RENAL IMMUNOBLASTIC SARCOMA COMPLICATING

IMMUNOSUPPRESSIVE THERAPY FOR

WEGENER GRANULOMATOSIS

GRANNUM R. SANT, M.D.

ANGELO A. UCCI, JR., M.D., PH.D.

EDWIN M. MEARES, JR., M.D.

From the Departments of Urology and Pathology, Tufts University School of Medicine and New England Medical Center Hospital, Boston, Massachusetts

ABSTRACT-A renal tumor developing in a patient receiving cyclophosphamide (Cytoxan) therapy for Wegener granulomatosis is reported. The tumor was similar histologically to the “im- munoblastic”sarcoma that develops in renal allograft recipients as a complication of immunosup- pressive therapy. This case report strengthens the cause and effect relationship between immuno- suppressive drug usage and the subsequent development of neoplasia.

De novo malignancy develops in 6 per cent of renal allograft recipients-an incidence 100 times greater than that found in the general population matched for age.’ The presumed basis of this increased risk is the effect on the body of immunosuppressive drugs used to pre- vent transplant rejection.1.2 Reports of ma- lignancies developing in nontransplant patients treated with immunosuppressive and cytotoxic agents for benign immunoinflammatory dis- eases have appeared in the literature with in- creasing frequency. D

We present a case of renal “immunoblastic sarcoma” that developed in a patient treated with immunosuppressive drugs for Wegener granulomatosis.

Case Report

A seventy-five-year-old woman was referred for evaluation of a right renal mass. In Novem- ber, 1976, she was found to have Wegener granulomatosis on nasal biopsy. At that time she experienced cough, fever, diffuse pulmonary in-

Presented at the Annual Meeting American Urological Associa- tion. Inc., ilay 10, 1981. Boston. Massachusetts.

filtrates, and otitis media. Treatment using cy- clophosphamide (Cytoxan) and prednisone was initiated, and within three weeks she improved significantly. The dosage of cyclophosphamide was reduced to 50 mg orally each day for five of seven days, and the dosage of prednisone was reduced to 50 mg orally every other day. In 1977, she was hospitalized for the treatment of disseminated herpes virus infection. The pred- nisone was subsequently discontinued, but therapy with cyclophosphamide was main- tained.

In April, 1979, right flank pain and gross he- maturia developed. Excretory urography with tomography and retrograde ureteropyelograms demonstrated a mass in the upper pole of the right kidney obliterating the collecting system of the upper pole. Renal arteriography con- firmed a relatively avascular mass involving the right upper pole suggestive of invasive transi- tional cell carcinoma or a secondary renal neo- plasm. A search for an extrarenal primary neo- plasm was negative. Although urinary cytologies were reported as Class IV, cystoscopy revealed a normal bladder. Metastatic workup, including lung tomograms, bone scan, and liver function tests were normal.

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Exploratory laparotomy was performed through a vertical midline incision. The intra- abdominal organs were normal, and there was no lymphadenopathy. A firm mass involving the upper pole of the right kidney was palpable. Radical right nephroureterectomy was per- formed, and the specimen was subjected to rapid frozen section examination. Multiple paracaval and para-aortic retroperitoneal lymph nodes were removed for pathologic stag- ing, and the incision was closed.

Pathologic examination of the surgical speci- mens revealed a 6-cm mass-lesion occupying the upper pole of the right kidney. The tumor con-

FIGURE 1. (A) Section from right kidney. Tzlmor consists of large cells containing large ovoid nuclei, prominent nu- cleoli, and abundant cyto- plasm characteristic of im- munoblastic sarcoma (hema- toxylin and eosin). (B) Elec- tron micrograph shou*ing pro- lierating cells with indented nuclei, distinct nucleoli, and cytoplasm u’ith abundant polysomes (original magnifi- cations x 400 and x 2,000, respectively).

sisted of lymphoma cells of variable cytology, including large lymphoblastic cells with nu- clear clefts and dispersed chromatin. Many of the cells had large, ovoid nuclei with prominent nucleoli and abundant pyroninophilic cyto- plasm (Fig. 1A). Electron microscopy showed the lymphoma cells were of the “immunoblas- tic” variety5e7 with prominent distinct nucleoli, irregularly shaped nuclei, and dispersed chro- matin with abundant polysomes in the cyto- plasm (Fig. 1B). The perinephric fat and retro- peritoneal lymph nodes were free of disease.

The patient’s postoperative recovery was un- eventful, and further evaluation revealed no

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evidence of residual or concurrent disease. Im- munosuppressive therapy was discontinued im- mediately after surgery, and the patient con- tinues in excellent health without evidence of residual disease at follow-up three years later.

Comment

That transplant recipients experience a greater than normal occurrence of malignan- cies is now well established.1-4 Unlike malignan- cies in the general population, 75 per cent of the neoplasms occurring in transplant recipients are lymphoproliferative malignancies, carcinomas of the skin, and carcinomas of the lip and cer- vix.’ These patients experience a striking inci- dence of lymphomas, particularly “reticulum cell” sarcomas which is 350 times greater than that found in the general population.2,4J The most common lymphomas occurring in trans- plant recipients are so-called reticulum cell sar- comas or histiocytic lymphomas. Currently, neither term is deemed appropriate. Since the tumor consists of large pyroninophilic cells with the appearance of antigen-stimulated lympho- cytes, a more descriptive and appropriate term-immunoblastic sarcoma-has emerged recently. 3-5 Modern immunologic techniques in- dicate that immunoblastic sarcomas consist of B lymphocytes.4.6

Clinicians now frequently use cytotoxic agents, i.e., cyclophosphamide, azathioprine, methotrexate, and chlorambucil, for the treat- ment of various nonmalignant diseases, such as systemic lupus erythematosis, rheumatoid arthritis, Sjorgren syndrome, and inflamma- tory bowel diseases. Among 109 patients with benign diseases who were treated with im- munosuppressive drugs and in whom neoplasms later developed, 22 per cent of the neoplasms were lymphomas .3 The development of ma- lignancies in patients treated with immunosup- pressive agents, particularly cyclophosphamide and other alkylating agents, for benign immu- noinflammatory diseases is being reported with increasing frequency. 3s Our case falls into this category.

Immunosuppressive drugs cause defective immunoregulation, and this allows chronic antigenic stimulation, chronic graft versus host disease, and viral activation to affect the host’s

lymphocytes.5-7 This leads to unchecked lym- phoid proliferation and the development of im- munoblastic sarcoma.6,7

The use of immunosuppressive drugs in the management of renal allograft recipients car- ries a definite risk for the development of de novo malignancies, especially lymphomas.’ Ini- tial reports concerning the use of cyclosporin A in clinical organ-grafting include a disturbing incidence of the subsequent occurrence of lym- phoma. For instance, in 3 of 57 renal allograft patients treated with cyclosporin-A lymphomas developed within one year of transplantation.s However, further experience has not borne this out, and new protocols encompassing better hy- dration and altered dosage schedules have proved to be safe.g

The use of immunosuppressive drugs for the treatment of benign disease carries an increased risk for the development of malignancy.1.3.5 Therefore when one uses these agents in therapy, especially in treating benign diseases, caution must be observed, and the indications must be sound.’ Although some still debate the cause and effect relationship between immuno- suppressive therapy and the development of neoplasia, case histories such as ours tend to quell the controversy.

171 Harrison Avenue Boston, Massachusetts 02111

(DR. SANT)

References

1. Penn I: Malignancies associated with immunosuppressive or cytotoxic therapy, Surgery 88: 492 (1978).

2. Hoover R, and Fraumeni JF Jr: Risk of cancer in renal transplant recipients, Lancet 2: 55 (1973).

3. Louie S, and Schwartz RS: Immunodeficiency and the pathogenesis of lpmphoma and leukemia, Sem Hematol 15: 117 (1978).

4. Penn I: Malignant lymphomas in organ transplant recipi- ents, Transulant Proc 13: 736 (1981).

5. Loui; S, Daoust PR, and Schwartz RS: Immunodeficienc\ and the pathogenesis of non-Hodgkin’s Iymphoma, Semin O&l 7: 267 (1980).

6. Frizzera G, ef al: Polymorphic diffuse B-cell hyperplasias and lymphomas in renal transplant recipients, Cancer Res 41: 4262 (1981).

7. Matas AJ, ef al: Post-transplant malignant lymphoma: dis- tinctive morphologic features related to its pathogenesis. Am J Med 61: 716 (1976).

8. Thiru S: Came RY, and Nagington J: Lymphoma in renal allograft patients treated with cyclosporin-A as one of the im- munosuppressive agents, Transplant Proc 13: 359 (1981).

9. Calne RY: Twenty-year experience of immunosupprebsion in organ transplantation, ibid 14: 91 (1982).

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