547 Bilateral Testicular Tumors Management and Outcome in 21 Patients Christopher L. Coogan, M.D. Richard S. Foster, M.D. Garrick R. Simmons, M.D. Piero G. Tognoni, M.D. Bruce J. Roth, M.D. John P. Donohue, M.D. Department of Urology and Department of Medicine, Section of Hematology/Oncology, Indiana University Medical Center, Indianapolis, Indiana. BACKGROUND. The authors examined the clinical course of patients with bilateral testicular tumors to determine whether the outcome after treatment was different from patients with unilateral tumors. METHODS. Using a computerized data base of 2088 patients with testicular carcinoma at Indiana University, 21 patients (1%) were identified with bilateral testicular carcinoma. A retrospective review of hospital and clinic charts was performed. Sixteen patients with metachronous and 5 patients with synchronous testicular tumors were identified. RESULTS. Treatment was based on clinical stage and was similar to therapy given for unilateral disease. The mean age at presentation of the first testicular tumor was 28.4 years (range, 16 – 47 years). Approximately 50% of the second primary tumors presented . 5 years after the contralateral tumor. At a mean follow-up of 49.9 months (range, 1–276 months), 18 patients were without evidence of disease, 2 were alive with disease, and 1 patient had died of disease. CONCLUSIONS. The treatment of patients with bilateral germ cell tumors is based on the pathology and clinical stage and should not be different from the traditional management of unilateral testicular carcinoma. Patients with unilateral testicular carcinoma should be informed of the necessity of long term follow-up because contralateral testicular carcinoma may occur as long as 25 years later. Cancer 1998; 83:547–52. © 1998 American Cancer Society. KEYWORDS: bilateral, testicular carcinoma metachronous, synchronous. T Presented in part at the North Central Section of the American Urological Association Meeting, Monterey, California, September 26, 1997. Dr. Coogan’s current address: Department of Urology, Rush-Presbyterian-St. Luke’s Medical Center, Chicago, Illinois. Address for reprints: Richard S. Foster, M.D., Department of Urology, 550 N. University Blvd., Indianapolis, IN 46202. Received October 10, 1997; revision received February 4, 1998; accepted February 10, 1998. © 1998 American Cancer Society esticular carcinoma is the most common solid malignancy in men ages 15–35 years.1,2 The incidence of testicular carcinoma is 4.5 per 100,000 and is increasing.3 In 1970, the mortality rate for testicular carcinoma was approximately 90% compared with , 10% in 1990.1 Patients who develop testicular carcinoma in one testis are 500 –1000 times more likely to develop testicular carcinoma in the contralateral testis.4,5 The incidence of bilateral testicular carcinoma varies between 0.5–7%.4 –10 Prior therapy for testicular carcinoma potentially could affect treatment decisions for subsequent contralateral tumors by increasing the morbidity of such therapy. Similarly, therapy for the initial tumor (retroperitoneal lymph node dissection [RPLND]) potentially could affect the behavior of a subsequent tumor (altered lymphatic drainage). The objectives of this study were to determine: 1) Is therapy for a second primary tumor different than therapy for the initial tumor? and 2) Is the chance for cure or morbidity of therapy different? MATERIALS AND METHODS Using a computerized data base of 2088 patients with testicular carcinoma at Indiana University, 21 patients (1%) were found to have 548 CANCER August 1, 1998 / Volume 83 / Number 3 TABLE 1 Bilateral Testicular Tumors: Presentation, Management, and Outcome in 21 Patients Patient (age) (yrs) Site/pathology 1st testis tumor Clinical stage Treatment (pathology) [courses] Interval to the 2nd primary (mos) 1 (28) L-seminoma A XRT 70 2 (32) R-seminoma A XRT 66 3 (32) R-seminoma A XRT 4 (34) L-seminoma B 5 (27) L-seminoma 6 (27) Treatment (pathology) [courses] Pathology 2nd testis Clinical stage Embryonal seminoma syncytiotropho blasts Embryonal C BEP PC RPLND (Teratoma) NED (10) B NED (29) 44 Embryonal teratoma C XRT 75 B A XRT 21 R-seminoma A XRT 29 Embryonal yolk sac seminoma Embryonal teratoma, Seminoma Embryonal seminoma 7 (50) R-seminoma A XRT 216 PNET, Embryonal teratoma A 8 (20) L-seminoma A XRT 24 Embryonal teratoma C 9 (29) L-yolk sac embryonal teratoma L-embryonal seminoma A 71 Seminoma A 13 Seminoma B BEP PC RPLND➩ Seminoma VIP➩AuBMT AWD (6) R-embryonal cell carcinoma B RPLND (No pathologic change) RPLND (One focus of seminoma)➩ Surveillance RPLND (No pathologic change) RPLND (Embryonal) BEP BEP PC RPLND (Teratoma) RPLND (embryonal) BEP RPLND (No pathologic change) BEP PC RPLND (Yolk sac) VIP, paclitaxel, doxorubicin RPLND (PNET, embryonal)➩ Surveillance BEP PC RPLND (Necrosis) XRT 180 Seminoma A XRT NED (1) 10 (29) 11 (26) A A C Outcome (mos) NED (6) NED (78) NED (79) AWD (54) NED (5) NED (5) NED (10) (continued) bilateral testicular carcinoma. A retrospective review of hospital charts and phone calls to follow-up physicians was performed in these 21 patients. The orchiectomy pathology, clinical and pathologic stage, treatments, morbidity, and outcome were evaluated. RESULTS The mean age of the patients at presentation of the first testicular tumor was 28.4 years (range, 16 –50 years). This was similar to the mean age of all patients in the Indiana data base (28.8 years). The patients’ presentation, treatment, and outcome are presented in Table 1. No patient had a history of cryptorchidism. No patient had any first-degree relatives with a history of testicular carcinoma. A summary of the outcome in the metachronous and synchronous group is presented in Table 2. Sixteen patients were found to have metachronous tumors at an average interval of 65.1 months (range, 5–216 months) between diagnosis. Approximately 50% of the second primary tumors occurred . 5 years after the initial testicular tumor. Five patients presented with synchronous tumors. Bilateral Testicular Tumors/Coogan et al. 549 TABLE 1 (continued) Bilateral Testicular Tumors: Presentation, Management, and Outcome in 21 Patients Patient (age) (yrs) Site/pathology 1st testis tumor Clinical stage Treatment (pathology) [courses] Interval to the 2nd primary (mos) 12 (22) R-teratoma C BEP, VIP XRT 13 (22) L-embryonal teratoma A 14 (23) R-embryonal sarcoma A 15 (28) L-seminoma A 16 (20) L-embryonal A 17 (47) Synchronous R-seminoma L-seminoma Synchronous R-seminoma L-seminoma Synchronous R-seminoma L-seminoma Synchronous R-seminoma L-embryonal Synchronous R-teratoma L-teratoma 18 (32) 19 (36) 20 (16) 21 (18) Pathology 2nd testis Clinical stage Treatment (pathology) [courses] 5 Atrophy with tumor necrosis C Surveillance➩ Recurrence➩ Stage C➩ BEP➩ PC RPLND (Teratoma) RPLND (Embryonal, seminoma)➩ Methotrexate, chlorambucil, actinomycin D ➩ XRT XRT 14 Yolk sac choriocarcinoma Syncytiotrophoblasts A Vincristine Cyclophosphamide Actinomycin D AuBMT PCRPLND (PNET) Surveillance 68 Embryonal seminoma C Bleomycin, Vincristine, Doxorubicin, Uinblastine PC RPLND (Necrosis) NED (276) 122 Embryonal yolk sac A NED (29) 24 Embryonal A B RPLND (Seminoma) ➩BEP BEP Surveillance➩ ➚Tumor markers➩ BEP Surveillance A XRT NED (22) A XRT NED (9) B BEP NED (113) C BEP PC RPLND (Teratoma) NED (168) Outcome (mos) DOD (52) NED (60) NED (12) NED (20) L: left; XRT: radiation therapy; BEP: bleomycin, etoposide, and cisplatin; PC RPLND: postchemotherapy retroperitoneal lymph node dissection; NED: no evidence of disease; R: right; VIP: etoposide, ifosfamide, and cisplatin; PNET: primitive neuroectodermal tumor; AuBMT: autologous bone marrow transplantation; DOD: dead of disease. Metachronous Tumors In the 16 patients with metachronous tumors, 13 initially presented with clinical Stage A disease, 2 presented with clinical Stage B disease, and 1 presented with clinical Stage C disease (Tables 1 and 2). Clinical staging at the time of presentation of the second testicular primary tumor revealed seven patients had clinical Stage A disease, three had clinical Stage B disease, and six patients had clinical Stage C disease. Nine patients initially presented with seminoma whereas seven presented with a nonseminomatous germ cell tumor in the metachronous group. Seven patients presented with clinical Stage A disease at the time of diagnosis of their second primary tumor. Two patients underwent RPLND, two patients received radiotherapy for seminoma, and three patients were placed in a surveillance protocol (one subsequently failed and required chemotherapy). Three patients presented with clinical Stage B disease. Two underwent RPLND (one patient with active disease) and one underwent chemotherapy followed by postchemotherapy RPLND (PC-RPLND). All six patients who pre- 550 CANCER August 1, 1998 / Volume 83 / Number 3 TABLE 2 Bilateral Testicular Tumors Disease Status No. Age at 1st primary (range) (yrs) Interval (range) (yrs) Metachronous 16 28.0 (20–50) 55.0 (5–276) Synchronous All 5 21 32.0 (16–47) 28.0 (16–50) Disease status (median follow-up) (mos) NED: 13 (12) AWD: 2 (30) DOD: 1 (52) NED: 5 (22) NED: 18 (25) AWD: 2 (30) DOD: 1 (52) NED: no evidence of disease; AWD: alive with disease; DOD: dead of disease. sented with clinical Stage C disease received chemotherapy followed by PC-RPLND. Two patients had active disease (both received chemotherapy postoperatively), two patients had teratoma in the resected specimen, and two patients had necrosis only in the resected specimen (Table 1). At a mean follow up of 44.5 months (range, 1–276 months), 13 had no evidence of disease (NED), 2 were alive with disease (AWD), and 1 was dead of disease (DOD). Synchronous Tumors Five patients presented with synchronous testicular carcinoma (Tables 1 and 2). Two presented with clinical Stage A disease, two presented with clinical Stage B disease, and one presented with clinical Stage C disease. Four patients had identical pathology in both testes (three-seminomas and one-teratoma) and one had different pathology in each testis (seminoma and embryonal). The treatment and outcome can be seen in Tables 1 and 2. At a mean follow-up of 66.4 months (range, 9 –168 months), all patients were classified NED. DISCUSSION Approximately 0.5–7% of patients with testicular carcinoma will develop a contralateral testicular tumor.4 –10 The incidence of testicular carcinoma is increasing5 and the improved survival in patients with testicular carcinoma may lead to an increased incidence of bilateral tumors.11 In the current report, 1% of our patients were found to have a second primary testicular tumor. The true incidence of bilateral testicular carcinoma is difficult to determine. The majority of patients in our computer bank are referred and often highly selected patients. However, it is important to note that patients with disease in one testicle are at a 500 –1000-fold increased risk of contralateral testicular carcinoma compared with the general pop- ulation, suggesting either a genetic predisposition or exposure to an environmental toxin.4,12,13 Testicular carcinoma is associated with cryptorchidism, atrophy, possibly trauma, and hormonal or genetic factors.14 Certain subgroups may be at an increased risk of developing carcinoma in situ (CIS) on the contralateral side. Risk factors include: 1) cryptorchidism, 2) testicular atrophy, 3) low sperm count, 4) elevated follicle stimulating hormone levels, and 5) age at diagnosis of the first primary tumor , 30 years.15,16 Although no patient in this study had a history of cryptorchidism, the incidence of cryptorchidism in patients with bilateral testicular carcinoma can be as high as 22%.5 The incidence of CIS in the contralateral testis in patients with testicular carcinoma ranges between 4.4 – 6.6%.9,16 It currently is standard practice in Denmark to perform a biopsy of the contralateral testis in patients with testicular carcinoma in one testis. Patients who are found to have CIS receive prophylactic radiotherapy to prevent tumor occurrence in the contralateral testis. Radiotherapy virtually eliminates the possibility of a contralateral tumor and preserves hormonal production in the testis, but eliminates any future fertility potential.9 Approximately 80 – 85% of bilateral testicular tumors occur metachronously, whereas 15–20% occur synchronously.17,18 Synchronous testicular tumors nearly are always of a similar pathology.5,7 In the current study, five patients presented with synchronous testicular tumors. Two patients presented with clinical Stage A disease, two patients presented with clinical Stage B disease, and one patient presented with clinical Stage C disease. Although the number of cases is small, patients with synchronous tumors may present at a higher stage disease compared with those with unilateral testicular carcinoma. However, the outcome remains excellent. All patients were NED after radiotherapy or chemotherapy and PC-RPLND at a mean follow-up of 66 months (range, 9 –168 months). Patients with synchronous testicular tumors should be treated based on their clinical stage and pathology. In our small cohort, survival was 100% and all patients have been continuously NED. Metachronous tumors occurred at a mean of 65.1 months after the first primary tumor. Although 13 of 16 patients (81%) presented with clinical Stage A disease at diagnosis of their first primary tumor, only 7 of 16 (44%) presented with clinical Stage A disease at the diagnosis of the second primary tumor. Delay in diagnosis is possible in patients with a second testicular primary tumor for several reasons. The consequence of losing both testicles is far greater than losing one testicle, which may lead to patient denial. Testicular self-examination may be difficult because there is no Bilateral Testicular Tumors/Coogan et al. contralateral testis for comparison. Patients often are only followed for 5 years, yet 50% of second primary tumors will occur . 5 years later. Some authors have speculated that systemic chemotherapy may have a prophylactic effect on the development of a second testicular primary tumor,12 but this has been refuted by others.19 Recently, van Basten et al. noted a 3% incidence of contralateral testicular tumors and a markedly reduced (1.8% vs. 5%) incidence of bilateral tumors in men treated with cisplatin-based chemotherapy.20 Dieckmann et al. found that approximately 50% of metachronous tumors in their study had a similar pathology.5 Seminoma accounted for 80% of the cases with a similar pathology, whereas 20% were nonseminomas.5 No patient in our study presented with metachronous seminoma. This may represent a selection bias based on the referral patterns at Indiana University. Only 3 of 16 patients (19%) presented with a similar histology of their second primary tumor. Of the nine patients who presented with seminoma in their first primary tumor, all presented with nonseminoma in their second primary tumor. Again, this may be a referral bias rather than true incidence. Treatment of bilateral testicular carcinoma is based on the pathology and clinical stage. Of the seven patients with clinical Stage A disease at presentation of a second primary tumor, two patients (nonseminoma) underwent RPLND, two received radiation therapy (seminoma), and three (nonseminomatous) were placed in a surveillance protocol. One surveillance patient required subsequent chemotherapy for elevated tumor markers. All were NED at a mean follow-up of 28 months. Patients with advanced disease (n 5 9) were treated with chemotherapy and/or PCRPLND (Table 1). The decision regarding use of RPLND must be based on prior therapy, pathology of the testis, clinical stage, and patient preference. No patients in this study underwent bilateral primary RPLND for metachronous tumors. The technical aspects of RPLND after radiotherapy are dependent on the field and dose of radiation, time from last treatment, and template necessary for treatment. Nervesparing techniques are not necessary because patients are anorchid. However, a recent study advocated partial orchiectomy in patients with a second primary tumor in highly selected patients.21 However, this approach must be considered investigational. Survival in our patients with bilateral testicular carcinoma does not appear to be worse than in patients with unilateral testicular carcinoma. In the current study, at last follow-up 18 patients were NED, 2 were AWD, and 1 was DOD. The one patient who was DOD presented with clinical Stage C disease and had 551 a primitive neuroendocrine tumor at PC-RPLND, a poor prognostic indicator. Survival is excellent in patients who receive proper staging and therapy and does not appear to differ from survival in patients with unilateral testicular carcinoma.19,22–25 The incidence of testicular carcinoma appears to be increasing.5 Second testicular primary tumors have been reported to be found up to 25 years later.12 The majority of second primary tumors are found by testicular self-examination, emphasizing the need for long term testicular self-examination.12 Patients should be counseled on the necessity and proper technique of testicular self-examination. Treatment options for the second primary tumor should be based on clinical stage, pathology of the testis, and prior therapy. Management of the second primary tumor should not be different from traditional management of testicular carcinoma. 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