmar keratoderma, and pachydermatoglyphy. It is a rare cutaneous finding. Tripe palms is associated with other cutaneous paraneoplastic syndromes such as malignant acanthosis nigricans (72% of cases) and Leser-Trélat sign (10% of cases). It affects more men than women (63% vs 37%) and is almost exclusively seen in adults (median age, 62 years).¹

The clinical appearance of tripe palms includes hypertrophy of the palms and often the soles with papillations producing a velvety or honeycomb appearance. In addition, the dermatoglyphics are pro­nounced. The histologic findings typically show hy­perkeratosis and acanthosis. Other features that can be seen include dermal mucinosis and increased mast cells in the dermis. To differentiate tripe palms from other keratodermas, substantial papillations can be seen with less diffuse hyperkeratosis.¹

Tripe palms has been associated with an underlying malignancy in more than 90% of published cases. In two-thirds of cases, tripe palms either appears before or concurrent with the diagnosis of cancer.² It is rarely reported as an idiopathic finding or associated with nonneoplastic disorders. Malignancies most common­ly associated are adenocarcinomas, especially of the stomach (27%) and lungs (22%). Other neoplasms, such as in our patient, include those of the genito­urinary tract and breast. In a patient with tripe palms in the absence of acanthosis nigricans, the most com­mon neoplasm is of the lung, especially when clubbing of the nails also is present.² Thus, after a diagnosis of tripe palms is established, a thorough investigation for an underlying malignancy is the next most important step to direct specific therapy.

The Diagnosis: Tripe Palms and Acanthosis Nigricans

A shave biopsy specimen from the left palm showed slight epidermal hyperplasia with substantial papillomatosis and compact orthokeratosis. The complete blood cell count, thy­rotropin level, uric acid level, liver function tests, mammogram, Papanicolaou test, and chest radio­graph were unremarkable. A basic metabolic panel showed mildly elevated blood glucose at 111 mg/dL (reference range, 70-99 mg/dL) and hemoglobin A_1c at 6.3% (reference range, <6.0%). Full-body com­puted tomography, endoscopy, and colonoscopy ini­tially were normal. One year later after presenting with tripe palms, the patient had a bowel obstruction secondary to omental carcinomatosis from a primary ovarian tumor.

The term tripe in tripe palms refers to the resem­blance to the edible lining of the bovine foregut. It originated in 1963 from a patient's own description of the rugose velvety texture of the palms.¹ In the lit­erature, tripe palms also is called acanthosis palmaris, acanthosis nigricans of the palms, palmar hyperkera­tosis, palmar keratoderma, and pachydermatoglyphy. It is a rare cutaneous finding. Tripe palms is associated with other cutaneous paraneoplastic syndromes such as malignant acanthosis nigricans (72% of cases) and Leser-Trélat sign (10% of cases). It affects more men than women (63% vs 37%) and is almost exclusively seen in adults (median age, 62 years).¹

The clinical appearance of tripe palms includes hypertrophy of the palms and often the soles with papillations producing a velvety or honeycomb appearance. In addition, the dermatoglyphics are pro­nounced. The histologic findings typically show hy­perkeratosis and acanthosis. Other features that can be seen include dermal mucinosis and increased mast cells in the dermis. To differentiate tripe palms from other keratodermas, substantial papillations can be seen with less diffuse hyperkeratosis.¹

Tripe palms has been associated with an underlying malignancy in more than 90% of published cases. In two-thirds of cases, tripe palms either appears before or concurrent with the diagnosis of cancer.² It is rarely reported as an idiopathic finding or associated with nonneoplastic disorders. Malignancies most common­ly associated are adenocarcinomas, especially of the stomach (27%) and lungs (22%). Other neoplasms, such as in our patient, include those of the genito­urinary tract and breast. In a patient with tripe palms in the absence of acanthosis nigricans, the most com­mon neoplasm is of the lung, especially when clubbing of the nails also is present.² Thus, after a diagnosis of tripe palms is established, a thorough investigation for an underlying malignancy is the next most important step to direct specific therapy.

The Diagnosis: Tripe Palms and Acanthosis Nigricans

A shave biopsy specimen from the left palm showed slight epidermal hyperplasia with substantial papillomatosis and compact orthokeratosis. The complete blood cell count, thy­rotropin level, uric acid level, liver function tests, mammogram, Papanicolaou test, and chest radio­graph were unremarkable. A basic metabolic panel showed mildly elevated blood glucose at 111 mg/dL (reference range, 70-99 mg/dL) and hemoglobin A_1c at 6.3% (reference range, <6.0%). Full-body com­puted tomography, endoscopy, and colonoscopy ini­tially were normal. One year later after presenting with tripe palms, the patient had a bowel obstruction secondary to omental carcinomatosis from a primary ovarian tumor.

The term tripe in tripe palms refers to the resem­blance to the edible lining of the bovine foregut. It originated in 1963 from a patient's own description of the rugose velvety texture of the palms.¹ In the lit­erature, tripe palms also is called acanthosis palmaris, acanthosis nigricans of the palms, palmar hyperkera­tosis, palmar keratoderma, and pachydermatoglyphy. It is a rare cutaneous finding. Tripe palms is associated with other cutaneous paraneoplastic syndromes such as malignant acanthosis nigricans (72% of cases) and Leser-Trélat sign (10% of cases). It affects more men than women (63% vs 37%) and is almost exclusively seen in adults (median age, 62 years).¹

The clinical appearance of tripe palms includes hypertrophy of the palms and often the soles with papillations producing a velvety or honeycomb appearance. In addition, the dermatoglyphics are pro­nounced. The histologic findings typically show hy­perkeratosis and acanthosis. Other features that can be seen include dermal mucinosis and increased mast cells in the dermis. To differentiate tripe palms from other keratodermas, substantial papillations can be seen with less diffuse hyperkeratosis.¹

Tripe palms has been associated with an underlying malignancy in more than 90% of published cases. In two-thirds of cases, tripe palms either appears before or concurrent with the diagnosis of cancer.² It is rarely reported as an idiopathic finding or associated with nonneoplastic disorders. Malignancies most common­ly associated are adenocarcinomas, especially of the stomach (27%) and lungs (22%). Other neoplasms, such as in our patient, include those of the genito­urinary tract and breast. In a patient with tripe palms in the absence of acanthosis nigricans, the most com­mon neoplasm is of the lung, especially when clubbing of the nails also is present.² Thus, after a diagnosis of tripe palms is established, a thorough investigation for an underlying malignancy is the next most important step to direct specific therapy.

The Diagnosis: Pilomatricoma

Pilomatricoma, first described by Malherbe and Chenantais¹ in 1880, is a benign appendageal tumor derived from hair follicle matrix cells. It classically manifests as a solitary, asymptomatic, firm dermal nodule with a normal overlying epidermis. Less common morphologic variants include perforating, lymphagiectatic, keratoacanthomalike, pigmented, and anetodermalike surface changes.² Inflammation and erosion through the skin surface are observed in the rare perforating variant, as seen in our patient. The average size is 1 cm, and it rarely exceeds 3 cm in diameter.³ The tumors predominantly occur on the head, neck, and upper extremities, with only 9.5% on the scalp.² It may occur at any age, though it has a bimodal distribution with peaks in childhood and in adults older than 60 years. A slight preponderance in females has been observed with a female to male ratio of 1.5 to 1.² Although our patient is black, most reported cases have occurred in individuals of European descent. Because cases of pilomatricoma are not systematically reported, it is uncertain if this finding represents a publication bias or if race is an actual risk factor. Multiple pilomatricomas and familial cases have been described in association with myotonic dystrophy, Turner syndrome, Gardner syndrome, Rubinstein-Taybi syndrome, polyfactorial coagulopathy, trisomy 9, xeroderma pigmentosum, and basal cell nevus syndrome.^2,4

It has been shown that the proliferating cells of pilomatricomas stain with antibodies directed against Lef1 (lymphoid enhancer binding factor 1), a marker from hair matrix cells, providing biochemical evidence for the morphologic appearance of these neoplasms.⁵ Pilomatricomas have been associated with B-cell/chronic lymphocytic leukemia lymphoma 2 gene, BCL2, expression, a proto-oncogene that suppresses apoptosis in benign and malignant neoplasms, which may contribute to the pathogenesis of these tumors.⁶ Pilomatricomas also have been associated with β-catenin mutation, expression of Bmp2 (bone morphogenetic protein 2), and human hair keratin basic 1.^7-9

Definitive diagnosis is obtained through biopsy, looking for characteristic histopathologic findings. The lesion usually is found in the lower dermis and subcutaneous fat. However, in the perforating variant, the lesion is more superficial, located in the papillary and mid dermis, as seen in our patient.¹⁰

Islands of pale eosinophilic shadow cells with an intense dermal infiltrate consisting of lymphocytes, histiocytes, plasma cells, and neutrophils (H&amp;E, original magnification ×400).

Pilomatricomas are sharply demarcated, often surrounded by a connective-tissue capsule. Histopathologic analysis reveals islands of epithelial cells comprised of 3 subtypes: basophilic cells with scant cytoplasm, shadow cells with a central pallor (Figure), and transitional cells between the former 2 cellular types.¹¹ The number of basophilic and transitional cells is inversely related to the number of shadow cells. In older lesions, the shadow cells predominate, while the basophilic cells are few in number or absent. Calcium deposits are seen in 80% of lesions with von Kossa staining.¹²

Transformation into malignancy, known as pilomatrical carcinoma, is rare. These malignant neoplasms are characterized by aggressive biologic behavior such as recurrence, diffuse spread, or metastasis, or by cytologic abnormalities such as poor cellular organization, squamous differentiation, and conspicuous mitotic activity.¹³ The recent growth of the long-standing lesion in our patient might be interpreted as a sign of malignant transformation. However, this observation may be related to the intense inflammatory reaction supported by the histopathology.

Pilomatricomas are not associated with mortality. Pilomatrical carcinomas are uncommon but are locally invasive and can cause visceral metastases and death. Spontaneous regression has never been observed and medical treatment is ineffective. The treatment of choice is incision and curettage or surgical excision.¹⁴ Although recurrence has only been reported in 2.6% of cases from a large case series (N=228), patients should be monitored after surgical excision.¹²

The Diagnosis: Pilomatricoma

Pilomatricoma, first described by Malherbe and Chenantais¹ in 1880, is a benign appendageal tumor derived from hair follicle matrix cells. It classically manifests as a solitary, asymptomatic, firm dermal nodule with a normal overlying epidermis. Less common morphologic variants include perforating, lymphagiectatic, keratoacanthomalike, pigmented, and anetodermalike surface changes.² Inflammation and erosion through the skin surface are observed in the rare perforating variant, as seen in our patient. The average size is 1 cm, and it rarely exceeds 3 cm in diameter.³ The tumors predominantly occur on the head, neck, and upper extremities, with only 9.5% on the scalp.² It may occur at any age, though it has a bimodal distribution with peaks in childhood and in adults older than 60 years. A slight preponderance in females has been observed with a female to male ratio of 1.5 to 1.² Although our patient is black, most reported cases have occurred in individuals of European descent. Because cases of pilomatricoma are not systematically reported, it is uncertain if this finding represents a publication bias or if race is an actual risk factor. Multiple pilomatricomas and familial cases have been described in association with myotonic dystrophy, Turner syndrome, Gardner syndrome, Rubinstein-Taybi syndrome, polyfactorial coagulopathy, trisomy 9, xeroderma pigmentosum, and basal cell nevus syndrome.^2,4

It has been shown that the proliferating cells of pilomatricomas stain with antibodies directed against Lef1 (lymphoid enhancer binding factor 1), a marker from hair matrix cells, providing biochemical evidence for the morphologic appearance of these neoplasms.⁵ Pilomatricomas have been associated with B-cell/chronic lymphocytic leukemia lymphoma 2 gene, BCL2, expression, a proto-oncogene that suppresses apoptosis in benign and malignant neoplasms, which may contribute to the pathogenesis of these tumors.⁶ Pilomatricomas also have been associated with β-catenin mutation, expression of Bmp2 (bone morphogenetic protein 2), and human hair keratin basic 1.^7-9

Definitive diagnosis is obtained through biopsy, looking for characteristic histopathologic findings. The lesion usually is found in the lower dermis and subcutaneous fat. However, in the perforating variant, the lesion is more superficial, located in the papillary and mid dermis, as seen in our patient.¹⁰

Islands of pale eosinophilic shadow cells with an intense dermal infiltrate consisting of lymphocytes, histiocytes, plasma cells, and neutrophils (H&amp;E, original magnification ×400).

Pilomatricomas are sharply demarcated, often surrounded by a connective-tissue capsule. Histopathologic analysis reveals islands of epithelial cells comprised of 3 subtypes: basophilic cells with scant cytoplasm, shadow cells with a central pallor (Figure), and transitional cells between the former 2 cellular types.¹¹ The number of basophilic and transitional cells is inversely related to the number of shadow cells. In older lesions, the shadow cells predominate, while the basophilic cells are few in number or absent. Calcium deposits are seen in 80% of lesions with von Kossa staining.¹²

Transformation into malignancy, known as pilomatrical carcinoma, is rare. These malignant neoplasms are characterized by aggressive biologic behavior such as recurrence, diffuse spread, or metastasis, or by cytologic abnormalities such as poor cellular organization, squamous differentiation, and conspicuous mitotic activity.¹³ The recent growth of the long-standing lesion in our patient might be interpreted as a sign of malignant transformation. However, this observation may be related to the intense inflammatory reaction supported by the histopathology.

Pilomatricomas are not associated with mortality. Pilomatrical carcinomas are uncommon but are locally invasive and can cause visceral metastases and death. Spontaneous regression has never been observed and medical treatment is ineffective. The treatment of choice is incision and curettage or surgical excision.¹⁴ Although recurrence has only been reported in 2.6% of cases from a large case series (N=228), patients should be monitored after surgical excision.¹²

The Diagnosis: Pilomatricoma

Pilomatricoma, first described by Malherbe and Chenantais¹ in 1880, is a benign appendageal tumor derived from hair follicle matrix cells. It classically manifests as a solitary, asymptomatic, firm dermal nodule with a normal overlying epidermis. Less common morphologic variants include perforating, lymphagiectatic, keratoacanthomalike, pigmented, and anetodermalike surface changes.² Inflammation and erosion through the skin surface are observed in the rare perforating variant, as seen in our patient. The average size is 1 cm, and it rarely exceeds 3 cm in diameter.³ The tumors predominantly occur on the head, neck, and upper extremities, with only 9.5% on the scalp.² It may occur at any age, though it has a bimodal distribution with peaks in childhood and in adults older than 60 years. A slight preponderance in females has been observed with a female to male ratio of 1.5 to 1.² Although our patient is black, most reported cases have occurred in individuals of European descent. Because cases of pilomatricoma are not systematically reported, it is uncertain if this finding represents a publication bias or if race is an actual risk factor. Multiple pilomatricomas and familial cases have been described in association with myotonic dystrophy, Turner syndrome, Gardner syndrome, Rubinstein-Taybi syndrome, polyfactorial coagulopathy, trisomy 9, xeroderma pigmentosum, and basal cell nevus syndrome.^2,4

It has been shown that the proliferating cells of pilomatricomas stain with antibodies directed against Lef1 (lymphoid enhancer binding factor 1), a marker from hair matrix cells, providing biochemical evidence for the morphologic appearance of these neoplasms.⁵ Pilomatricomas have been associated with B-cell/chronic lymphocytic leukemia lymphoma 2 gene, BCL2, expression, a proto-oncogene that suppresses apoptosis in benign and malignant neoplasms, which may contribute to the pathogenesis of these tumors.⁶ Pilomatricomas also have been associated with β-catenin mutation, expression of Bmp2 (bone morphogenetic protein 2), and human hair keratin basic 1.^7-9

Definitive diagnosis is obtained through biopsy, looking for characteristic histopathologic findings. The lesion usually is found in the lower dermis and subcutaneous fat. However, in the perforating variant, the lesion is more superficial, located in the papillary and mid dermis, as seen in our patient.¹⁰

Islands of pale eosinophilic shadow cells with an intense dermal infiltrate consisting of lymphocytes, histiocytes, plasma cells, and neutrophils (H&amp;E, original magnification ×400).

Pilomatricomas are sharply demarcated, often surrounded by a connective-tissue capsule. Histopathologic analysis reveals islands of epithelial cells comprised of 3 subtypes: basophilic cells with scant cytoplasm, shadow cells with a central pallor (Figure), and transitional cells between the former 2 cellular types.¹¹ The number of basophilic and transitional cells is inversely related to the number of shadow cells. In older lesions, the shadow cells predominate, while the basophilic cells are few in number or absent. Calcium deposits are seen in 80% of lesions with von Kossa staining.¹²

Transformation into malignancy, known as pilomatrical carcinoma, is rare. These malignant neoplasms are characterized by aggressive biologic behavior such as recurrence, diffuse spread, or metastasis, or by cytologic abnormalities such as poor cellular organization, squamous differentiation, and conspicuous mitotic activity.¹³ The recent growth of the long-standing lesion in our patient might be interpreted as a sign of malignant transformation. However, this observation may be related to the intense inflammatory reaction supported by the histopathology.

Pilomatricomas are not associated with mortality. Pilomatrical carcinomas are uncommon but are locally invasive and can cause visceral metastases and death. Spontaneous regression has never been observed and medical treatment is ineffective. The treatment of choice is incision and curettage or surgical excision.¹⁴ Although recurrence has only been reported in 2.6% of cases from a large case series (N=228), patients should be monitored after surgical excision.¹²