I protect against the development of malig-

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1 KAPOSI S SARCOMA IN RENAL ALLOGRAFT RECIPIENTS JOSEPH STRIBLING, MD,* STANLEY WEITZNER, MD,? AND GEORGE V. SMITH, MDS The development of Kaposi s sarcoma in immunosuppressed patients is a rare occurrence, but poses a real threat to the patient due to the rapid progression of the unchecked disease. The suspicion of this disease will prompt early diagnosis by scrutiny of histologic preparations and prompt interruption of antirejection therapy. Four of five patients in whom a diagnosis was made preterminally responded favorably to withdrawal of immunosuppressive agents. In renal *allograft recipients with mucocutaneous vascular lesions, Kaposi s sarcoma should be considered as a cause of gastrointestinal bleeding. Cancer 42~ , MMUNOLOGIC SURVEILLANCE MECHANISMS I protect against the development of malig- nant tumors which suggests that immunologic incompetence of a host should lead to a greater incidence of de nouo neoplasms. This hypothesis has been tested clinically over the past two decades incidental to the increase in renal transplantation and the required use of immunosuppressive therapy for graft prolongation. Birkeland et al.,2 and Penn have compiled many cases of malignant neoplasms arising in immunosuppressed renal transplant recipients, and report an incidence of 1.1% and 5.6%, respectively. The former report is based on data from the Scandia Transplant program and consists of twenty-one cases; fourteen carcinomas without apparent predilection for any site. There were six lymphomas, of which two of four reticulum cell sarcomas were intracerebral, and one case of Kaposi s sarcoma. Of the 184 cases in the Denver Transplant Tumor Registry, 125 were carcinomas, especially of the skin, lip, and cervix, and 61 were mesenchymal neoplasms. Almost 90% of the latter were malignant lymphomas, most often reticulum cell sarcomas, one-half of which were intracerebral. A survey of the literature di scloses seven cases of Kaposi s sarcoma arising in renal allograft recipients in addition to the case reported by Birkeland et al2 We now From the University of Mississippi Medical Center, 2500 North State Street, Jackson, Mississippi. * Associate Resident, Surgery. t Professor, Surgical Pathology. t Associate Professor, Surgery. Address for reprints: George V. Smith, MD, The University of Mississippi Medical Center, 2500 N. State St., Jackson, MS Accepted for publication December 3, X report the ninth case of Kaposi s sarcoma in a renal allograft patient and summarize the natural course of the disease in this clinical situation. CASE REPORT A 59-year-old black man was admitted to the University of Mississippi Medical Center in May 1972 for hemodialysis for chronic renal failure due to malignant nephrosclerosis. In November 1972, he underwent bilateral nephrectomy, splenectomy, and appendectomy in preparation for a future renal allograft. The patient was maintained on hemodialysis until June 1973, when he received a cadaveric renal allograft. The kidney donor was a healthy black male with no evidence of Kaposi s sarcoma who suffered a mortal head injury. The opposite kidney was transplanted into a black male who enjoyed three years of function prior to rejection of the transplant and return to hemodialysis. This recipient did not develop any evidence of neoplasm subsequent to transplantation of the kidney. The patient was maintained on an average daily dose of 2 mg/kg of azathioprine and his prednisone dose was reduced from 50 mg/day at the end of the first month to 20 mg/day at the end of the sixth month, and to 15 mg/day at the eleventh month. His renal function was excellent and he suffered only two clinical bouts of rejection. The first rejection required a 500 mg bolus of Solu-Medrol with a daily dose of 30 mg prednisone, and the second rejection required four injections of 500 mg Solu-Medrol each with a daily dose of 15 mg prednisone. In March 1974, he noticed an ulcer of the hard palate which was biopsied and interpreted as being an acute ulcer with granulation tissue. In July 1974, he developed pneumonitis and a urinary tract infection. Appropriate cultures were taken which grew out Proteus sensitive to ampicillin. These infections were controlled by institution of ampicillin therapy and there was no need for reduction of immuno- 0 American Cancer Society

2 No. 2 KAPOSI S SARCOMA- RENAL ALLOGRAFTS * Stribling et al. 443 suppressive therapy. Later in that month, a single lesion of the forearm was biopsied as an outpatient, and the slides were interpreted as demonstrating sclerosing hemangioma. He was rehospitalized in August 1974 for evaluation of multiple new and rapidly enlarging lesions of the head, trunk, and extremities (Fig. 1). The patient recalled the appearance of a skin lesion on his face shortly after transplantation, but all other lesions had appeared during the month prior to this last hospitalization. On his second hospital day, the patient developed massive gastrointestinal bleeding which necessitated laparotomy. At that time, multiple vascular nodules were noted throughout the gastrointestinal tract and a segmental resection of the most prominent lesions was performed, hoping to control the hemorrhage, but the patient died on the second postoperative day due to exsanguination. Autopsy Findings Multiple red-blue nodules were present on the head, trunk, and extremities. The entire gastrointestinal tract was filled with blood, and numerous nodules were present in the esophagus, stomach, small and large intestines (Figs. 2, 3) as well as the epicardium, liver, pancreas, adrenals, and retroperitoneal area. Microscopically, the diagnosis was Kaposi s sarcoma (Fig. 4). DISCUSSION The nine patients summarized in Table 1 apparently developed Kaposi s sarcoma as a complication of immunosuppressive therapy for prolongation of renal allografts. The interval between transplantation and the diagnosis of Kaposi s sarcoma varied from 8 to 43 months. In 6, including our patient with a retrospective diagnosis of the palatal lesion, this period was 8 to 12 months. Seven patients had some degree of clinical allograft rejection, but this factor did not appear to influence the development of the neoplasm or the prognosis of the patients. However, the hypothesis of Warner and O Loughlinll relating tumor rejection to the development of Kaposi s sarcoma suggests that chronic immunologic interaction between normal and antigenically altered or transformed lymphocytes (such as occurs in a graft-versus-host reaction) results in the production of an angiogenesis factor which produces intense proliferation of mesenchymal and endothelial cells, eventually leading to the development of Kaposi s sarcoma. However, Birkeland et al.,2 found no significant relationship between the number of graft rejection episodes and FIG. 1. Photograph of left knee showing multiple Kaposi s lesions. the development of malignant neoplasms. This suggests that a chronic low-grade immune response rather than severe crises is important and invokes the role of enhancing or blocking factors. If rejection crises develop, then evidently immunosuppression is not complete. They also invoke the possibility of recruitment or oncogenic viruses during this reaction and mention herpes virus, C-type oncornavirus, and cytomegalovirus as those probably involved in the final malignant change. The patients presented in this paper certainly meet the criteria of chronic immunologic stimulation, probably have altered lymphocytes due to suppressive therapy directed against them, and nearly half developed viral infections. Three of four viral infections were documented as being herpetic and one of those developed Kaposi s lesions at the site FIG. 2. Resected jejunum showing large, intraluminal Kaposi s lesion which had ulcerated and bled.

3 444 CANCER August 1978 VOl. 42 FIG. 3. Photomicrograph of lesion seen in Fig. 2 (X 16). FIG. 4. Photomicrograph of jejunal lesion demonstrating small irrrgular vascular spaces lined by irregular endothelial cells admixed with interlacing fascicles of spindle cells with hyperchromatic nuclei. There is extravasation of erythrocytes between the spindle cells and foci of iron pigment. The diagnosis is Kaposi s sarcoma (~320).

4 No. 2 KAPOSI'SARCOMA-RENAL ALLOGRAFTS. Stribling et al. 445 TABLE 1. Kaposi's Sarcoma in Renal 'Transplant Recipients post- Survival after Viral transplant diagnosis of Author Age Sex Type infection (months) Treatment Kaposi's sarcoma Siegal et al.$ 35 F Visceral, Herpes 10 (1969) disseminated Haim et nl." 24 M Cutaneous No 36 (1972) Not stated 1,000 rad to skin lesions, reduction of azathioprine. Kaposi's sarcoma diagnosed at autopsy. Respiratory failure. Alive 16 months. New skin lesions continued to appear. No visceral involvement. Birkeland et al.* 51 F Not stated Yes ( 1975) 12 Not stated Died 28 months. No autopsy findings noted. Myers et a F Cutaneous Herpes ( 1974) 9 Cerebral reticulum cell carcinoma excised about 2 months after diagnosis of Kaposi's sarcoma. Azathioprine then discontinued with total regression of cutaneous lesions. Died 22 months. No evidence of Kaposi's sarcoma at autopsy. Brain examination not allowed. Septicemia. Myers et a M Cutaneous Herpes ( 1974) Buccal mucosa Nasal mucosa Farmanand Uys3 52 M Oral No (1975) Antilymphocyte serum discontinued and azathioprine reduced. (New skin lesions appeared.) Azathioprine discontinued, irradiation to buccal lesion. (Skin lesions persisted.) Renal graft removed. Prednisone discontinued. X-ray to nose. 2,200 rad to oral lesions. Immunosuppression therapy ceased. Alive 36 months. Complete regression of skin lesions following removal of renal graft and cessation of remaining immunosuppression. Died 6 months later. Respiratory failure. No Kaposi's sarcoma at autopsy. Straehley et a1.i0 61 M Visceral No (1975) 46 None Died of complications after gastrectomy- Billroth 11. Visceral and skin lesions doted at autopsy. of Kaposi's sarcoma 2 months earlier in retrospect by examination of gastric specimens.

5 446 CANCER August 1978 Vol. 42 TABLE 1. (Continued) post- Survival after Viral transplant diagnosis of Author Age Sex Type infection (months) Treatment Kaposi's sarcoma Hardy et ~ 1. ~ 56 M Cutaneous No, but 9 Azathioprine reduced. 20 months ( 1976) elevated X-ray to all skin EBV lesions. Five months 1/164 later, azathioprine ceased followed by involution of all skin lesions. Present case 59 M Cutaneous No 13 None Died following severe gastrointestinal hemorrhage from multiple ulcerated Kaposi's sarcoma of the GI tract. retrospective of palate and skin biopsy. of the prior oronasal viral infection. The causative role of viruses in malignancy is questioned by Allen and Cole' who feel that viral infections commonly seen in cancer patients are due to a disturbed equilibrium between the host cell and the virus related to the preexistent malignancy. The development of malignant neoplasms following renal transplantation appears to be dependent on immunosuppressive therapy. This is supported by the complete regression of the cutaneous lesions in three patients and of the oral lesions in the fourth following cessation of immunosuppressive therapy. In two of these who died later, no tumor was found at autopsy. Stopping immunosuppressive therapy therefore appears to be the most effective therapy for Kaposi's sarcoma arising in renal allograft patients. Local radiotherapy and systemic chemotherapy (methotrexate) were of apparent benefit in some patients. One-third of those patients who died with Kaposi's sarcoma succumbed to massive gastrointestinal bleeding. Such sequellae appear to be preventable if the diagiibsis of Kaposi's sarcoma is made early. Any hemangioma, new or enlarging, should be viewed with suspicion and critically examined microscopically. Kaposi's sarcoma should be included in the differential diagnosis of all vascular lesions of the skin and mucous membranes, and of gastrointestinal bleeding in renal transplant patients. 1. Allen, D. W., and Cole, P.: Viruses and human cancer. N. Engl. J. Med. 286:70-82, Birkeland, S. A., Kemp, E., and Haugh, N.: Renal transplantation and cancer. Scand. Transplant. Material. Tissue Antigens 6:28-36, Farman, A. G. and Uys, P. B.: Oral kaposi's sarcoma. Oral Surg. 39: , Haim, S., Shafrir, A., Better, 0. S., Robinson, E., Chaimowitz, C., and Erlik, D.: Kaposi's sarcoma in association with immunosuppressive therapy. Isr. J. Med. Sci. 8: , Hardy, M. A., Goldfarb, P., Levine, S., Dattner, A., Muggia, F. M., Levitt, S., and Weinstein, E.: De now kaposi's sarcoma in renal transplantation. Cancer 38: , Myers, B. D., Kessler, E., Levi, J., Pick, A., Rosen- REFERENCES feld, J. B., and Tikvah, P.: Kaposi's sarcoma in kidney transplant recipients. Arch. Intern. Med. 133: , Penn, I.: Chemical immunosuppression and human cancer. Cancer 34: , Pisanty, S., and Garfunkel, A.: Kaposi's sarcoma. J. Oral Med. 25:89-92, Siege], J. H., Janis, R., Alper, J. C., Schutte, H., Robbins, L., and Blanfox, M. D.: Disseminated visceral kaposi's sarcoma.jama 207: , Straehley, C. J., Santos, J. I., Downey, D. M., and Lewin, K. J.: Kaposi's sarcoma in a renal transplant recipient. Arch Pathol. 99: , Warner, T. F. C. S., and O'Loughlin, S.: Kaposi's sarcoma: A byproduct of tumor rejection. Lancet 2: , 1975.