Immune Complex–Mediated Vasculitis

The three well-characterized forms of immune complex–mediated paraneoplastic vasculitis are leukocytoclastic vasculitis (LCV), cryoglobulinemic vasculitis, and Henoch-Schönlein purpura (HSP).

LCV accounts for 50% to 60% of paraneoplastic vasculitis and is the most frequently seen paraneoplastic vasculitis in both hematologic and solid malignancies. LCV is diagnosed on skin biopsy and it histologically demonstrates neutrophilic inflammation of vessel walls with endothelial swelling and fibrinoid necrosis in postcapillary venules. LCV occurs more frequently in hematologic malignancies and, when present in plasma cell dyscrasias, tends to be due to cryoglobulinemia. There has been no consistent association of LCV with a particular solid tumor. Cases have been reported with lung, prostate, breast, endometrial, ovarian, colon, renal, and head and neck cancers.

Paraneoplastic LCV usually presents as palpable purpura but rare cases of erythema elevatum diutinum (EED) and urticarial vasculitis (UV) have been reported. EED presents as violaceous plaques or nodules found predominantly over the extensor surfaces of hands and elbows, whereas UV ( Fig. 1 ) is characterized by erythematous wheals that last for greater than 24 hours. Paraneoplastic EED has been reported with breast cancer, B-cell lymphoma, hairy cell leukemia, and lymphoepithelioma-like carcinoma. On literature review, only six case reports of paraneoplastic urticarial vasculitis were found: two with Hodgkin’s lymphoma, one with non–Hodgkin’s lymphoma, two with metastatic colon cancer, and one with malignant teratoma of the testes. Although paraneoplastic cases of EED and UV are rare, numerous cases of medication-induced EED and UV have been reported. Hence, an atypical LCV presentation such as EED and UV would make medication-induced vasculitis more likely than a paraneoplastic process.

Urticarial vasculitis.

Cryoglobulins are cold-precipitated immunoglobulins associated with hepatitis C and HIV infections, lymphoproliferative diseases, and other chronic inflammatory conditions. Neoplastic cryoglobulinemia, accounting for 15% of all cryoglobulinemia, rarely causes vasculitis. Neoplastic cryoglobulinemia is usually monoclonal (type I) and due to lymphoproliferative disorders such as Waldenström’s macroglobulinemia, multiple myeloma, non–Hodgkin’s lymphoma, and chronic lymphocytic leukemia. Type I cryoglobulins do not have rheumatoid factor activity and, hence, do not easily activate the classical complement pathway. However, a few cases of paraneoplastic cryoglobulinemic vasculitis manifesting only with cutaneous involvement and one case of type I cryoglobulinemic glomerulonephritis have been described. Most patients with type I cryoglobulins are asymptomatic until concentrations of cryoglobulins reach levels high enough to cause hyperviscosity. Manifestations of hyperviscosity include acrocyanosis, digital gangrene, and strokes.

HSP is an immune complex–mediated small vessel vasculitis defined by IgA deposition in blood vessel walls. Almost all adult patients have palpable purpura and arthralgias, whereas 30% have renal involvement and 50% have gastrointestinal involvement. Paraneoplastic HSP accounts for 15% of paraneoplastic vasculitis and occurs more commonly with carcinomas of the lung, urogenital, and gastrointestinal tracts. Zurada and colleagues looked at 31 reported cases of paraneoplastic HSP and noted two key patient characteristics: male gender (95%) and older age (mean age of 68 years with a range of 46–86). When compared with non–malignancy-associated HSP, patients with paraneoplastic HSP tended to have more renal involvement (87%). Mitsui and colleagues retrospectively examined 23 cases of malignancy-associated and 80 cases of non–malignancy-associated HSP during a 20-year period and also found older age (67.2 years vs 41.3 years) to be a risk factor for paraneoplastic HSP but not male gender. Another study comparing 19 HSP patients with known malignancies to 158 HSP patients without a known malignancy concluded that male gender (90% vs 65%) and age greater than 40, combined with a lack of clear infectious or medication triggers, were risk factors for paraneoplastic HSP.

ANCA-Associated Vasculitis

ANCA-associated vasculitides, as a class, is the most common systemic small vessel vasculitis. This class is further divided into granulomatosis with polyangiitis (GPA, formerly known as Wegener’s granulomatosis), Churg-Strauss syndrome, and microscopic polyangiitis (MPA) based on clinical manifestations and whether ANCA is perinuclear or cytoplasmic in pattern and whether it binds to myeloperoxidase or proteinase 3.

Although many reports of ANCA-associated vasculitis with a concurrent malignancy exist, paraneoplastic ANCA-associated vasculitides account for less than 5% of paraneoplastic vasculitis, although a positive ANCA can frequently be seen in the setting of malignancy. During an 18.5 year period, Hutson and Hoffman reported one case of GPA, which did not run a concordant course with the patient’s malignancy. Solans-Laque and colleagues found no patients with paraneoplastic ANCA-associated vasculitis among 15 patients with paraneoplastic vasculitis during a 15-year period. Tatsis and colleagues reported 14 patients diagnosed with GPA and a concurrent malignancy, but only 4 of the 14 patients had a paraneoplastic manifestation of GPA. Three of the four patients had renal cell carcinomas. One case of paraneoplastic MPA presenting with fevers, mononeuritis multiplex, and glomerulonephritis associated with gastroduodenal carcinoma has been reported. Based on these reports and a retrospective review of 200 patients with MPA or GPA, one can discern that, although paraneoplastic ANCA-associated vasculitis is rare, concurrent diagnoses with independent courses are common. In this study, the largest cohort examined to date, when compared with age-matched groups, the relative risk of having a malignancy at the time of vasculitis diagnosis was 6.02 (95% confidence interval 3.72–9.74).

One case of systemic Churg-Strauss vasculitis associated with recurrence of malignant melanoma has been reported. There are a few case reports of a cutaneous form of Churg-Strauss vasculitis associated with lymphoproliferative disorders. These cases are characterized by pruritic nodules on the upper limbs with histology showing dermal eosinophilic collagen necrosis with cellular debris, surrounded by a granulomatous infiltrate of eosinophils and neutrophils.

Other Vasculitis

Primary angiitis of the central nervous system (PACNS) is a rare multifocal, segmental vasculitis affecting the small leptomeningeal and intracerebral arteries. A brain biopsy with surrounding leptomeninges demonstrating vasculitis is the gold standard for diagnosis but, often not obtained owing to its invasive nature. MRI is the most sensitive imaging modality and has a positive predictive value of 43% to 72%, whereas that of cerebral angiography is 37% to 50%. If incidence is based only on cases with confirmed biopsies, paraneoplastic PACNS is rare. Although there are case reports of primary PACNS associated with breast cancer and non–Hodgkin’s lymphoma, the strongest association seems to be with Hodgkin’s lymphoma because 13 cases have been reported. Symptoms include headaches, seizures, and altered mental status from varied clinical presentations such as encephalopathy, hemorrhage, and infarcts. Unlike other paraneoplastic vasculitides, due to the poor prognosis often associated with paraneoplastic PACNS, the current recommendation is not only to treat the underlying malignancy but to also treat the vasculitis early with corticosteroids and other immunosuppressants.

Giant cell arteritis (GCA) is a large vessel vasculitis predominantly affecting branches of the aorta, especially the extracranial arteries. Many case reports of a synchronous diagnosis of GCA and various malignancies exist, but only five cases clearly ran a concordant course with an associated malignancy. The five cases included two cases of lung cancer and one each of cholangiocarcinoma, prostate cancer, and colorectal carcinoma. As a result, some have argued that patients with newly diagnosed GCA have an increased risk of malignancy, but a large prospective case-control study demonstrated no increased risk.

Polyarteritis nodosa (PAN) is a vasculitis affecting small and medium-sized vessels of the peripheral nervous, gastrointestinal, and renal systems. Clinical presentations in paraneoplastic PAN are similar to classical PAN. Paraneoplastic PAN accounts for 15% of all paraneoplastic vasculitides and, although higher percentages have been cited (around 30%), the cases described in these reports are not clearly demonstrated to be paraneoplastic. Paraneoplastic PAN has been frequently described in association with various solid tumors, including bladder, colorectal, gastric, lung, liver, and hypopharyngeal tumors and with hematologic diseases such as myelodysplastic syndrome, hairy cell leukemia and chronic myelomonocytic leukemia.

Of numerous malignancy associations, hairy cell leukemia is the most strongly associated with paraneoplastic PAN. Hairy cell leukemia is a relatively rare leukemia, accounting for only 2% of leukemias. First described by Hughes and colleagues in 1979, the association of hairy cell leukemia and paraneoplastic PAN has been validated by numerous case reports, with more than 50 reported cases in literature. Proposed mechanisms for this association include cross-reactivity of antibodies against hairy cell leukemic cell surface antigens and those on vascular endothelial cells.

Immune Complex–Mediated Vasculitis

The three well-characterized forms of immune complex–mediated paraneoplastic vasculitis are leukocytoclastic vasculitis (LCV), cryoglobulinemic vasculitis, and Henoch-Schönlein purpura (HSP).

LCV accounts for 50% to 60% of paraneoplastic vasculitis and is the most frequently seen paraneoplastic vasculitis in both hematologic and solid malignancies. LCV is diagnosed on skin biopsy and it histologically demonstrates neutrophilic inflammation of vessel walls with endothelial swelling and fibrinoid necrosis in postcapillary venules. LCV occurs more frequently in hematologic malignancies and, when present in plasma cell dyscrasias, tends to be due to cryoglobulinemia. There has been no consistent association of LCV with a particular solid tumor. Cases have been reported with lung, prostate, breast, endometrial, ovarian, colon, renal, and head and neck cancers.

Paraneoplastic LCV usually presents as palpable purpura but rare cases of erythema elevatum diutinum (EED) and urticarial vasculitis (UV) have been reported. EED presents as violaceous plaques or nodules found predominantly over the extensor surfaces of hands and elbows, whereas UV ( Fig. 1 ) is characterized by erythematous wheals that last for greater than 24 hours. Paraneoplastic EED has been reported with breast cancer, B-cell lymphoma, hairy cell leukemia, and lymphoepithelioma-like carcinoma. On literature review, only six case reports of paraneoplastic urticarial vasculitis were found: two with Hodgkin’s lymphoma, one with non–Hodgkin’s lymphoma, two with metastatic colon cancer, and one with malignant teratoma of the testes. Although paraneoplastic cases of EED and UV are rare, numerous cases of medication-induced EED and UV have been reported. Hence, an atypical LCV presentation such as EED and UV would make medication-induced vasculitis more likely than a paraneoplastic process.

Urticarial vasculitis.

Cryoglobulins are cold-precipitated immunoglobulins associated with hepatitis C and HIV infections, lymphoproliferative diseases, and other chronic inflammatory conditions. Neoplastic cryoglobulinemia, accounting for 15% of all cryoglobulinemia, rarely causes vasculitis. Neoplastic cryoglobulinemia is usually monoclonal (type I) and due to lymphoproliferative disorders such as Waldenström’s macroglobulinemia, multiple myeloma, non–Hodgkin’s lymphoma, and chronic lymphocytic leukemia. Type I cryoglobulins do not have rheumatoid factor activity and, hence, do not easily activate the classical complement pathway. However, a few cases of paraneoplastic cryoglobulinemic vasculitis manifesting only with cutaneous involvement and one case of type I cryoglobulinemic glomerulonephritis have been described. Most patients with type I cryoglobulins are asymptomatic until concentrations of cryoglobulins reach levels high enough to cause hyperviscosity. Manifestations of hyperviscosity include acrocyanosis, digital gangrene, and strokes.

HSP is an immune complex–mediated small vessel vasculitis defined by IgA deposition in blood vessel walls. Almost all adult patients have palpable purpura and arthralgias, whereas 30% have renal involvement and 50% have gastrointestinal involvement. Paraneoplastic HSP accounts for 15% of paraneoplastic vasculitis and occurs more commonly with carcinomas of the lung, urogenital, and gastrointestinal tracts. Zurada and colleagues looked at 31 reported cases of paraneoplastic HSP and noted two key patient characteristics: male gender (95%) and older age (mean age of 68 years with a range of 46–86). When compared with non–malignancy-associated HSP, patients with paraneoplastic HSP tended to have more renal involvement (87%). Mitsui and colleagues retrospectively examined 23 cases of malignancy-associated and 80 cases of non–malignancy-associated HSP during a 20-year period and also found older age (67.2 years vs 41.3 years) to be a risk factor for paraneoplastic HSP but not male gender. Another study comparing 19 HSP patients with known malignancies to 158 HSP patients without a known malignancy concluded that male gender (90% vs 65%) and age greater than 40, combined with a lack of clear infectious or medication triggers, were risk factors for paraneoplastic HSP.

ANCA-Associated Vasculitis

ANCA-associated vasculitides, as a class, is the most common systemic small vessel vasculitis. This class is further divided into granulomatosis with polyangiitis (GPA, formerly known as Wegener’s granulomatosis), Churg-Strauss syndrome, and microscopic polyangiitis (MPA) based on clinical manifestations and whether ANCA is perinuclear or cytoplasmic in pattern and whether it binds to myeloperoxidase or proteinase 3.

Although many reports of ANCA-associated vasculitis with a concurrent malignancy exist, paraneoplastic ANCA-associated vasculitides account for less than 5% of paraneoplastic vasculitis, although a positive ANCA can frequently be seen in the setting of malignancy. During an 18.5 year period, Hutson and Hoffman reported one case of GPA, which did not run a concordant course with the patient’s malignancy. Solans-Laque and colleagues found no patients with paraneoplastic ANCA-associated vasculitis among 15 patients with paraneoplastic vasculitis during a 15-year period. Tatsis and colleagues reported 14 patients diagnosed with GPA and a concurrent malignancy, but only 4 of the 14 patients had a paraneoplastic manifestation of GPA. Three of the four patients had renal cell carcinomas. One case of paraneoplastic MPA presenting with fevers, mononeuritis multiplex, and glomerulonephritis associated with gastroduodenal carcinoma has been reported. Based on these reports and a retrospective review of 200 patients with MPA or GPA, one can discern that, although paraneoplastic ANCA-associated vasculitis is rare, concurrent diagnoses with independent courses are common. In this study, the largest cohort examined to date, when compared with age-matched groups, the relative risk of having a malignancy at the time of vasculitis diagnosis was 6.02 (95% confidence interval 3.72–9.74).

One case of systemic Churg-Strauss vasculitis associated with recurrence of malignant melanoma has been reported. There are a few case reports of a cutaneous form of Churg-Strauss vasculitis associated with lymphoproliferative disorders. These cases are characterized by pruritic nodules on the upper limbs with histology showing dermal eosinophilic collagen necrosis with cellular debris, surrounded by a granulomatous infiltrate of eosinophils and neutrophils.

Other Vasculitis

Primary angiitis of the central nervous system (PACNS) is a rare multifocal, segmental vasculitis affecting the small leptomeningeal and intracerebral arteries. A brain biopsy with surrounding leptomeninges demonstrating vasculitis is the gold standard for diagnosis but, often not obtained owing to its invasive nature. MRI is the most sensitive imaging modality and has a positive predictive value of 43% to 72%, whereas that of cerebral angiography is 37% to 50%. If incidence is based only on cases with confirmed biopsies, paraneoplastic PACNS is rare. Although there are case reports of primary PACNS associated with breast cancer and non–Hodgkin’s lymphoma, the strongest association seems to be with Hodgkin’s lymphoma because 13 cases have been reported. Symptoms include headaches, seizures, and altered mental status from varied clinical presentations such as encephalopathy, hemorrhage, and infarcts. Unlike other paraneoplastic vasculitides, due to the poor prognosis often associated with paraneoplastic PACNS, the current recommendation is not only to treat the underlying malignancy but to also treat the vasculitis early with corticosteroids and other immunosuppressants.

Giant cell arteritis (GCA) is a large vessel vasculitis predominantly affecting branches of the aorta, especially the extracranial arteries. Many case reports of a synchronous diagnosis of GCA and various malignancies exist, but only five cases clearly ran a concordant course with an associated malignancy. The five cases included two cases of lung cancer and one each of cholangiocarcinoma, prostate cancer, and colorectal carcinoma. As a result, some have argued that patients with newly diagnosed GCA have an increased risk of malignancy, but a large prospective case-control study demonstrated no increased risk.

Polyarteritis nodosa (PAN) is a vasculitis affecting small and medium-sized vessels of the peripheral nervous, gastrointestinal, and renal systems. Clinical presentations in paraneoplastic PAN are similar to classical PAN. Paraneoplastic PAN accounts for 15% of all paraneoplastic vasculitides and, although higher percentages have been cited (around 30%), the cases described in these reports are not clearly demonstrated to be paraneoplastic. Paraneoplastic PAN has been frequently described in association with various solid tumors, including bladder, colorectal, gastric, lung, liver, and hypopharyngeal tumors and with hematologic diseases such as myelodysplastic syndrome, hairy cell leukemia and chronic myelomonocytic leukemia.

Of numerous malignancy associations, hairy cell leukemia is the most strongly associated with paraneoplastic PAN. Hairy cell leukemia is a relatively rare leukemia, accounting for only 2% of leukemias. First described by Hughes and colleagues in 1979, the association of hairy cell leukemia and paraneoplastic PAN has been validated by numerous case reports, with more than 50 reported cases in literature. Proposed mechanisms for this association include cross-reactivity of antibodies against hairy cell leukemic cell surface antigens and those on vascular endothelial cells.