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IS BIOPSY OF THE CONTRALATERAL TESTIS NECESSARY IN PATIENTS WITH GERM CELL TUMORS?
0022-5347/97/1584-133 1$03.00/0 THEJOURNAL OF UROLOGY copyright (9 1997 by AMERICAN UROLDGXCAL. A s s o c u r n ~INC. ~,
VOl. 168*1951-1394,oetobar 1997 Printed in U . S A
Review Article IS BIOPSY OF THE CONTRALATERAL TESTIS NECESSARY IN PATIENTS WITH GERM CELL TUMORS? HARRY W.HERR
AND
JOEL SHEINFELD
From the Urology Service, Department of Surgery, Memorial Shn-Kettering Cancer Center. New York,New York
ABSTRACT
Purpose: Carcinoma in situ is present in the contralateral testis in up to 5% of patients with a primary germ cell tumor and w i l l progress in the majority of cases to a second primary invasive cancer. We address the question of whether the other testis should be biopsied in patients with testis tumors. Materials and Methods: The literature on carcinoma in situ of the testis h m 1972 to the present was critically evaluated in an attempt to address the issue of carcinoma in situ in the opposite testis. Results: Carcinoma in situ of the opposite testis in patients with a primary germ cell tumor is easily diagnosed by biopsy and cured by orchiednmy or radiation. The problem is that biopsy is unnecessary in the majority of patients, and treatment of carcinoma in situ may have undesirable physical and emotional consequences. The rare patient who has an asynchronous second primary cancer can be cured with current treatment regimens. Conclusions: We do not advocate nor does the literature support routine biopsy of the opposite testis in patients with unilateral testis tumor. Patient education and close followup are rational alternatives to intervention in all cases to diagnose a small subset who are risk for bilateral tumors. KEY WORDS: carcinoma in mtu, testicular neoplasms, biopsy Carcinoma in situ of the testis and subsequent develop is predicated on several unanswered questions, including the ment of testicular cancer is now widely accepted. In 1972 accuT8cy of diagnosis and the incidence of contralateral carSkakkebaek first recognized carcinoma in situ as a precursor cinoma in situ in the United States germ cell population, of testis cancer.1 Early studies in infertile men2 and testis protracted natural history of d o m a in situ, impact on tumor patients3 showed that 50% of men in whom carcinoma survival in the event of a delay in asynchrimous tumor diagin situ is found on biopsy, if left untreated, have invasive nosis,and potential complicationsimposed by the testicular growth within 5 years, and after 5 years even more patients biopsy itself, as well as the subsequent consequencesof treatwill have a tumor if followed for a longer period. Because to ment of carcinomain situ on fertility and long-tenn androgen our knowledge spontaneous disappearance of carcinoma in function of the remaining testis. We address these issues and situ has not been observed in men in whom biopsies were attempt to determine "whether the other teatis should be repeated Skakkebaek believed that all untreated cases of biopsied in patients with primary germ cell tumors." Comcarcinoma in situ will progress eventually into invasive tea- prehensive review of the literature fmm 1972 to the present, titular germ cell tumors." as well as our experience in treating and following large Carcinoma in situ is found in more than 90% of gonads numbers of testis tumor patients, form the basis of this harboring a germ cell tumofl.6 and at least 5% of opposite review. testes have carcinoma in 8itu.s Furthermore, it is recognized that men with 811 initial testis tumor are at risk for a second primary in the contralateral testicle. The magniDIAGNOSIS tude of this risk has been estimated to be 2 to 5QSs7and A surgical testicular biopsy provides the only reliable dimay be greater if other risk factors, such as infertility, maldescent or low testicular volume (smaller than 12 CC), agnosis of carcinoma in situ, with an accuracy of 8596.10 Carcinoma in situ is spread throughout the gonad in almost are also present.* Since carcinoma in situ gives rise to the second primary, all c88e8,so that a 3 mm. biopsy is sufficient. Diagnosis of a Skabkebaek," and Daugaard et a l 9 believed that a biopsy Of germ cell tumor after a negative biopy for carcinoma in mtu the opposite testis is necessary to detect and direct optimal is rare," although 7 cases have been reported.12 Other biopsy treatment of precursor d o m a in situ before it becomes an procedures, such as needle biopsyls and fine needle aspirainvwive tumor. Despite the favorableimpact of a diagnosh of tion," are more rapid and may cause less discomfort to the carcinoma in situ on the clinical outcome of a testis tumor, patient. However, the sensitivity of these procedures in dimutine or even selected biopsy of the normal gonad in pa- agnosis of early malignancyremains to be pmved.~Furthertients undergoing orcbiectorny for unilateral germ cell tumor more, clm followup ie warranted in all geam cell tumor i s not widely p r d d in the United states.such reluckuice patiente, including those with negative bio1331
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BIOPSY OF CONTRALATERAL TESTIS IN PATIENTS WITH GERM CELL TUMORS
WHAT IS THE INCIDENCE O F CARCINOMA IN SITU AND ITS RELATION TO BILATERAL GERM CELL TUMOR?
In Denmark, where the incidence of germ cell tumor is among the greatest in the world, 73 of 2,850 men (2.6%)with primary germ cell tumors had a contralateral neoplasm.’G The cumulative risk 25 years after diagnosis was estimated to be 5.2%,which is similar to the prevalence of carcinoma in situ in the contralateral testicle.8 This figure was recently confirmed by a German study based on nearly 1,500 biopsies.” The prevalence of carcinoma in situ in the general population of European men is close to the lifetime risk of testicular cancer, which strengthens the hypothesis that virtually all cases of carcinoma in situ become invasive. In the United States Grigor and Rorth reported a 2%18and Soloman et a1 noted a 1.5% (6 of 410 cases)’g incidence of bilateral testis cancer, which is significantly less than the estimated risk in the Scandinavian and European literature. These figures probably underestimate the true incidence of bilateral germ cell tumors, since cisplatin based chemotherapy has significantly prolonged survival and, thus, the risk of a contralateral tumor developing. Indeed, at the Mayo Clinic the incidence of bilateral testicular cancer increased from 1% before to 3.2% after the advent of modern chemotherapy.20 Contralateral testis tumors occurred 1 to 25 years after diagnosis. Even if all cases of carcinoma in situ evolve into cancer, to our knowledge the incidence of carcinoma in situ in the contralateral testicle has not been investigated systematically in the United States and it is possible that the prevalence is lower than in other countries. DOES EARLY TREATMENT OF CARCINOMA IN SITU IMPACT ON SURVIVAL IN THE MODERN CHEMOTHERAPY ERA?
It has not been the policy in the United States to perform contralateral biopsy subsequent to the initial orchiectomy, possibly because development of a secondary testicular tumor is not assumed to be a survival issue. Historically, this has not always been true. Of patients with bilateral testis tumors 30 to 50% had disseminated disease at diagnosis of the second tumor and 10 to 20% died of the secondary tumor.21.22 Although these data include patients from the precisplatin era, a second testicular cancer is not without risk. Recent series have reported predominantly stage I or early stage I1 testis tumors a t the second 0rchiectomy.4.~~ Although a second primary in the contralateral testis might present a t a higher stage, it is expected that the majority of patients can be rescued by current therapeutic regimens. In the Mayo Clinic experience,20 as well as our own, all patients with bilateral testicular tumors diagnosed in the postcisplatin era were cured. Since all germ cell patients, even those with a negative biopsy of the remaining testis, need close followup the rationale for a biopsy providing a diagnosis of carcinoma in situ is that earlier therapy provides superior survival and less functional sacrifice than the results of treatment required later for an invasive neoplasm. There is currently no evidence to suggest that patient survival suffers after appropriate therapy for a delayed invasive tumor. The therapeutic burden, in terms of additional chemotherapy andor surgery, required to control a second testis tumor might be greater in those unfortunate few than if lesser treatment had been directed earlier to carcinoma in situ. On the other hand. the emotional consequences of facing treatment of carcinoma in situ that does not pose an immediate threat may place an undue and perhaps unnessary burden on some patients. Certainly it is reasonable to discuss such issues with the patient before recommending a contralateral testis biopsy.
rience with testicular biopsy as an outpatient procedure in 209 patients.23 Superficial serous exudate, localized indura. tion and postoperative pain lasting for a few hours up to 30 days occurred in 23% of the patients. Hospitalization for drainage of pus from the wound was needed on 3 separate occasions. Of greater concern, Berthelsen and Skakkebaek Suggested that biopsy of the remaining testicle affects spermatogene. sis.24 In their series patients who underwent semen analysis after no biopsy or within 21 days of a biopsy had greater sperm counts than those tested more than 21 days after biopsy. To our knowledge such adverse effects of biopsy on subsequent fertility have not been corroborated and it is difficult to understand how the trauma of a small biopsy could permanently damage spermatogenesis. Alternatively, if fertility is a prime concern, it might be better to avoid any risk and leave the testis undisturbed. Carroll et a1 reported that two-thirds of the patients with severe oligospermia at unilateral orchiectomy for tumor (and no contralateral biopsy) had normal spermatogenesis 6 to 10 months later.25 We showed among 105 stage I cancer patients who chose surveillance (orchiectomy alone) between 1980 and 1984 and followed longer than 10 years that 81% of married men have fathered children (unpublished data). These patients chose close followup largely to preserve fertility potential, and in the majority fear of damage to the remaining testis outweighed the fear of a second testis cancer when informed of the risk. Finally, if there is no intent to treat carcinoma in situ biopsy is unnecessary, and even the minor trauma of a biopsy may compromise early detection of an invasive neoplasm by palpation or sonogram. HOW DOES TREATMENT OF CARCINOMA IN SITU IN THE REMAINING TESTIS IMPACT PATIENT QUALITY OF LIFE”
Treatment options for carcinoma in situ in the opposite testicle include orchiectomy, radiation therapy, chemotherapy and observation. In favor of diagnosis and some type of intervention for carcinoma in situ is the fact that usually the testis harboring carcinoma in situ contributes little or nothing to total sperm production. Furthermore, local treatment with orchiectomy or radiation therapy uniformly results in cure, and in the case with radiation it may preserve natural androgen function. Orchiectorny. Orchiectomy is curative but results in anorchia and necessitates lifelong hormonal replacement. The emotional consequences of surgical anorchia are unquantified but are undoubtedly significant for some young men. Hormonal replacement therapy, even the depot variety, can result in varying androgen levels. In our experience this may contribute to fatigue and mood changes. Testosterone patches help to smooth out the effects of androgen replacement but more study is needed in this area. Radiotherapy. A dose of 2,000 cCy. delivered in 10 fractions or a dose of 20 Gy. delivered in 10 fractions of 2 Gy. to the testicle is sufficient to eradicate malignant cells.2” Testicular biopsies 24 months after radiation show a uniform Sertolicell-only pattern. Since gonocytes and carcinoma in situ are sensitive to irradiation, infertility is a common consequence of therapy. Although such radiotherapy is not believed to affect endogenous testosterone production in the short term, impairment in Leydig’s cell function has been ~bserved.~’ Therefore, the radiation dose has been lowered to 18, 16 and now 14 Cy.4 Long-term effects of direct low dose radiation to the testicle on androgen function remain unknown. The passibility exists that even low doses of rtidiation may cause testicular atrophy and impaired endocrine function. WHAT ARE THE CONSEQUENCES ASSOCIATED WITH Chemotherapy. Cisplatin based chcmothc~rapy may adeROtJTINE BIOPSY OF THE CONTRALATERAL TESTICLE? quately treat invasi\sr germ cell tumor of the testis but it has Although a testis biopsy is relatively simple, it is not de- no permanent effect against carcinoma in s i t i i . l * Contralatvoid of minor complications. Brunn et al reported their expe- era1 tumors have dc.ve1opt.d i n patients previously treated
BIOPSY OF CONTRALATERAL TESTIS IN PATIENTS WITH GERM CELL TUMORS
with The toxicity of chemotherapy also prohibits its routine use in cases with only testis carcinoma in situ. Observation. Observation (with or without contralateral biopsy) of the remaining testicle is an alternative option after orchiectomy for germ cell tumor, which obviates the need for hormonal replacement and preserves the inherent potential to father children. Patients should be monitored closely by self and physician testicular examinations and sonograms. Regular testicular ultrasound in the hands of a dedicated radiologist is particularly helpful. Subtle changes in internal testis architecture, microcalcification and so forth may prompt early biopsy in the absence of suspicious palpable findings. Patients must be informed that total castration and loss of endogenous androgen production are likely if a second primary tumor occurs. At the same time they also need to be reassured that a second primary tumor can be cured in virtually all cases. Obviously, a cooperative, compliant and informed patient who will participate in long-term followup is required. CONCLUSIONS
Carcinoma in situ of the opposite testis evolves into invasive cancer in probably most, if not all, patients with germ cell tumors but it is easily diagnosed by biopsy and cured by radiation. The question is whether diagnosis and treatment of carcinoma in situ are necessary, since only 5%of patients have carcinoma in situ in the other testis, and treatment may have undesirable physical and emotional consequences. We do not advocate contralateral testis biopsy in patients with germ cell tumor because of the protracted natural history of carcinoma in situ, the realization that patients with a second primary can be salvaged, and the short and potentially longterm dual adverse effect that treatment of carcinoma in situ may have on fertility and male hormonal function. If carcinoma in situ is present in 2 to 5% of opposite testes and half or more of these will progress to invasive cancer (at least within 5 years), then biopsy in all patients leading to treatment benefits at the least 1to 2% and at most up to 5%of the germ cell population. The majority of patients are subjected to the risk, albeit small, of an invasive procedure and perhaps functional consequences. Restricting biopsy to informed patients at high risk for carcinoma in situ (that is prior infertility, cryptorchidism or atrophic testis) represents a more selective and equally rational approach to the potential problem of bilateral testes tumors. By doing so, 85% of all patients harboring carcinoma in situ in the contralateral testis could be identified and the majority of testicular cancer patients could avoid unnecessary biopsy. Even in such cases, if the potential for paternity exists coupled with patient desire to maintain natural hormonal function, deferring biopsy and treatment of carcinoma in situ (or invasive tumor) in favor of close observation may be advised. Finally, searching for more disease in the opposite testis in a patient who has just lost a gonad may impose unnecessary emotional stress. "he counter-argument is that if a second neoplasm develops, the patient most likely will lose both testes, whereas if carcinoma in situ is found and radiated, he will retain 1 testis and at least in the short term normal hormonal function. He will also be spared the additional burden of therapy (that is orchiectomy and perhaps Wroperitoneal lymphadenectomy, radiation or chemotherapy) needed to treat the secondary primary tumor. Despite these possibilities, we prefer a conservative watch and follow Policy to the problem of carcinoma in situ in the opposite testis, since the risk is low and newly diagnosed patients face Physical and emotional challenges presented to them by the diagnosis and impending treatment of the existing tumor.
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REFERENC'ES
1. Skakkebaek. N. E.: Possible carcinoma-in-situ of the testis. Lancet, 2: 516,1972. 2. Skakkebaek, N. E., Berthelsen, J. C.and Muller. J.: Carcinoma in situ of the undescended testis. Urol. Clin. N. Amer.. 9: 377. 1982. 3. von der Maase, H.. Rorth, M.. Walbom-Jorgensen. S., Sorenson, B. L., Christophersen, I. S., Hald, T., Jacobsen. G. K.. Berthelsen, J. G. and Skakkebaek. N. E.: Carcinoma in situ of the contralateral testis in patients with tcsticular germ cell cancer: study of 27 cases in 500 patients. Brit. Med. J.. 293 1398. 1986. 4. Skakkebaek, N.E.: Carcinoma in situ of the testis. Read at the Fourth International Congress on Pediatric Andrology, Philadelphia, Pennsylvania, November 1995. 5. Klein, F. A., Melamed, M. R. and Whitmore, W. F., Jr.: Intratubular malignant germ cells (carcinoma in situ) accompanying invasive testicular germ cell tumors. J . Urol., 153: 413, 1985. 6. Jacobsen, G. K., Henriksen, 0. B. and von der Maase. H. V.: Carcinoma in situ of testicular tissue adjacent to malignant germ-cell tumors: a study of 105 cases. Cancer, 4 7 2660,1981. 7. b y , V. and Dieckmann, K.-P.: Prevalence of contralateral testicular intraepithelial neoplasia (carcinoma in situ) in patients with testicular germ cell cancer. Results of the German Multicentre Study. Eur. Urol., 23: 120, 1993. 8. Berthelsen, J. G., Skakkebaek, N. E., von der Maase, H., Sorenson, B. L. and Mogensen, P.: Screening for carcinoma in situ of the contralateral testis in patients with germinal testicular cancer. Brit. Med.J., 285. 1683,1982. 9. Daugaard, G., Giwercman, A. and Skakkebaek, N. E.: Should the other testis be biopsied? Sem. Urol. Oncol., 1 4 8,1996. 10. Berthelsen, J. G. and Skakkebaek, N. E.: Value of testicular biopsy in diagnosing carcinoma in situ testis. Scand. J. Urol. Nephrol.. 1 3 166, 1991. 11. Giwercman, A., Berthelsen, J., Muller, J . and von der Maase, H.: Screening for carcinoma in situ of the testis. Int. J. Androl., la 173,1987. 12. Dieckmann, K.-P., Kaup, P. and b y , V.: False-negative biopsy for testicular intraepithelial neoplasia. J . Cancer Res. Clin. Oncol.. 119: 1, 1992. 13. Rajfer, J. and Binder, S.: Use of Biopty-Gun for transcutaneous testicular biopsy. J. Urol., 142: 1021, 1989. 14. Nagler, H. M.,Kaufmann, D. G.. OToole, K. M. and Sawczuk, I. S.: Carcinoma in situ of the testes: diagnosis by aspiration flow cytometry. J. Uml., 143:359,1990. 15. Heidenreich, A., Zumbe, J. and Engelmann, U. H.: Diagnosis and follow-up of testicular carcinoma in situ by DNA image cytometry. Eur. Urol., 28: 13, 1995. 16. Osterlind, A., Berthelsen, J. G., Abildgaard, N., Hansen, S. O., Jensen, H., Johansen, B., Munck-Hansen, J. and Rasmussen, L. H.: Rise of bilateral testicular germ cell cancer in Denmark: 1960-1984. J. Nat. Cancer Inst., 85: 1391, 1991. 17. Dieckmann, K-P., b y , V. and Buttner, P.: Prevalence of bilateral testicular germ cell tumours and early detection based on contralateral testicular intraepithelial neoplasia. Eur. Uml., 23: 22, 1993. 18. Grigor, K.M. and Rorth, M.: Should the contralateral testis be biopsied? Round table discussion. Eur. Urol., 23: 129, 1993. 19. Soloman, M., Sheinfeld, J . and Herr, H. W.: Testis tumor data base, MSKCC, 1989-95. 20. Patel, S. R., Richardson, R. I. and Kvols, L.: Synchronous and metachronous bilateral testicular tumors: Mayo Clinic experience. Cancer, 65: 1, 1990. 21. Scheiber, K., Ackermann, D. and Studer, U. E.: Bilateral testicular germ cell tumors: a report of 20 cases. J. Urol., 1sB: 73, 1987. 22. Dieckmann, K.-P., Bmkmann, W., Brosig, W., Jonas, D. and Bauer, H. W.: Bilateral testicular germ cell tumors: report on nine cases and review of the literature. Cancer, 87: 1254,1986. 23. BIUM, E., Frimodt-Moiler, C., Giwercman, A, Lenz, S. and Skakkebaek, N. E.: Testicular biopsy as an outpatient procedure in screening for carcinoma in situ: complications and patient's acceptance. Int. J. Androl., 10. 199, 1987. 24. Berthelsen, J . G. and Skakkebaek, N. E.: Gonadal function in men with testis cancer. Fertil. Steril., 39:68,1983. 25. Carroll, P. R., Whitmore, W.F., Jr., Herr, H. W.,Morse, M.J.. Sogani, P. C., Bajorunas, D., Fair, W. R. and Chaganti. R. S. K: Endocrine and exocrine profile of men witb teetieakr
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BIOPSY OF CONTRALATERAL TESTIS IN PATIENTS WITH GERM CELL TUMORS
tumor before chemotherapy. J. Urol.. 131: 420, 1987. 26. von der Maase, H., Gowercman, A. and Skakkebaek, N. E.: Radiation treatment of carcinoma-in-situ of testis. Lancet, 1: 624, 1986. 27. Giwercman, A., von der Maase, H., Berthelsen, J. G., Rorth, M., Bertelsen, A. and Skakkebaek, N. E.: Localized irradiation of testes with carcinoma in situ: effects on Leydig cell function and eradication of malignant germ cells in 20 patients. J. Clin. Endocr. Metab., 73: 596, 1991. 28. Dieckmann, K.-P. and Loy, V.: Intratesticular effects of cisplatinbased chemotherapy. Eur. Urol., 2 8 25, 1995. 29. Daugaard, G. and Christensen, T. B.: Relapse of carcinoma in situ testis after chemotherapy. Ann. Oncol., suppl., 5 63, abstract, 1994. EDITORIAL COMMENT These authors raise the question of whether contralateral biopsy is needed in patients with testicular cancer. They conclude that contralateral biopsy is unnecessary in the majority of patients and treatment of carcinoma in situ may have undesirable physical and emotional consequences. From their point of view this conclusion is based on several unanswered questions. One question concerns the accuracy of diagnosis. A 3 mm. surgical biopsy has a diagnostic sensitivity close to loo%, not 8 5 9 , as stated in this article. In a recent study by Dieckmann and Loy 1,948 patients with testicular cancer had a contralateral biopsy performed.I Of 1,853 carcinoma in situ negative cases a second testicular tumor developed in 3, including 1 in which carcinoma in situ was evident at reexamination and 2 were truly negative. In few cases carcinoma in situ is only evident in a few tubules but in the majority of testicles a random distribution of carcinoma in situ is observed. The incidence of a contralateral tumor is less than 0.5%’ in biopsy negative patients compared to 54 in those who have had no biopsy or treatment for the primary tumor. It is important to stress that restricting biopsies to patients a t high risk for carcinoma in situ, such a s those with prior infertility, cryptorchidism or atrophic testis, is insufficient. In the study of Dieckmann and Loy patients with testicular atrophy had a 4.3-fold increased risk of contralateral carcinoma in situ but 6 4 1 of carcinoma in situ was found in normal sized, noncryptorchid testes. Another question raised concerns the incidence of carcinoma in situ. The incidence of contralateral carcinoma in situ in 2 large European studies was approximately 58.1.2 Whether this incidence is the same or lower in America remains unknown until it is evaluated. The next question is whether treatment of carcinoma in situ has an impact on survival. Despite excellent treatment results for testicular cancer in the cisplatin era secondary testicular cancer is not without risk. The 5-year survival rates for patients with stage 1 testicular cancer are approximately 98’%, and with disseminated disease 91 and 79% for a good and intermediate prognosis, respectively:’ It is a survival issue and some patients who have secondaq testicular cancer die of disease. The authors mention that all pa. tients with testicular cancer need close followup. However, in most cases followup can be limited to 6 years. In patients who have not undergone contralateral biopsy this period must be extended to 25 years or lifelong. This is an unnecessary psychological burden to the patient as wrll as an economical issue. Concerning the consequences associated with routine biopsy of the contralateral testis. an adverse ctffcct on fertility is mentioned. As far as WP know. it has never bccn proved that testicular biopsy causes pcwnanrnt dam:ig:r to sperm production. Actually. more professional xlvicc conc~~rninp krtility c;in be providctl to patients who have
undergone contralateral biopsy. Carcinoma in situ positive patients can be advised to have semen cryopreserved before secondary cancer develops. Patients with azoospermia 1 to 2 years after chemotherapy can be advised on future fertility based on the state of spermatogenesis in the pre-chemotherapy biopsy. The last question concerns management of carcinoma in situ and its influence on patient quality of life. The authors recommend observation of the remaining testicle as an option after orchiectomy. As mentioned, 5% of men with a germ cell tumor harbor carcinoma in situ in the remaining gonad. If these patients are not treated with cytotoxic drugs for metastatic disease. the policy of surveillance or retroperitoneal lymph node dissection almost inevitably leads to development of secondary cancer and total castration. Therefore. the patient loses androgen production, which in turn has a serious negative impact on life quality despite androgen replacement. We think that this leads to serious psychological stress, and doubt that this watch and follow policy will be elected by many patients after careful information. Few Danish men refuse the offer of contralateral biopsy and patients with a negative biopsy are happy to know that the risk of a second tumor is not higher than 0.5%. Patients with carcinoma in situ in the biopsy are offered sperm banking before radiotherapy, Radiotherapy can erradicate carcinoma in situ and, thereby, prevent subsequent cancer development. At doses of 20 Gy. Leydig cell function is affected. Therefore, the radiation dose has been decreased to 18.16 and now 14 Gy. Followup has not been long enough to predict whether Leydig cell function is affected by lower doses. Control biopsies after a radiation dose of 14 Gy. show a Sertoli-cell-only pattern. Patients treated with radiotherapy have excellent quality of life, the majority without hormonal substitution, and they are satisfied that the risk of secondary testicular cancer is close to 0%. Even those needing a n androgen supplement are better off than fully testosterone deficient castrated men. Chemotherapy for disseminated disease does not completely prevent the development of a secondary tumor. We have followed 32 patients with carcinoma in situ treated with cisplatin containing chemotherapy of whom 16% had recurrent carcinoma in situ or a secondary tumor. If future fertility is a major issue for this group, followup biopsies are recommended. Otherwise radiotherapy should also be offered to these patients. The diagnosis of carcinoma in situ is not of mere academic interest but it makes it possible to offer the patient optimal, evidence based treatment. Gedske Daugaard, Aleksander Giuiercnian and Niels Erik Skakkebaek Departments of Oncology, and Growth and Reproduction Rigshospitalet Copenhagen, Denmark 1. Dieckmann. K. P. and Loy, V.: Prevalence of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell neoplasms. J. Clin. Oncol., 1 4 3126. 1996. 2. von der Maase, H., R ~ r t hM., , Walbom-Jorgensen, S., Sorensen, B. L.. Christopherson, I. S., Hald, T., Jacobsen, G. K., Berthelsen, J . G. and Skakkebaek, N. E.: Carcinoma in situ of contralateral testis in patients with testicular germ cell cancer: study of 27 cases in 500 patients. Brit. Med. J.. 2 9 3 1398, 1986. 3. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J . C h . Oncol., 15: 594, 1997. 4. Christensen. T. R., Daugaard. G.. Geertsen, P. and von der Maase, H.: Effect of chemotherapy o n carcinoma In situ of the testis.
VOl. 168*1951-1394,oetobar 1997 Printed in U . S A
Review Article IS BIOPSY OF THE CONTRALATERAL TESTIS NECESSARY IN PATIENTS WITH GERM CELL TUMORS? HARRY W.HERR
AND
JOEL SHEINFELD
From the Urology Service, Department of Surgery, Memorial Shn-Kettering Cancer Center. New York,New York
ABSTRACT
Purpose: Carcinoma in situ is present in the contralateral testis in up to 5% of patients with a primary germ cell tumor and w i l l progress in the majority of cases to a second primary invasive cancer. We address the question of whether the other testis should be biopsied in patients with testis tumors. Materials and Methods: The literature on carcinoma in situ of the testis h m 1972 to the present was critically evaluated in an attempt to address the issue of carcinoma in situ in the opposite testis. Results: Carcinoma in situ of the opposite testis in patients with a primary germ cell tumor is easily diagnosed by biopsy and cured by orchiednmy or radiation. The problem is that biopsy is unnecessary in the majority of patients, and treatment of carcinoma in situ may have undesirable physical and emotional consequences. The rare patient who has an asynchronous second primary cancer can be cured with current treatment regimens. Conclusions: We do not advocate nor does the literature support routine biopsy of the opposite testis in patients with unilateral testis tumor. Patient education and close followup are rational alternatives to intervention in all cases to diagnose a small subset who are risk for bilateral tumors. KEY WORDS: carcinoma in mtu, testicular neoplasms, biopsy Carcinoma in situ of the testis and subsequent develop is predicated on several unanswered questions, including the ment of testicular cancer is now widely accepted. In 1972 accuT8cy of diagnosis and the incidence of contralateral carSkakkebaek first recognized carcinoma in situ as a precursor cinoma in situ in the United States germ cell population, of testis cancer.1 Early studies in infertile men2 and testis protracted natural history of d o m a in situ, impact on tumor patients3 showed that 50% of men in whom carcinoma survival in the event of a delay in asynchrimous tumor diagin situ is found on biopsy, if left untreated, have invasive nosis,and potential complicationsimposed by the testicular growth within 5 years, and after 5 years even more patients biopsy itself, as well as the subsequent consequencesof treatwill have a tumor if followed for a longer period. Because to ment of carcinomain situ on fertility and long-tenn androgen our knowledge spontaneous disappearance of carcinoma in function of the remaining testis. We address these issues and situ has not been observed in men in whom biopsies were attempt to determine "whether the other teatis should be repeated Skakkebaek believed that all untreated cases of biopsied in patients with primary germ cell tumors." Comcarcinoma in situ will progress eventually into invasive tea- prehensive review of the literature fmm 1972 to the present, titular germ cell tumors." as well as our experience in treating and following large Carcinoma in situ is found in more than 90% of gonads numbers of testis tumor patients, form the basis of this harboring a germ cell tumofl.6 and at least 5% of opposite review. testes have carcinoma in 8itu.s Furthermore, it is recognized that men with 811 initial testis tumor are at risk for a second primary in the contralateral testicle. The magniDIAGNOSIS tude of this risk has been estimated to be 2 to 5QSs7and A surgical testicular biopsy provides the only reliable dimay be greater if other risk factors, such as infertility, maldescent or low testicular volume (smaller than 12 CC), agnosis of carcinoma in situ, with an accuracy of 8596.10 Carcinoma in situ is spread throughout the gonad in almost are also present.* Since carcinoma in situ gives rise to the second primary, all c88e8,so that a 3 mm. biopsy is sufficient. Diagnosis of a Skabkebaek," and Daugaard et a l 9 believed that a biopsy Of germ cell tumor after a negative biopy for carcinoma in mtu the opposite testis is necessary to detect and direct optimal is rare," although 7 cases have been reported.12 Other biopsy treatment of precursor d o m a in situ before it becomes an procedures, such as needle biopsyls and fine needle aspirainvwive tumor. Despite the favorableimpact of a diagnosh of tion," are more rapid and may cause less discomfort to the carcinoma in situ on the clinical outcome of a testis tumor, patient. However, the sensitivity of these procedures in dimutine or even selected biopsy of the normal gonad in pa- agnosis of early malignancyremains to be pmved.~Furthertients undergoing orcbiectorny for unilateral germ cell tumor more, clm followup ie warranted in all geam cell tumor i s not widely p r d d in the United states.such reluckuice patiente, including those with negative bio1331
1332
BIOPSY OF CONTRALATERAL TESTIS IN PATIENTS WITH GERM CELL TUMORS
WHAT IS THE INCIDENCE O F CARCINOMA IN SITU AND ITS RELATION TO BILATERAL GERM CELL TUMOR?
In Denmark, where the incidence of germ cell tumor is among the greatest in the world, 73 of 2,850 men (2.6%)with primary germ cell tumors had a contralateral neoplasm.’G The cumulative risk 25 years after diagnosis was estimated to be 5.2%,which is similar to the prevalence of carcinoma in situ in the contralateral testicle.8 This figure was recently confirmed by a German study based on nearly 1,500 biopsies.” The prevalence of carcinoma in situ in the general population of European men is close to the lifetime risk of testicular cancer, which strengthens the hypothesis that virtually all cases of carcinoma in situ become invasive. In the United States Grigor and Rorth reported a 2%18and Soloman et a1 noted a 1.5% (6 of 410 cases)’g incidence of bilateral testis cancer, which is significantly less than the estimated risk in the Scandinavian and European literature. These figures probably underestimate the true incidence of bilateral germ cell tumors, since cisplatin based chemotherapy has significantly prolonged survival and, thus, the risk of a contralateral tumor developing. Indeed, at the Mayo Clinic the incidence of bilateral testicular cancer increased from 1% before to 3.2% after the advent of modern chemotherapy.20 Contralateral testis tumors occurred 1 to 25 years after diagnosis. Even if all cases of carcinoma in situ evolve into cancer, to our knowledge the incidence of carcinoma in situ in the contralateral testicle has not been investigated systematically in the United States and it is possible that the prevalence is lower than in other countries. DOES EARLY TREATMENT OF CARCINOMA IN SITU IMPACT ON SURVIVAL IN THE MODERN CHEMOTHERAPY ERA?
It has not been the policy in the United States to perform contralateral biopsy subsequent to the initial orchiectomy, possibly because development of a secondary testicular tumor is not assumed to be a survival issue. Historically, this has not always been true. Of patients with bilateral testis tumors 30 to 50% had disseminated disease at diagnosis of the second tumor and 10 to 20% died of the secondary tumor.21.22 Although these data include patients from the precisplatin era, a second testicular cancer is not without risk. Recent series have reported predominantly stage I or early stage I1 testis tumors a t the second 0rchiectomy.4.~~ Although a second primary in the contralateral testis might present a t a higher stage, it is expected that the majority of patients can be rescued by current therapeutic regimens. In the Mayo Clinic experience,20 as well as our own, all patients with bilateral testicular tumors diagnosed in the postcisplatin era were cured. Since all germ cell patients, even those with a negative biopsy of the remaining testis, need close followup the rationale for a biopsy providing a diagnosis of carcinoma in situ is that earlier therapy provides superior survival and less functional sacrifice than the results of treatment required later for an invasive neoplasm. There is currently no evidence to suggest that patient survival suffers after appropriate therapy for a delayed invasive tumor. The therapeutic burden, in terms of additional chemotherapy andor surgery, required to control a second testis tumor might be greater in those unfortunate few than if lesser treatment had been directed earlier to carcinoma in situ. On the other hand. the emotional consequences of facing treatment of carcinoma in situ that does not pose an immediate threat may place an undue and perhaps unnessary burden on some patients. Certainly it is reasonable to discuss such issues with the patient before recommending a contralateral testis biopsy.
rience with testicular biopsy as an outpatient procedure in 209 patients.23 Superficial serous exudate, localized indura. tion and postoperative pain lasting for a few hours up to 30 days occurred in 23% of the patients. Hospitalization for drainage of pus from the wound was needed on 3 separate occasions. Of greater concern, Berthelsen and Skakkebaek Suggested that biopsy of the remaining testicle affects spermatogene. sis.24 In their series patients who underwent semen analysis after no biopsy or within 21 days of a biopsy had greater sperm counts than those tested more than 21 days after biopsy. To our knowledge such adverse effects of biopsy on subsequent fertility have not been corroborated and it is difficult to understand how the trauma of a small biopsy could permanently damage spermatogenesis. Alternatively, if fertility is a prime concern, it might be better to avoid any risk and leave the testis undisturbed. Carroll et a1 reported that two-thirds of the patients with severe oligospermia at unilateral orchiectomy for tumor (and no contralateral biopsy) had normal spermatogenesis 6 to 10 months later.25 We showed among 105 stage I cancer patients who chose surveillance (orchiectomy alone) between 1980 and 1984 and followed longer than 10 years that 81% of married men have fathered children (unpublished data). These patients chose close followup largely to preserve fertility potential, and in the majority fear of damage to the remaining testis outweighed the fear of a second testis cancer when informed of the risk. Finally, if there is no intent to treat carcinoma in situ biopsy is unnecessary, and even the minor trauma of a biopsy may compromise early detection of an invasive neoplasm by palpation or sonogram. HOW DOES TREATMENT OF CARCINOMA IN SITU IN THE REMAINING TESTIS IMPACT PATIENT QUALITY OF LIFE”
Treatment options for carcinoma in situ in the opposite testicle include orchiectomy, radiation therapy, chemotherapy and observation. In favor of diagnosis and some type of intervention for carcinoma in situ is the fact that usually the testis harboring carcinoma in situ contributes little or nothing to total sperm production. Furthermore, local treatment with orchiectomy or radiation therapy uniformly results in cure, and in the case with radiation it may preserve natural androgen function. Orchiectorny. Orchiectomy is curative but results in anorchia and necessitates lifelong hormonal replacement. The emotional consequences of surgical anorchia are unquantified but are undoubtedly significant for some young men. Hormonal replacement therapy, even the depot variety, can result in varying androgen levels. In our experience this may contribute to fatigue and mood changes. Testosterone patches help to smooth out the effects of androgen replacement but more study is needed in this area. Radiotherapy. A dose of 2,000 cCy. delivered in 10 fractions or a dose of 20 Gy. delivered in 10 fractions of 2 Gy. to the testicle is sufficient to eradicate malignant cells.2” Testicular biopsies 24 months after radiation show a uniform Sertolicell-only pattern. Since gonocytes and carcinoma in situ are sensitive to irradiation, infertility is a common consequence of therapy. Although such radiotherapy is not believed to affect endogenous testosterone production in the short term, impairment in Leydig’s cell function has been ~bserved.~’ Therefore, the radiation dose has been lowered to 18, 16 and now 14 Cy.4 Long-term effects of direct low dose radiation to the testicle on androgen function remain unknown. The passibility exists that even low doses of rtidiation may cause testicular atrophy and impaired endocrine function. WHAT ARE THE CONSEQUENCES ASSOCIATED WITH Chemotherapy. Cisplatin based chcmothc~rapy may adeROtJTINE BIOPSY OF THE CONTRALATERAL TESTICLE? quately treat invasi\sr germ cell tumor of the testis but it has Although a testis biopsy is relatively simple, it is not de- no permanent effect against carcinoma in s i t i i . l * Contralatvoid of minor complications. Brunn et al reported their expe- era1 tumors have dc.ve1opt.d i n patients previously treated
BIOPSY OF CONTRALATERAL TESTIS IN PATIENTS WITH GERM CELL TUMORS
with The toxicity of chemotherapy also prohibits its routine use in cases with only testis carcinoma in situ. Observation. Observation (with or without contralateral biopsy) of the remaining testicle is an alternative option after orchiectomy for germ cell tumor, which obviates the need for hormonal replacement and preserves the inherent potential to father children. Patients should be monitored closely by self and physician testicular examinations and sonograms. Regular testicular ultrasound in the hands of a dedicated radiologist is particularly helpful. Subtle changes in internal testis architecture, microcalcification and so forth may prompt early biopsy in the absence of suspicious palpable findings. Patients must be informed that total castration and loss of endogenous androgen production are likely if a second primary tumor occurs. At the same time they also need to be reassured that a second primary tumor can be cured in virtually all cases. Obviously, a cooperative, compliant and informed patient who will participate in long-term followup is required. CONCLUSIONS
Carcinoma in situ of the opposite testis evolves into invasive cancer in probably most, if not all, patients with germ cell tumors but it is easily diagnosed by biopsy and cured by radiation. The question is whether diagnosis and treatment of carcinoma in situ are necessary, since only 5%of patients have carcinoma in situ in the other testis, and treatment may have undesirable physical and emotional consequences. We do not advocate contralateral testis biopsy in patients with germ cell tumor because of the protracted natural history of carcinoma in situ, the realization that patients with a second primary can be salvaged, and the short and potentially longterm dual adverse effect that treatment of carcinoma in situ may have on fertility and male hormonal function. If carcinoma in situ is present in 2 to 5% of opposite testes and half or more of these will progress to invasive cancer (at least within 5 years), then biopsy in all patients leading to treatment benefits at the least 1to 2% and at most up to 5%of the germ cell population. The majority of patients are subjected to the risk, albeit small, of an invasive procedure and perhaps functional consequences. Restricting biopsy to informed patients at high risk for carcinoma in situ (that is prior infertility, cryptorchidism or atrophic testis) represents a more selective and equally rational approach to the potential problem of bilateral testes tumors. By doing so, 85% of all patients harboring carcinoma in situ in the contralateral testis could be identified and the majority of testicular cancer patients could avoid unnecessary biopsy. Even in such cases, if the potential for paternity exists coupled with patient desire to maintain natural hormonal function, deferring biopsy and treatment of carcinoma in situ (or invasive tumor) in favor of close observation may be advised. Finally, searching for more disease in the opposite testis in a patient who has just lost a gonad may impose unnecessary emotional stress. "he counter-argument is that if a second neoplasm develops, the patient most likely will lose both testes, whereas if carcinoma in situ is found and radiated, he will retain 1 testis and at least in the short term normal hormonal function. He will also be spared the additional burden of therapy (that is orchiectomy and perhaps Wroperitoneal lymphadenectomy, radiation or chemotherapy) needed to treat the secondary primary tumor. Despite these possibilities, we prefer a conservative watch and follow Policy to the problem of carcinoma in situ in the opposite testis, since the risk is low and newly diagnosed patients face Physical and emotional challenges presented to them by the diagnosis and impending treatment of the existing tumor.
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REFERENC'ES
1. Skakkebaek. N. E.: Possible carcinoma-in-situ of the testis. Lancet, 2: 516,1972. 2. Skakkebaek, N. E., Berthelsen, J. C.and Muller. J.: Carcinoma in situ of the undescended testis. Urol. Clin. N. Amer.. 9: 377. 1982. 3. von der Maase, H.. Rorth, M.. Walbom-Jorgensen. S., Sorenson, B. L., Christophersen, I. S., Hald, T., Jacobsen. G. K.. Berthelsen, J. G. and Skakkebaek. N. E.: Carcinoma in situ of the contralateral testis in patients with tcsticular germ cell cancer: study of 27 cases in 500 patients. Brit. Med. J.. 293 1398. 1986. 4. Skakkebaek, N.E.: Carcinoma in situ of the testis. Read at the Fourth International Congress on Pediatric Andrology, Philadelphia, Pennsylvania, November 1995. 5. Klein, F. A., Melamed, M. R. and Whitmore, W. F., Jr.: Intratubular malignant germ cells (carcinoma in situ) accompanying invasive testicular germ cell tumors. J . Urol., 153: 413, 1985. 6. Jacobsen, G. K., Henriksen, 0. B. and von der Maase. H. V.: Carcinoma in situ of testicular tissue adjacent to malignant germ-cell tumors: a study of 105 cases. Cancer, 4 7 2660,1981. 7. b y , V. and Dieckmann, K.-P.: Prevalence of contralateral testicular intraepithelial neoplasia (carcinoma in situ) in patients with testicular germ cell cancer. Results of the German Multicentre Study. Eur. Urol., 23: 120, 1993. 8. Berthelsen, J. G., Skakkebaek, N. E., von der Maase, H., Sorenson, B. L. and Mogensen, P.: Screening for carcinoma in situ of the contralateral testis in patients with germinal testicular cancer. Brit. Med.J., 285. 1683,1982. 9. Daugaard, G., Giwercman, A. and Skakkebaek, N. E.: Should the other testis be biopsied? Sem. Urol. Oncol., 1 4 8,1996. 10. Berthelsen, J. G. and Skakkebaek, N. E.: Value of testicular biopsy in diagnosing carcinoma in situ testis. Scand. J. Urol. Nephrol.. 1 3 166, 1991. 11. Giwercman, A., Berthelsen, J., Muller, J . and von der Maase, H.: Screening for carcinoma in situ of the testis. Int. J. Androl., la 173,1987. 12. Dieckmann, K.-P., Kaup, P. and b y , V.: False-negative biopsy for testicular intraepithelial neoplasia. J . Cancer Res. Clin. Oncol.. 119: 1, 1992. 13. Rajfer, J. and Binder, S.: Use of Biopty-Gun for transcutaneous testicular biopsy. J. Urol., 142: 1021, 1989. 14. Nagler, H. M.,Kaufmann, D. G.. OToole, K. M. and Sawczuk, I. S.: Carcinoma in situ of the testes: diagnosis by aspiration flow cytometry. J. Uml., 143:359,1990. 15. Heidenreich, A., Zumbe, J. and Engelmann, U. H.: Diagnosis and follow-up of testicular carcinoma in situ by DNA image cytometry. Eur. Urol., 28: 13, 1995. 16. Osterlind, A., Berthelsen, J. G., Abildgaard, N., Hansen, S. O., Jensen, H., Johansen, B., Munck-Hansen, J. and Rasmussen, L. H.: Rise of bilateral testicular germ cell cancer in Denmark: 1960-1984. J. Nat. Cancer Inst., 85: 1391, 1991. 17. Dieckmann, K-P., b y , V. and Buttner, P.: Prevalence of bilateral testicular germ cell tumours and early detection based on contralateral testicular intraepithelial neoplasia. Eur. Uml., 23: 22, 1993. 18. Grigor, K.M. and Rorth, M.: Should the contralateral testis be biopsied? Round table discussion. Eur. Urol., 23: 129, 1993. 19. Soloman, M., Sheinfeld, J . and Herr, H. W.: Testis tumor data base, MSKCC, 1989-95. 20. Patel, S. R., Richardson, R. I. and Kvols, L.: Synchronous and metachronous bilateral testicular tumors: Mayo Clinic experience. Cancer, 65: 1, 1990. 21. Scheiber, K., Ackermann, D. and Studer, U. E.: Bilateral testicular germ cell tumors: a report of 20 cases. J. Urol., 1sB: 73, 1987. 22. Dieckmann, K.-P., Bmkmann, W., Brosig, W., Jonas, D. and Bauer, H. W.: Bilateral testicular germ cell tumors: report on nine cases and review of the literature. Cancer, 87: 1254,1986. 23. BIUM, E., Frimodt-Moiler, C., Giwercman, A, Lenz, S. and Skakkebaek, N. E.: Testicular biopsy as an outpatient procedure in screening for carcinoma in situ: complications and patient's acceptance. Int. J. Androl., 10. 199, 1987. 24. Berthelsen, J . G. and Skakkebaek, N. E.: Gonadal function in men with testis cancer. Fertil. Steril., 39:68,1983. 25. Carroll, P. R., Whitmore, W.F., Jr., Herr, H. W.,Morse, M.J.. Sogani, P. C., Bajorunas, D., Fair, W. R. and Chaganti. R. S. K: Endocrine and exocrine profile of men witb teetieakr
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BIOPSY OF CONTRALATERAL TESTIS IN PATIENTS WITH GERM CELL TUMORS
tumor before chemotherapy. J. Urol.. 131: 420, 1987. 26. von der Maase, H., Gowercman, A. and Skakkebaek, N. E.: Radiation treatment of carcinoma-in-situ of testis. Lancet, 1: 624, 1986. 27. Giwercman, A., von der Maase, H., Berthelsen, J. G., Rorth, M., Bertelsen, A. and Skakkebaek, N. E.: Localized irradiation of testes with carcinoma in situ: effects on Leydig cell function and eradication of malignant germ cells in 20 patients. J. Clin. Endocr. Metab., 73: 596, 1991. 28. Dieckmann, K.-P. and Loy, V.: Intratesticular effects of cisplatinbased chemotherapy. Eur. Urol., 2 8 25, 1995. 29. Daugaard, G. and Christensen, T. B.: Relapse of carcinoma in situ testis after chemotherapy. Ann. Oncol., suppl., 5 63, abstract, 1994. EDITORIAL COMMENT These authors raise the question of whether contralateral biopsy is needed in patients with testicular cancer. They conclude that contralateral biopsy is unnecessary in the majority of patients and treatment of carcinoma in situ may have undesirable physical and emotional consequences. From their point of view this conclusion is based on several unanswered questions. One question concerns the accuracy of diagnosis. A 3 mm. surgical biopsy has a diagnostic sensitivity close to loo%, not 8 5 9 , as stated in this article. In a recent study by Dieckmann and Loy 1,948 patients with testicular cancer had a contralateral biopsy performed.I Of 1,853 carcinoma in situ negative cases a second testicular tumor developed in 3, including 1 in which carcinoma in situ was evident at reexamination and 2 were truly negative. In few cases carcinoma in situ is only evident in a few tubules but in the majority of testicles a random distribution of carcinoma in situ is observed. The incidence of a contralateral tumor is less than 0.5%’ in biopsy negative patients compared to 54 in those who have had no biopsy or treatment for the primary tumor. It is important to stress that restricting biopsies to patients a t high risk for carcinoma in situ, such a s those with prior infertility, cryptorchidism or atrophic testis, is insufficient. In the study of Dieckmann and Loy patients with testicular atrophy had a 4.3-fold increased risk of contralateral carcinoma in situ but 6 4 1 of carcinoma in situ was found in normal sized, noncryptorchid testes. Another question raised concerns the incidence of carcinoma in situ. The incidence of contralateral carcinoma in situ in 2 large European studies was approximately 58.1.2 Whether this incidence is the same or lower in America remains unknown until it is evaluated. The next question is whether treatment of carcinoma in situ has an impact on survival. Despite excellent treatment results for testicular cancer in the cisplatin era secondary testicular cancer is not without risk. The 5-year survival rates for patients with stage 1 testicular cancer are approximately 98’%, and with disseminated disease 91 and 79% for a good and intermediate prognosis, respectively:’ It is a survival issue and some patients who have secondaq testicular cancer die of disease. The authors mention that all pa. tients with testicular cancer need close followup. However, in most cases followup can be limited to 6 years. In patients who have not undergone contralateral biopsy this period must be extended to 25 years or lifelong. This is an unnecessary psychological burden to the patient as wrll as an economical issue. Concerning the consequences associated with routine biopsy of the contralateral testis. an adverse ctffcct on fertility is mentioned. As far as WP know. it has never bccn proved that testicular biopsy causes pcwnanrnt dam:ig:r to sperm production. Actually. more professional xlvicc conc~~rninp krtility c;in be providctl to patients who have
undergone contralateral biopsy. Carcinoma in situ positive patients can be advised to have semen cryopreserved before secondary cancer develops. Patients with azoospermia 1 to 2 years after chemotherapy can be advised on future fertility based on the state of spermatogenesis in the pre-chemotherapy biopsy. The last question concerns management of carcinoma in situ and its influence on patient quality of life. The authors recommend observation of the remaining testicle as an option after orchiectomy. As mentioned, 5% of men with a germ cell tumor harbor carcinoma in situ in the remaining gonad. If these patients are not treated with cytotoxic drugs for metastatic disease. the policy of surveillance or retroperitoneal lymph node dissection almost inevitably leads to development of secondary cancer and total castration. Therefore. the patient loses androgen production, which in turn has a serious negative impact on life quality despite androgen replacement. We think that this leads to serious psychological stress, and doubt that this watch and follow policy will be elected by many patients after careful information. Few Danish men refuse the offer of contralateral biopsy and patients with a negative biopsy are happy to know that the risk of a second tumor is not higher than 0.5%. Patients with carcinoma in situ in the biopsy are offered sperm banking before radiotherapy, Radiotherapy can erradicate carcinoma in situ and, thereby, prevent subsequent cancer development. At doses of 20 Gy. Leydig cell function is affected. Therefore, the radiation dose has been decreased to 18.16 and now 14 Gy. Followup has not been long enough to predict whether Leydig cell function is affected by lower doses. Control biopsies after a radiation dose of 14 Gy. show a Sertoli-cell-only pattern. Patients treated with radiotherapy have excellent quality of life, the majority without hormonal substitution, and they are satisfied that the risk of secondary testicular cancer is close to 0%. Even those needing a n androgen supplement are better off than fully testosterone deficient castrated men. Chemotherapy for disseminated disease does not completely prevent the development of a secondary tumor. We have followed 32 patients with carcinoma in situ treated with cisplatin containing chemotherapy of whom 16% had recurrent carcinoma in situ or a secondary tumor. If future fertility is a major issue for this group, followup biopsies are recommended. Otherwise radiotherapy should also be offered to these patients. The diagnosis of carcinoma in situ is not of mere academic interest but it makes it possible to offer the patient optimal, evidence based treatment. Gedske Daugaard, Aleksander Giuiercnian and Niels Erik Skakkebaek Departments of Oncology, and Growth and Reproduction Rigshospitalet Copenhagen, Denmark 1. Dieckmann. K. P. and Loy, V.: Prevalence of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell neoplasms. J. Clin. Oncol., 1 4 3126. 1996. 2. von der Maase, H., R ~ r t hM., , Walbom-Jorgensen, S., Sorensen, B. L.. Christopherson, I. S., Hald, T., Jacobsen, G. K., Berthelsen, J . G. and Skakkebaek, N. E.: Carcinoma in situ of contralateral testis in patients with testicular germ cell cancer: study of 27 cases in 500 patients. Brit. Med. J.. 2 9 3 1398, 1986. 3. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J . C h . Oncol., 15: 594, 1997. 4. Christensen. T. R., Daugaard. G.. Geertsen, P. and von der Maase, H.: Effect of chemotherapy o n carcinoma In situ of the testis.