Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients

OBJECTIVE: To describe the incidence of malignancies in a cohort of Danish patients with Wegener's granulomatosis (WG) and to investigate the cancer risk associated with cyclophosphamide (CYC) -therapy in WG. METHODS: In total, 293 patients diagnosed with WG between 1973 and 1999 were studied. Cancer incidence in the cohort was assessed through 2003 by linkage to the Danish Cancer Registry and compared to that of the general population by calculation of standardized incidence ratios (SIR). Analyses were stratified according to treatment with low cumulative CYC doses (< or = 36 g) and high doses (> 36 g, corresponding to treatment with 100 mg CYC/day for > 1 year). RESULTS: Fifty cancers occurred during 2121 person-years of followup (SIR of cancer of 2.1, 95% CI 1.5-2.7). Significantly increased SIR were observed for acute myeloid leukemia (AML; SIR 19.6, 95% CI 4.0-57), bladder cancer (SIR 3.6, 95% CI 1.2-8.3), and non-melanoma skin cancers (SIR 4.7, 95% CI 2.8-7.3). Leukemias and bladder cancers were diagnosed 6.9-18.5 years after initiation of CYC therapy. The risk of these malignancies was not increased for patients who never received CYC or for patients treated with cumulative CYC doses < or = 36 g. In contrast, high risks of AML (SIR 59.0, 95% CI 12-172) and bladder cancer (SIR 9.5, 95% CI 2.6-24) were observed for patients treated with cumulative CYC doses > 36 g. CONCLUSION: Treatment with high cumulative CYC doses implies a substantial risk of late-occurring, serious malignancies in WG. Patients with WG should be monitored for development of cancer for several decades after cessation of CYC therapy. These findings emphasize the need for development of new treatment regimens in WG.     

Failure of cyclophosphamide to prevent cerebritis in Wegener's granulomatosis

Two patients with diffuse cerebritis due to Wegener's granulomatosis are described. The cerebritis developed despite prolonged treatment with cyclophosphamide. This may be the first report of such an occurrence. Both patients had excellent functional recovery with intravenous corticosteroids.     

Cyclophosphamide-induced bladder toxicity in Wegener's granulomatosis

In a series of 111 patients with Wegener's granulomatosis who were given cyclophosphamide therapy, hemorrhagic cystitis, diagnosed on the basis of gross hematuria or at cystoscopy (or both), developed in 17 (15%). Most of these patients recovered uneventfully, with or without the discontinuation of cyclophosphamide, but 4 patients suffered a significant loss of blood, and bladder carcinoma developed in 3. New microhematuria also occurred in 52 patients (47%). The dose and duration of cyclophosphamide were greater in the group that had urotoxicity. Long-term followup of patients with hemorrhagic cystitis is mandatory for the detection of late recurrences or the development of bladder malignancy. New therapies are being directed at protecting the bladder from urotoxicity during cyclophosphamide treatment.     

Pulse cyclophosphamide therapy in Wegener's granulomatosis: a pilot study.

Five patients with Wegener's granulomatosis (WG) have been treated with 6- to 8-monthly pulses of intravenous cyclophosphamide (CP) and glucocorticoids in an open pilot study. One patient achieved complete remission sustained during 30 months of follow-up; one patient had features of active disease after 28 months of remission; two patients after an initial remission had an exacerbation of the disease and received continuous oral administration of CP, and one patient required continuous oral CP to control the symptoms. These results suggest that this regimen may not achieve a high degree of sustained remission in patients with WG.     

Wegener's granulomatosis: long-term follow-up of patients treated with pulse cyclophosphamide

Treatment with daily oral cyclophosphamide (CY) has improved survival in Wegener's granulomatosis (WG), but is associated with severe and potentially lethal adverse effects. Less toxic treatment regimens, such as pulse CY, have been used, but the effect has been questioned. We have treated 11 patients with WG with pulse CY (15 mg/kg initially every second week, gradually increasing the pulse interval). After 4.5 yr follow-up and a total of 501 pulses of CY, one patient died and eight patients (73%) were in complete remission. Remission was induced in 91% of the patients after a median period of 3.5 months and relapses were seen in 60%. With the same treatment protocol, a new complete remission was induced in 75% of those relapsing. Except for one patient who died, no patient developed end-stage renal failure. Haemorrhagic cystitis was not observed and no malignancies recorded. Severe infections were seen in 36%, but none caused by Pneumocystis carinii. Nausea was the most frequent side-effect, seen in 64% of the patients. We conclude that treatment with pulse CY every second week is safe and effective in inducing remission and treating relapses in WG. The relapse rate seems to be higher than with low-dose oral CY, but the cumulative dose of CY is less.      

Hodgkin's lymphoma in a patient treated for Wegener's granulomatosis with cyclophosphamide and azathioprine

Only 5 neoplasms have been reported associated with the use of cytotoxic drugs in the treatment of Wegener's granulomatosis. Described here for the first time, to our knowledge, is a patient with Wegener's granulomatosis treated with cyclophosphamide and azathioprine who later developed Hodgkin's lymphoma.     

Diffuse histiocytic lymphoma in a patient treated with cyclophosphamide for Wegener's granulomatosis

Diffuse histiocytic lymphoma developed in a 48-year-old man with Wegener's granulomatosis after nine years of therapy with cyclophosphamide. He died despite aggressive surgical and medical therapy for the lymphoma. This may be the first report of diffuse histiocytic lymphoma following treatment of Wegener's granulomatosis with cyclophosphamide. Recommendations for the approach towards extended therapy of smoldering Wegener's granulomatosis are discussed.     

Wegener's granulomatosis. Long-term followup of patients treated with cyclophosphamide.

Ten patients with Wegener's granulomatosis were treated with cyclophosphamide and followed for periods up to 7 years. In all cases cyclophosphamide induced complete remissions. The mean duration of remission (to date) was 38 months. Six patients have been in remission for a mean of 46 months after cyclophosphamide was discontinued; 2 have been disease-free for 7 years. Of the 10 patients treated, only 1 relapsed and she responded to a second course of cyclophosphamide. These results indicate that cyclophosphamide is the drug of choice in Wegener's granulomatosis. The long-term effectiveness of this drug suggests that it may induce permanent remissions in certain patients with Wegener's granulomatosis.     

Panhypopituitarism due to Wegener's granulomatosis

Wegener's granulomatosis (WG) is a multi-system necrotizing granulomatous vasculitis which classically affects the upper respiratory tract, lungs and kidneys. Pituitary participation has been described in 24 patients in the literature to date. The aim of this article is to report a case of pituitary involvement in WG, and to present a literature review on this association. We present a female patient with WG who evolved with central diabetes insipidus (CDI), panhypopituitarism, and mild hyperprolactinemia. MRI showed an infiltrative pattern. Pituitary involvement has been reported in around 1% of patients with WG, mostly in women. It is represented by CDI and hypopituitarism. MRI generally shows pituitary enlargement, stalk thickening and loss of hyperintensity of the neurohypophysis. Permanent endocrine therapy is generally needed. WG should be considered in cases of CDI and hypopituitarism, essentially if a vasculitis is suspected and more common sellar disorders have been ruled out.     

Kaposi's sarcoma in an elderly man with Wegener's granulomatosis treated with cyclophosphamide and corticosteroids

The association of Kaposi's sarcoma with malignant lymphoreticular diseases and immunosuppressive therapy is well documented. This report describes an elderly man who presented with fulminant Wegener's granulomatosis that responded to treatment with cyclophosphamide and corticosteroids. Rapidly progressing cutaneous Kaposi's sarcoma developed ten weeks after the start of immunosuppressive therapy yet regressed on discontinuation of the corticosteroid therapy, despite continuation of cyclophosphamide therapy. To our knowledge, this is the first reported case of Kaposi's sarcoma occurring in association with Wegener's granulomatosis. The literature on Kaposi's sarcoma in immunosuppressed patients is reviewed.     

Wegener's granulomatosis in pregnancy

This report describes a case of severe limited Wegener's granulomatosis (WG) presenting in the third trimester of pregnancy with pansinusitis and necrotizing pneumonitis. The patient was treated successfully with a combination of corticosteroids and cyclo-phosphamide (CYC). The outcomes in the mother and the newborn were excellent. In a review of the English-language literature, we found 10 similar cases of WG with 13 pregnancies. WG occurring during pregnancy may have a more aggressive course and may require more aggressive treatment compared with WG occurring at other times. The treatment options for WG in pregnancy are discussed.     

Etoposide in Wegener's granulomatosis

SIR, Further to the letter of Papo et al. [1], we would liketo report on five more patients with Wegener's granulomatosis(WG) who have been treated with etoposide. The indications wereas follows: (1) induction of remission in severe cyclophosphamide-and steroid-resistant disease (patients 1 and 2); (2) inductionof remission in patients with severe disease who were intolerantof cyclophosphamide (patients 3, 4 and 5). Patient 1 is a 28-yr-old lady who presented to our unit witha severe flare of scleritis and sinusitis whilst taking azathioprine.WG had been diagnosed 8 yr earlier, with an average prednisolonedose during