Nonmelanoma Skin Cancer

Henoch-Schönlein purpura (HSP) is a systemic leukocytoclastic vasculitis involving arterioles and venules most commonly in the skin, glomeruli, and gastrointestinal tract. In skin, it is associated with IgA deposition around dermal blood vessels. While an exact cause of HSP has not been elucidated, several processes have been implicated in its development, including infections; drugs; and allergic, rheumatologic, and neoplastic diseases. We present a 57-year-old woman with a history of follicular lymphoma who developed HSP likely associated with myelodysplastic syndrome. This case is clinically significant because the patient was thought to be in remission of her hematologic disease until her skin findings prompted further evaluation. Her diagnosis of HSP was based on clinical presentation with palpable purpura and abdominal pain, and was confirmed with biopsy and immunohistochemical analyses of purpuric papules demonstrating leukocytoclastic vasculitis and strong anti-IgA labeling in the dermal endothelial cells consistent with immunocomplex deposition. The occurrence of vasculitis and malignant disease in the same patient often is difficult to interpret, as some patients may exhibit both diseases independently and by chance, while others may have vasculitis as a paraneoplastic syndrome. We review cases of adult HSP associated with malignancy in the literature.
Case Report
A 57-year-old woman with a history of follicular lymphoma in complete remission presented to the dermatology clinic with a 3-week history of a new asymptomatic erythematous rash distributed across her arms, legs, and buttocks. She denied the use of any new medications but did report resuming use of pilocarpine 3 months prior to presentation and ursodiol 2 months prior to presentation. She had previously taken both of these medications without adverse effects. On initial presentation, the patient denied fever, chills, nausea, vomiting, dyspnea, arthralgia, or myalgia. She denied any upper respiratory tract symptoms or preceding viral illness. The patient's prior medical history included diabetes mellitus, hypertension, follicular lymphoma in remission, and severe chemotherapy-induced peripheral neuropathy. Her follicular lymphoma initially was treated with chemotherapy. She relapsed and was treated with an allogeneic bone marrow–derived stem cell transplant from an HLA antigen–identical sister approximately 9 years prior to presentation. The patient's medications included pilocarpine, ursodiol, a fentanyl citrate patch, gabapentin, nortriptyline, duloxetine, clonidine hydrochloride, magnesium oxide, methylphenidate hydrochloride, metformin, and glyburide. She reported no known drug allergies. Full cutaneous examination revealed nonblanching erythematous macules and papules on the bilateral lower extremities, with scattered macules and papules on the upper arms, abdomen, and buttocks. Results of a punch biopsy showed a predominant perivascular infiltrate of lymphocytes, neutrophils, and eosinophils. There was focal endothelial swelling with mural fibrin deposits, extravasation of red blood cells, and rare necrotic keratinocytes consistent with leukocytoclastic vasculitis (Figure 1). Triamcinolone acetonide cream 0.1% was prescribed pending laboratory evaluation, which ultimately revealed a negative antinuclear antibody, negative rheumatoid factor, white blood cell count of 4.2 k/µL (reference range, 4–11 k/µL), hemoglobin level of 7.8 g/dL (reference range, 12–16 g/dL), and platelet count of 192 k/µL (reference range, 140–440 k/µL). A urinalysis was negative for red blood cells, proteins, and nitrites, but did show small leukocyte esterase and 5 to 10 white blood cells per high-power field.

Two weeks later, the patient complained of crampy abdominal pain (requiring morphine); decreased appetite; weakness; headache, as well as nausea; and extension of the eruption to involve her arms, legs, and entire trunk. She denied melena, hematochezia, and any urinary tract symptoms. Physical examination revealed diffuse tenderness in the epigastric area and a nonpalpable liver and spleen. Full cutaneous examination showed hemorrhagic bullae on the patient's lower extremities (Figure 2) and palpable purpura on her arms. Since the initial presentation 2 months prior, the patient's hematocrit level had dropped approximately 10% from 34.6% to 24.3% (reference range, 41.0%–50.0%). Her white blood cell count was slightly lower (3.6 k/µL) and her platelet count was 144 k/µL. Of note, her D-dimer level was elevated (1846 ng/mL; reference range, 0–230 ng/mL), as was her fibrinogen level (613 mg/dL; reference range, 220–530 mg/dL). Repeat urinalysis showed no proteinuria, hematuria, or nitrites.

The patient subsequently was admitted to the hospital. A workup of her gastrointestinal tract, including a computed tomographic scan of the abdomen and endoscopy, failed to show an etiology for the abdominal pain. Her amylase and lipase levels were normal, and stool cultures and guaiac occult blood tests were negative. Biopsies performed during endoscopy showed mild acute colitis of the hepatic flexure and the ileocecal valve. The patient was prescribed a prophylactic regimen of meropenem and metronidazole for colitis, though no precise etiology was identified. An anti-IgA immunostudy was performed on paraffin sections of the original skin biopsy and showed strong labeling in the dermal endothelial cells consistent with immunocomplex deposition (Figure 3). The patient was diagnosed with Henoch-Schönlein purpura (HSP) and her rash and abdominal pain improved with prednisone 60 mg daily. Biopsy of a bone marrow specimen showed myelodysplastic changes and a cellular bone marrow with trilineage dyspoiesis and increased blasts.

Ten days after discharge, the patient's cutaneous eruption had greatly improved, with residual macules present on the dorsum of both feet and only faint reticulated erythema and rare purpura across the lower abdomen and lower extremities. She was scheduled for a second stem cell transplant to treat the myelodysplasia.

Comment
HSP is a systemic leukocytoclastic vasculitis involving arterioles and venules most commonly in the skin, glomeruli, and gastrointestinal tract.1,2 It is common for affected tissues to histologically demonstrate the presence of IgA in vessel walls. Fever and palpable purpura, predominantly on the buttocks and extremities, often are the first signs of HSP and may be accompanied by arthralgia, abdominal pain, and renal disease.2 The arthritis can be characterized as transient and oligoarticular, commonly affecting large joints and often with pain out of proportion to objective evidence of synovitis.2 Signs of peritoneal inflammation may occur and melena is common; more severe gastrointestinal tract complications that may warrant surgical intervention also have been described.2,3 Renal pathology in patients with HSP involves a spectrum ranging from mild focal glomerulitis to rapidly proliferative glomerulonephritis accompanied by variable amounts of proteinuria and hematuria.2 In 1990, the American College of Rheumatology identified 4 criteria for separating HSP cases from controls: (1) age 20 years or younger at disease onset, (2) palpable purpura, (3) acute abdominal pain, and (4) biopsy showing granulocytes in the walls of small arterioles or venules. When 2 or more of any of these criteria were present, HSP was distinguished from other forms of vasculitis with a sensitivity of 87.1% and a specificity of 87.7%.2 HSP is the most common systemic vasculitis of childhood and has been historically and predominantly viewed as a pediatric disease. HSP is believed to affect adults less frequently but has been reported to be responsible for a substantial percentage of all cases of cutaneous vasculitis among adults.4 In a retrospective study of patients with HSP, Blanco et al5 found that HSP represents a more severe clinical syndrome in adulthood than in childhood, but the prognosis of patients is equally good in both adult and pediatric populations. An exact cause of HSP has not been identified; however, many processes have been implicated in its development, including infections; drugs; and allergic, rheumatologic, and neoplastic diseases. Neoplasia in adults with systemic or cutaneous vasculitis has an estimated prevalence of 2.5% to 5.0%, with hematopoietic malignancies occurring more commonly than solid tumors.6 Although malignancy has been reported to occur in association with nearly all forms of vasculitis, the association between cutaneous hypersensitivity vasculitis and hematopoietic malignancies is most notable.7 In 1996, Fortin8 outlined several classic hypotheses explaining the role of neoplastic disease in the development of vasculitic syndromes such as HSP, including the impaired clearance of normally deposited immune complexes, abnormal production of immunoglobulins that may either directly react to vascular antigens and cause in situ immune complex formation or form circulating immune complexes that can then deposit in vessel walls, and common antigens presenting on the surface of malignant cells that may stimulate T-cell activation or the production of immunoglobulin directed not only toward malignant cells but healthy epithelium as well. The association of vasculitis with malignancy has been reviewed extensively in the literature.9-12 Sanchez-Guerrero et al9 found that 11 of 222 patients with vasculitis had associated neoplasia, with both hematologic and solid tumors implicated. Importantly, the authors noted that in 4 of 11 patients with paraneoplastic vasculitis, symptoms of vascular inflammation were evidence of the initial presentation of neoplasia or its recurrence.9 Kurzrock et al10 reviewed the manifestation of vasculitis in patients with solid tumors and found that in 71% of cases (25/35), symptoms of vasculitis appeared before or concurrent with the initial recognition or relapse of the tumor. Greer et al11 described 13 patients with both vasculitis and lymphoproliferative or myeloproliferative syndromes and reported a statistically significant (P<.0000001) association between the 2 when compared with all other tumors. The authors further asserted that tumor-associated vasculitis is a heterogeneous group of syndromes that share clinical features; malignancy or its recurrence should be considered in patients with unexplained vasculitis; and although treatment of the underlying neoplasm may lead to resolution of vasculitis, specific therapy for vascular inflammation often is not effective.11
HSP specifically has been described in patients with malignancy and vasculitis (Table).6,13-36 In 2000, Pertuiset et al6 reviewed 14 cases of adult HSP and found malignant neoplasm in 4 cases. They also identified 15 reports of adult HSP with malignant disease in the literature. Collectively, these 19 cases were compared with 158 adults who had HSP but no malignancy. The authors reported that 63% (12/19) of neoplasms associated with adult HSP were solid tumors, while the remaining 37% (7/19) were hematologic malignancies. Patients with paraneoplastic HSP were older, more likely to be male, more frequently had joint involvement, and had a lower frequency of prior infection compared with patients with HSP not associated with malignancy. There was no reported statistically significant difference in percentage of patients with cutaneous purpura, gastrointestinal tract involvement, renal involvement, or polyclonal IgA increase between the 2 groups.6

More recently, Zurada et al23 presented the cases of 3 adults who developed HSP within months of diagnosis of a solid tumor or metastasis of a previously diagnosed malignancy. In their review of the world literature, the authors found that 31 cases of malignancy-associated HSP had been reported, and in most cases, the patients were male (94%; 29/31), presented with solid tumors (61%; 19/31), and developed HSP within one month of cancer diagnosis or detection of metastases (55%; 17/31).23

The occurrence of vasculitis and malignant disease in the same patient often is difficult to interpret because some patients may exhibit both diseases independently and by chance, while others may have vasculitis as a paraneoplastic syndrome.6 Currently, the principal sources of data on the association between HSP and malignancy are anecdotal case reports, which can be difficult to use to determine causality and relationship with significance. However, because of the relative rarity of paraneoplastic vasculitis, large studies are difficult, making case reports and smaller literature reviews of unusual presentations valuable.8

Conclusion
In summary, we present a 57-year-old woman with a history of follicular lymphoma who developed HSP likely associated with myelodysplastic syndrome. This case is clinically significant because the patient was thought to be in remission of her hematologic disease until her skin findings prompted further evaluation. Her diagnosis of HSP was based on clinical presentation with palpable purpura and abdominal pain, and was confirmed with biopsy and immunohistochemical analyses of purpuric papules that demonstrated leukocytoclastic vasculitis and strong anti-IgA labeling in the dermal endothelial cells consistent with immunocomplex deposition. The patient was placed on a corticosteroid taper and scheduled for stem cell transplantation, with marked improvement demonstrated clinically at her most recent visit.

Henoch-Schönlein purpura (HSP) is a systemic leukocytoclastic vasculitis involving arterioles and venules most commonly in the skin, glomeruli, and gastrointestinal tract. In skin, it is associated with IgA deposition around dermal blood vessels. While an exact cause of HSP has not been elucidated, several processes have been implicated in its development, including infections; drugs; and allergic, rheumatologic, and neoplastic diseases. We present a 57-year-old woman with a history of follicular lymphoma who developed HSP likely associated with myelodysplastic syndrome. This case is clinically significant because the patient was thought to be in remission of her hematologic disease until her skin findings prompted further evaluation. Her diagnosis of HSP was based on clinical presentation with palpable purpura and abdominal pain, and was confirmed with biopsy and immunohistochemical analyses of purpuric papules demonstrating leukocytoclastic vasculitis and strong anti-IgA labeling in the dermal endothelial cells consistent with immunocomplex deposition. The occurrence of vasculitis and malignant disease in the same patient often is difficult to interpret, as some patients may exhibit both diseases independently and by chance, while others may have vasculitis as a paraneoplastic syndrome. We review cases of adult HSP associated with malignancy in the literature.
Case Report
A 57-year-old woman with a history of follicular lymphoma in complete remission presented to the dermatology clinic with a 3-week history of a new asymptomatic erythematous rash distributed across her arms, legs, and buttocks. She denied the use of any new medications but did report resuming use of pilocarpine 3 months prior to presentation and ursodiol 2 months prior to presentation. She had previously taken both of these medications without adverse effects. On initial presentation, the patient denied fever, chills, nausea, vomiting, dyspnea, arthralgia, or myalgia. She denied any upper respiratory tract symptoms or preceding viral illness. The patient's prior medical history included diabetes mellitus, hypertension, follicular lymphoma in remission, and severe chemotherapy-induced peripheral neuropathy. Her follicular lymphoma initially was treated with chemotherapy. She relapsed and was treated with an allogeneic bone marrow–derived stem cell transplant from an HLA antigen–identical sister approximately 9 years prior to presentation. The patient's medications included pilocarpine, ursodiol, a fentanyl citrate patch, gabapentin, nortriptyline, duloxetine, clonidine hydrochloride, magnesium oxide, methylphenidate hydrochloride, metformin, and glyburide. She reported no known drug allergies. Full cutaneous examination revealed nonblanching erythematous macules and papules on the bilateral lower extremities, with scattered macules and papules on the upper arms, abdomen, and buttocks. Results of a punch biopsy showed a predominant perivascular infiltrate of lymphocytes, neutrophils, and eosinophils. There was focal endothelial swelling with mural fibrin deposits, extravasation of red blood cells, and rare necrotic keratinocytes consistent with leukocytoclastic vasculitis (Figure 1). Triamcinolone acetonide cream 0.1% was prescribed pending laboratory evaluation, which ultimately revealed a negative antinuclear antibody, negative rheumatoid factor, white blood cell count of 4.2 k/µL (reference range, 4–11 k/µL), hemoglobin level of 7.8 g/dL (reference range, 12–16 g/dL), and platelet count of 192 k/µL (reference range, 140–440 k/µL). A urinalysis was negative for red blood cells, proteins, and nitrites, but did show small leukocyte esterase and 5 to 10 white blood cells per high-power field.

Two weeks later, the patient complained of crampy abdominal pain (requiring morphine); decreased appetite; weakness; headache, as well as nausea; and extension of the eruption to involve her arms, legs, and entire trunk. She denied melena, hematochezia, and any urinary tract symptoms. Physical examination revealed diffuse tenderness in the epigastric area and a nonpalpable liver and spleen. Full cutaneous examination showed hemorrhagic bullae on the patient's lower extremities (Figure 2) and palpable purpura on her arms. Since the initial presentation 2 months prior, the patient's hematocrit level had dropped approximately 10% from 34.6% to 24.3% (reference range, 41.0%–50.0%). Her white blood cell count was slightly lower (3.6 k/µL) and her platelet count was 144 k/µL. Of note, her D-dimer level was elevated (1846 ng/mL; reference range, 0–230 ng/mL), as was her fibrinogen level (613 mg/dL; reference range, 220–530 mg/dL). Repeat urinalysis showed no proteinuria, hematuria, or nitrites.

The patient subsequently was admitted to the hospital. A workup of her gastrointestinal tract, including a computed tomographic scan of the abdomen and endoscopy, failed to show an etiology for the abdominal pain. Her amylase and lipase levels were normal, and stool cultures and guaiac occult blood tests were negative. Biopsies performed during endoscopy showed mild acute colitis of the hepatic flexure and the ileocecal valve. The patient was prescribed a prophylactic regimen of meropenem and metronidazole for colitis, though no precise etiology was identified. An anti-IgA immunostudy was performed on paraffin sections of the original skin biopsy and showed strong labeling in the dermal endothelial cells consistent with immunocomplex deposition (Figure 3). The patient was diagnosed with Henoch-Schönlein purpura (HSP) and her rash and abdominal pain improved with prednisone 60 mg daily. Biopsy of a bone marrow specimen showed myelodysplastic changes and a cellular bone marrow with trilineage dyspoiesis and increased blasts.

Ten days after discharge, the patient's cutaneous eruption had greatly improved, with residual macules present on the dorsum of both feet and only faint reticulated erythema and rare purpura across the lower abdomen and lower extremities. She was scheduled for a second stem cell transplant to treat the myelodysplasia.

Comment
HSP is a systemic leukocytoclastic vasculitis involving arterioles and venules most commonly in the skin, glomeruli, and gastrointestinal tract.1,2 It is common for affected tissues to histologically demonstrate the presence of IgA in vessel walls. Fever and palpable purpura, predominantly on the buttocks and extremities, often are the first signs of HSP and may be accompanied by arthralgia, abdominal pain, and renal disease.2 The arthritis can be characterized as transient and oligoarticular, commonly affecting large joints and often with pain out of proportion to objective evidence of synovitis.2 Signs of peritoneal inflammation may occur and melena is common; more severe gastrointestinal tract complications that may warrant surgical intervention also have been described.2,3 Renal pathology in patients with HSP involves a spectrum ranging from mild focal glomerulitis to rapidly proliferative glomerulonephritis accompanied by variable amounts of proteinuria and hematuria.2 In 1990, the American College of Rheumatology identified 4 criteria for separating HSP cases from controls: (1) age 20 years or younger at disease onset, (2) palpable purpura, (3) acute abdominal pain, and (4) biopsy showing granulocytes in the walls of small arterioles or venules. When 2 or more of any of these criteria were present, HSP was distinguished from other forms of vasculitis with a sensitivity of 87.1% and a specificity of 87.7%.2 HSP is the most common systemic vasculitis of childhood and has been historically and predominantly viewed as a pediatric disease. HSP is believed to affect adults less frequently but has been reported to be responsible for a substantial percentage of all cases of cutaneous vasculitis among adults.4 In a retrospective study of patients with HSP, Blanco et al5 found that HSP represents a more severe clinical syndrome in adulthood than in childhood, but the prognosis of patients is equally good in both adult and pediatric populations. An exact cause of HSP has not been identified; however, many processes have been implicated in its development, including infections; drugs; and allergic, rheumatologic, and neoplastic diseases. Neoplasia in adults with systemic or cutaneous vasculitis has an estimated prevalence of 2.5% to 5.0%, with hematopoietic malignancies occurring more commonly than solid tumors.6 Although malignancy has been reported to occur in association with nearly all forms of vasculitis, the association between cutaneous hypersensitivity vasculitis and hematopoietic malignancies is most notable.7 In 1996, Fortin8 outlined several classic hypotheses explaining the role of neoplastic disease in the development of vasculitic syndromes such as HSP, including the impaired clearance of normally deposited immune complexes, abnormal production of immunoglobulins that may either directly react to vascular antigens and cause in situ immune complex formation or form circulating immune complexes that can then deposit in vessel walls, and common antigens presenting on the surface of malignant cells that may stimulate T-cell activation or the production of immunoglobulin directed not only toward malignant cells but healthy epithelium as well. The association of vasculitis with malignancy has been reviewed extensively in the literature.9-12 Sanchez-Guerrero et al9 found that 11 of 222 patients with vasculitis had associated neoplasia, with both hematologic and solid tumors implicated. Importantly, the authors noted that in 4 of 11 patients with paraneoplastic vasculitis, symptoms of vascular inflammation were evidence of the initial presentation of neoplasia or its recurrence.9 Kurzrock et al10 reviewed the manifestation of vasculitis in patients with solid tumors and found that in 71% of cases (25/35), symptoms of vasculitis appeared before or concurrent with the initial recognition or relapse of the tumor. Greer et al11 described 13 patients with both vasculitis and lymphoproliferative or myeloproliferative syndromes and reported a statistically significant (P<.0000001) association between the 2 when compared with all other tumors. The authors further asserted that tumor-associated vasculitis is a heterogeneous group of syndromes that share clinical features; malignancy or its recurrence should be considered in patients with unexplained vasculitis; and although treatment of the underlying neoplasm may lead to resolution of vasculitis, specific therapy for vascular inflammation often is not effective.11
HSP specifically has been described in patients with malignancy and vasculitis (Table).6,13-36 In 2000, Pertuiset et al6 reviewed 14 cases of adult HSP and found malignant neoplasm in 4 cases. They also identified 15 reports of adult HSP with malignant disease in the literature. Collectively, these 19 cases were compared with 158 adults who had HSP but no malignancy. The authors reported that 63% (12/19) of neoplasms associated with adult HSP were solid tumors, while the remaining 37% (7/19) were hematologic malignancies. Patients with paraneoplastic HSP were older, more likely to be male, more frequently had joint involvement, and had a lower frequency of prior infection compared with patients with HSP not associated with malignancy. There was no reported statistically significant difference in percentage of patients with cutaneous purpura, gastrointestinal tract involvement, renal involvement, or polyclonal IgA increase between the 2 groups.6

More recently, Zurada et al23 presented the cases of 3 adults who developed HSP within months of diagnosis of a solid tumor or metastasis of a previously diagnosed malignancy. In their review of the world literature, the authors found that 31 cases of malignancy-associated HSP had been reported, and in most cases, the patients were male (94%; 29/31), presented with solid tumors (61%; 19/31), and developed HSP within one month of cancer diagnosis or detection of metastases (55%; 17/31).23

The occurrence of vasculitis and malignant disease in the same patient often is difficult to interpret because some patients may exhibit both diseases independently and by chance, while others may have vasculitis as a paraneoplastic syndrome.6 Currently, the principal sources of data on the association between HSP and malignancy are anecdotal case reports, which can be difficult to use to determine causality and relationship with significance. However, because of the relative rarity of paraneoplastic vasculitis, large studies are difficult, making case reports and smaller literature reviews of unusual presentations valuable.8

Conclusion
In summary, we present a 57-year-old woman with a history of follicular lymphoma who developed HSP likely associated with myelodysplastic syndrome. This case is clinically significant because the patient was thought to be in remission of her hematologic disease until her skin findings prompted further evaluation. Her diagnosis of HSP was based on clinical presentation with palpable purpura and abdominal pain, and was confirmed with biopsy and immunohistochemical analyses of purpuric papules that demonstrated leukocytoclastic vasculitis and strong anti-IgA labeling in the dermal endothelial cells consistent with immunocomplex deposition. The patient was placed on a corticosteroid taper and scheduled for stem cell transplantation, with marked improvement demonstrated clinically at her most recent visit.

Henoch-Schönlein purpura (HSP) is a systemic leukocytoclastic vasculitis involving arterioles and venules most commonly in the skin, glomeruli, and gastrointestinal tract. In skin, it is associated with IgA deposition around dermal blood vessels. While an exact cause of HSP has not been elucidated, several processes have been implicated in its development, including infections; drugs; and allergic, rheumatologic, and neoplastic diseases. We present a 57-year-old woman with a history of follicular lymphoma who developed HSP likely associated with myelodysplastic syndrome. This case is clinically significant because the patient was thought to be in remission of her hematologic disease until her skin findings prompted further evaluation. Her diagnosis of HSP was based on clinical presentation with palpable purpura and abdominal pain, and was confirmed with biopsy and immunohistochemical analyses of purpuric papules demonstrating leukocytoclastic vasculitis and strong anti-IgA labeling in the dermal endothelial cells consistent with immunocomplex deposition. The occurrence of vasculitis and malignant disease in the same patient often is difficult to interpret, as some patients may exhibit both diseases independently and by chance, while others may have vasculitis as a paraneoplastic syndrome. We review cases of adult HSP associated with malignancy in the literature.
Case Report
A 57-year-old woman with a history of follicular lymphoma in complete remission presented to the dermatology clinic with a 3-week history of a new asymptomatic erythematous rash distributed across her arms, legs, and buttocks. She denied the use of any new medications but did report resuming use of pilocarpine 3 months prior to presentation and ursodiol 2 months prior to presentation. She had previously taken both of these medications without adverse effects. On initial presentation, the patient denied fever, chills, nausea, vomiting, dyspnea, arthralgia, or myalgia. She denied any upper respiratory tract symptoms or preceding viral illness. The patient's prior medical history included diabetes mellitus, hypertension, follicular lymphoma in remission, and severe chemotherapy-induced peripheral neuropathy. Her follicular lymphoma initially was treated with chemotherapy. She relapsed and was treated with an allogeneic bone marrow–derived stem cell transplant from an HLA antigen–identical sister approximately 9 years prior to presentation. The patient's medications included pilocarpine, ursodiol, a fentanyl citrate patch, gabapentin, nortriptyline, duloxetine, clonidine hydrochloride, magnesium oxide, methylphenidate hydrochloride, metformin, and glyburide. She reported no known drug allergies. Full cutaneous examination revealed nonblanching erythematous macules and papules on the bilateral lower extremities, with scattered macules and papules on the upper arms, abdomen, and buttocks. Results of a punch biopsy showed a predominant perivascular infiltrate of lymphocytes, neutrophils, and eosinophils. There was focal endothelial swelling with mural fibrin deposits, extravasation of red blood cells, and rare necrotic keratinocytes consistent with leukocytoclastic vasculitis (Figure 1). Triamcinolone acetonide cream 0.1% was prescribed pending laboratory evaluation, which ultimately revealed a negative antinuclear antibody, negative rheumatoid factor, white blood cell count of 4.2 k/µL (reference range, 4–11 k/µL), hemoglobin level of 7.8 g/dL (reference range, 12–16 g/dL), and platelet count of 192 k/µL (reference range, 140–440 k/µL). A urinalysis was negative for red blood cells, proteins, and nitrites, but did show small leukocyte esterase and 5 to 10 white blood cells per high-power field.

Two weeks later, the patient complained of crampy abdominal pain (requiring morphine); decreased appetite; weakness; headache, as well as nausea; and extension of the eruption to involve her arms, legs, and entire trunk. She denied melena, hematochezia, and any urinary tract symptoms. Physical examination revealed diffuse tenderness in the epigastric area and a nonpalpable liver and spleen. Full cutaneous examination showed hemorrhagic bullae on the patient's lower extremities (Figure 2) and palpable purpura on her arms. Since the initial presentation 2 months prior, the patient's hematocrit level had dropped approximately 10% from 34.6% to 24.3% (reference range, 41.0%–50.0%). Her white blood cell count was slightly lower (3.6 k/µL) and her platelet count was 144 k/µL. Of note, her D-dimer level was elevated (1846 ng/mL; reference range, 0–230 ng/mL), as was her fibrinogen level (613 mg/dL; reference range, 220–530 mg/dL). Repeat urinalysis showed no proteinuria, hematuria, or nitrites.

The patient subsequently was admitted to the hospital. A workup of her gastrointestinal tract, including a computed tomographic scan of the abdomen and endoscopy, failed to show an etiology for the abdominal pain. Her amylase and lipase levels were normal, and stool cultures and guaiac occult blood tests were negative. Biopsies performed during endoscopy showed mild acute colitis of the hepatic flexure and the ileocecal valve. The patient was prescribed a prophylactic regimen of meropenem and metronidazole for colitis, though no precise etiology was identified. An anti-IgA immunostudy was performed on paraffin sections of the original skin biopsy and showed strong labeling in the dermal endothelial cells consistent with immunocomplex deposition (Figure 3). The patient was diagnosed with Henoch-Schönlein purpura (HSP) and her rash and abdominal pain improved with prednisone 60 mg daily. Biopsy of a bone marrow specimen showed myelodysplastic changes and a cellular bone marrow with trilineage dyspoiesis and increased blasts.

Ten days after discharge, the patient's cutaneous eruption had greatly improved, with residual macules present on the dorsum of both feet and only faint reticulated erythema and rare purpura across the lower abdomen and lower extremities. She was scheduled for a second stem cell transplant to treat the myelodysplasia.

Comment
HSP is a systemic leukocytoclastic vasculitis involving arterioles and venules most commonly in the skin, glomeruli, and gastrointestinal tract.1,2 It is common for affected tissues to histologically demonstrate the presence of IgA in vessel walls. Fever and palpable purpura, predominantly on the buttocks and extremities, often are the first signs of HSP and may be accompanied by arthralgia, abdominal pain, and renal disease.2 The arthritis can be characterized as transient and oligoarticular, commonly affecting large joints and often with pain out of proportion to objective evidence of synovitis.2 Signs of peritoneal inflammation may occur and melena is common; more severe gastrointestinal tract complications that may warrant surgical intervention also have been described.2,3 Renal pathology in patients with HSP involves a spectrum ranging from mild focal glomerulitis to rapidly proliferative glomerulonephritis accompanied by variable amounts of proteinuria and hematuria.2 In 1990, the American College of Rheumatology identified 4 criteria for separating HSP cases from controls: (1) age 20 years or younger at disease onset, (2) palpable purpura, (3) acute abdominal pain, and (4) biopsy showing granulocytes in the walls of small arterioles or venules. When 2 or more of any of these criteria were present, HSP was distinguished from other forms of vasculitis with a sensitivity of 87.1% and a specificity of 87.7%.2 HSP is the most common systemic vasculitis of childhood and has been historically and predominantly viewed as a pediatric disease. HSP is believed to affect adults less frequently but has been reported to be responsible for a substantial percentage of all cases of cutaneous vasculitis among adults.4 In a retrospective study of patients with HSP, Blanco et al5 found that HSP represents a more severe clinical syndrome in adulthood than in childhood, but the prognosis of patients is equally good in both adult and pediatric populations. An exact cause of HSP has not been identified; however, many processes have been implicated in its development, including infections; drugs; and allergic, rheumatologic, and neoplastic diseases. Neoplasia in adults with systemic or cutaneous vasculitis has an estimated prevalence of 2.5% to 5.0%, with hematopoietic malignancies occurring more commonly than solid tumors.6 Although malignancy has been reported to occur in association with nearly all forms of vasculitis, the association between cutaneous hypersensitivity vasculitis and hematopoietic malignancies is most notable.7 In 1996, Fortin8 outlined several classic hypotheses explaining the role of neoplastic disease in the development of vasculitic syndromes such as HSP, including the impaired clearance of normally deposited immune complexes, abnormal production of immunoglobulins that may either directly react to vascular antigens and cause in situ immune complex formation or form circulating immune complexes that can then deposit in vessel walls, and common antigens presenting on the surface of malignant cells that may stimulate T-cell activation or the production of immunoglobulin directed not only toward malignant cells but healthy epithelium as well. The association of vasculitis with malignancy has been reviewed extensively in the literature.9-12 Sanchez-Guerrero et al9 found that 11 of 222 patients with vasculitis had associated neoplasia, with both hematologic and solid tumors implicated. Importantly, the authors noted that in 4 of 11 patients with paraneoplastic vasculitis, symptoms of vascular inflammation were evidence of the initial presentation of neoplasia or its recurrence.9 Kurzrock et al10 reviewed the manifestation of vasculitis in patients with solid tumors and found that in 71% of cases (25/35), symptoms of vasculitis appeared before or concurrent with the initial recognition or relapse of the tumor. Greer et al11 described 13 patients with both vasculitis and lymphoproliferative or myeloproliferative syndromes and reported a statistically significant (P<.0000001) association between the 2 when compared with all other tumors. The authors further asserted that tumor-associated vasculitis is a heterogeneous group of syndromes that share clinical features; malignancy or its recurrence should be considered in patients with unexplained vasculitis; and although treatment of the underlying neoplasm may lead to resolution of vasculitis, specific therapy for vascular inflammation often is not effective.11
HSP specifically has been described in patients with malignancy and vasculitis (Table).6,13-36 In 2000, Pertuiset et al6 reviewed 14 cases of adult HSP and found malignant neoplasm in 4 cases. They also identified 15 reports of adult HSP with malignant disease in the literature. Collectively, these 19 cases were compared with 158 adults who had HSP but no malignancy. The authors reported that 63% (12/19) of neoplasms associated with adult HSP were solid tumors, while the remaining 37% (7/19) were hematologic malignancies. Patients with paraneoplastic HSP were older, more likely to be male, more frequently had joint involvement, and had a lower frequency of prior infection compared with patients with HSP not associated with malignancy. There was no reported statistically significant difference in percentage of patients with cutaneous purpura, gastrointestinal tract involvement, renal involvement, or polyclonal IgA increase between the 2 groups.6

More recently, Zurada et al23 presented the cases of 3 adults who developed HSP within months of diagnosis of a solid tumor or metastasis of a previously diagnosed malignancy. In their review of the world literature, the authors found that 31 cases of malignancy-associated HSP had been reported, and in most cases, the patients were male (94%; 29/31), presented with solid tumors (61%; 19/31), and developed HSP within one month of cancer diagnosis or detection of metastases (55%; 17/31).23

The occurrence of vasculitis and malignant disease in the same patient often is difficult to interpret because some patients may exhibit both diseases independently and by chance, while others may have vasculitis as a paraneoplastic syndrome.6 Currently, the principal sources of data on the association between HSP and malignancy are anecdotal case reports, which can be difficult to use to determine causality and relationship with significance. However, because of the relative rarity of paraneoplastic vasculitis, large studies are difficult, making case reports and smaller literature reviews of unusual presentations valuable.8

Conclusion
In summary, we present a 57-year-old woman with a history of follicular lymphoma who developed HSP likely associated with myelodysplastic syndrome. This case is clinically significant because the patient was thought to be in remission of her hematologic disease until her skin findings prompted further evaluation. Her diagnosis of HSP was based on clinical presentation with palpable purpura and abdominal pain, and was confirmed with biopsy and immunohistochemical analyses of purpuric papules that demonstrated leukocytoclastic vasculitis and strong anti-IgA labeling in the dermal endothelial cells consistent with immunocomplex deposition. The patient was placed on a corticosteroid taper and scheduled for stem cell transplantation, with marked improvement demonstrated clinically at her most recent visit.

Dermatologists have a unique opportunity to recognize hereditary syndromes associated with renal tumors. By doing so, it may be possible to diagnose these tumors before they become life threatening. Although these syndromes are rare, it is incumbent upon dermatologists to recognize these disorders and recommend appropriate screening tests and referral to other specialists, including urologists, oncologists, and geneticists. Of the 9 known hereditary syndromes with renal tumors, 4 demonstrate cutaneous manifestations: von Hippel-Lindau (VHL) syndrome, Birt-Hogg-Dube (BHD) syndrome, tuberous sclerosis (TS), and hereditary leiomyoma renal cell carcinoma (HLRCC) syndrome. Renal cell carcinoma (RCC) is diagnosed in more than 30,000 individuals in the United States each year, causes 12,000 deaths annually, and is increasing in incidence.1 Known risk factors for sporadic renal cancer include smoking, chemical exposure, asbestosis, obesity, hypertension, and end-stage renal disease. There is growing recognition that heredity also plays a role, and it is estimated that approximately 4% of renal cancers are hereditary. In these individuals, a germ line mutation is associated with a predisposition to develop renal tumors of specific histologic types.2 In the past 10 years, advances in genomics and the widespread use of modern imaging techniques have contributed to the awareness of hereditary renal cancer syndromes. Increased knowledge of these syndromes will allow dermatologists to screen and counsel family members as well as identify those patients at risk for multiple cancer development. Early screening to identify localized tumors will provide opportunities to therapeutically intervene while cancers are still treatable.3 Because 4 of these syndromes involve cutaneous manifestations, the dermatologist may have the opportunity to make the diagnosis at an early stage. Hereditary renal cancers differ from sporadic renal cancers in several important respects.2 A hallmark of hereditary renal cancer is that tumors often are multiple and bilateral. Unlike sporadic renal cancers, which develop in the sixth and seventh decades of life, hereditary renal cancers may develop much earlier, even in teenaged individuals. Although sporadic renal tumors are more common in men, hereditary renal cancers often are found with equal frequency in both sexes. Disease severity can be highly variable, even within a family, and the absence of a family history never completely excludes the possibility of a hereditary cause for renal cancer.2 

Renal Tumor Classification
There are several histologic types of renal cancer in adults and each is linked with a specific hereditary syndrome.2 The most common histologic subtype is clear cell carcinoma, which accounts for 75% of renal cancers. Clear cell carcinomas arise from the proximal tubular epithelium. Grossly, they appear yellow because of their high lipid content. Microscopically, these cells appear lucent because of their high glycogen content. Clear cell carcinomas are seen in VHL syndrome and TS.2 The second most common type of renal cancer is papillary cell carcinoma (15%).4 It is subclassified into type 1 and type 2. Type 1 is found in hereditary papillary renal cancer and is associated with a good long-term prognosis. It is characterized by cells with scant pale cytoplasm arranged in a single layer. Type 2 is found in HLRCC syndrome and is a more aggressive form. Type 2 cells are pseudostratified with an eosinophilic cytoplasm.4 Chromophobe carcinoma is the third most common cell type.3 This tumor contains cells with well-defined borders, large eosinophilic cytoplasm, and pyknotic nuclei with a perinuclear halo. The cell of origin is most likely the intercalated cell of the cortical collecting duct. Chromophobe carcinomas account for approximately 5% of renal cancers and are found in BHD syndrome.3 Oncocytomas account for 2% to 3% of renal tumors and are considered to be benign renal neoplasms.5 Grossly, they are mahogany brown and are not necrotic. Histologically, they are composed of tightly packed tubular structures or nesting cells surrounded by a reticulin skeleton. They commonly grow centrifugally from a central avascular scar. Oncocytomas can be found in BHD syndrome and hereditary renal oncocytoma.5 Rare malignant tumors of the kidney include collecting duct and medullary carcinomas, which represent only 1% of renal tumors. Transitional cell carcinoma of the renal pelvis is another cause of malignancy in the kidneys and is associated with hereditary nonpolyposis colon cancer syndrome (Lynch syndrome).6 A common benign tumor of the renal parenchyma is angiomyolipoma, which is a hamartoma of the kidneys that contains vascular, lipomatous, and myeloid elements. Most of these tumors are small and slow growing. The primary risk associated with angiomyolipoma is hemorrhage. These tumors are found in TS.7 The Table lists the hereditary renal cancers and their respective chromosomal and clinical associations.

 
Clinical Manifestations of Renal Tumors
Because of their insidious course and varied clinical presentations, renal tumors most commonly are diagnosed as incidental findings during radiologic procedures.8 The classic triad of symptoms—hematuria, flank pain, and an abdominal mass—is seen only in approximately 10% of patients; in most cases, only one of these symptoms is the initial manifestation of the tumor. Systemic symptoms may be present, including weight loss, fatigue, and fever. RCC also is associated with several paraneoplastic syndromes, such as polycythemia (from ectopic erythropoietin production) and hypercalcemia (from ectopic production of parathyroid hormone–related peptide). Metastases mainly are through hematologic spread, and the lungs, bones, and liver are the most frequent sites. 8 back to top

Prognosis and Staging of Renal Tumors
RCC remains a major source of morbidity and mortality.9 Approximately 40% of patients eventually die of cancer progression, making RCC the most lethal of the common urologic malignancies. Although modern imaging has led to earlier diagnosis of RCC, more than 20% of patients present with metastatic disease. Tumor stage remains the most important prognostic factor for RCC. When renal cancers are organ confined, the 5-year survival rate is between 74% and 96%. This rate decreases to 40% to 60% when the renal veins are involved. With locally advanced renal cancers, as well as those with lymphatic involvement or metastasis, the 5-year survival rate is 0% to 20%.9

Treatment of Renal Tumors
Surgical resection (nephrectomy, partial nephrectomy) remains the most viable treatment option for RCC, regardless of the stage of disease at presentation. For localized tumors, surgical cure of disease is strongly dependent on stage and grade of disease.10 For locally advanced or metastatic disease, nephrectomy should be considered for palliation or as part of an adjuvant therapy protocol. Curative lymphadenectomy is not possible in most cases, and the value of lymphadenectomy is limited to those patients with lymph node involvement. Limited dissection of tissue and resection of the visible or palpable nodes usually is sufficient.11 Renal tumors respond poorly to radiation, chemotherapy, and immunotherapy, with response rates of less than 20%.12 However, advances in the understanding of immune responses to RCC have led to new therapeutic strategies based on immune manipulation. The identification of numerous T-cell epitopes associated with RCC has led to the development of new treatment approaches using DNA vaccination, peptide vaccination, and dendritic cell therapy; combined with new and more efficient gene-delivery techniques, these treatments may have considerable clinical implications for patients with RCC.12 Targeted therapies that are currently being investigated for metastatic RCC include tyrosine kinase inhibitors (ie, sorafenib), anti–vascular endothelial growth factor therapy (ie, bevacizumab), and inhibition of the mammalian target of rapamycin (mTOR) pathway (ie, temsirolimus).13 back to top

VHL Syndrome
VHL syndrome represents a constellation of central nervous system (CNS) and visceral neoplasms that result from a germ line mutation of the VHL tumor suppressor gene on chromosome arm 3p25-26.14 In this autosomal dominant neurocutaneous syndrome, 80% of cases are hereditary and 20% are sporadic. The incidence of VHL syndrome is approximately 1 in 36,000 individuals.15 Patients with VHL syndrome typically present before the age of 40 years.16 Although less than 5% of cases of VHL syndrome have dermatologic manifestations, capillary malformations are the most common cutaneous features. Thus, the dermatologist must be vigilant to observe for VHL syndrome in the appropriate clinical context. More than 70% of sporadic clear cell RCCs display mutations in the VHL gene.17 The VHL protein produced via this gene is a ubiquitin ligase that degrades hypoxia-inducible factors (HIFs) including HIF-1α and HIF-2α. A mutation of the VHL gene can increase the levels of HIF, which subsequently activate additional genes that produce vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor α, and carbonic anhydrase IX. In concert, these factors facilitate neoangiogenesis and tumorigenesis.17 The mutation of the VHL gene leads to the development of both benign and malignant tumors that affect multiple organ systems. CNS tumors include retinal hemangioblastomas (20%–60%); endolymphatic sac tumors (11%–16%); and craniospinal hemangiomas, most frequently of the cerebellum (44%–72%), brainstem (10%–25%), and spinal cord (13%–50%). Additional manifestations of VHL syndrome include RCC or kidney cyst (25%–60%), epididymal cystadenoma (25%–60% of men), pancreatic cyst or cystadenoma (17%–56%), pheochromocytoma or paraganglioma (10%–20%), and broad ligament cystadenoma (10% of women).18 The capillary malformations of VHL syndrome often occur in but are not limited to the head and neck. Also, café au lait spots that frequently are associated with neurofibromatosis may be evident in VHL syndrome, suggesting overlap between these phakomatoses.19 VHL syndrome is a progressive disease, with death characteristically occurring by the fourth decade of life. The diagnosis of VHL syndrome is based on clinical criteria. Patients with a family history of VHL syndrome and a CNS hemangioblastoma, pheochromocytoma, or clear cell RCC are diagnosed with the syndrome. In the absence of a family history, the diagnosis can be made with 2 or more CNS hemangioblastomas and a visceral tumor, with the exclusion of renal and epididymal cysts. Confirmation of diagnosis and screening for possibly affected family members can be achieved with DNA testing for mutation in the VHL gene. Recommended laboratory tests include a complete blood count and screenings for serum catecholamine and urine vanillylmandelic acid levels, as well as a computed tomographic scan (CT scan) and/or magnetic resonance imaging of the brain, spinal cord, and abdomen. Patients diagnosed with VHL syndrome should be referred to an ophthalmologist for photocoagulation or cryocoagulation of tumors. Neurosurgeons and urologists may surgically remove CNS and renal tumors, respectively, with preoperative angiography. Patients with VHL syndrome also may consider renal transplantation.

BHD Syndrome
BHD syndrome, an autosomal dominant genodermatosis occurring in 1 in 200,000 individuals, is characterized by the cutaneous triad of fibrofolliculomas, trichodiscomas, and acrochordons. Vincent and colleagues20 offer a comprehensive analysis of these papules, which frequently appear in the third to fourth decades of life. Protein-truncating mutations of the BHD gene on chromosome arm 17p11.2 encode the BHD protein folliculin, which is expressed in the kidneys, lungs, and skin.21 Although the function of the protein is unknown, the BHD gene is presumptively involved in tumor suppression. Fibrofolliculomas and trichodiscomas are clinically indistinguishable; both are skin-colored, well-circumscribed, smooth, firm, 2- to 4-mm papules distributed over the forehead, nose, and cheeks.22 Acrochordons appear as soft pedunculated lesions. The clinical appearance of fibrofolliculomas and trichodiscomas is associated with familial spontaneous pneumothorax and RCCs. Notably, patients with BHD syndrome have a 50-fold increased risk of pneumothorax presenting with tachypnea, decreased breath sounds, and hyperresonance.23 Lung cysts and bullous emphysema also have been associated with BHD syndrome. In addition to the cutaneous and pulmonary features, a 7-fold increase in renal tumors with varying histology has been associated with BHD syndrome, including hybrid chromophobe and oncocytoma (50%), chromophobe (34%), clear cell RCC (9%), and oncocytoma (5%).23 Multiple histologic types can be found in the same family, patient, and kidney, suggesting a role for the BHD gene in the differentiation processes of renal cells. Fibrofolliculomas possess a circumscribed fibrous tissue layer around the hair follicles.24 These follicles demonstrate a widened infundibulum containing laminated keratin. Encasing the follicle is a mantle of loose connective tissue embedded in a mucoid ground substance with high concentrations of hyaluronic acid. The elastin fibers may not be visible or appear sparse. Radiating from the follicular epithelium are 2 to 4 thin layers of epithelial strands that extend into the fibrous tissue where they combine with epithelial strands or connect with follicular or sebaceous epithelium. In contrast, the histology of the trichodiscomas demonstrates hair follicles at the margin of these tumors. The stroma is highly vascularized, with collagen fibers and cells containing melanin.24 A diagnosis of BHD syndrome requires 5 or more facial or truncal papules; 1 papule must be confirmed as a fibrofolliculoma or trichodiscoma using the histologic criteria above. The differential diagnosis includes TS, Cowden syndrome, Brooke-Spiegler syndrome, Rombo syndrome, and basaloid follicular hamartoma syndrome. It is recommended that all patients who are diagnosed with BHD syndrome get a chest x-ray, abdominal CT scan, and renal ultrasound. Thereafter, patients may be screened every 3 to 5 years. Siblings of patients require physical examinations and biopsies of suspicious skin lesions as early as the second decade of life. Treatment options for fibrofolliculomas and trichodiscomas include CO2 laser ablation and/or erbium:YAG laser, copper vapor laser, and systemic isotretinoin, though these therapies have shown variable results in some patients.24 Resection is recommended for RCC. If the tumor is less than 3 cm in size, surgery that conserves the parenchyma may be appropriate to optimize renal function without increasing the risk of metastases. The prognosis depends on the renal and pulmonary sequelae. 

Tuberous Sclerosis
TS, also called tuberous sclerosis complex (TSC), is a rare genetic disease that causes benign tumors to grow in the brain and other organs, such as the kidneys, lungs, skin, and eyes.25 Its incidence is 1 in 10,000 individuals and the age of presentation is variable. TS is an autosomal dominant disorder; approximately 40% of cases are hereditary and 60% are sporadic.26 Two gene mutations have been identified in contributing to the development of TS: the hamartin gene TSC1 on the chromosome arm 9q34 and tuberin gene TSC2 on the chromosome arm 16p13.3. The latter is adjacent to the PKD1 site, which is responsible for autosomal dominant polycystic kidney disease, thereby explaining the association of these 2 disorders in patients with contiguous gene defects. Hamartin and tuberin associate in vivo to form a tumor suppressor complex. This complex functions within the P13K-Akt-mTOR pathway and regulates nutrient and growth factor signaling to mTOR. As a result, rapamycin has potential therapeutic use in TS.26 The clinical features of TS include neurologic involvement with mental cognitive deficiency and epilepsy; psychiatric and behavioral problems such as attention deficit hyperactivity disorder and generalized development delays; and organic brain anomalies such as cortical tubera, subependymal giant cell astrocytomas, and subependymal nodules.25 Cardiac rhabdomyomas, retinal hamartomas, and dental pits also are typical findings of TS. Pulmonary lymphangioleiomyomatosis related to TS has been described, usually presenting exclusively in women. Classic cutaneous lesions include facial angiofibromas (adenoma sebaceum), the shagreen patch, and periungual or subungual fibromas (Koenen tumors).25 Renal manifestations are mainly angiomyolipomas, renal cysts, and cancer.27 In patients with TS, multiple lesions appear concomitantly and are likely to be bilateral. Larger lesions may present with flank pain, hypertension, hematuria, and renal failure. These lesions characteristically are benign, though there are some reports of sarcomatous degeneration and rare malignant epithelioid variants.27 Angiomyolipomas are not hamartomas per se, rather they are clonal perivascular epithelioid cell tumors (PEComas).28 PEComas are tumors composed of mostly epithelioid cells positive for HMB-45 and/or melan-A as well as actin- and/or desmin-positive cells. These PEComas have a perivascular propensity. They belong to a family of me-senchymal neoplasms that include angiomyolipomas, lymphangioleiomyomatosis, clear cell tumor (sugar tumor) of the lung, and other soft tissue and visceral neoplasms with similar histology and immunohistochemistry. Pan et al29 studied the cytogenetic feature of these tumors and reported that all cells studied had gross chromosomal anomalies, with the most frequent being a deletion of chromosome arm 16p, in which TSC2 is located. Alam et al30 concluded that PEComas are distinctive tumors based on the common chromosomal changes found in both renal and extrarenal tumors. Starting in childhood, renal ultrasounds can be used to detect and monitor the growth of angiomyolipomas. Because complications correlate with increasing size, surgery is recommended when the tumor is greater than 3.5 to 4.0 cm in size. Surgical options include tumor embolization, tumor enucleation, partial nephrectomy, or total nephrectomy depending on the presentation. Patients with TS are at a higher risk for renal cancer than the general population (2.0%–4.0% vs 1.27%, respectively) and are more likely to present at a younger age (30 years vs 60 years, respectively). Renal cancer in patients with TS is most commonly of the clear cell carcinoma type and is more likely to be multifocal and bilateral.2 For these reasons, lifelong periodic radiologic evaluation is essential. 

HLRCC Syndrome
HLRCC syndrome is an autosomal dominant disease that is an expansion of Reed syndrome (multiple cutaneous and uterine leiomyoma syndrome). It is characterized by the presence of leiomyomas in the skin and uterus of affected females and in the skin of affected males. Its prevalence in the general population is not known, though one limited study estimated the presence of a heterozygous fumarate hydratase, FH, gene mutation at 1 in 676 individuals.30 Germ line mutations in the FH gene at chromosome arm 1q42.3-43 are associated with the HLRCC syndrome.31 In the Krebs cycle, the FH and succinate dehydrogenase, SD, genes act as tumor suppressors. Mutations in the SD gene are associated with pheochromocytomas and paragangliomas. Mutations in the FH gene lead to the overexpression of HIF-1α and its targets (eg, vascular endothelial growth factor), which contributes to tumorigenesis by the so-called pseudohypoxic drive. There is a low frequency of FH mutations in sporadic cases of leiomyomas and leiomyosarcomas.31 The clinical features of patients with HLRCC syndrome include benign cutaneous and uterine leiomyomas and, more rarely, cutaneous leiomyosarcomas and uterine leiomyosarcomas. Cutaneous leiomyomas usually present in late childhood to early adulthood. They typically present as multiple disseminated lesions, most commonly on the face, trunk, and extremities, though segmental distribution also has been described.30 The individual lesions appear as intradermal papules. Alam et al30 stated that 90% of patients complain of pain from cutaneous leiomyoma, which is exacerbated by cold or trauma. Although leiomyomas may be solitary and sporadic lesions, Chuang et al32 noted that the finding of a cutaneous leiomyoma in a patient should compel dermatologists to examine the individual and his/her family for multiple lesions and to screen for the FH gene, which is crucial because FH mutations in HLRCC syndrome lead to increased susceptibility to early-onset RCC. These RCCs usually are solitary, fast growing, and very aggressive, and they display papillary cell carcinoma type 2 or renal collecting duct histology. Alam et al30 reported a case of a 16-year-old patient who presented with metastatic renal disease, which led the authors to urge the consideration of early screenings for FH mutations for patients. Toro et al33 screened 35 families with cutaneous leiomyomas for mutations in the FH gene. They identified mutations in 31 families (89%). Eighty-one individuals had cutaneous leiomyomas, of which 47 were women and 34 were men. Forty-six of 47 women (98%) had uterine leiomyomas. The authors also found 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from 4 families had papillary cell carcinoma type 2, and 1 individual from 1 of these families had renal collecting duct carcinoma.33 Patients who present with lesions that are diagnosed as cutaneous leiomyomas should prompt a complete history, including a history of fibroids in women as well as a family history of fibroids or renal tumors.34 Tests for mutations in the FH gene may be of value. Renal imaging studies should be performed in suspect cases. Although some papillary cell carcinoma type 2 or collecting duct RCCs can be found only with a CT scan or magnetic resonance imaging, a simple ultrasound is successful in most cases and can sometimes provide superior information about the characteristics of the renal tumor.34 

Conclusion
Dermatologists have a unique opportunity to diagnose hereditary renal tumors before they become life threatening. When examining patients with capillary malformations, fibrofolliculomas, angiofibromas, or leiomyomas, the dermatologist should consider the possibility of VHL syndrome, BHD syndrome, TS, or HLRCC syndrome, respectively. With a positive family history, renal imaging studies should be obtained. Although these syndromes are rare, it is essential that dermatologists recognize them for the benefit of the patients and their kin.

Dermatologists have a unique opportunity to recognize hereditary syndromes associated with renal tumors. By doing so, it may be possible to diagnose these tumors before they become life threatening. Although these syndromes are rare, it is incumbent upon dermatologists to recognize these disorders and recommend appropriate screening tests and referral to other specialists, including urologists, oncologists, and geneticists. Of the 9 known hereditary syndromes with renal tumors, 4 demonstrate cutaneous manifestations: von Hippel-Lindau (VHL) syndrome, Birt-Hogg-Dube (BHD) syndrome, tuberous sclerosis (TS), and hereditary leiomyoma renal cell carcinoma (HLRCC) syndrome. Renal cell carcinoma (RCC) is diagnosed in more than 30,000 individuals in the United States each year, causes 12,000 deaths annually, and is increasing in incidence.1 Known risk factors for sporadic renal cancer include smoking, chemical exposure, asbestosis, obesity, hypertension, and end-stage renal disease. There is growing recognition that heredity also plays a role, and it is estimated that approximately 4% of renal cancers are hereditary. In these individuals, a germ line mutation is associated with a predisposition to develop renal tumors of specific histologic types.2 In the past 10 years, advances in genomics and the widespread use of modern imaging techniques have contributed to the awareness of hereditary renal cancer syndromes. Increased knowledge of these syndromes will allow dermatologists to screen and counsel family members as well as identify those patients at risk for multiple cancer development. Early screening to identify localized tumors will provide opportunities to therapeutically intervene while cancers are still treatable.3 Because 4 of these syndromes involve cutaneous manifestations, the dermatologist may have the opportunity to make the diagnosis at an early stage. Hereditary renal cancers differ from sporadic renal cancers in several important respects.2 A hallmark of hereditary renal cancer is that tumors often are multiple and bilateral. Unlike sporadic renal cancers, which develop in the sixth and seventh decades of life, hereditary renal cancers may develop much earlier, even in teenaged individuals. Although sporadic renal tumors are more common in men, hereditary renal cancers often are found with equal frequency in both sexes. Disease severity can be highly variable, even within a family, and the absence of a family history never completely excludes the possibility of a hereditary cause for renal cancer.2 

Renal Tumor Classification
There are several histologic types of renal cancer in adults and each is linked with a specific hereditary syndrome.2 The most common histologic subtype is clear cell carcinoma, which accounts for 75% of renal cancers. Clear cell carcinomas arise from the proximal tubular epithelium. Grossly, they appear yellow because of their high lipid content. Microscopically, these cells appear lucent because of their high glycogen content. Clear cell carcinomas are seen in VHL syndrome and TS.2 The second most common type of renal cancer is papillary cell carcinoma (15%).4 It is subclassified into type 1 and type 2. Type 1 is found in hereditary papillary renal cancer and is associated with a good long-term prognosis. It is characterized by cells with scant pale cytoplasm arranged in a single layer. Type 2 is found in HLRCC syndrome and is a more aggressive form. Type 2 cells are pseudostratified with an eosinophilic cytoplasm.4 Chromophobe carcinoma is the third most common cell type.3 This tumor contains cells with well-defined borders, large eosinophilic cytoplasm, and pyknotic nuclei with a perinuclear halo. The cell of origin is most likely the intercalated cell of the cortical collecting duct. Chromophobe carcinomas account for approximately 5% of renal cancers and are found in BHD syndrome.3 Oncocytomas account for 2% to 3% of renal tumors and are considered to be benign renal neoplasms.5 Grossly, they are mahogany brown and are not necrotic. Histologically, they are composed of tightly packed tubular structures or nesting cells surrounded by a reticulin skeleton. They commonly grow centrifugally from a central avascular scar. Oncocytomas can be found in BHD syndrome and hereditary renal oncocytoma.5 Rare malignant tumors of the kidney include collecting duct and medullary carcinomas, which represent only 1% of renal tumors. Transitional cell carcinoma of the renal pelvis is another cause of malignancy in the kidneys and is associated with hereditary nonpolyposis colon cancer syndrome (Lynch syndrome).6 A common benign tumor of the renal parenchyma is angiomyolipoma, which is a hamartoma of the kidneys that contains vascular, lipomatous, and myeloid elements. Most of these tumors are small and slow growing. The primary risk associated with angiomyolipoma is hemorrhage. These tumors are found in TS.7 The Table lists the hereditary renal cancers and their respective chromosomal and clinical associations.

 
Clinical Manifestations of Renal Tumors
Because of their insidious course and varied clinical presentations, renal tumors most commonly are diagnosed as incidental findings during radiologic procedures.8 The classic triad of symptoms—hematuria, flank pain, and an abdominal mass—is seen only in approximately 10% of patients; in most cases, only one of these symptoms is the initial manifestation of the tumor. Systemic symptoms may be present, including weight loss, fatigue, and fever. RCC also is associated with several paraneoplastic syndromes, such as polycythemia (from ectopic erythropoietin production) and hypercalcemia (from ectopic production of parathyroid hormone–related peptide). Metastases mainly are through hematologic spread, and the lungs, bones, and liver are the most frequent sites. 8 back to top

Prognosis and Staging of Renal Tumors
RCC remains a major source of morbidity and mortality.9 Approximately 40% of patients eventually die of cancer progression, making RCC the most lethal of the common urologic malignancies. Although modern imaging has led to earlier diagnosis of RCC, more than 20% of patients present with metastatic disease. Tumor stage remains the most important prognostic factor for RCC. When renal cancers are organ confined, the 5-year survival rate is between 74% and 96%. This rate decreases to 40% to 60% when the renal veins are involved. With locally advanced renal cancers, as well as those with lymphatic involvement or metastasis, the 5-year survival rate is 0% to 20%.9

Treatment of Renal Tumors
Surgical resection (nephrectomy, partial nephrectomy) remains the most viable treatment option for RCC, regardless of the stage of disease at presentation. For localized tumors, surgical cure of disease is strongly dependent on stage and grade of disease.10 For locally advanced or metastatic disease, nephrectomy should be considered for palliation or as part of an adjuvant therapy protocol. Curative lymphadenectomy is not possible in most cases, and the value of lymphadenectomy is limited to those patients with lymph node involvement. Limited dissection of tissue and resection of the visible or palpable nodes usually is sufficient.11 Renal tumors respond poorly to radiation, chemotherapy, and immunotherapy, with response rates of less than 20%.12 However, advances in the understanding of immune responses to RCC have led to new therapeutic strategies based on immune manipulation. The identification of numerous T-cell epitopes associated with RCC has led to the development of new treatment approaches using DNA vaccination, peptide vaccination, and dendritic cell therapy; combined with new and more efficient gene-delivery techniques, these treatments may have considerable clinical implications for patients with RCC.12 Targeted therapies that are currently being investigated for metastatic RCC include tyrosine kinase inhibitors (ie, sorafenib), anti–vascular endothelial growth factor therapy (ie, bevacizumab), and inhibition of the mammalian target of rapamycin (mTOR) pathway (ie, temsirolimus).13 back to top

VHL Syndrome
VHL syndrome represents a constellation of central nervous system (CNS) and visceral neoplasms that result from a germ line mutation of the VHL tumor suppressor gene on chromosome arm 3p25-26.14 In this autosomal dominant neurocutaneous syndrome, 80% of cases are hereditary and 20% are sporadic. The incidence of VHL syndrome is approximately 1 in 36,000 individuals.15 Patients with VHL syndrome typically present before the age of 40 years.16 Although less than 5% of cases of VHL syndrome have dermatologic manifestations, capillary malformations are the most common cutaneous features. Thus, the dermatologist must be vigilant to observe for VHL syndrome in the appropriate clinical context. More than 70% of sporadic clear cell RCCs display mutations in the VHL gene.17 The VHL protein produced via this gene is a ubiquitin ligase that degrades hypoxia-inducible factors (HIFs) including HIF-1α and HIF-2α. A mutation of the VHL gene can increase the levels of HIF, which subsequently activate additional genes that produce vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor α, and carbonic anhydrase IX. In concert, these factors facilitate neoangiogenesis and tumorigenesis.17 The mutation of the VHL gene leads to the development of both benign and malignant tumors that affect multiple organ systems. CNS tumors include retinal hemangioblastomas (20%–60%); endolymphatic sac tumors (11%–16%); and craniospinal hemangiomas, most frequently of the cerebellum (44%–72%), brainstem (10%–25%), and spinal cord (13%–50%). Additional manifestations of VHL syndrome include RCC or kidney cyst (25%–60%), epididymal cystadenoma (25%–60% of men), pancreatic cyst or cystadenoma (17%–56%), pheochromocytoma or paraganglioma (10%–20%), and broad ligament cystadenoma (10% of women).18 The capillary malformations of VHL syndrome often occur in but are not limited to the head and neck. Also, café au lait spots that frequently are associated with neurofibromatosis may be evident in VHL syndrome, suggesting overlap between these phakomatoses.19 VHL syndrome is a progressive disease, with death characteristically occurring by the fourth decade of life. The diagnosis of VHL syndrome is based on clinical criteria. Patients with a family history of VHL syndrome and a CNS hemangioblastoma, pheochromocytoma, or clear cell RCC are diagnosed with the syndrome. In the absence of a family history, the diagnosis can be made with 2 or more CNS hemangioblastomas and a visceral tumor, with the exclusion of renal and epididymal cysts. Confirmation of diagnosis and screening for possibly affected family members can be achieved with DNA testing for mutation in the VHL gene. Recommended laboratory tests include a complete blood count and screenings for serum catecholamine and urine vanillylmandelic acid levels, as well as a computed tomographic scan (CT scan) and/or magnetic resonance imaging of the brain, spinal cord, and abdomen. Patients diagnosed with VHL syndrome should be referred to an ophthalmologist for photocoagulation or cryocoagulation of tumors. Neurosurgeons and urologists may surgically remove CNS and renal tumors, respectively, with preoperative angiography. Patients with VHL syndrome also may consider renal transplantation.

BHD Syndrome
BHD syndrome, an autosomal dominant genodermatosis occurring in 1 in 200,000 individuals, is characterized by the cutaneous triad of fibrofolliculomas, trichodiscomas, and acrochordons. Vincent and colleagues20 offer a comprehensive analysis of these papules, which frequently appear in the third to fourth decades of life. Protein-truncating mutations of the BHD gene on chromosome arm 17p11.2 encode the BHD protein folliculin, which is expressed in the kidneys, lungs, and skin.21 Although the function of the protein is unknown, the BHD gene is presumptively involved in tumor suppression. Fibrofolliculomas and trichodiscomas are clinically indistinguishable; both are skin-colored, well-circumscribed, smooth, firm, 2- to 4-mm papules distributed over the forehead, nose, and cheeks.22 Acrochordons appear as soft pedunculated lesions. The clinical appearance of fibrofolliculomas and trichodiscomas is associated with familial spontaneous pneumothorax and RCCs. Notably, patients with BHD syndrome have a 50-fold increased risk of pneumothorax presenting with tachypnea, decreased breath sounds, and hyperresonance.23 Lung cysts and bullous emphysema also have been associated with BHD syndrome. In addition to the cutaneous and pulmonary features, a 7-fold increase in renal tumors with varying histology has been associated with BHD syndrome, including hybrid chromophobe and oncocytoma (50%), chromophobe (34%), clear cell RCC (9%), and oncocytoma (5%).23 Multiple histologic types can be found in the same family, patient, and kidney, suggesting a role for the BHD gene in the differentiation processes of renal cells. Fibrofolliculomas possess a circumscribed fibrous tissue layer around the hair follicles.24 These follicles demonstrate a widened infundibulum containing laminated keratin. Encasing the follicle is a mantle of loose connective tissue embedded in a mucoid ground substance with high concentrations of hyaluronic acid. The elastin fibers may not be visible or appear sparse. Radiating from the follicular epithelium are 2 to 4 thin layers of epithelial strands that extend into the fibrous tissue where they combine with epithelial strands or connect with follicular or sebaceous epithelium. In contrast, the histology of the trichodiscomas demonstrates hair follicles at the margin of these tumors. The stroma is highly vascularized, with collagen fibers and cells containing melanin.24 A diagnosis of BHD syndrome requires 5 or more facial or truncal papules; 1 papule must be confirmed as a fibrofolliculoma or trichodiscoma using the histologic criteria above. The differential diagnosis includes TS, Cowden syndrome, Brooke-Spiegler syndrome, Rombo syndrome, and basaloid follicular hamartoma syndrome. It is recommended that all patients who are diagnosed with BHD syndrome get a chest x-ray, abdominal CT scan, and renal ultrasound. Thereafter, patients may be screened every 3 to 5 years. Siblings of patients require physical examinations and biopsies of suspicious skin lesions as early as the second decade of life. Treatment options for fibrofolliculomas and trichodiscomas include CO2 laser ablation and/or erbium:YAG laser, copper vapor laser, and systemic isotretinoin, though these therapies have shown variable results in some patients.24 Resection is recommended for RCC. If the tumor is less than 3 cm in size, surgery that conserves the parenchyma may be appropriate to optimize renal function without increasing the risk of metastases. The prognosis depends on the renal and pulmonary sequelae. 

Tuberous Sclerosis
TS, also called tuberous sclerosis complex (TSC), is a rare genetic disease that causes benign tumors to grow in the brain and other organs, such as the kidneys, lungs, skin, and eyes.25 Its incidence is 1 in 10,000 individuals and the age of presentation is variable. TS is an autosomal dominant disorder; approximately 40% of cases are hereditary and 60% are sporadic.26 Two gene mutations have been identified in contributing to the development of TS: the hamartin gene TSC1 on the chromosome arm 9q34 and tuberin gene TSC2 on the chromosome arm 16p13.3. The latter is adjacent to the PKD1 site, which is responsible for autosomal dominant polycystic kidney disease, thereby explaining the association of these 2 disorders in patients with contiguous gene defects. Hamartin and tuberin associate in vivo to form a tumor suppressor complex. This complex functions within the P13K-Akt-mTOR pathway and regulates nutrient and growth factor signaling to mTOR. As a result, rapamycin has potential therapeutic use in TS.26 The clinical features of TS include neurologic involvement with mental cognitive deficiency and epilepsy; psychiatric and behavioral problems such as attention deficit hyperactivity disorder and generalized development delays; and organic brain anomalies such as cortical tubera, subependymal giant cell astrocytomas, and subependymal nodules.25 Cardiac rhabdomyomas, retinal hamartomas, and dental pits also are typical findings of TS. Pulmonary lymphangioleiomyomatosis related to TS has been described, usually presenting exclusively in women. Classic cutaneous lesions include facial angiofibromas (adenoma sebaceum), the shagreen patch, and periungual or subungual fibromas (Koenen tumors).25 Renal manifestations are mainly angiomyolipomas, renal cysts, and cancer.27 In patients with TS, multiple lesions appear concomitantly and are likely to be bilateral. Larger lesions may present with flank pain, hypertension, hematuria, and renal failure. These lesions characteristically are benign, though there are some reports of sarcomatous degeneration and rare malignant epithelioid variants.27 Angiomyolipomas are not hamartomas per se, rather they are clonal perivascular epithelioid cell tumors (PEComas).28 PEComas are tumors composed of mostly epithelioid cells positive for HMB-45 and/or melan-A as well as actin- and/or desmin-positive cells. These PEComas have a perivascular propensity. They belong to a family of me-senchymal neoplasms that include angiomyolipomas, lymphangioleiomyomatosis, clear cell tumor (sugar tumor) of the lung, and other soft tissue and visceral neoplasms with similar histology and immunohistochemistry. Pan et al29 studied the cytogenetic feature of these tumors and reported that all cells studied had gross chromosomal anomalies, with the most frequent being a deletion of chromosome arm 16p, in which TSC2 is located. Alam et al30 concluded that PEComas are distinctive tumors based on the common chromosomal changes found in both renal and extrarenal tumors. Starting in childhood, renal ultrasounds can be used to detect and monitor the growth of angiomyolipomas. Because complications correlate with increasing size, surgery is recommended when the tumor is greater than 3.5 to 4.0 cm in size. Surgical options include tumor embolization, tumor enucleation, partial nephrectomy, or total nephrectomy depending on the presentation. Patients with TS are at a higher risk for renal cancer than the general population (2.0%–4.0% vs 1.27%, respectively) and are more likely to present at a younger age (30 years vs 60 years, respectively). Renal cancer in patients with TS is most commonly of the clear cell carcinoma type and is more likely to be multifocal and bilateral.2 For these reasons, lifelong periodic radiologic evaluation is essential. 

HLRCC Syndrome
HLRCC syndrome is an autosomal dominant disease that is an expansion of Reed syndrome (multiple cutaneous and uterine leiomyoma syndrome). It is characterized by the presence of leiomyomas in the skin and uterus of affected females and in the skin of affected males. Its prevalence in the general population is not known, though one limited study estimated the presence of a heterozygous fumarate hydratase, FH, gene mutation at 1 in 676 individuals.30 Germ line mutations in the FH gene at chromosome arm 1q42.3-43 are associated with the HLRCC syndrome.31 In the Krebs cycle, the FH and succinate dehydrogenase, SD, genes act as tumor suppressors. Mutations in the SD gene are associated with pheochromocytomas and paragangliomas. Mutations in the FH gene lead to the overexpression of HIF-1α and its targets (eg, vascular endothelial growth factor), which contributes to tumorigenesis by the so-called pseudohypoxic drive. There is a low frequency of FH mutations in sporadic cases of leiomyomas and leiomyosarcomas.31 The clinical features of patients with HLRCC syndrome include benign cutaneous and uterine leiomyomas and, more rarely, cutaneous leiomyosarcomas and uterine leiomyosarcomas. Cutaneous leiomyomas usually present in late childhood to early adulthood. They typically present as multiple disseminated lesions, most commonly on the face, trunk, and extremities, though segmental distribution also has been described.30 The individual lesions appear as intradermal papules. Alam et al30 stated that 90% of patients complain of pain from cutaneous leiomyoma, which is exacerbated by cold or trauma. Although leiomyomas may be solitary and sporadic lesions, Chuang et al32 noted that the finding of a cutaneous leiomyoma in a patient should compel dermatologists to examine the individual and his/her family for multiple lesions and to screen for the FH gene, which is crucial because FH mutations in HLRCC syndrome lead to increased susceptibility to early-onset RCC. These RCCs usually are solitary, fast growing, and very aggressive, and they display papillary cell carcinoma type 2 or renal collecting duct histology. Alam et al30 reported a case of a 16-year-old patient who presented with metastatic renal disease, which led the authors to urge the consideration of early screenings for FH mutations for patients. Toro et al33 screened 35 families with cutaneous leiomyomas for mutations in the FH gene. They identified mutations in 31 families (89%). Eighty-one individuals had cutaneous leiomyomas, of which 47 were women and 34 were men. Forty-six of 47 women (98%) had uterine leiomyomas. The authors also found 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from 4 families had papillary cell carcinoma type 2, and 1 individual from 1 of these families had renal collecting duct carcinoma.33 Patients who present with lesions that are diagnosed as cutaneous leiomyomas should prompt a complete history, including a history of fibroids in women as well as a family history of fibroids or renal tumors.34 Tests for mutations in the FH gene may be of value. Renal imaging studies should be performed in suspect cases. Although some papillary cell carcinoma type 2 or collecting duct RCCs can be found only with a CT scan or magnetic resonance imaging, a simple ultrasound is successful in most cases and can sometimes provide superior information about the characteristics of the renal tumor.34 

Conclusion
Dermatologists have a unique opportunity to diagnose hereditary renal tumors before they become life threatening. When examining patients with capillary malformations, fibrofolliculomas, angiofibromas, or leiomyomas, the dermatologist should consider the possibility of VHL syndrome, BHD syndrome, TS, or HLRCC syndrome, respectively. With a positive family history, renal imaging studies should be obtained. Although these syndromes are rare, it is essential that dermatologists recognize them for the benefit of the patients and their kin.

Dermatologists have a unique opportunity to recognize hereditary syndromes associated with renal tumors. By doing so, it may be possible to diagnose these tumors before they become life threatening. Although these syndromes are rare, it is incumbent upon dermatologists to recognize these disorders and recommend appropriate screening tests and referral to other specialists, including urologists, oncologists, and geneticists. Of the 9 known hereditary syndromes with renal tumors, 4 demonstrate cutaneous manifestations: von Hippel-Lindau (VHL) syndrome, Birt-Hogg-Dube (BHD) syndrome, tuberous sclerosis (TS), and hereditary leiomyoma renal cell carcinoma (HLRCC) syndrome. Renal cell carcinoma (RCC) is diagnosed in more than 30,000 individuals in the United States each year, causes 12,000 deaths annually, and is increasing in incidence.1 Known risk factors for sporadic renal cancer include smoking, chemical exposure, asbestosis, obesity, hypertension, and end-stage renal disease. There is growing recognition that heredity also plays a role, and it is estimated that approximately 4% of renal cancers are hereditary. In these individuals, a germ line mutation is associated with a predisposition to develop renal tumors of specific histologic types.2 In the past 10 years, advances in genomics and the widespread use of modern imaging techniques have contributed to the awareness of hereditary renal cancer syndromes. Increased knowledge of these syndromes will allow dermatologists to screen and counsel family members as well as identify those patients at risk for multiple cancer development. Early screening to identify localized tumors will provide opportunities to therapeutically intervene while cancers are still treatable.3 Because 4 of these syndromes involve cutaneous manifestations, the dermatologist may have the opportunity to make the diagnosis at an early stage. Hereditary renal cancers differ from sporadic renal cancers in several important respects.2 A hallmark of hereditary renal cancer is that tumors often are multiple and bilateral. Unlike sporadic renal cancers, which develop in the sixth and seventh decades of life, hereditary renal cancers may develop much earlier, even in teenaged individuals. Although sporadic renal tumors are more common in men, hereditary renal cancers often are found with equal frequency in both sexes. Disease severity can be highly variable, even within a family, and the absence of a family history never completely excludes the possibility of a hereditary cause for renal cancer.2 

Renal Tumor Classification
There are several histologic types of renal cancer in adults and each is linked with a specific hereditary syndrome.2 The most common histologic subtype is clear cell carcinoma, which accounts for 75% of renal cancers. Clear cell carcinomas arise from the proximal tubular epithelium. Grossly, they appear yellow because of their high lipid content. Microscopically, these cells appear lucent because of their high glycogen content. Clear cell carcinomas are seen in VHL syndrome and TS.2 The second most common type of renal cancer is papillary cell carcinoma (15%).4 It is subclassified into type 1 and type 2. Type 1 is found in hereditary papillary renal cancer and is associated with a good long-term prognosis. It is characterized by cells with scant pale cytoplasm arranged in a single layer. Type 2 is found in HLRCC syndrome and is a more aggressive form. Type 2 cells are pseudostratified with an eosinophilic cytoplasm.4 Chromophobe carcinoma is the third most common cell type.3 This tumor contains cells with well-defined borders, large eosinophilic cytoplasm, and pyknotic nuclei with a perinuclear halo. The cell of origin is most likely the intercalated cell of the cortical collecting duct. Chromophobe carcinomas account for approximately 5% of renal cancers and are found in BHD syndrome.3 Oncocytomas account for 2% to 3% of renal tumors and are considered to be benign renal neoplasms.5 Grossly, they are mahogany brown and are not necrotic. Histologically, they are composed of tightly packed tubular structures or nesting cells surrounded by a reticulin skeleton. They commonly grow centrifugally from a central avascular scar. Oncocytomas can be found in BHD syndrome and hereditary renal oncocytoma.5 Rare malignant tumors of the kidney include collecting duct and medullary carcinomas, which represent only 1% of renal tumors. Transitional cell carcinoma of the renal pelvis is another cause of malignancy in the kidneys and is associated with hereditary nonpolyposis colon cancer syndrome (Lynch syndrome).6 A common benign tumor of the renal parenchyma is angiomyolipoma, which is a hamartoma of the kidneys that contains vascular, lipomatous, and myeloid elements. Most of these tumors are small and slow growing. The primary risk associated with angiomyolipoma is hemorrhage. These tumors are found in TS.7 The Table lists the hereditary renal cancers and their respective chromosomal and clinical associations.

 
Clinical Manifestations of Renal Tumors
Because of their insidious course and varied clinical presentations, renal tumors most commonly are diagnosed as incidental findings during radiologic procedures.8 The classic triad of symptoms—hematuria, flank pain, and an abdominal mass—is seen only in approximately 10% of patients; in most cases, only one of these symptoms is the initial manifestation of the tumor. Systemic symptoms may be present, including weight loss, fatigue, and fever. RCC also is associated with several paraneoplastic syndromes, such as polycythemia (from ectopic erythropoietin production) and hypercalcemia (from ectopic production of parathyroid hormone–related peptide). Metastases mainly are through hematologic spread, and the lungs, bones, and liver are the most frequent sites. 8 back to top

Prognosis and Staging of Renal Tumors
RCC remains a major source of morbidity and mortality.9 Approximately 40% of patients eventually die of cancer progression, making RCC the most lethal of the common urologic malignancies. Although modern imaging has led to earlier diagnosis of RCC, more than 20% of patients present with metastatic disease. Tumor stage remains the most important prognostic factor for RCC. When renal cancers are organ confined, the 5-year survival rate is between 74% and 96%. This rate decreases to 40% to 60% when the renal veins are involved. With locally advanced renal cancers, as well as those with lymphatic involvement or metastasis, the 5-year survival rate is 0% to 20%.9

Treatment of Renal Tumors
Surgical resection (nephrectomy, partial nephrectomy) remains the most viable treatment option for RCC, regardless of the stage of disease at presentation. For localized tumors, surgical cure of disease is strongly dependent on stage and grade of disease.10 For locally advanced or metastatic disease, nephrectomy should be considered for palliation or as part of an adjuvant therapy protocol. Curative lymphadenectomy is not possible in most cases, and the value of lymphadenectomy is limited to those patients with lymph node involvement. Limited dissection of tissue and resection of the visible or palpable nodes usually is sufficient.11 Renal tumors respond poorly to radiation, chemotherapy, and immunotherapy, with response rates of less than 20%.12 However, advances in the understanding of immune responses to RCC have led to new therapeutic strategies based on immune manipulation. The identification of numerous T-cell epitopes associated with RCC has led to the development of new treatment approaches using DNA vaccination, peptide vaccination, and dendritic cell therapy; combined with new and more efficient gene-delivery techniques, these treatments may have considerable clinical implications for patients with RCC.12 Targeted therapies that are currently being investigated for metastatic RCC include tyrosine kinase inhibitors (ie, sorafenib), anti–vascular endothelial growth factor therapy (ie, bevacizumab), and inhibition of the mammalian target of rapamycin (mTOR) pathway (ie, temsirolimus).13 back to top

VHL Syndrome
VHL syndrome represents a constellation of central nervous system (CNS) and visceral neoplasms that result from a germ line mutation of the VHL tumor suppressor gene on chromosome arm 3p25-26.14 In this autosomal dominant neurocutaneous syndrome, 80% of cases are hereditary and 20% are sporadic. The incidence of VHL syndrome is approximately 1 in 36,000 individuals.15 Patients with VHL syndrome typically present before the age of 40 years.16 Although less than 5% of cases of VHL syndrome have dermatologic manifestations, capillary malformations are the most common cutaneous features. Thus, the dermatologist must be vigilant to observe for VHL syndrome in the appropriate clinical context. More than 70% of sporadic clear cell RCCs display mutations in the VHL gene.17 The VHL protein produced via this gene is a ubiquitin ligase that degrades hypoxia-inducible factors (HIFs) including HIF-1α and HIF-2α. A mutation of the VHL gene can increase the levels of HIF, which subsequently activate additional genes that produce vascular endothelial growth factor, platelet-derived growth factor, transforming growth factor α, and carbonic anhydrase IX. In concert, these factors facilitate neoangiogenesis and tumorigenesis.17 The mutation of the VHL gene leads to the development of both benign and malignant tumors that affect multiple organ systems. CNS tumors include retinal hemangioblastomas (20%–60%); endolymphatic sac tumors (11%–16%); and craniospinal hemangiomas, most frequently of the cerebellum (44%–72%), brainstem (10%–25%), and spinal cord (13%–50%). Additional manifestations of VHL syndrome include RCC or kidney cyst (25%–60%), epididymal cystadenoma (25%–60% of men), pancreatic cyst or cystadenoma (17%–56%), pheochromocytoma or paraganglioma (10%–20%), and broad ligament cystadenoma (10% of women).18 The capillary malformations of VHL syndrome often occur in but are not limited to the head and neck. Also, café au lait spots that frequently are associated with neurofibromatosis may be evident in VHL syndrome, suggesting overlap between these phakomatoses.19 VHL syndrome is a progressive disease, with death characteristically occurring by the fourth decade of life. The diagnosis of VHL syndrome is based on clinical criteria. Patients with a family history of VHL syndrome and a CNS hemangioblastoma, pheochromocytoma, or clear cell RCC are diagnosed with the syndrome. In the absence of a family history, the diagnosis can be made with 2 or more CNS hemangioblastomas and a visceral tumor, with the exclusion of renal and epididymal cysts. Confirmation of diagnosis and screening for possibly affected family members can be achieved with DNA testing for mutation in the VHL gene. Recommended laboratory tests include a complete blood count and screenings for serum catecholamine and urine vanillylmandelic acid levels, as well as a computed tomographic scan (CT scan) and/or magnetic resonance imaging of the brain, spinal cord, and abdomen. Patients diagnosed with VHL syndrome should be referred to an ophthalmologist for photocoagulation or cryocoagulation of tumors. Neurosurgeons and urologists may surgically remove CNS and renal tumors, respectively, with preoperative angiography. Patients with VHL syndrome also may consider renal transplantation.

BHD Syndrome
BHD syndrome, an autosomal dominant genodermatosis occurring in 1 in 200,000 individuals, is characterized by the cutaneous triad of fibrofolliculomas, trichodiscomas, and acrochordons. Vincent and colleagues20 offer a comprehensive analysis of these papules, which frequently appear in the third to fourth decades of life. Protein-truncating mutations of the BHD gene on chromosome arm 17p11.2 encode the BHD protein folliculin, which is expressed in the kidneys, lungs, and skin.21 Although the function of the protein is unknown, the BHD gene is presumptively involved in tumor suppression. Fibrofolliculomas and trichodiscomas are clinically indistinguishable; both are skin-colored, well-circumscribed, smooth, firm, 2- to 4-mm papules distributed over the forehead, nose, and cheeks.22 Acrochordons appear as soft pedunculated lesions. The clinical appearance of fibrofolliculomas and trichodiscomas is associated with familial spontaneous pneumothorax and RCCs. Notably, patients with BHD syndrome have a 50-fold increased risk of pneumothorax presenting with tachypnea, decreased breath sounds, and hyperresonance.23 Lung cysts and bullous emphysema also have been associated with BHD syndrome. In addition to the cutaneous and pulmonary features, a 7-fold increase in renal tumors with varying histology has been associated with BHD syndrome, including hybrid chromophobe and oncocytoma (50%), chromophobe (34%), clear cell RCC (9%), and oncocytoma (5%).23 Multiple histologic types can be found in the same family, patient, and kidney, suggesting a role for the BHD gene in the differentiation processes of renal cells. Fibrofolliculomas possess a circumscribed fibrous tissue layer around the hair follicles.24 These follicles demonstrate a widened infundibulum containing laminated keratin. Encasing the follicle is a mantle of loose connective tissue embedded in a mucoid ground substance with high concentrations of hyaluronic acid. The elastin fibers may not be visible or appear sparse. Radiating from the follicular epithelium are 2 to 4 thin layers of epithelial strands that extend into the fibrous tissue where they combine with epithelial strands or connect with follicular or sebaceous epithelium. In contrast, the histology of the trichodiscomas demonstrates hair follicles at the margin of these tumors. The stroma is highly vascularized, with collagen fibers and cells containing melanin.24 A diagnosis of BHD syndrome requires 5 or more facial or truncal papules; 1 papule must be confirmed as a fibrofolliculoma or trichodiscoma using the histologic criteria above. The differential diagnosis includes TS, Cowden syndrome, Brooke-Spiegler syndrome, Rombo syndrome, and basaloid follicular hamartoma syndrome. It is recommended that all patients who are diagnosed with BHD syndrome get a chest x-ray, abdominal CT scan, and renal ultrasound. Thereafter, patients may be screened every 3 to 5 years. Siblings of patients require physical examinations and biopsies of suspicious skin lesions as early as the second decade of life. Treatment options for fibrofolliculomas and trichodiscomas include CO2 laser ablation and/or erbium:YAG laser, copper vapor laser, and systemic isotretinoin, though these therapies have shown variable results in some patients.24 Resection is recommended for RCC. If the tumor is less than 3 cm in size, surgery that conserves the parenchyma may be appropriate to optimize renal function without increasing the risk of metastases. The prognosis depends on the renal and pulmonary sequelae. 

Tuberous Sclerosis
TS, also called tuberous sclerosis complex (TSC), is a rare genetic disease that causes benign tumors to grow in the brain and other organs, such as the kidneys, lungs, skin, and eyes.25 Its incidence is 1 in 10,000 individuals and the age of presentation is variable. TS is an autosomal dominant disorder; approximately 40% of cases are hereditary and 60% are sporadic.26 Two gene mutations have been identified in contributing to the development of TS: the hamartin gene TSC1 on the chromosome arm 9q34 and tuberin gene TSC2 on the chromosome arm 16p13.3. The latter is adjacent to the PKD1 site, which is responsible for autosomal dominant polycystic kidney disease, thereby explaining the association of these 2 disorders in patients with contiguous gene defects. Hamartin and tuberin associate in vivo to form a tumor suppressor complex. This complex functions within the P13K-Akt-mTOR pathway and regulates nutrient and growth factor signaling to mTOR. As a result, rapamycin has potential therapeutic use in TS.26 The clinical features of TS include neurologic involvement with mental cognitive deficiency and epilepsy; psychiatric and behavioral problems such as attention deficit hyperactivity disorder and generalized development delays; and organic brain anomalies such as cortical tubera, subependymal giant cell astrocytomas, and subependymal nodules.25 Cardiac rhabdomyomas, retinal hamartomas, and dental pits also are typical findings of TS. Pulmonary lymphangioleiomyomatosis related to TS has been described, usually presenting exclusively in women. Classic cutaneous lesions include facial angiofibromas (adenoma sebaceum), the shagreen patch, and periungual or subungual fibromas (Koenen tumors).25 Renal manifestations are mainly angiomyolipomas, renal cysts, and cancer.27 In patients with TS, multiple lesions appear concomitantly and are likely to be bilateral. Larger lesions may present with flank pain, hypertension, hematuria, and renal failure. These lesions characteristically are benign, though there are some reports of sarcomatous degeneration and rare malignant epithelioid variants.27 Angiomyolipomas are not hamartomas per se, rather they are clonal perivascular epithelioid cell tumors (PEComas).28 PEComas are tumors composed of mostly epithelioid cells positive for HMB-45 and/or melan-A as well as actin- and/or desmin-positive cells. These PEComas have a perivascular propensity. They belong to a family of me-senchymal neoplasms that include angiomyolipomas, lymphangioleiomyomatosis, clear cell tumor (sugar tumor) of the lung, and other soft tissue and visceral neoplasms with similar histology and immunohistochemistry. Pan et al29 studied the cytogenetic feature of these tumors and reported that all cells studied had gross chromosomal anomalies, with the most frequent being a deletion of chromosome arm 16p, in which TSC2 is located. Alam et al30 concluded that PEComas are distinctive tumors based on the common chromosomal changes found in both renal and extrarenal tumors. Starting in childhood, renal ultrasounds can be used to detect and monitor the growth of angiomyolipomas. Because complications correlate with increasing size, surgery is recommended when the tumor is greater than 3.5 to 4.0 cm in size. Surgical options include tumor embolization, tumor enucleation, partial nephrectomy, or total nephrectomy depending on the presentation. Patients with TS are at a higher risk for renal cancer than the general population (2.0%–4.0% vs 1.27%, respectively) and are more likely to present at a younger age (30 years vs 60 years, respectively). Renal cancer in patients with TS is most commonly of the clear cell carcinoma type and is more likely to be multifocal and bilateral.2 For these reasons, lifelong periodic radiologic evaluation is essential. 

HLRCC Syndrome
HLRCC syndrome is an autosomal dominant disease that is an expansion of Reed syndrome (multiple cutaneous and uterine leiomyoma syndrome). It is characterized by the presence of leiomyomas in the skin and uterus of affected females and in the skin of affected males. Its prevalence in the general population is not known, though one limited study estimated the presence of a heterozygous fumarate hydratase, FH, gene mutation at 1 in 676 individuals.30 Germ line mutations in the FH gene at chromosome arm 1q42.3-43 are associated with the HLRCC syndrome.31 In the Krebs cycle, the FH and succinate dehydrogenase, SD, genes act as tumor suppressors. Mutations in the SD gene are associated with pheochromocytomas and paragangliomas. Mutations in the FH gene lead to the overexpression of HIF-1α and its targets (eg, vascular endothelial growth factor), which contributes to tumorigenesis by the so-called pseudohypoxic drive. There is a low frequency of FH mutations in sporadic cases of leiomyomas and leiomyosarcomas.31 The clinical features of patients with HLRCC syndrome include benign cutaneous and uterine leiomyomas and, more rarely, cutaneous leiomyosarcomas and uterine leiomyosarcomas. Cutaneous leiomyomas usually present in late childhood to early adulthood. They typically present as multiple disseminated lesions, most commonly on the face, trunk, and extremities, though segmental distribution also has been described.30 The individual lesions appear as intradermal papules. Alam et al30 stated that 90% of patients complain of pain from cutaneous leiomyoma, which is exacerbated by cold or trauma. Although leiomyomas may be solitary and sporadic lesions, Chuang et al32 noted that the finding of a cutaneous leiomyoma in a patient should compel dermatologists to examine the individual and his/her family for multiple lesions and to screen for the FH gene, which is crucial because FH mutations in HLRCC syndrome lead to increased susceptibility to early-onset RCC. These RCCs usually are solitary, fast growing, and very aggressive, and they display papillary cell carcinoma type 2 or renal collecting duct histology. Alam et al30 reported a case of a 16-year-old patient who presented with metastatic renal disease, which led the authors to urge the consideration of early screenings for FH mutations for patients. Toro et al33 screened 35 families with cutaneous leiomyomas for mutations in the FH gene. They identified mutations in 31 families (89%). Eighty-one individuals had cutaneous leiomyomas, of which 47 were women and 34 were men. Forty-six of 47 women (98%) had uterine leiomyomas. The authors also found 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from 4 families had papillary cell carcinoma type 2, and 1 individual from 1 of these families had renal collecting duct carcinoma.33 Patients who present with lesions that are diagnosed as cutaneous leiomyomas should prompt a complete history, including a history of fibroids in women as well as a family history of fibroids or renal tumors.34 Tests for mutations in the FH gene may be of value. Renal imaging studies should be performed in suspect cases. Although some papillary cell carcinoma type 2 or collecting duct RCCs can be found only with a CT scan or magnetic resonance imaging, a simple ultrasound is successful in most cases and can sometimes provide superior information about the characteristics of the renal tumor.34 

Conclusion
Dermatologists have a unique opportunity to diagnose hereditary renal tumors before they become life threatening. When examining patients with capillary malformations, fibrofolliculomas, angiofibromas, or leiomyomas, the dermatologist should consider the possibility of VHL syndrome, BHD syndrome, TS, or HLRCC syndrome, respectively. With a positive family history, renal imaging studies should be obtained. Although these syndromes are rare, it is essential that dermatologists recognize them for the benefit of the patients and their kin.

A metastatic malignancy of the umbilicus is commonly termed Sister Mary Joseph nodule (SMJN). It is a rare occurrence but may represent the first sign of a visceral malignancy and therefore should prompt a thorough search for the primary tumor. Typically, the most common origin of an umbilical metastasis is an adenocarcinoma from a gastrointestinal or gynecologic primary malignancy. The presence of SMJN carries a poor prognosis with the average survival time at the appearance of an umbilical metastasis being 10 months. We report a case of a 66-year-old man who was referred for evaluation of an enlarging umbilical lesion. Histopathology revealed adenocarcinoma. After a full metastatic workup, the tumor of origin was identified as adenocarcinoma of the sigmoid colon. Benign tumors of the umbilicus are uncommon. This case report serves to emphasize the importance of obtaining a histologic diagnosis when any new lesion presents in the umbilical region.

Case Report
A 66-year-old white man presented for evaluation of an umbilical lesion of 3 weeks' duration. The lesion was asymptomatic and nontender but was bleeding and oozing. The lesion, diagnosed by the patient's primary care physician as an infected pyogenic granuloma, was treated with oral antibiotics, without relief. His past medical history was unremarkable. He took no medications at that time and had an allergy to quinolones. His dermatologic history was positive for numerous actinic keratoses and a basal cell carcinoma on the forehead. Physical examination upon presentation revealed a 3-cm fungating polypoid umbilical mass with copious purulent exudates similar to Figure 1.1 The clinical differential diagnosis at that time included a pyogenic granuloma versus a Sister Mary Joseph nodule (SMJN). A shave biopsy was performed. Histopathology revealed multiple cystic and ductal spaces lined by atypical epithelial cells with numerous mitotic figures in the dermis (Figures 2 and 3). These changes favored a gastrointestinal primary lesion, supporting the clinical diagnosis of SMJN. The patient subsequently underwent a full metastatic workup. A computed tomographic scan of the abdomen and pelvis demonstrated no definite metastases to the lungs or liver but suggested a near-obstructing distal bowel primary tumor. A colonoscopy demonstrated a near-obstructing sigmoid colon carcinoma. The patient subsequently underwent an exploratory laparotomy, sigmoid resection, and primary colonic reanastomosis. Liver biopsies and resection of the omentum and the periumbilical abdominal wall including the eroding metastasis were performed as well as multiple peritoneal biopsies. Pathologic evaluation confirmed the presence of extensive carcinomatosis. The primary tumor was a 5.0X3.0-cm moderately differentiated adenocarcinoma of the sigmoid colon with extension through the bowel wall. Biopsies of the liver, lymph nodes, periumbilical soft tissue, omentum, and peritoneum were all positive for metastatic carcinoma. Postoperatively, the patient was started on the FOLFOX regimen incorporating folinic acid, 5-fluorouracil, and oxaliplatin. Currently, the patient remains clinically stable and without evidence of progressive sigmoid colon carcinoma.

Comment
SMJN is the term applied to an uncommon metastatic malignancy of the umbilicus. This eponym, coined by Sir Hamilton Bailey in his book Physical Signs in Clinical Surgery,2 honors Sister Mary Joseph Dempsey, a nun in the Franciscan order who was the first surgical assistant to Dr. William J. Mayo at St. Mary's Hospital in Rochester, Minnesota.3,4 Sister Mary Joseph made the astute observation that patients with gastrointestinal and gynecologic tumors may have involvement of the umbilicus; if there is involvement of the umbilicus, the prognosis is poor.5 Although Dr. Mayo gives credit to Sister Mary Joseph, contrary to what some believe, he is not responsible for the eponym. Dr. Mayo used the term pants button umbilicus in his article; Sir Bailey definitively coined the term SMJN. Some authors argue that the correct name is Sister Joseph's nodule; however, SMJN remains the more commonly used term.6 Frequency—Cutaneous metastasis, in and of itself, is a rare feature of visceral malignancy, occurring in about 1% to 2% of cases, with umbilical metastasis occurring even less frequently. There are approximately 265 cases of SMJN reported in the literature up to 1990, emphasizing its infrequency. The most common origin of an umbilical metastasis is an adenocarcinoma from a gastrointestinal or gynecologic primary malignancy. In a review of the world literature on metastatic umbilical tumors, Barrow7 found that the most common primary tumor identified was carcinoma of the stomach. The second most common was ovarian tumor,7 with colon, rectal, and pancreatic cancers following in descending order of frequency.8 In very rare cases, the primary tumor involved the breast, cervix, endometrium, small bowel, liver, gallbladder, lung, prostate, kidney, fallopian tube, appendix, and penis.9 In approximately 20% to 30% of cases, the primary tumor could not be identified.9 Umbilical Anatomy—A neoplasm may metastasize to the umbilicus by one of many mechanisms, most commonly direct extension from the anterior peritoneal surface from adjacent organs. Other mechanisms of metastasis include vascular spread via arterial and venous channels, lymphatic spread, and umbilical ligamentous spread. The rich vascular supply to the anterior abdominal wall facilitates metastasis of a neoplasm. The main arteries supplying the umbilical region are the inferior epigastric, deep circumflex iliac, and superior epigastric arteries. Venous drainage of the umbilical region stems from a network of veins radiating from the umbilicus, including the axillary vein above and the femoral vein below the umbilicus. There also are small paraumbilical veins that connect with the portal system along the ligamentum teres hepatis, the superior portion of the falciform ligament.10 The superficial lymphatic drainage of the periumbilical region leads to axillary lymph nodes above and inguinal lymph nodes below the periumbilical region. The deep lymphatic drainage runs along the falciform ligament of the liver and then enters the anterior mediastinum by traversing the diaphragm. Inferiorly, the deep lymphatics communicate by coursing to the lymph nodes of the iliac arteries. Because the lymphatic channels of the periumbilical region communicate with the deep inguinal, axillary, deep femoral, and periaortic lymph nodes, once a neoplasm is established at the umbilicus, it can metastasize to any part of the body,8 supporting the notion that the presence of SMJN portends a poor prognosis. In the fetus, the umbilicus serves as the opening for the umbilical vessels. In the adult, there are several ligaments that contain remnants of obliterated fetal structures and connect to the umbilicus. For example, the median umbilical ligament, also known as the urachus, represents the obliterated umbilical arteries that formerly connected the umbilicus to the bladder. The falciform ligament in the adult contains the obliterated umbilical vein and runs along the hepatic surface. Therefore, a firm command of the anatomy and embryology of the periumbilical region is essential for an accurate clinical workup once the diagnosis of SMJN has been established. Physical Examination—Clinically, SMJN usually presents as a firm indurated plaque or nodule that is 0.5 to 2 cm in size, though lesions up to 10 cm have been reported. The lesion is occasionally painful and may have a fibrous consistency with irregular edges that are attached to the anterior abdominal wall. It tends to have a vascular appearance and can be fissured, ulcerated, or necrotic. Purulent discharge may be present if it is secondarily infected. Typically, there are no gross features to distinguish between a primary and secondary umbilical tumor. Differential Diagnosis—The differential diagnosis of SMJN includes a primary carcinoma of the umbilicus, a benign umbilical lesion, and a metastatic lesion of the umbilicus. Primary umbilical carcinomas are rare and include malignant melanoma, basal cell carcinoma, and omphalomesenteric duct carcinoma. Endometriosis is the most common benign lesion of the umbilicus. Other benign umbilical lesions include papillomas, epidermal/inclusion cysts, seborrheic keratoses, dermal nevi, polyps, congenital malformations, foreign bodies, talc granulomas, angiomas, pyogenic and pilonidal granulomas, keloids, incarcerated hernias, angiokeratomas, and lymphangiomas.11 Histopathology—In general, the histology of a cutaneous metastatic lesion is of finite value in determining the site of the primary malignancy. In contrast, when speaking of an umbilical metastasis, histologic sampling more often aids in determining the derivation.11 The histopathology is dependent on the primary tumor and is most often adenocarcinoma, which was the case with our patient. Prognosis—Although the presence of umbilical disease indicates metastasis, it does not suggest unresectability and, in fact, may be the first sign of a recurrence.11 However, in general, SMJN portends a poor prognosis and is considered an ominous sign. The presence of SMJN should prompt a thorough metastatic workup and appropriate clinical staging. Survival time in untreated patients ranges from 2 to 11 months, with 10 months as the average survival time from the appearance of an umbilical metastasis.6,9 This rapid deterioration may be, in part, caused by the rich lymphatic network in the abdominal wall providing communication with the deep inguinal, axillary, deep femoral, and periaortic lymph nodes. Therefore, from the umbilicus, a tumor may spread to many parts of the body.

Conclusion
Cutaneous metastasis is a rare occurrence, making SMJN exceptionally infrequent. The finding of SMJN should prompt a thorough search for the primary malignancy. As demonstrated by our patient, SMJN may be the first sign of a visceral malignancy, making proper and timely diagnosis lifesaving.

A metastatic malignancy of the umbilicus is commonly termed Sister Mary Joseph nodule (SMJN). It is a rare occurrence but may represent the first sign of a visceral malignancy and therefore should prompt a thorough search for the primary tumor. Typically, the most common origin of an umbilical metastasis is an adenocarcinoma from a gastrointestinal or gynecologic primary malignancy. The presence of SMJN carries a poor prognosis with the average survival time at the appearance of an umbilical metastasis being 10 months. We report a case of a 66-year-old man who was referred for evaluation of an enlarging umbilical lesion. Histopathology revealed adenocarcinoma. After a full metastatic workup, the tumor of origin was identified as adenocarcinoma of the sigmoid colon. Benign tumors of the umbilicus are uncommon. This case report serves to emphasize the importance of obtaining a histologic diagnosis when any new lesion presents in the umbilical region.

Case Report
A 66-year-old white man presented for evaluation of an umbilical lesion of 3 weeks' duration. The lesion was asymptomatic and nontender but was bleeding and oozing. The lesion, diagnosed by the patient's primary care physician as an infected pyogenic granuloma, was treated with oral antibiotics, without relief. His past medical history was unremarkable. He took no medications at that time and had an allergy to quinolones. His dermatologic history was positive for numerous actinic keratoses and a basal cell carcinoma on the forehead. Physical examination upon presentation revealed a 3-cm fungating polypoid umbilical mass with copious purulent exudates similar to Figure 1.1 The clinical differential diagnosis at that time included a pyogenic granuloma versus a Sister Mary Joseph nodule (SMJN). A shave biopsy was performed. Histopathology revealed multiple cystic and ductal spaces lined by atypical epithelial cells with numerous mitotic figures in the dermis (Figures 2 and 3). These changes favored a gastrointestinal primary lesion, supporting the clinical diagnosis of SMJN. The patient subsequently underwent a full metastatic workup. A computed tomographic scan of the abdomen and pelvis demonstrated no definite metastases to the lungs or liver but suggested a near-obstructing distal bowel primary tumor. A colonoscopy demonstrated a near-obstructing sigmoid colon carcinoma. The patient subsequently underwent an exploratory laparotomy, sigmoid resection, and primary colonic reanastomosis. Liver biopsies and resection of the omentum and the periumbilical abdominal wall including the eroding metastasis were performed as well as multiple peritoneal biopsies. Pathologic evaluation confirmed the presence of extensive carcinomatosis. The primary tumor was a 5.0X3.0-cm moderately differentiated adenocarcinoma of the sigmoid colon with extension through the bowel wall. Biopsies of the liver, lymph nodes, periumbilical soft tissue, omentum, and peritoneum were all positive for metastatic carcinoma. Postoperatively, the patient was started on the FOLFOX regimen incorporating folinic acid, 5-fluorouracil, and oxaliplatin. Currently, the patient remains clinically stable and without evidence of progressive sigmoid colon carcinoma.

Comment
SMJN is the term applied to an uncommon metastatic malignancy of the umbilicus. This eponym, coined by Sir Hamilton Bailey in his book Physical Signs in Clinical Surgery,2 honors Sister Mary Joseph Dempsey, a nun in the Franciscan order who was the first surgical assistant to Dr. William J. Mayo at St. Mary's Hospital in Rochester, Minnesota.3,4 Sister Mary Joseph made the astute observation that patients with gastrointestinal and gynecologic tumors may have involvement of the umbilicus; if there is involvement of the umbilicus, the prognosis is poor.5 Although Dr. Mayo gives credit to Sister Mary Joseph, contrary to what some believe, he is not responsible for the eponym. Dr. Mayo used the term pants button umbilicus in his article; Sir Bailey definitively coined the term SMJN. Some authors argue that the correct name is Sister Joseph's nodule; however, SMJN remains the more commonly used term.6 Frequency—Cutaneous metastasis, in and of itself, is a rare feature of visceral malignancy, occurring in about 1% to 2% of cases, with umbilical metastasis occurring even less frequently. There are approximately 265 cases of SMJN reported in the literature up to 1990, emphasizing its infrequency. The most common origin of an umbilical metastasis is an adenocarcinoma from a gastrointestinal or gynecologic primary malignancy. In a review of the world literature on metastatic umbilical tumors, Barrow7 found that the most common primary tumor identified was carcinoma of the stomach. The second most common was ovarian tumor,7 with colon, rectal, and pancreatic cancers following in descending order of frequency.8 In very rare cases, the primary tumor involved the breast, cervix, endometrium, small bowel, liver, gallbladder, lung, prostate, kidney, fallopian tube, appendix, and penis.9 In approximately 20% to 30% of cases, the primary tumor could not be identified.9 Umbilical Anatomy—A neoplasm may metastasize to the umbilicus by one of many mechanisms, most commonly direct extension from the anterior peritoneal surface from adjacent organs. Other mechanisms of metastasis include vascular spread via arterial and venous channels, lymphatic spread, and umbilical ligamentous spread. The rich vascular supply to the anterior abdominal wall facilitates metastasis of a neoplasm. The main arteries supplying the umbilical region are the inferior epigastric, deep circumflex iliac, and superior epigastric arteries. Venous drainage of the umbilical region stems from a network of veins radiating from the umbilicus, including the axillary vein above and the femoral vein below the umbilicus. There also are small paraumbilical veins that connect with the portal system along the ligamentum teres hepatis, the superior portion of the falciform ligament.10 The superficial lymphatic drainage of the periumbilical region leads to axillary lymph nodes above and inguinal lymph nodes below the periumbilical region. The deep lymphatic drainage runs along the falciform ligament of the liver and then enters the anterior mediastinum by traversing the diaphragm. Inferiorly, the deep lymphatics communicate by coursing to the lymph nodes of the iliac arteries. Because the lymphatic channels of the periumbilical region communicate with the deep inguinal, axillary, deep femoral, and periaortic lymph nodes, once a neoplasm is established at the umbilicus, it can metastasize to any part of the body,8 supporting the notion that the presence of SMJN portends a poor prognosis. In the fetus, the umbilicus serves as the opening for the umbilical vessels. In the adult, there are several ligaments that contain remnants of obliterated fetal structures and connect to the umbilicus. For example, the median umbilical ligament, also known as the urachus, represents the obliterated umbilical arteries that formerly connected the umbilicus to the bladder. The falciform ligament in the adult contains the obliterated umbilical vein and runs along the hepatic surface. Therefore, a firm command of the anatomy and embryology of the periumbilical region is essential for an accurate clinical workup once the diagnosis of SMJN has been established. Physical Examination—Clinically, SMJN usually presents as a firm indurated plaque or nodule that is 0.5 to 2 cm in size, though lesions up to 10 cm have been reported. The lesion is occasionally painful and may have a fibrous consistency with irregular edges that are attached to the anterior abdominal wall. It tends to have a vascular appearance and can be fissured, ulcerated, or necrotic. Purulent discharge may be present if it is secondarily infected. Typically, there are no gross features to distinguish between a primary and secondary umbilical tumor. Differential Diagnosis—The differential diagnosis of SMJN includes a primary carcinoma of the umbilicus, a benign umbilical lesion, and a metastatic lesion of the umbilicus. Primary umbilical carcinomas are rare and include malignant melanoma, basal cell carcinoma, and omphalomesenteric duct carcinoma. Endometriosis is the most common benign lesion of the umbilicus. Other benign umbilical lesions include papillomas, epidermal/inclusion cysts, seborrheic keratoses, dermal nevi, polyps, congenital malformations, foreign bodies, talc granulomas, angiomas, pyogenic and pilonidal granulomas, keloids, incarcerated hernias, angiokeratomas, and lymphangiomas.11 Histopathology—In general, the histology of a cutaneous metastatic lesion is of finite value in determining the site of the primary malignancy. In contrast, when speaking of an umbilical metastasis, histologic sampling more often aids in determining the derivation.11 The histopathology is dependent on the primary tumor and is most often adenocarcinoma, which was the case with our patient. Prognosis—Although the presence of umbilical disease indicates metastasis, it does not suggest unresectability and, in fact, may be the first sign of a recurrence.11 However, in general, SMJN portends a poor prognosis and is considered an ominous sign. The presence of SMJN should prompt a thorough metastatic workup and appropriate clinical staging. Survival time in untreated patients ranges from 2 to 11 months, with 10 months as the average survival time from the appearance of an umbilical metastasis.6,9 This rapid deterioration may be, in part, caused by the rich lymphatic network in the abdominal wall providing communication with the deep inguinal, axillary, deep femoral, and periaortic lymph nodes. Therefore, from the umbilicus, a tumor may spread to many parts of the body.

Conclusion
Cutaneous metastasis is a rare occurrence, making SMJN exceptionally infrequent. The finding of SMJN should prompt a thorough search for the primary malignancy. As demonstrated by our patient, SMJN may be the first sign of a visceral malignancy, making proper and timely diagnosis lifesaving.

A metastatic malignancy of the umbilicus is commonly termed Sister Mary Joseph nodule (SMJN). It is a rare occurrence but may represent the first sign of a visceral malignancy and therefore should prompt a thorough search for the primary tumor. Typically, the most common origin of an umbilical metastasis is an adenocarcinoma from a gastrointestinal or gynecologic primary malignancy. The presence of SMJN carries a poor prognosis with the average survival time at the appearance of an umbilical metastasis being 10 months. We report a case of a 66-year-old man who was referred for evaluation of an enlarging umbilical lesion. Histopathology revealed adenocarcinoma. After a full metastatic workup, the tumor of origin was identified as adenocarcinoma of the sigmoid colon. Benign tumors of the umbilicus are uncommon. This case report serves to emphasize the importance of obtaining a histologic diagnosis when any new lesion presents in the umbilical region.

Case Report
A 66-year-old white man presented for evaluation of an umbilical lesion of 3 weeks' duration. The lesion was asymptomatic and nontender but was bleeding and oozing. The lesion, diagnosed by the patient's primary care physician as an infected pyogenic granuloma, was treated with oral antibiotics, without relief. His past medical history was unremarkable. He took no medications at that time and had an allergy to quinolones. His dermatologic history was positive for numerous actinic keratoses and a basal cell carcinoma on the forehead. Physical examination upon presentation revealed a 3-cm fungating polypoid umbilical mass with copious purulent exudates similar to Figure 1.1 The clinical differential diagnosis at that time included a pyogenic granuloma versus a Sister Mary Joseph nodule (SMJN). A shave biopsy was performed. Histopathology revealed multiple cystic and ductal spaces lined by atypical epithelial cells with numerous mitotic figures in the dermis (Figures 2 and 3). These changes favored a gastrointestinal primary lesion, supporting the clinical diagnosis of SMJN. The patient subsequently underwent a full metastatic workup. A computed tomographic scan of the abdomen and pelvis demonstrated no definite metastases to the lungs or liver but suggested a near-obstructing distal bowel primary tumor. A colonoscopy demonstrated a near-obstructing sigmoid colon carcinoma. The patient subsequently underwent an exploratory laparotomy, sigmoid resection, and primary colonic reanastomosis. Liver biopsies and resection of the omentum and the periumbilical abdominal wall including the eroding metastasis were performed as well as multiple peritoneal biopsies. Pathologic evaluation confirmed the presence of extensive carcinomatosis. The primary tumor was a 5.0X3.0-cm moderately differentiated adenocarcinoma of the sigmoid colon with extension through the bowel wall. Biopsies of the liver, lymph nodes, periumbilical soft tissue, omentum, and peritoneum were all positive for metastatic carcinoma. Postoperatively, the patient was started on the FOLFOX regimen incorporating folinic acid, 5-fluorouracil, and oxaliplatin. Currently, the patient remains clinically stable and without evidence of progressive sigmoid colon carcinoma.

Comment
SMJN is the term applied to an uncommon metastatic malignancy of the umbilicus. This eponym, coined by Sir Hamilton Bailey in his book Physical Signs in Clinical Surgery,2 honors Sister Mary Joseph Dempsey, a nun in the Franciscan order who was the first surgical assistant to Dr. William J. Mayo at St. Mary's Hospital in Rochester, Minnesota.3,4 Sister Mary Joseph made the astute observation that patients with gastrointestinal and gynecologic tumors may have involvement of the umbilicus; if there is involvement of the umbilicus, the prognosis is poor.5 Although Dr. Mayo gives credit to Sister Mary Joseph, contrary to what some believe, he is not responsible for the eponym. Dr. Mayo used the term pants button umbilicus in his article; Sir Bailey definitively coined the term SMJN. Some authors argue that the correct name is Sister Joseph's nodule; however, SMJN remains the more commonly used term.6 Frequency—Cutaneous metastasis, in and of itself, is a rare feature of visceral malignancy, occurring in about 1% to 2% of cases, with umbilical metastasis occurring even less frequently. There are approximately 265 cases of SMJN reported in the literature up to 1990, emphasizing its infrequency. The most common origin of an umbilical metastasis is an adenocarcinoma from a gastrointestinal or gynecologic primary malignancy. In a review of the world literature on metastatic umbilical tumors, Barrow7 found that the most common primary tumor identified was carcinoma of the stomach. The second most common was ovarian tumor,7 with colon, rectal, and pancreatic cancers following in descending order of frequency.8 In very rare cases, the primary tumor involved the breast, cervix, endometrium, small bowel, liver, gallbladder, lung, prostate, kidney, fallopian tube, appendix, and penis.9 In approximately 20% to 30% of cases, the primary tumor could not be identified.9 Umbilical Anatomy—A neoplasm may metastasize to the umbilicus by one of many mechanisms, most commonly direct extension from the anterior peritoneal surface from adjacent organs. Other mechanisms of metastasis include vascular spread via arterial and venous channels, lymphatic spread, and umbilical ligamentous spread. The rich vascular supply to the anterior abdominal wall facilitates metastasis of a neoplasm. The main arteries supplying the umbilical region are the inferior epigastric, deep circumflex iliac, and superior epigastric arteries. Venous drainage of the umbilical region stems from a network of veins radiating from the umbilicus, including the axillary vein above and the femoral vein below the umbilicus. There also are small paraumbilical veins that connect with the portal system along the ligamentum teres hepatis, the superior portion of the falciform ligament.10 The superficial lymphatic drainage of the periumbilical region leads to axillary lymph nodes above and inguinal lymph nodes below the periumbilical region. The deep lymphatic drainage runs along the falciform ligament of the liver and then enters the anterior mediastinum by traversing the diaphragm. Inferiorly, the deep lymphatics communicate by coursing to the lymph nodes of the iliac arteries. Because the lymphatic channels of the periumbilical region communicate with the deep inguinal, axillary, deep femoral, and periaortic lymph nodes, once a neoplasm is established at the umbilicus, it can metastasize to any part of the body,8 supporting the notion that the presence of SMJN portends a poor prognosis. In the fetus, the umbilicus serves as the opening for the umbilical vessels. In the adult, there are several ligaments that contain remnants of obliterated fetal structures and connect to the umbilicus. For example, the median umbilical ligament, also known as the urachus, represents the obliterated umbilical arteries that formerly connected the umbilicus to the bladder. The falciform ligament in the adult contains the obliterated umbilical vein and runs along the hepatic surface. Therefore, a firm command of the anatomy and embryology of the periumbilical region is essential for an accurate clinical workup once the diagnosis of SMJN has been established. Physical Examination—Clinically, SMJN usually presents as a firm indurated plaque or nodule that is 0.5 to 2 cm in size, though lesions up to 10 cm have been reported. The lesion is occasionally painful and may have a fibrous consistency with irregular edges that are attached to the anterior abdominal wall. It tends to have a vascular appearance and can be fissured, ulcerated, or necrotic. Purulent discharge may be present if it is secondarily infected. Typically, there are no gross features to distinguish between a primary and secondary umbilical tumor. Differential Diagnosis—The differential diagnosis of SMJN includes a primary carcinoma of the umbilicus, a benign umbilical lesion, and a metastatic lesion of the umbilicus. Primary umbilical carcinomas are rare and include malignant melanoma, basal cell carcinoma, and omphalomesenteric duct carcinoma. Endometriosis is the most common benign lesion of the umbilicus. Other benign umbilical lesions include papillomas, epidermal/inclusion cysts, seborrheic keratoses, dermal nevi, polyps, congenital malformations, foreign bodies, talc granulomas, angiomas, pyogenic and pilonidal granulomas, keloids, incarcerated hernias, angiokeratomas, and lymphangiomas.11 Histopathology—In general, the histology of a cutaneous metastatic lesion is of finite value in determining the site of the primary malignancy. In contrast, when speaking of an umbilical metastasis, histologic sampling more often aids in determining the derivation.11 The histopathology is dependent on the primary tumor and is most often adenocarcinoma, which was the case with our patient. Prognosis—Although the presence of umbilical disease indicates metastasis, it does not suggest unresectability and, in fact, may be the first sign of a recurrence.11 However, in general, SMJN portends a poor prognosis and is considered an ominous sign. The presence of SMJN should prompt a thorough metastatic workup and appropriate clinical staging. Survival time in untreated patients ranges from 2 to 11 months, with 10 months as the average survival time from the appearance of an umbilical metastasis.6,9 This rapid deterioration may be, in part, caused by the rich lymphatic network in the abdominal wall providing communication with the deep inguinal, axillary, deep femoral, and periaortic lymph nodes. Therefore, from the umbilicus, a tumor may spread to many parts of the body.

Conclusion
Cutaneous metastasis is a rare occurrence, making SMJN exceptionally infrequent. The finding of SMJN should prompt a thorough search for the primary malignancy. As demonstrated by our patient, SMJN may be the first sign of a visceral malignancy, making proper and timely diagnosis lifesaving.