Vasculitides associated with malignancies: Analysis of sixty patients

Authors


  • Presented in part at the 68th Annual Scientific Meeting of the American College of Rheumatology, San Antonio, TX, October 2004.

Abstract

Objective

To describe characteristics and outcomes of vasculitides associated with malignancies.

Methods

The requirement for inclusion in this retrospective, 10-year study was development of vasculitis in patients with a progressing malignancy. Malignancies secondary to immunosuppressants used to treat vasculitis were excluded. The main characteristics of vasculitides were analyzed and compared according to the type of malignancy.

Results

Sixty patients were included (male/female sex ratio 2.53, mean age 62.4 years). Mean followup duration was 45.2 months. Vasculitides were cutaneous leukocytoclastic (45%), polyarteritis nodosa (36.7%), Wegener's granulomatosis (6.7%), microscopic polyangiitis (5%), and Henoch-Schönlein purpura (5%). Malignancies were distributed as follows: hematologic in 63.1%, myelodysplastic syndrome (MDS) in 32.3%, lymphoid in 29.2%, and solid tumor in 36.9%. Vasculitides were diagnosed concurrently with malignancy in 38% of the cases. Manifestations of vasculitides were fever (41.7%), cutaneous involvement (78.3%), arthralgias (46.7%), peripheral neuropathy (31.7%), renal involvement (23.3%; 11.7% glomerulonephritis, 11.7% microaneurysms, 6.7% renal insufficiency), and antineutrophil cytoplasmic antibody (20.4%). Vasculitis treatments were corticosteroids (78.3%) and immunosuppressant(s) (41.7%). Vasculitis was cured in 65% of patients, but 58.3% died, with 1 death secondary to vasculitis. Independent of subtype, patients with vasculitides associated with MDS more frequently had renal manifestations (P = 0.02) and steroid dependence (P = 0.04) and achieved complete remission less often (P = 0.04) than patients with vasculitides associated with other malignancies. Patients with vasculitides associated with a solid tumor more frequently had peripheral neurologic involvement (P = 0.05). Patients with vasculitides associated with lymphoid malignancy had less frequent arthralgias (P = 0.01) and renal involvement (P = 0.02).

Conclusion

Vasculitides occurring during malignancies present distinctive features according to the vasculitis subtype and nature of the malignancy.

INTRODUCTION

The spectrum of vasculitides is large and etiologies or associated conditions are diverse. Some vasculitides can be the consequence of infections, allergy, rheumatologic and/or autoimmune diseases, or drugs. In some patients, vasculitis occurs during the course of or prior to malignancies, most often hematologic rather than solid tumors. The vasculitides that have been described are cutaneous leukocytoclastic vasculitis, polyarteritis nodosa, Churg-Strauss syndrome, microscopic polyangiitis, Wegener's granulomatosis, and Henoch-Schönlein purpura (1). The relationship between vasculitis and malignancy remains unclear: fortuitous association, paraneoplastic syndrome, neoplasms induced by immunosuppressive drugs prescribed to treat vasculitis, etc. In this report, we describe the results of a retrospective study of 60 patients with vasculitis-associated malignancies in which we determined the main characteristics of these vasculitides, particularly according to the type of associated cancer.

PATIENTS AND METHODS

We collected and retrospectively analyzed the medical files of patients with vasculitis-associated malignancies, treated by members of the French Society of Internal Medicine and the French Vasculitis Study Groups (FVSG), between June 1992 and June 2002. The requirement for inclusion in the study was development of vasculitis in patients with malignancies, either hematologic or solid tumor. Patients with vasculitides occurring at the time of cancer remission were excluded, as were those with giant cell arteritis, relapsing polychondritis, cryoglobulinemia, vasculitis induced by infectious disease or drugs, and malignancy secondary to the use of immunosuppressants prescribed to treat vasculitis. Vasculitis and cancer were biopsy proven for all patients.

Vasculitides were classified according to the American College of Rheumatology criteria and Chapel Hill consensus conference definitions (2). Then their main characteristics were compared as a function of their association with solid tumors, lymphoid malignancies, or myelodysplastic syndromes (MDS).

Statistical analysis.

Statistical analyses were conducted using SPSS software (SPSS, Chicago, IL) and STATXACT (Cytel, Cambridge, MA). Data were expressed as the mean ± SD (range) or number (percentage). Means were compared using the Mann-Whitney rank sum test or the Kruskal-Wallis nonparametric analysis of variance. We tested the associations in 2 × 2 cross tabulations using Fisher's exact test. For larger cross tabulations, associations were tested by computing Pearson's chi-square, or by computing the exact probability value or the Monte Carlo estimate of the exact probability value. All probabilities were 2-sided, with P values less than 0.05 considered statistically significant.

RESULTS

Sixty patients from 15 French internal medicine departments, 4 rheumatology departments, and 1 nephrology unit were included over 10 years. During the same period (June 1992 to June 2002), the FVSG entered into their database 557 new patients with vasculitis (polyarteritis nodosa, Churg-Strauss syndrome, microscopic polyangiitis, Wegener's granulomatosis) who originated from the majority of departments participating in this study. Among our 60 patients, 29 (48.3%) had polyarteritis nodosa, Churg-Strauss syndrome, microscopic polyangiitis, or Wegener's granulomatosis. These vasculitides associated with malignancies represented 5.2% of the vasculitides registered in the FVSG database. No data were available on the numbers of patients with leukocytoclastic vasculitis or Henoch-Schönlein purpura.

The main characteristics of our 60 patients are detailed in Table 1. The male/female sex ratio was 2.53, and mean ± SD age was 62.4 ± 12.9 years (range 22–89 years). Mean followup was 45.2 ± 41.1 months.

Table 1. Vasculitides associated with malignancy, the 65 malignancies associated with vasculitis, and demographic data*
ParameterValue
  • *

    Values are the number (percentage) unless otherwise indicated. Five patients developed 2 malignancies: myelodysplastic syndrome and Hodgkin's disease, refractory anemia with excess blasts and renal carcinoma, chronic lymphocytic leukemia and then non-Hodgkin's lymphoma, small intestine carcinoid tumor and schwannoma, breast carcinoma and then ovarian carcinoma.

  • One angioimmunoblastic lymphadenopathy.

Sex, no. (%) male/female43 (71.7)/17 (28.3)
Age, mean ± SD (range)62.4 ± 12.9 (22–89)
Type of vasculitis associated with malignancy (n = 60) 
 Leukocytoclastic vasculitis27 (45)
  With digital necrosis4 (6.7)
  With Sweet's syndrome2 (3.3)
  With nerve microvasculitis1 (1.7)
 Polyarteritis nodosa22 (36.7)
 Wegener's granulomatosis4 (6.7)
 Microscopic polyangiitis3 (5)
 Henoch-Schönlein purpura3 (5)
 Granulomatous cutaneous vasculitis1 (1.7)
Malignancies associated with vasculitis (n = 65) 
 Hematologic41 (63.1)
  Myelodysplastic syndrome21 (32.3)
   Refractory anemia with excess blasts11 (16.9)
   Refractory anemia3 (4.6)
   Chronic myelomonocytic leukemia7 (10.8)
  Lymphoid malignancy19 (29.2)
   Non-Hodgkin's lymphoma6 (9.2)
    Diffuse large B cell3 (4.6)
    Mantle zone1 (1.5)
    T cell lymphoma2 (3.1)
  Hodgkin's disease4 (6.2)
 Chronic lymphocytic leukemia4 (6.2)
  Hairy cell leukemia1 (1.5)
  Multiple myeloma4 (6.2)
   IgGκ3 (4.6)
   IgAκ1 (1.5)
  Myelofibrosis1 (1.5)
 Solid tumors24 (36.9)
  Lung cancer5 (7.7)
   Adenocarcinoma3 (4.6)
   Small-cell carcinoma1 (1.5)
   Squamous-cell carcinoma1 (1.5)
  Genitourinary plus gynecologic9 (13.8)
   Renal cancer3 (4.6)
   Bladder1 (1.5)
   Ovarian2 (3.1)
   Endometrial1 (1.5)
   Breast cancer2 (3.1)
  Gastrointestinal cancer7 (10.8)
   Colon2 (3.1)
   Stomach2 (3.1)
   Small intestine2 (3.1)
   Hepatocellular carcinoma1 (1.5)
  Nasopharyngeal1 (1.5)
  Mesothelioma1 (1.5)
  Adenocarcinoma, origin unknown1 (1.5)

The most frequently observed vasculitides were cutaneous leukocytoclastic (45%) and polyarteritis nodosa (36.7%). No statistically significant association could be established between a given vasculitis and a type of malignancy (Table 2). Cancers were predominantly hematologic, including MDS and lymphoid malignancies, followed by solid tumors (Table 1).

Table 2. Comparisons of type of vasculitis according to the type of malignancy*
MalignancynVasculitis
PAN (n = 22)LV (n = 27)WG (n = 4)MPA (n = 3)HSP (n = 3)
  • *

    Values are the number. Only the patients' first malignancy is reported. None of the comparisons were statistically significant. PAN = polyarteritis nodosa; LV = leukocytoclastic vasculitis; WG = Wegener's granulomatosis; MPA = microscopic polyangiitis; HSP = Henoch-Schönlein purpura.

Myelodysplastic syndrome2199110
Lymphoid malignancies1969120
Solid tumors2479213

Vasculitis was diagnosed before the cancer in 14 patients (within a mean ± SD interval of 11.9 ± 2 months [range 3.8–24.6 months]), simultaneously in 24 patients, and afterwards in 22 patients (within a mean ± SD interval of 37.9 ± 8.5 months [range 7–172.4 months]) (Table 3). For 14 patients, the interval between vasculitis and malignancy diagnoses exceeded 12 months. For 11 patients, vasculitis was diagnosed within a mean interval of 49 ± 22.9 months (range 15–172 months) after their malignancies, which progressed slowly: 3 chronic lymphocytic leukemias, 1 non-Hodgkin's lymphoma, 1 refractory anemia with excess blasts, 1 chronic myelomonocytic leukemia, 3 multiple myelomas, 1 colon cancer, and 1 bladder cancer.

Table 3. Characteristics of patients according to the time vasculitis occurred in relationship to the malignancy*
CharacteristicVasculitis occurred
Before malignancy (n = 14)Simultaneously (n = 24)After malignancy (n = 22)
  • *

    Values are the number (percentage) unless otherwise indicated.

Interval between vasculitis and malignancy, months   
 Mean ± SD11.9 ± 2037.9 ± 8.5
 Median9.6023.3
Age, mean ± SD59.1 ± 12.663.5 ± 8.863.3 ± 8.7
Sex ratio, male/female2.52.42.7
Type of vasculitis   
 Leukocytoclastic vasculitis3 (23.1)10 (41.7)14 (60.9)
 Polyarteritis nodosa10 (71.4)6 (25)6 (27.3)
 Microscopic polyangiitis0 (0)3 (12.5)0 (0)
 Wegener's granulomatosis0 (0)3 (12.5)1 (4.3)
 Henoch-Schönlein purpura1 (7.7)1 (4.2)1 (4.3)
 Granulomatous cutaneous vasculitis0 (0)1 (4.2)0 (0)
Malignancy   
 Hemopathies5 (38.5)17 (70.8)17 (73.9)
  Myelodysplastic syndrome1 (7.7)13 (54.2)7 (30.4)
   Refractory anemia with excess blasts, no.074
   Refractory anemia, no.111
   Chronic myelomonocytic leukemia, no.052
  Non-Hodgkin's leukemia, no.022
  Hodgkin's disease, no.000
  Chronic lymphocytic leukemia, no.104
  Hairy cell leukemia, no.310
  Myeloma, no.013
  Myelofibrosis, no.001
 Solid tumors9 (64.3)7 (29.2)5 (22.7)
  Lung, no.320
  Genitourinary plus gynecologic, no.232
  Gastrointestinal, no.311
  Other, no.112

The vasculitides in 8 of 11 patients were diagnosed during the 3 months preceding malignancy progression: chronic lymphocytic leukemias transformed into non-Hodgkin's lymphoma in 2 patients and refractory anemia with excess blasts transformed into acute leukemia in 1 patient, at the termination of chemotherapy in 1 patient with chronic myelomonocytic leukemia, monoclonal gammopathy levels increased in 3 patients with multiple myeloma, and colon cancer progressed in 1 patient. The interval exceeded 12 months for the other 3 patients whose vasculitides diagnoses preceded malignancy within a mean ± SD of 22 ± 1.3 months (range 21–24 months). None of these vasculitides were controlled when malignancies were diagnosed: 1 lung carcinoma with metastases, 1 gastric carcinoma, and 1 non-Hodgkin's lymphoma.

Other events were temporally associated with vasculitis diagnosis: dissemination of 4 lymphoid malignancies and 2 splenectomies. For 8 of 21 patients with MDS, vasculitis appeared within a median of 2.5 months (range 0–12 months), before transformation into acute leukemia in 9 of 21 patients with acute leukemia.

Vasculitis manifestations are reported in Table 4. Cutaneous involvement (>75%) was the most frequent sign, followed by joint symptoms, peripheral neuropathy, and kidney involvement. The predominant biologic anomaly was an inflammatory syndrome (70%), followed by monoclonal gammopathy and eosinophilia. Antineutrophil cytoplasmic antibodies (ANCAs) were detected in 20.4% of the 44 patients tested.

Table 4. Clinical and biologic manifestations of vasculitides associated with malignancies*
ManifestationsValue
  • *

    Values are the number (percentage) unless otherwise indicated. ANCA = antineutrophil cytoplasmic antibody.

  • Retinal vasculitis, orchiepididymitis, chondritis, temporal arteritis in a Wegener's granulomatosis, 1 each.

  • Defined as erythrocyte sedimentation rate >20 mm/hour and elevated acute-phase reactants (C-reactive protein >10 mg/liter and/or fibrinogen >4 gm/liter).

  • §

    Five patients had ANCA specific to proteinase 3: 3 Wegener's granulomatosis, 1 microscopic polyangiitis, 1 leukocytoclastic vasculitis; and 1 microscopic polyangiitis patient had ANCA specific to myeloperoxidase.

Clinical 
 Fever25 (41.7)
 General symptoms35 (58.3)
 Skin involvement47 (78.3)
  Purpura, no.27
   Necrotic purpura, no.6
  Nodule, no.13
  Livedo, no.6
  Ulceration, no.4
  Edema, no.5
  Bullae, no.2
 Arthralgias or arthritis28 (46.7)
 Arthralgias, no.16
  Polyarthritis, no.11
  Monarthritis, no.1
 Myalgias15 (25)
 Peripheral neuropathy19 (31.7)
 Kidney involvement14 (23.3)
  Glomerulonephritis7 (11.7)
  Microaneurysms7 (11.7)
  Renal insufficiency4 (6.7)
 Lung involvement6 (10)
 Gastrointestinal involvement8 (13.3)
 Sinusitis, deafness, dizziness5 (8.3)
 Heart involvement2 (3.3)
 Other manifestations, no.4
Biologic 
 Inflammatory syndrome42 (70)
 Eosinophilia9 (15)
 Monoclonal gammopathy10 (16.7)
  IgGκ/IgGλ, no.5/1
  IgAκ/IgGλ, no.2/1
  IgMκ, no.1
 Antinuclear factor, no./total no. (%)8/57 (14.0)
 Rheumatoid factor, no./total no. (%)3/45 (6.7)
 ANCA, no./total no. (%)§9/44 (20.4)
  Cytoplasmic-labeling pattern, no.7
  Perinuclear-labeling pattern, no.2
  Antiproteinase 3, no.5
  Antimyeloperoxidase, no.1
  Undetermined, no.3

Vasculitis and cancer treatments are detailed in Table 5. Tumor excision (pneumonectomy, nephrectomy, and cystectomy, 1 each) effectively treated cancer and vasculitis in 3 patients. Complete remission of vasculitides was initially achieved in 65% of the patients, but 33.3% relapsed. For cancers, 26.7% entered complete remission. Among the 35 deaths recorded, 19 (54.3%) were attributed to cancer, 16 (45.7%) to secondary infections, and 1 of the latter was linked to gastrointestinal vasculitis (hemorrhage). Vasculitis was not controlled at the time of 20% of the deaths. Nine of the 21 patients with MDS died of infectious complications, and 7 of 9 received immunosuppressants: 4 received cyclophosphamide or methotrexate to treat polyarteritis nodosa and 3 received etoposide or hydroxyurea chemotherapy for MDS.

Table 5. Treatments and patient outcomes*
TreatmentValue
  • *

    Values are the percentage.

  • Cyclophosphamide, dapsone, plasma exchange, intravenous immunoglobulins.

Vasculitis 
 Corticosteroids78.3
 Immunosuppressant(s)41.7
 None6.7
Malignancy 
 Chemotherapy61.7
 Surgery26.7
 Radiotherapy15
Outcome 
 Vasculitis complete remission65
 Vasculitis relapse33.3
 Steroid dependence (prednisone >20 mg/day)33.3
 Cancer complete remission26.7
 Death58.3

According to our univariate analysis (Table 6), patients with vasculitides, independent of their type, associated with MDS were characterized by significantly more frequent renal involvement (microaneurysms or glomerulonephritis), steroid dependence, and less common complete remission. Patients with vasculitides associated with solid tumors more frequently had peripheral neuropathies, arthralgias, and renal involvement than those with vasculitides associated with lymphoid malignancies.

Table 6. Comparisons of vasculitis characteristics according to the type of malignancy*
Vasculitis characteristicType of malignancyP
Solid tumorLymphoidMDS
  • *

    Values are the percentage unless otherwise indicated. MDS = myelodysplastic syndrome; NS = not significant; ANCA = antineutrophil cytoplasmic antibody.

  • Polyarteritis nodosa, Wegener's granulomatosis, and microscopic polyangiitis.

Necrotizing vasculitides47.647.152.4NS
Cutaneous manifestations76.376.581NS
Arthralgias57.117.661.90.01
Peripheral neuropathy47.635.314.30.05
Renal involvement195.942.90.02
Lung involvement4.85.919NS
Gastrointestinal involvement14.3023.8NS
Inflammatory syndrome76.252.981NS
Monoclonal gammopathy9.542.9100.02
ANCA positivity2518.220NS
Steroid dependence27.82563.20.04
Vasculitis complete remission66.787.547.60.04
Cancer complete remission42.935.34.80.01
Death47.647.176.2NS

DISCUSSION

We described the characteristics and outcomes of 60 patients with vasculitis-associated malignancies. Vasculitis was reported to occur during the course of malignancies in 2.3–8% of the patients (1, 3). Vasculitis frequency during cancer was estimated at 1 in 1,800 for hemopathies and 1 in 80,800 for solid tumors (4). Over an 18.5-year period, Hutson and Hoffman (5) identified 2,800 patients with vasculitis and 69,000 with cancer. Among these patients, 69 had a malignancy and systemic vasculitis (2.5% of patients with vasculitis and 0.1% of those with cancer); 12 (17%) were diagnosed with vasculitis and cancer within 12 months (5), compared with 60% of our 60 patients.

In patients with cancer, the development of vasculitis can be linked to infections, drug reactions, or cryoglobulin deposits. These factors were detected in 39% of the patients who developed cutaneous vasculitis during the course of hematologic malignancies (6). Nevertheless, independently of these factors, some vasculitides occurred in patients with cancer. However, real paraneoplastic syndromes were rarely observed. Indeed, cancer appeared more like a vasculitis-triggering factor, and the outcomes of the 2 diseases were not strictly chronologically parallel.

The malignancy rate in patients with any small-vessel vasculitis (microscopic polyangiitis or Wegener's granulomatosis) was significantly higher than that of a normal age-matched general population (relative risk [RR] 7.5). The risk was higher for patients with ANCA-associated vasculitides than for those with Henoch-Schönlein purpura (RR 6.02 and 5.25, respectively, compared with controls). The malignancy rate was also higher in patients with ANCA-associated vasculitis than in those with systemic lupus erythematosus (7). As for our patients, vasculitides were more frequently associated with hematologic malignancies than solid tumors (1).

Although different vasculitides were described in our study, leukocytoclastic vasculitis (45%) and polyarteritis nodosa (36.7%) predominated. This high percentage of polyarteritis nodosa is uncommon in the general population, whereas Wegener's granulomatosis and microscopic polyangiitis are more frequent (8), and it was not linked to the presence of hepatitis B surface antigen because none of the 54 of 60 patients tested were infected. Nevertheless, based on our literature review of vasculitis-associated malignancies, polyarteritis nodosa represented 39 (24.2%) of all 161 vasculitides (1). We did not find a statistically significant association between vasculitis type and malignancy type (Table 3), perhaps because of the limited number of patients, but some preferential associations seemed to exist, such as between polyarteritis nodosa and MDS, and Wegener's granulomatosis and Henoch-Schönlein purpura with solid tumors. We did not include patients with cancer and giant cell arteritis because a fortuitous association is probable in elderly patients, as Myklebust et al demonstrated in their prospective study with matched population controls (9). However, Liozon et al recently reported that 7.4% of patients with giant cell arteritis were diagnosed with a concurrent (±1 year) malignancy (10).

Malignancies associated with vasculitides were predominantly hematologic (MDS and lymphoid). We observed only 1 (1.7%) patient with hairy cell leukemia, perhaps because of its rarity in internal medicine, rheumatology, and nephrology departments. However, hairy cell leukemia represents 2% of all leukemias and 1.5–19% have been reported to be particularly associated with vasculitis (1, 11). Indeed, >40 of these leukemias, equally associated with cutaneous leukocytoclastic vasculitis or polyarteritis nodosa, have been described (1, 11). Vasculitis was diagnosed in 51% of the patients within the first 12 months following leukemia diagnosis (range −72–120 months). Splenectomy appeared to be a vasculitis-triggering factor in 55% of those cases (1). Clinical manifestations were consistent with the vasculitis involved. Some patients had peripheral artery (radial, temporal) aneurysms (1). Farcet et al (12) found an underlying infection for 9 of their 10 patients. Other pathogenic mechanisms are suspected: neutropenia, impaired monocyte and macrophage functions, splenectomy, reticuloendothelial system infiltration by hairy cells, and immunoglobulin production leading to immune complex deposits responsible for vasculitis. Corticosteroids were usually effective. Pertinently, prognosis was more closely linked to hairy cell leukemia outcome than vasculitis outcome. Only 3 deaths directly related to vasculitis (abdominal aneurysm rupture, 2 intestinal infarctions) were reported (1).

MDS can be associated with vasculitis, with a predilection for leukocytoclastic and, more rarely, polyarteritis nodosa (1). Systemic ANCA-negative polyarteritis nodosa–type vasculitis seems to be closely associated with chronic myelomonocytic leukemia (13), as it was found in 6 (27%) of our 22 patients with polyarteritis nodosa. Cutaneous manifestations were frequent and nonspecific: papules, nodules, bullae, purpura, ulcerations, and/or necrotic lesions. Articular manifestations were more rare. Bilateral perirenal hemorrhage was described in polyarteritis nodosa associated with chronic myelomonocytic leukemia (14). Refractory anemia with excess blasts, chronic myelomonocytic leukemia, or MDS during the period around transformation into acute leukemia appears to trigger vasculitis onset. Indeed, vasculitis often appeared to be a sign preceding transformation, and responded to corticosteroids with or without immunosuppressants. In this context, immunosuppressive drugs should be used prudently and reserved for uncontrolled vasculitides or severe involvement because they increase infectious risk, especially for patients who have previously been treated with etoposide or hydroxyurea for MDS, and accelerate transformation into acute leukemia. Nine of our patients died of infectious complications; 4 of them had received immunosuppressants for polyarteritis nodosa.

In our comparative study of vasculitides associated with other malignancies, we found that vasculitides associated with MDS were more severe. The overall prognosis reflected MDS status but vasculitis was rarely controlled at the time of death.

Non-Hodgkin's lymphomas were more often associated with vasculitis (leukocytoclastic vasculitis, lymphocytic, cutaneous granulomatous, polyarteritis nodosa, and Henoch-Schönlein purpura) than Hodgkin's disease (1). Cryoglobulins were found in 22% of patients with vasculitis–non-Hodgkin's lymphoma and were considered to be the origin of the vasculitis rather than the lymphoma (1). To avoid this situation of which came first, we excluded patients with cryoglobulinemia. Vasculitis and lymphoma were diagnosed simultaneously for >70% of the reported cases, but the responses of the 2 diseases to treatment showed no parallelism. In agreement with our findings, corticosteroids and/or chemotherapy were often effective (1).

Monoclonal gammopathies were detected in cryoglobulinemic vasculitis and other cutaneous vasculitides (leukocytoclastic, erythema elevatum diutinum), mostly monoclonal IgA type. Indeed, 66% of multiple myelomas associated with vasculitis reported by Sanchez et al were of the IgA type; vasculitis was always cutaneous, and the outcome was favorable in all cases, either spontaneously or with treatment of the myeloma (15). Among our 4 multiple myelomas, only 1 was IgA type.

Solid tumors, predominantly lung, colon, and renal, are more rarely associated with vasculitis than hematologic malignancies. Polyarteritis nodosa and Henoch-Schönlein purpura were reported more frequently than leukocytoclastic vasculitis or Wegener's granulomatosis. Vasculitis could appear as early as 25 months before cancer was diagnosed. Vasculitis complete remission was reported after tumor excision for 3 of our patients and for 10 reported patients (1). The search for a cancer (solid tumor in two-thirds of the cases) is recommended in elderly men with Henoch-Schönlein purpura, especially when joint manifestations are present (16). Our 3 cases of Henoch-Schönlein purpura were associated with solid tumors in 3 men over 55 years of age. Wegener's granulomatosis and renal cancer appeared simultaneously in 60% of the 23 cases described by Tatsis et al (17) and the cancer seemed to be a triggering factor. Wegener's granulomatosis outcome thereafter was independent of the malignancy. Only 1 of our patients had renal cancer and Wegener's granulomatosis. Renal cancer developed significantly more frequently in patients with Wegener's granulomatosis than those with rheumatoid arthritis. A pathogenetic link is not clear because proteinase 3 was not detected in the tumors. However, a pathogenic role of IgA was suggested for cancers associated with Henoch-Schönlein purpura, which could also explain the connection between IgA multiple myeloma and vasculitis, and renal cancer and IgA nephropathy (18). In those settings, IgA1 had an O-linked glycosylation deficiency (sialic acid deficient) that activates the complement pathway and favors mesangial deposits (19).

Nerve and muscle microvasculitides are defined as mononuclear cell infiltrations into the walls of small arteries whose calibers are <70 mm, but without leukocytoclastic or fibrinoid necrosis (20). Their association with cancer, mainly a solid tumor, was reported in 10–28% of cases (20). Clinical manifestations were primarily peripheral neuropathies: mononeuropathy multiplex or sensorimotor polyneuropathy. Cutaneous signs or muscle lesions were rare. Our only patient with lung cancer had associated leukocytoclastic vasculitis. The cerebrospinal fluid protein concentration was elevated. Histologic lesions were found particularly in nerves and in epimysial and perimysial connective tissues. Outcomes varied widely: remission after cancer treatment or under corticosteroid treatment, or disease progression.

Digital ischemia was associated with cancer (mostly solid tumors rather than hematologic malignancies) in 0.07% of the cases (21). Vasculitis is only one of the mechanisms and other factors were involved: sympathetic nerve hyperreactivity, enhanced viscosity or coagulability, tumor secretion of vasoactive substances, bleomycin chemotherapy. A cancer of the digestive tract (esophagus, stomach, small intestine, or colon) was found in one-third of the reported patients. Digital ischemia disappeared after cancer therapy in >50% of patients who achieved complete remission of cancer (1). For our 4 cases, digital ischemia disappeared, 2 after cancer surgery and 2 with chemotherapy.

The diagnosis of vasculitis requires a search for cancer, as well as other potential etiologies. When vasculitis is initially diagnosed, a complete physical examination, with standard biologic and radiologic examinations, appears to be sufficient. But the search for a cancer is particularly mandatory when the vasculitis becomes chronic, treatment is no longer effective, or the disease escapes control. In these situations, more complete exploratory examinations are necessary, e.g., computed tomography scans and, perhaps in the near future, fluorodeoxyglucose positron emission tomography. Tumor relapse or cytologic transformation should come to mind when vasculitis develops in a patient followed for a malignancy. Vasculitides occurring during malignancy present distinctive features according to the vasculitis subtype and also the nature of the malignancy. MDS-associated vasculitides are more frequent and severe.

AUTHOR CONTRIBUTIONS

Dr. Fain had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Fain, Kahn, Guillevin.

Acquisition of data. Fain, Hamidou, Cacoub, Godeau, Wechsler, Stirnemann, Morin, Gatfosse, Hanslik, Belmatoug, Blétry, Cevallos, Delevaux, Fisher, Hayem, Kahn, Kaplan, Le Hello, Mouthon, Larroche, Lemaire, Anne-Marie Piette, Jean-Charles Piette, Ponge, Puechal, Rossert, Sarrot-Reynauld, Sicard, Ziza, Guillevin.

Analysis and interpretation of data. Fain.

Manuscript preparation. Fain.

Statistical analysis. Pariés.

Acknowledgements

We thank Janet Jacobson for editorial assistance. Data collection was organized under the auspices of and with the help of the French Society of Internal Medicine and the French Vasculitis Study Group.

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