Kaposi's sarcoma in recipients of renal transplants

Kaposi’s Sarcoma in Recipients of Renal Transplants

ANDREW

R. HARWOOD,

M.B., Ch.B.,

F.R.C.P. (C) DAVID

OSOBA,

SOPHIE

B.Sc.. M.D., F.R.C.P.(C)

L. HOFSTADER,

M.D., C.M..

F.R.C.P.(C) MARC

B. GOLDSTEIN,

CARL J. CARDELLA.

M.D.. F.R.C.P.(C)

B.Sc., M.D.,

F.R.C.P.(C) MILAN

J. HOLECEK,

B.S., M.B.,

M.R.A.C.R.* RODION

KUNYNETZ,

ROSE A.GIAMMARCO,

BSc.,

M.D.

M.D., F.R.C.P.(C)

‘I’oronto, Ontario, Canadu

From the Department of Radiation Oncology, The Princess Margaret Hospital Toronto, Ontario. Canada. Requests for reprints should be addressed to Dr. Andrew R. Harwood, Depart-

ment of Radiation Oncology, The Princess Margaret Hospital, 500 Sherbourne Street, Toronto, Ontario M4X 1K9, Canada. Manuscript accepted June 21. 1979. * Present address: Radiation Department, Royal North Shore Hospital, St. Leonardo, Sydney, Australia 2065.

The purpose of this study was threefold; to ascertain if immunosuppression may be a factor in the causation of Kaposi’s sarcoma, to find out if there is a correlation between abnormalities in in vitro studies of cellular immune function and the extent of the disease, and to analyze the literature on Kaposi’s sarcoma arising in renal transplant recipients to determine a management policy for these patients. The charts of 44 patients with Kaposi’s sarcoma seen in a 20 year period at The Princess Margaret Hospital were reviewed in a search for evidence of immunosuppression as a possible risk factor. Such evidence was found in seven patients. Four of these seven patients were renal transplant recipients, two had generalized lymphomas and were receiving chemotherapy whereas one had a glioblastoma multiforme and was receiving chemotherapy. Studies of cellular immunity using phytohemagglutinin, conconavaljn A, pokeweed mitogen, the mixed leukocyte reaction and dinitrochlorobenzene skin testing, in eight patients with Kaposi’s sarcoma, three of whom had previous renal transplants, indicate that a correlation exists between the degree of immunologic deficiency and the extent of the Kaposi’s sarcoma. Our seven patients were all of Jewish or Mediterranean ancestry. The four cases of Kaposi’s sarcoma arising in renal transplant recipients developed in a population of 100 renal transplant recipients of similar ethnic background (4 per cent). This incidence, when compared with our experience of 40 cases arising in 500,000 people of similar ancestry in the Toronto area, represents a 400 to 500 fold greater incidence in renal transplant recipients than in the control population. A literature review has yielded 12 additional cases of Kaposi’s sarcoma developing in renal transplant recipients. On the basis of this review and our own experience we have proposed a management policy for these patients. It is proposed that the etiology of Kaposi’s sarcoma is multifactorial and that a combination of immunosuppression and/or immunologic stimulation combined with a hereditary predisposition to the disease are responsible for the major increase in its incidence. Kaposi’s sarcoma was originally described by Moricz Kaposi in 1872. It is generally regarded as a tumor of the lymphoproliferative system primarily affecting the skin and subcutaneous tissues [l]. In Western Europe and North America the disease is rare and occurs mainly in people over the age of 50 years [l]. It pursues a slowly progressive course and only rarely causes death. In some areas of Africa the disease is 200 times more common than in North America, occurs in a younger age group and pursues a more aggressive course [l].

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Recently there have been several reports of Kaposi’s sarcoma arising in patients who may have undergone antecedent immunosuppression [Z-12]. Therefore, we have analyzed our experience in 44 cases of Kaposi’s sarcoma in an effort to shed some light on the risk factors responsible for this disease.

TABLE I

1

2

3

Our experience indicates a major increase in the in cidence of Kaposi’s sarcoma in renal transplant recipi ents who are of Mediterrean or Jewish origin. Studie, of cellular immune function in Kaposi’s sarcoma arisiq either de novo or in renal transplant recipients suggest, a relationship between the degree of impairment o

Kaposi’s Sarcoma in lmmunosuppressed Patients (PMH Cases)

Age(yrh Sex Case

ET AL.

Ethnic Origin

Dale of Transplant

Immunosuppressive Therapy

Time from Transplant to Kaposi’s Sarcoma

ho)

50, M Jewish

Sept 1973

lmuran + steroids

7

41, F Greek

1971

lmuran + steroids

36

31, F Greek

4

53, F Italian

5

66, M Italian

6

60, F ftalian

7

65, M

May 1974

Jan 1978

Jewish

...

lmuran + steroids

lmuran + steroids

Generalized lymphosarcoma, pancytopenia, septic shock Generalized Hodgkin’s disease, chemotherapy, pancytopenia Glioblastoma multiforme treated with surgery, RT and chemotherapy May 1977

4

3

Therapy lmuran discontinued, RT 25 rads X 4, prednisone continued lntralesional vincristine + RT, lmuran discontinued Feb 78 lmuran restarted extended field RT, legs 800 rads X 2 April 78 extended field RT, arms 800 rads X 2 lmuran discontinued Jan 78 Extended field RT 800 rads X 2 Feb 78 Extended field RT, legs 800 rads X 2, lmuran + prednisone continued June 78

...

RT to lower limbs for Kaposi’s sarcoma April 66

...

NOTE: PMH = Princess Margaret Hospital. RT = radiotherapy.

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Course Alive and well no Kaposi’s sarcoma 4 yr after Rx Progression Kaposi’s sarcoma renal rejection

Partial remission legs (Kaposi’s sarcoma)

Complete remission (Kaposi’s sarcoma) No effect

Partial remission Kaposi’s sarcoma Complete remission Kaposi’s sarcoma

Jan 73, Kaposi’s sarcoma lower limbs, Ott 73, dead of lymphosarcoma Complete remission Kaposi’s sarcoma June 67, dead of Hodgkin’s dlsease Sept 77, Kaposi’s sarcoma on lower limbs noted to progress with each course of chemotherapy; Aug 78, terminal phase glioblastoma multiforme

KAPOSI’S SARCOMA IN RENAL TRANSPLANT RECIPIESTS--~-IlARWO00

cellular immunity and the extent of the disease. We propose a management policy for these patients based upon a review of the literature on Kaposi’s sarcoma in renal transplant recipients and on our own experience. METHODS AND MATERIALS The charts of all patients with Kaposi’s sarcoma referred to The

Princess Margaret Hospital between 1958 and June 30.1978, were reviewed for evidence of immunosuppression as a risk factor. Seven such patients were found: four were renal transplant recipients (two previously described briefly [13]], two had generalized lymphomas and the seventh patient had glioblastoma multiforme and was receiving chemotherapy. The responses of peripheral blood mononuclear cells (obtaincd by Hypaqueficoll separation) to the mitogens phytohcmagglutinin (PHA], conconavalin A (Con A], pokeweed (PWM) and to allogeneic cells in the mixed leukocyte reaction were tested in eight patients using previously described methods [14,15]. Skin reactivity to 2, 4-dinitrochlorobenzene (DNCR) was tested in two patients.

RESULTS Of 90,000 patients with cancer seen in our hospital during this time period, 44 had Kaposi’s sarcoma. There was evidence in seven patients of immunosuppression as a possible risk factor; four were renal transplant recipients, two had generalized lymphomas and in the seventh patient Kaposi’s sarcoma developed while he was receiving chemotherapy for a glioblastoma multiforme (Table I]. In the four renal transplant recipients, Kaposi’s sarcoma developed initially on the lower limbs from three months to three years after the transplant. In TABLE II Case

Date

2 5131178

10/26/7a

3

2fl3178

10/26/76

4

il/l3f7a

two patients

the first lesions developed

ET .4L.

at sites of pre-

vious trauma; in one (Case 1) at the site of pressure injury

to the leg and in the other (Case 3) at the site of a previously infected arteriovenous shunt for dialysis access. In one patient (Case 2) Kaposi’s sarcoma eventually developed on the trunk, nose and upper extremities. In no patients has disseminated visceral Kaposi’s sarcoma developed. Studies of cellular immune function were carried out in three transplant recipients (Cases 2, 3 and 4) (Table II]. Two (Cases 2 and 3) were tested prior to radiotherapy while they had active disease. The responses to PHA, Con A, PWM and the mixed leukocyte reaction were subnormal, and DNCB skin testing was negative. One patient (Case 2) was retested when the sarcoma was in almost complete clinical remission and the other patient (Case 3) was retested when the sarcoma was in partial remission. The low responses of the former patient’s cells had returned to normal levels (the administration of azathioprine had been stopped and prednisone was continued) whereas the response of the latter patient’s cells had improved but was still subnormal [no change in immunosuppressive therapy). In the third patient (Case 4) testing was carried out following radiation when the sarcoma was in complete clinical remission (this patient was receiving azathioprine and steroids, and her general medical condition was only fair). The responses of her cells were significantly less than those of the normal control subjects but not as low as the pretreatment responses of the cells of the dther two patients (Cases 2 and 3). Five other patients all previously treated for uncomplicated,

benign

Kaposi’s

sarcoma

by ex-

Immunologic Testing in Renal Transplant Recipients with Kaposi’s Sarcoma Druas

lmuran 25 mg orally, prednisone 7.5 mg orally Prednisone 7.5 mg orally Prednisone 15 mg orally Prednisone 15mg orally

Prednisone 20 mg orally, lmuran 50 mg orally

PHA 2,140 f 960

16,610 f 4,090

1,460 f 790

PWM

MLR

DNCB

2,490 f 470

870 f 610

Neg

15,660 f 610

._.

Con A 2,810 f 2,180

24,640 f

390 f

1.830

19,060 f

170

1,640

205 f 200

110 f

110

19,160 f 2,380

20,120 f

1,370

1.760 f 520

1,020 f

1090

5,330 f 2,410

10,970 f

1,510

3,160 f a80

6,620 f

1,670

Neg

ClinicalStatus Kaposi’s sarcoma in relapse just prior to RT

Kaposi’s sarcoma in almost complete remission after RT Kaposi’s sarcoma in relapse just prior to RT Kaposi’s sarcoma in partial remission after RT (more disease than in Case 1) Kaposi’s sarcoma in complete remission after extended field RT

NOTE: PHA = phytohemagglutinin; Con A = conconavalin A; PWM = pokeweed mitogen; MLR = mixed leukocyte reaction: DNCB = dinitrochlorobenzene. Data presented in form of counts per minute f 2 standard errors

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tended field radiotherapy, were also tested. Four were in complete clinical remission, and one was in very early relapse (Case 8). Results of in vitro tests in these five patients were within normal limits (Table III). The management of the renal transplant patients was individualized. Azathioprine therapy was discontinued in three of the four cases. One patient (Case I), went into complete remission and remains so with normal renal function four years later. Another patient (Case 2) started to reject the transplanted kidney, so the azathioprine therapy was restarted (and subsequently discontinued without problems]. In Case 3 stopping the azathioprine therapy resulted in no improvement. In Case 4 it was decided not to stop the azathioprine as the patient had tolerated dialysis poorly. She was treated with extended field [l3] radiotherapy to her lower limbs. Extended field radiotherapy was used in eight extremities (six lower and two upper) in three patients (800 rads X 2). Complete remission was obtained in four extremities and partial remission i.n four extremities, Combining our experience (Table I) with that of others reported in the literature [Table IV) the disease in four of eight patients responded to either stopping or reducing the dose of azathioprine without loss of the transplanted kidney. The response could not be evaluated in five patients, and in three patients the azathioprine was continued while the patient was being treated with radiotherapy. There are approximately 500,000 people of MediterTABLE III Case

ranean or Jewish ancestry in the Toronto area (Ontaria statistics, 19761, and 40 of our 44 cases of Kaposi’s sarcoma developed in these populations [an incidence of 0.008 per cent). Between 1958 and 1978, 507 renal transplants were carried out in the Toronto area, and the patients have been followed for at least one month: 100 were of Jewish or Mediterranean origin. Kaposi’s sarcoma developed in four; all four were of Mediterranean or Jewish ancestry. Thus, there is a 4 per cent incidence of Kaposi’s sarcoma in these particular populations, an increase of between 400-500 fold compared to a control group of the same ethnic origin. The average age of the transplant recipients in OUI series is 47 years (Table I). This is 17 years less than the average age of 64 years in the 37 patients with uncom. plicated Kaposi’s sarcoma. Combining Tables I and IV, three of 15 (20 per cent] patients with renal transplants died as a result of their Kaposi’s sarcoma as compared to two of 37 (6 per cent] patients with uncomplicated sarcoma. The evolution 01 the Kaposi’s sarcoma in the four renal transplant recipients was faster than that in the patients with un. complicated sarcoma. Immunosuppression may have been an important factor in our other three patients. Two of them (Cases 5 and 6) had been receiving chemotherapy for generalized lymphoma and were pancytopenic In both cases the sarcoma arose in the terminal phase of their illnesses. The sarcoma in Case 7 developed while the

Immunologic Testing in Patients with Uncomplicated Kaposi’s Sarcoma Dale

PHA

ConA

8

11/10/78

22,740 f 3,830

28,720 f 2,050

9

11/13/78

14,850 f 2,160

30,720 f 3,640

10

1 l/20/78

23,970 f 8,020

11

1 l/20/78

12

11120178

762

ET AL.

November

1979

PWM 12,970 f 2,720

30,090 f

1,860

1,150

18,500 f 4,520

23,630 f 2,980

26,970 f 2,480

16,370 f 5,420

22,520 f 2,040

31,080 f

1,450

10,970 f 2,540

8,880 f 2,880

14,930 f

23,110 f 3,140

22,200 f 5,960

8,830 f 2,470

1,460

The American Journal of Medicine

5,140 f

MLR

Volume 67

ClinicalStatus Kaposi’s sarcoma in minimal relapse after extended field RT (2 small nodules on one extremity) Kaposi’s sarcoma in complete remission after extended field RT Kaposi’s sarcoma in complete remission after extended field RT Kaposi’s sarcoma in complete remission after extended field RT Kaposi’s sarcoma in complete remission after extended fielg! RT

KAI'OSI'S SARCOMA

TABLE IV

(yr) and ._ Sex

Siegel et al. (1969) [ 101

3.5, F

Haim et al.

24, M

(1972) 141

Myers et al.

36, F

(1974) 171

Myers et al.

27, M

(1974) 171

Birkeland et al.

(1976) [PI Straehley et al. (1975) [ll]

Farman et al.

50, F

(1976)

[El

Nissenkorn, Servadio (1977) 161 Rudolf

10

Disseminated Kaposi’s sarcoma found at autopsy

March 1966

36

Kaposi’s sarcoma controlled with radiotherapy + reduced dose of lmuran Kaposi’s sarcoma in remission after stopping Imuran; dead ? lymphoma of brain

Feb. 1969

9

Oct. 1969

a

?

?

19

48, M

lmuran + steroids

1972

9

41, M

lmuran + steroids

1974

6

41, F

lmuran + steroids

42, M

lmuran + steroids

1974

59, M

lmuran + steroids

1973

?

November

No response to stopping Imuran, Kaposi’s sarcoma in remission after stopping prednisone and removing kidney Dead 26 months - ? cause Dead gastrointestinal hemorrhage from Kaposi’s sarcoma

12

1971

54, M

Course

May 1967

46

(1977) [91 Stribling et al. (1978) [12]

lmuran + steroids + radiotherapy + actinomycin lmuran + steroids + radiotherapy lmuran + steroids + radiotherapy + actinomycin D lmuran + steroids + antilymphocytic globulin

Transplant

July 1969

(1976) [61

Meyers et al.

Immunosuppressive iherapy

Time for Kaposi’s Sarcoma to Develop After Transplant(mo)

lmuran + steroids + actinomycin Endoxan + steroids

61, M

(1976) [31

Hardy et al.

RECIPJENTS~~~~AP~~OC)D ET AL.

Kaposi’s Sarcoma in Renal Transplant Recipients (A Review of the Literature)

Age Reference

IN RENAI, TRANSPIANT

6

?

13

1979

Local radiotherapy controlled Kaposi’s sarcoma until death, immunosuppression continued Local radiotherapy partially effective disease into remission with lmuran discontinued + chemotherapy Local radiotherapy + prednisone dose reduced Kaposi’s sarcoma into remission Local excision curative; immunosuppression continued Local radiotherapy to Kaposi’s sarcoma, improved Dead, gastrointestinal hemorrhage from Kaposi’s sarcoma

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patient was receiving chemotherapy for glioblastoma multiforme. It was noted to progress each time chemotherapy was given. COMMENTS A high incidence of lymphoproliferative tumors has been noted in renal transplant recipients [16]. It has been suggested that Kaposi’s sarcoma is a lymphoproliferative disorder [l]. The increased incidence of Kaposi’s sarcoma in renal transplant recipients suggests that immunosuppression may be important in the development of the disease. Support for this suggestion is the observation that the Kaposi’s sarcoma remits in one half of the renal transplant recipients in whom immunosuppressive therapy was stopped, in contrast it undergoes spontaneous remission in only 2 per cent of those who do not receive transplants. Further support comes from the association between lymphomas and Kaposi’s sarcoma [17,18], it is well known that generalized lymphomas are frequently associated with depression of the cellular immune system. Our case of glioblastoma multiforme is a further indication of a possible relationship. With each course of chemotherapy there was such a striking exacerbation in the sarcoma that the chemotherapy had to be stopped. However, the precise mechanism by which the tumor arises in the presence of immunosuppression is not known [16]. The combination of drugs (azathioprine and prednisone) used in renal transplant recipients may be of importance in the causation of Kaposi’s sarcoma. There is only one case report of Kaposi’s sarcoma developing in a patient without a transplant who was taking only azathioprine [no], and there are only isolated case reports of Kaposi’s sarcoma in patients taking only prednisone [21,22]. There are reports [23,24] of defects principally in the cell-mediated immunity of patients with Kaposi’s sarcoma. In cases arising in Africa the most marked defect was in patients with the malignant form of the disease [24]. In one case, deterioration of immunologic parameters was associated with progression of the Kaposi’s sarcoma [5]. In our experience, the Kaposi’s sarcoma was associated with deficient responses of peripheral blood mononuclear cells in in vitro assays of immunologic function. These responses returned to normal when the disease was in remission. Immunosuppressive drugs were not responsible for the deficient responses in cell culture. Thus, the immunologic deficiency, as measured by these tests, correlated with the extent of the disease and is compatible with the view that immunologic deficiency is secondary to the presence of the tumor. Further immunologic testing will be required to precisely quantify this relationship. An alternative hypothesis, compatible with these observations, is that Kaposi’s sarcoma may arise in hosts that are subjected to a high degree of immunologic

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ET AL

stimulation, e.g., partially-matched kidney allotransplant recipients. This hypothesis is supported by the experimental evidence that in some strains of mice leukemia or lymphoma frequently develop while they are undergoing intense immunologic stimulation during a chronic graft-versus-host reaction [25]. The frequency of Kaposi’s sarcoma is 0.05 per cent of all cancers seen at The Princess Margaret Hospital and is similar to that reported by others [17,18]. Indicating that a similar proportion of patients in our area were referred to us for management. It has been postulated that genetic factors are important in the etiology of the disease to explain its occurrence predominantly in Jewish and Mediterranean people [l]. The frequency of Kaposi’s sarcoma in a renal transplant population of Jewish or Mediterranean ancestry is increased by 400-500 fold over that found in patients without transplants of the same ancestry, an increase that is similar to that seen in the incidence of lymphomas arising in transplant recipients [16,26]. In contrast, no cases of Kaposi’s sarcoma have been seen in a large series of renal transplant recipients (predominantly Anglo Saxon] in Australia and New Zealand [27] and also in our own transplant recipients who are not of Jewish or Mediterranean ancestry. In Africa the disease is 200 times more common than in North America [l], and it behaves similarly to Kaposi’s sarcoma developing in transplant recipients. It is rare, however, in Americans of African ancestry and in Asians and Europeans living in Africa (11. These observations can be explained by postulating that the etiology of Kaposi’s sarcomas is multifactorial. The combination of a hereditary predisposition combined with immunologic factors associated with renal transplantation or chronic malaria [21] result in a major increase in the risk of developing the disease. In contrast, a renal transplant carried out in a less susceptible population (e.g., Anglo Saxon) does not result in a major increase in risk. There is increasing awareness that the etiology of cancer in man is multifactorial [28]. The development of Kaposi’s sarcoma at the site of surgical trauma is similar to the development of reticulum cell sarcoma at the site of antilymphocytic globulin injection [29,30]. The relationship of trauma and Kaposi’s lesions may be only coincidental. Kaposi’s sarcoma in the renal transplant recipient occurs in a younger age group and pursues a more aggressive course than uncomplicated Kaposi’s sarcoma. The response of the Kaposi’s sarcoma in the renal transplant recipients to radiotherapy is less predictable, with higher doses of irradiation producing lower response rates than in patients without transplants [13]. In the lymphoma patients the Kaposi’s sarcoma developed in the terminal phase of the disease. It did not pursue the aggressive course seen in the transplant recipients and did not present a problem in management. Based on the accumulated data available we recom-

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KAPOSI’S

SARCOMA

mend the following guidelines for management of Kaposi’s sarcoma arising in renal transplant recipients: 1. Investigation to exclude gastrointestinal or pulmonary involvement should be undertaken since this is a frequent cause of death. If either is present, this represents a greater risk to the patient’s life than does the loss of a transplanted kidney. In this situation, administration of the azathioprine should be stopped and the transplanted kidney sacrificed, if necessary. 2. If there is localized disease in the limbs or oral cavity,

[N REN.\I,

I’RANSI’IANT

RECIPIENl’S~

i IAKLVOODET AI..

administration of the azathioprine should be stopped if it is possible to do so without sacrificing the kidney. If there is no response or if a severe, uncontrollable rejection phenomenon occurs, then radiotherapy should be given. Similarly, if it is believed that the risk of the kidney being rejected on stopping the azathioprine therapy is too great, radiotherapy should be used. In short, the management of these cases should be based on the relative risks to the patient’s life of losing the kidney by stopping the immunosuppression versus the risk of death from generalized Kaposi’s sarcoma.

REFERENCES Tcmplcton AC: Kaposi’s sarcoma, chap 52. Cancer of the Skin. Biology, Diagnosis, Management (Andrade R, ed], Philadelphia, Sanders, 1976. 2. Birkeland SA, Kemo E. Haune M: Renal transDlantation and cancer. The Scaidia transplant material. Tissue Antigens 6: 28, 1975. 3. Farman AG, Uys PB: Oral Kaposi’s sarcoma. Oral Surg 39:

288,1975. Haim S, Shafrir A, Better OS, et al.: Kaposi’s sarcoma in association with immunosuppressive therapy. Isr j Med Sci

a: 1993, 1972.

713, 1972.

Klein MB, Pcreira FA, Kantor I: Kaposi’s sarcoma complicating s\stcmic luaus ervthematosus treated with immunosu~pression. A;ch Dcrmatol 110: 602, 1974. 21. (&me RW. Wilson-Tones E: Kaposi’s sarcoma and immun;,suppression thc;apy. An appraisal, Clin Exp Dermatol 3: 135, 1978. 22. Pisanb S, Garfunkcl A: Kaposi’s sarcoma. 1Oral Med 25: 89, 1970. 23. Dobosy A, tiusz S. Hunyadi J, et al.: Immune deficiencies and Kapnsi’s sarcoma. Lancct 2: 625, 1973. 24. Master SP. Taylor JF, Kyalwazi SK. ct al.: Immunological studies in Kaposi’s sarcoma in IJganda. Br Med J I: 600, 20.

MA, Goldfarb P, Levine S. et al.: De novo Kaposi’s sarcoma in renal transplantation. Cancer 38: 144, 1976. A. Meyers AD, Barker C, Grossman R. et al.: Kaposi’s sarcoma of the oropharynx following renal transplantation. Trans Am Acad Opthal Oto183: 560,1976. 7. Myers BD, Kessler E, Levi J, et al.: Kaposi’s sarcoma in kidney transplant recipients. Arch Intern Med 133: 307,1974. a. Nissenkorn I. Servadio C: Kaposi’s sarcoma in a patient with a renal transplant. Int Surg 62: 163,1977. 9. Rudolf RI: Kaposi’s sarcoma after renal transplantation. Arch Dcrmatol 113: 1307, 1977. 10. Siegel JH, Janis R. Alper JC. et al.: Disseminated viscera1 Kaposi’s sarcoma. JAMA 207: 1493, 1969. 11. Straehley CJ, Santos JI, Downey DM, et al.: Kaposi’ssarcoma in a renal transplant recipient. Arch Path01 99: 611, 5.

Iransplantation. Transplant Proc 9: 1121, 1977. Mocrtcl C: Multiple Primary Malignant Neoplasms. Recent Results In Cancer Research, No. 7, Berlin, Springer-Verlag, 1966, p 44. la, Reynolds WA, Winkclmann RK, Soule EH: Kaposi’s sarcoma: a clinicopathologic study with particular reference to its relationship to the reticuloendothclial system. Medicine (Baltimore) 44: 419, 1964. 19. Editorial: Immnnosuppression and malignancy. Br Med ] 2: I 7.

Hardy

1975.

Stribling J. Wcitzner S, Smith GV: Kaposi’s sarcoma in renal alloaraft recipients. Cancer 42: 442, 1978. HolecGk MJ. H&wood AR: Radiotherapy of Kaposi’s sarco13. ma. Cancer 41: 1733,1978. JJ, Schecter B: Lymphocytic transformation. 14. Oppcnheim Manual of Clinical Immunology (Rose NR, Friedman H, cds). Washington, American Society of Microbiology, 1976. p ai. 15. Osob;l D. Falk J. Daj ko M, et al.: A simple freezing and storage method to preserve the stimulating function of leucocytes in the mixed leucocyte reaction. Tissue Antigens 5: 226, 1975. 16. Penn 1: Development of cancer as a complication of clinical II.

November

25.

1970. Phillips SM, Gleichmann

H, Hirsch

MS: Cellular

immunity

in

the mouse, altered thymic dependent lymphocytic reactivity in the chronic graft versus host reaction and leukemia vilus activation. Cell Immunol 15: 152. 1975. 26 Sloan (GM, Cole P, Wilson RE: Risk indicators of De Novo malignancy in IWIill transplant recipients. Transplant Proc 9: 1129. 1977. 27. Shcil AGR: Cancer in renal allograft recipients in Australia and New Zealand. Transolant Proc 9: 1133.1977. 28. Etiitc)rial: Multifactorial caicer. Lancet 2: 411. 1978. 29. Catton JR, Sarles HE, Rcmmcrs ARJ, et al.: The appearance of reticulum cell sarcoma at the site of antilymphocytic glotmlin injection. Transplantation 16: 156. 1973. 30. Docdhar SD, Kuklinca AG, Vidt DG, et al.: Development of reticulum cell sarcoma at the site of antilymphocyte globulin injection in a patient with renal tr~ansplant. N Engl J bled 280: 1104. 1969.

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