0022-534 7/79/1223-0421$02.00/0 Vol. 122, September Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright© 1979 by The Williams & Wilkins Co.

SEQUENTIAL BILATERAL GERM CELL TUMORS OF THE TESTIS DESPITE INTERVAL CHEMOTHERAPY JACKSON E. FOWLER, JR.,* DAVOR VUGRIN, ESTEBAN CVITKOVIC AND WILLET F. WHITMORE, JR. From the Urologic Service and The Solid Tumor Service, Memorial Sloan-Kettering Cancer Center, New York, New York

ABSTRACT

We report on 3 patients who had a second primary germ cell tumor of the testis despite prior or ongoing systemic chemotherapy for the original tumor. Evidence favoring the designation of the tumors as separate primary lesions is presented. The clinical and theoretical implications of this phenomenon are discussed. Among patients with germ cell tumors of the testis the incidence of bilateral tumors is reported to range from 0.6 to 3.8 per cent. 1- 7 The contralateral tumor may develop simultaneously or sequentially. Herein we report on 3 patients who had bilateral germ cell tumors of the testis, despite interval or ongoing systemic chemotherapy for the initial malignancy. CASE REPORTS

Case 1. D. W., a 21-year-old white man, underwent a right transscrotal orchiectomy in November 1971 for a testicular tumor containing embryonal carcinoma and seminoma. A chest x-ray and excretory urogram (IVP) at the time of referral to our hospital were normal and there was no measurable urinary human chorionic gonadotropin (HCG). A modified bilateral retroperitoneal lymphadenectomy, right hemiscrotectomy and excision of the residual spermatic cord were performed in December. One inter-aortocaval node contained metastatic embryonal carcinoma. Adjuvant chemotherapy was instituted postoperatively and continued for 37 months. During the first 19 months of therapy the patient received actinomycin D and chlorambucil, while the last 18 months of treatment included vinblastine and chlorambucil. The patient was clinically free of disease during chemotherapy. In July 1975, 44 months after the right orchiectomy and 7 months after the termination of systemic chemotherapy for the initial tumor, a left inguinal orchiectomy was done for a mixed germ cell tumor comprised predominantly of seminoma, some of which was in situ (fig. 1), with areas of embryonal carcinoma and choriocarcinoma. A chest x-ray and IVP were normal and a left unilateral pedal lymphangiogram revealed residual but normal left retroperitoneal nodes (fig. 2). Urinary HCG and serum a-fetoprotein (AFP) were normal before orchiectomy and the serum /:I-subunit of human chorionic gonadotropin (/:1HCG) was normal 7 days after orchiectomy. Left retroperitoneal lymphadenectomy revealed no metastases and the patient remains well 30 months postoperatively without further therapy. Case 2. N. W., a 30-year-old white man, underwent thoracotomy and excision of an asymptomatic mediastinal seminomatous tumor of the thymus in June 1967. We performed a left inguinal orchiectomy in October 1973 for a testicular tumor comprised primarily of seminoma but with a focus of embryonal carcinoma. A chest x-ray was normal but the IVP suggested retroperitoneal metastases. The serum AFP after orchiectomy Accepted for publication December 15, 1978. Read at annual meeting of Mid-Atlantic Section, American Urological Association, White Sulphur Springs, West Virginia, October 29November 1, 1978. Requests for reprints: Urologic Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, New York 10021. * Current address: Walter Reed Army Medical Center, Washington, D. C. 20012.

was normal but the urinary HCG titer was elevated. A retroperitoneal lymphadenectomy was attempted but was incomplete owing to bulky, adherent tumor posterior to the great vessels. The excised tissue contained choriocarcinoma, embryonal carcinoma and teratoma. Postoperatively, the patient was treated for 4 months with vinblastine, actinomycin D and bleomycin (VAB I protocol). 8 During the next 3 months he received actinomycin D, chlorambucil and methotrexate. A second look retroperitoneal lymphadenectomy in July 1974 revealed no residual retroperitoneal disease but intraoperative injury to the aorta necessitated replacement of the infrarenal abdominal aorta with a Dacron graft. Postoperatively, systemic chemotherapy was continued for 28 months and consisted of vinblastine, actinomycin D, bleomycin and chlorambucil. The patient remained well until March 1978, 53 months after the left orchiectomy and 15 months after the termination of chemotherapy, at which time a right inguinal orchiectomy was done for a testicular mass comprised of anaplastic seminoma. A chest x-ray and IVP were normal before orchiectomy as was the serum f:/-HCG and AFP. A right unilateral pedal lymphangiogram revealed normal residual retroperitoneal nodes (fig. 3). The patient is now on a 6-month course of intravenous cyclophosphamide. Case 3. G. W., a 27-year-old white man, underwent a right inguinal orchiectomy in June 1974 for a mixed germ cell tumor of embryonal carcinoma and teratoma. A chest x-ray revealed multiple pulmonary nodules. The IVP was normal but a right unilateral pedal lymphangiogram demonstrated probable tumor involvement of the retroperitoneal nodes. In July the patient was given vinblastine, actinomycin D, bleomycin and cis-platinum (VAB II protocol), which was continued for 6 months. 9 In February 1975 the chest x-ray showed complete resolution of the pulmonary nodules but residual bibasilar infiltrates. An open lung biopsy revealed necrosis and fibrosis of the pulmonary tissue but no malignant elements. In April a modified bilateral retroperitoneal lymphadenectomy revealed no evidence of viable metastases. Postoperatively, the patient was maintained on adriamycin and cis-platinum for 6 months. This regimen was then changed to actinomycin D and chlorambucil. In September 1977, 39 months after the right orchiectomy and during maintenance chemotherapy, a left testicular mass and an enlarged liver were palpated. The chest x-ray revealed no metastatic lesions but a liver scan showed multiple defects consistent with metastatic disease. The serum /5-HCG and AFP, which had been normal 4 months earlier, were elevated. Left inguinal orchiectomy and simultaneous open liver biopsy were done. The testis tumor contained choriocarcinoma, embryonal carcinoma and teratoma and the liver biopsy revealed metastatic embryonal carcinoma. The serum f:1-HCG had reverted to near normal limits and 421

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FOWLER AND ASSOCIATES

FIG. 1. Seminiferous tubule in case 1 with in situ seminoma cells (arrow) found adjacent to invasive seminoma

FIG. 2. Left unilateral pedal lymphangiogram in case 1, 44 months after modified bilateral retroperitoneal lymphadenectomy. A, injection phase. B, 24-hour phase.

the serum AFP was normal 6 days postoperatively. The patient was given vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum (V AB V protocol). During the first 6 months of this treatment the serum ,B-HCG and AFP have remained normal. The serum lactic dehydrogenase and alkaline phosphatase, markedly elevated at the initiation of therapy, have reverted to normal and the liver is no longer palpable. However, the liver scan continues to demonstrate defects compatible with metastatic lesions. DISCUSSION

Small series of patients with sequentially developing bilateral germ cell tumors of the testis have been reported recently in an effort to define optimal methods of staging and treatment of

the second neoplasm. 1- 5 These well documented cases display features that favor their designation as separate primary tumors rather than a single primary tumor with metastatic deposits in the contralateral testis. Our cases also possess features supporting this concept (see table). The experience at our center and at other institutions indicates that after the initiation of chemotherapy for testicular neoplasms most relapses will occur within 2 years. 10 However, in our cases the interval between the initial and sequential tumor ranged from 39 to 53 months and chemotherapy was administered for 37 to 38 months without evidence of relapse. In cases 1 and 3 malignant germ cell elements not present in the initial tumor were identified in the second testis tumor. Although this finding provides circumstantial evidence that the second malignancy was not a metastatic lesion, this interpretation must be tempered by the observation

423

SEQUENTIAL BILATERAL GERM CELL TUMORS OF TESTIS

FIG. 3. Right unilateral pedal lymphangiogram in case 2, 53 months after retroperitoneal lymphadenectomy. A, injection phase. B, 24-hour phase.

Clinical and histologic summary

Case No.

2

3

Initial Testis Tumor

Embryonal, seminoma Embryonal, seminoma

Embryonal, toma

tera-

Metastasis of Initial Tumor

Embryonal Chorioca., embryonal, teratoma

Chemotherapy for Initial Tumor Duration (mos.)

Agents Actinomycin D, chlorambucil, vinblastine Actinomycin D, bleomycin, chlorambucil, methotrexate, vinblastine Actinomycin D, adriamycin, bleomycin, chlorambucil, cisplatinum, vinblastine

that metastatic lesions of testicular germ cell origin may have a different histologic composition than the primary lesion, a phenomenon demonstrated in case 2. 11 The most persuasive evidence favoring the de novo origin of the second tumor, however, was the identification of an in situ component of seminoma in the second tumor of case 1. In situ carcinoma may be the .earliest histologic expression of many, if not all, epithelial tumors and, when found adjacent to histologically identical invasive carcinoma, it provides strong evidence for the primary nature of the invasive tumor. Skakkebaek has noted the frequent occurrence of atypical intratubular germ cells in the testicular tissue surrounding primary invasive germ cell tumors. 12 This cellular atypia, which may represent a carcinoma in situ, also has been found in the testis biopsies of 2 infertile patients who subsequently had histologically invasive germ cell tumors of the same testis 16 and 54 months after biopsy. 13 These observations are consistent with the possibility that germ cell tumors may arise from subclinical foci of in situ carcinoma of variable latency. Our cases are most interesting because the sequential germ cell tumor developed despite aggressive and effective chemotherapy for the initial testis tumor. In case 3 the contralateral tumor became evident clinically during maintenance chemo-

37

38

38

Sequential Testis Tumor

Chorioca., embryonal, seminoma Seminoma

Chorioca., embryonal, teratoma

Interval Between Initial and Sequential Tumor (mos.)

Interval Between Termination of Chemotherapy and Sequential Tumor (mos.)

44

7

53

15

39

0

therapy, while in cases 1 and 2 the second malignancy appeared 7 and 15 months, respectively, after termination of chemotherapy. With the exception of 1 case described by LeFevre and associates, no previously reported cases of sequential bilateral germ cell tumors of the testis have been associated with interval chemotherapy. 2 The impact of systemic chemotherapy on the genesis and proliferation of germ cell tumors of the remaining testis in patients who have sequential malignancies is not known. One may speculate that anticancer agents could suppress the growth of a subclinical contralateral testis tumor. This is suggested by cases 1 and 2 in which the second tumor did not become evident clinically until treatment for the original neoplasm was terminated. Alternatively, however, these cases illustrate the possibility that cytotoxic agents do not alter the potential for malignant differentiation of the germinal epithelium or the capacity of pre-existing, subclinical neoplasms for progressive growth. The failure of ongoing and effective chemotherapy for the initial tumor to prevent the emergence of a rapidly metastasizing tumor in the remaining testis is clearly evident in case 3. Although this phenomenon is disturbing the metastatic lesions from the sequential neoplasm exhibited a favorable response to a more intensive chemotherapeutic regimen.

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This seemingly ineffective prophylactic effect of systemic chemotherapy on the development of sequential germ cell tumors of the testis may not be unexpected. The testis is a well recognized site of extramedullary relapse in childhood leukemia despite bone marrow remission and has been characterized by some investigators as a chemotherapeutically privileged organ. 14 • 15 Evidence that the testis may be an immunologically privileged site raises the possibility that neoplasms susceptible to eradication through the combined influence of chemotherapy and host immune response may be less amenable to such destruction in the testis than in other sites. 16 Finally, recent studies suggest that primary tumors may be less susceptible to anticancer agents than metastatic lesions owing to a differential distribution of these agents. 17 Our cases also prompt consideration of the possible influences of systemic chemotherapy in potentiating the development of a second testicular malignancy. The carcinogenic potential of anticancer drugs, including actinomycin D, chlorambucil and cyclophosphamide, is well known. 18 These compounds may promote the development of malignant tumors by direct oncogenic effects, by acting as cocarcinogens or by impairment of immunologic defenses. Moreover, cyclophosphamide and chlorambucil exert a direct toxic effect on the male germinal epithelium with resulting spermatogenic arrest or germinal aplasia. 19' 2° Cyclophosphamide also has been shown to induce chromosomal damage in the male mouse germ cell. 21 The immunosuppressive effects of chemotherapeutic agents may have relevance to our cases. Nielsen and associates have found that patients with atypical intratubular germ cells on testis biopsy frequently have identical changes in the contralateral testis. 22 Such cellular atypia or carcinoma in situ may have been present in the remaining testis of our patients and the immunosuppressive effects of systemic chemotherapy may have permitted its proliferation. Although these possible mechanisms by which systemic chemotherapy might influence the emergence of a sequential testis tumor are of interest, several considerations suggest that the interval chemotherapy had no effect on the development of the second malignancy in our patients. The absence of the long latent period typically noted between exposure to a carcinogen and the clinical recognition of cancer, and the fact that the specific chemotherapeutic agents used have never been associated directly with the development of germ cell tumors of the testis argue against a cause-and-effect relationship. Furthermore, of approximately 300 patients with stage B or C nonseminomatous germ cell tumors of the testis who have been treated with systemic chemotherapy at our center since 1972, the 3 cases reported herein are the only patients known to have had sequential tumors. Thus, the incidence of sequential germ cell tumors is approximately 1 per cent and similar to that expected for patients not receiving chemotherapy for their initial tumor. Sequential germ cell tumors of the testis present a challenge to all therapeutic disciplines because therapy for the second malignancy must be tempered by the prior treatment of the initial tumor. Each of our patients had undergone prior retroperitoneal lymphadenectomy and the management of the sequential tumors deserves comment. In general, our treatment policy for non-seminomatous tumors is designed to obviate adjuvant therapy in cases in which orchiectomy has been apparently curative, to use adjuvant chemotherapy in cases in which the risks of residual tumor after therapeutic lymphadenectomy are judged to be high and to withhold lymphadenectomy in cases in which parenchymal metastases prove resistant to chemotherapy. In case 1, therefore, a second retroperitoneal lymphadenectomy was performed for staging and surgical treatment of the sequential tumor but no further treatment was recommended owing to the absence of metastases. In case 3 liver metastases were documented at the time of recognition of

the sequential tumor and chemotherapy alone was used for treatment. Johnson and Morneau have cited the unpredictable pattern of retroperitoneal lymphatic drainage after lymphadenectomy as a rationale for omitting a second lymphadenectomy in the treatment of sequential non-seminomatous germ cell tumors.4 However, in cases 1 and 2 the unilateral pedal lymphangiogram performed after the second orchiectomy revealed normal ipsilateral retroperitoneal lymphatic anatomy (figs. 2 and 3). This finding is explained by the fact that each of these patients had undergone prior modified bilateral retroperitoneal lymphadenectomy and the subsequent lymphangiogram was a unilateral study. The potential hazards of a second retroperitoneal lymphadenectomy are underscored by case 2 in which irreparable injury to the abdominal aorta occurred because of obliteration of normal surgical planes as a result of the first lymphadenectomy and the interval chemotherapy. It is tentatively suggested that a second retroperitoneal lymphadenectomy for staging and therapy of sequential non-seminomatous neoplasms be considered only in patients with normal ipsilateral lymphatic anatomy as judged by unilateral pedal lymphangiography. The staging and treatment of a patient who has undergone previous retroperitoneal lymphadenectomy and who has a second tumor of pure seminoma are subject to the same uncertainties as for sequential non-seminomatous tumors. Aberrant retroperitoneal lymphatic spread of the tumor may preclude cure by the conventional radiation therapy. This possibility and the anaplastic nature of the neoplasm were considerations in the decision to treat case 2 with cyclophosphamide after orchiectomy. While the impact of chemotherapeutic agents on the development of a second primary germ cell testis tumor is conjectural and while no categorical recommendations can be made concerning the staging and treatment of sequential germ cell tumors when the first tumor was treated with retroperitoneal lymphadenectomy, our cases do prompt a seemingly indisputable recommendation-surveillance of all patients having had a germ cell tumor of the testis should include periodic examination of the remaining testis. REFERENCES 1.

2. 3. 4. 5. 6. 7. 8.

9.

10.

Willis, G. W. and Hajdu, S. I.: Bilateral primary malignant germ cell tumors of the testis: report of 2 cases. J. Urol., 107: 279, 1972. LeFevre, R. E., Levin, H. S., Banowsky, L. H., Straffon, R. A., Stewart, B. H. and Hewitt, C. B.: Bilateral testicular tumors of germ cell origin. J. Urol., 114: 556, 1975. Morris, S. A., Vaughan, E. D., Jr. and Constable, W. C.: Problems in management of primary bilateral germ cell testicular tumors: report of 3 cases and review of literature. J. Urol., 115: 566, 1976. Johnson, D. E. and Morneau, J. E.: Bilateral sequential germ cell tumors of testis. Urology, 4: 567, 1974. Stutzman, R. E., Dunnington, G., McAninch, J. W., Peterson, L. J., Scott, J. and Nachtsheim, D.: Multiple germ cell tumors: report of 3 cases, 1 with 3 primary lesions. J. Urol., 117: 733, 1977. Hamilton, J. B. and Gilbert, J. B.: Studies in malignant tumor of the testis. IV. Bilateral testicular cancer. Cancer Res., 2: 125, 1942. Mostofi, F. K. and Price, E. B., Jr.: Tumors of the male genital system. In: Atlas of Tumor Pathology. Washington, D. C.: Armed Forces Institute of Pathology, 2nd series, fasc. 8, 1973. Silvay, 0., Yagoda, A., Wittes, R., Whitmore, W. F., Jr. and Golbey, R.: Treatment of germ cell carcinomas with a combination of actinomycin D, vinblastine, and bleomycin. Proc. Amer. Ass. Cancer Res., 14: 68, 1973. Cvitkovic, E., Wittes, R., Golbey, R. and Krakoff, I. H.: Primary combination chemotherapy (VAB II) for metastatic or unresectable germ cell tumors. Proc. Amer. Ass. Cancer Res., 16: 174, 1975. Klepp, 0., Klepp, R., Host, H., Asbjornsen, G., Talle, K. and Stenwig, A. E.: Combination chemotherapy of germ cell tumors

SEQUENTIAL BILATERAL GERM CELL TUMORS OF TESTIS

11. 12.

13. 14.

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of the testis with vincristine, adriamycin, cyclophosphamide, actinomycin D, and medroxy progesterone acetate. Cancer, 40: 638, 1977. Mostofi, F. K.: Testicular tumors. Epidemiologic, etiologic, and pathologic features. Cancer, 32: 1186, 1973. Skakkebaek, N. E.: Atypical germ cells in the adjacent "normal" tissue of testicular tumours. Acta Path. Microbiol. Scand., 83: 127, 1975. Skakkebaek, N. E.: Possible carcinoma-in-situ of the testis. Lancet, 2: 516, 1972. Finklestein, J. Z., Dyment, P. G. and Hammond, G.D.: Leukemic infiltration of the testes during bone marrow remission. Pediatrics, 43: 1042, 1969. Stoffel, T. J., Nesbit, M. E. and Levitt, S. H.: Extran1edullary involvement of the testis in childhood leukemia. Cancer, 35: 1203, 1975. Whitmore, W. F., III and Gittes, R. F.: Intratesticular testis as an exceptional immunologically privileged Amer. Ass. Genito-Urin. Surg., 70: 76, 1978. Donelli, M. G., Colombo, T., Broggini, M. and Garattini, S.: Differential distribution of antitumor agents in primary and secondary tumors. Cancer Treat. Rep., 61: 1319, 1977. Harris, C. C.: The carcinogenicity of anticancer drugs: a hazard in man. Cancer, 37: 1014, 1976. Richter, P., Calamera, Jo C., Morgenfeld, M. C., Kierszenbaum, A. L., Lavie.ri, J. C. and Mancini, R. E.: Effect of chlorambucil on spermatogenesis in the human with malignant lymphoma. Cancer, 25: 1026, 1970. Fairley, K. F., Barrie, J. U. and Johnson, W.: Sterility and testicular atrophy :related to cyc!ophosphamide therapy. Lancet, 1: 568, 1972. Sotomayor, R. E. and Cumming, R. B.: Induction of translocations by cyclophosphamide in different germ cell stages of male mice: cytological characterization and transmission. Mutation Res., 27: 375, 1975. Nielsen, H., Nielsen, M. and Skakkebaek, N. E.: The fine structure of a possible carcinoma-in-situ in the seminiferous tubules in the testis of four infertile men. Acta Path. Microbiol. Scando, 82: 235, 1974.

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EDITORIAL COMMENT The authors present 3 cases that underscore biologic characteristics peculiar to testis tumors. Sequential bilateral germ cell tumors of the testis despite interval chemotherapy may well be more common than reported. If the incidence of sequential germ cell tumors is approximately 1 to 2 per cent, I expect that the application of interval chemotherapy as treatment for the initial tumor will not have a lasting effect on the malignant potential of its remaining contralateral mate. Our own experience reveals 3 cases in the last 10 years. case presented as seminoma treated with Lukeran by retn>P!ff1to11e,1l radiation. Contralateral testicular Pnn nrv,:m?.1 '"" re m,nn~ 4 years later. therapy was given. The remains ,_;vith embryonal carcinoma of the m1nh2rlPnPct.rnmv revealed Bl disease, embryonal. A

Sequential bilateral germ cell tumors of the testis despite interval chemotherapy.

0022-534 7/79/1223-0421$02.00/0 Vol. 122, September Printed in U.S.A. THE JOURNAL OF UROLOGY Copyright© 1979 by The Williams & Wilkins Co. SEQUENTI...
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