Bilateral Testicular Germ Cell Tumors

Transcription

1 1228 Bilateral Testicular Germ Cell Tumors Twenty-Year Experience at M. D. Anderson Cancer Center Mingxin Che, M.D., Ph.D. 1 Pheroze Tamboli, M.D. 1 Jae Y. Ro, M.D., Ph.D. 1 Dong Soo Park, M.D. 2 Jung Sil Ro, M.D. 3 Robert J. Amato, D.O. 4 Alberto G. Ayala, M.D. 1 1 Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. 2 Department of Urology, Pundang Cha Hospital, Pochon Cha University, Sungnam, Korea. 3 Department of Medical Oncology, MacGregor Medical Center, Houston, Texas. 4 Scott Department of Urology, Baylor College of Medicine, Houston, Texas. Address for reprints: Pheroze Tamboli, M.D., Department of Pathology, Box 85, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030; Fax: ; ptamboli@mdanderson.org Received July 2, 2001; revision received March 30, 2002; accepted April 23, BACKGROUND. The incidence of testicular carcinoma in the United States has increased significantly over the last two decades. Germ cell tumors form the majority of malignant testicular tumors. With advances in diagnosis and therapeutic approaches, germ cell tumors are now highly sensitive to treatment, providing long-term survival. It has been speculated that the incidence of bilateral germ cell tumors may increase due to the improved survival of patients with unilateral germ cell tumors. In this report, the authors present a study of bilateral germ cell tumors of the testis in men who were treated at The University of Texas M. D. Anderson Cancer Center over a 20-year period with emphasis on their incidence, histologic features, and clinical features. METHODS. Between 1978 and 1999, 2431 patients with testicular germ cell tumors were treated at The University of Texas M. D. Anderson Cancer Center. Among these, 24 patients with bilateral germ cell tumors were identified. Clinical records and all available pathology slides of the tumors were reviewed. RESULTS. The overall incidence of bilateral germ cell tumors in the patients with testicular germ cell tumors was 1% (24 of 2431 patients). The incidence was 1.8% (14 of 776 patients) in patients with seminoma and 0.6% (10 of 1655 patients) in patients with nonseminomatous germ cell tumors. Patients with seminoma who were age 30 years at the time of initial diagnosis had a higher incidence of bilateral tumors compared with older men. Twenty of 24 patients with bilateral germ cell tumors had metachronous tumors, and 4 patients had synchronous tumors. Among the patients with metachronous tumors, 70% of second tumors occurred within 5 years; the longest interval between the first and second tumors was 15 years. The outcome of patients with bilateral germ cell tumors was excellent; only 1 of 24 patients died of metastatic disease. CONCLUSIONS. The overall incidence of bilateral testicular germ cell tumors was 1% in patients who were treated at The University of Texas M. D. Anderson Cancer Center over the past two decades. The incidence of bilateral germ cell tumors was related to the histologic type of the initial tumor and to the patient s age at initial presentation in patients with seminoma. Thus, patients in the second or third decade of life who presented with seminomas as their initial tumor were more likely to develop a second germ cell tumor compared with patients in the fourth or fifth decade of life. These findings have potentially important implications for clinical management by identifying a population of patients with germ cell tumors who are at risk of developing a second tumor and also for studying risk factors of bilateral germ cell tumors of the testis. Cancer 2002;95: American Cancer Society. DOI /cncr KEYWORDS: incidence, bilateral testicular germ cell tumors, seminoma, nonseminomatous germ cell tumor, intervals, outcome, histology, age American Cancer Society

2 Bilateral Testicular Germ Cell Tumors/Che et al Although testicular carcinoma is a rare tumor, accounting for only 1% of all malignant tumors in men, the incidence of testicular carcinoma in the United States has increased more than 50% between 1973 and ,2 Moreover, the age for peak incidence of testicular carcinoma seems to be decreasing in the United States. 1 The American Cancer Society estimates that, in the year 2001, about 7200 men will be newly diagnosed with testicular carcinoma in the United States and that 400 patients will die of their disease. 3 Germ cell tumors are the most frequent type of testicular tumors and the most common malignancies in men between the ages of 15 years and 34 years. It has been well recognized that men who have had one testicular germ cell tumor have an increased risk of developing a second germ cell tumor in the opposite testis. The incidence of testicular germ cell tumors in the general population is 0.005%, whereas, in patients with a history of testicular germ cell tumor, the incidence of a second germ cell tumor in the contralateral testis ranges from 1% to 5%. Compared with agematched populations, the relative risk of developing a germ cell tumor is times greater in patients with a history of testicular germ cell tumor. 4 6 To assess the incidence of bilateral testicular germ cell tumors in relation to clinical presentation and tumor type, we report 24 patients who developed a second primary tumor from a population of 2431 patients with testicular germ cell tumors who were treated over a 20-year period at The University of Texas M.D. Anderson Cancer Center in Houston, Texas. MATERIALS AND METHODS Between 1978 and 1999, 2431 patients with testicular germ cell tumors were treated at The University of Texas M. D. Anderson Cancer Center. Among these 2431 patients, there were 24 patients with bilateral testicular germ cell tumors. The medical records of these 24 patients were evaluated in detail, including clinical information, histopathology, and follow-up. Six patients underwent both orchiectomies at other institutions but received adjuvant treatment at our institution; 12 patients underwent their first orchiectomy at an outside institution and underwent a second orchiectomy at our institution; and the remaining 6 patients underwent both orchiectomies at our institution. Hematoxylin and eosin-stained slides of both testicular tumors were available for 21 patients, and slides of only the second tumor were available for 2 patients. There were no slides available for one patient at the time of this study, but these had been reviewed previously at our institution. All tumors were staged according to the TNM staging system, which is based on the extent of primary tumor, the status of retroperitoneal lymph nodes, distant metastasis, and serum tumor markers. The 2431 patients were divided into two groups based on the histologic type of their initial tumors: patients with seminoma and patients with nonseminomatous germ cell tumors (NSGCT). The former group included only patients with pure seminoma. The NSGCT group included patients with any pure form of a germ cell tumor other than seminoma or any mixture of germ cell tumor components. Patients in each histologic subgroup were divided further into 10-year age groups. Patients were treated based on the histologic type and clinical stage. All patients underwent a radical orchiectomy. Patients with seminoma localized to the testis or with small retroperitoneal lymph node disease underwent radical orchiectomy followed by radiation therapy, whereas patients with large retroperitoneal masses or distant metastasis received chemotherapy. All patients with NSGCT underwent radical orchiectomy, retroperitoneal lymphadenectomy and chemotherapy. The data were analyzed using the chi-square test; P values 0.05 were considered statistically significant. RESULTS Incidence Of 2431 patients who were treated at The University of Texas M. D. Anderson Cancer Center between 1978 and 1999, 24 patients (1%) developed bilateral germ cell tumors of the testis. Twenty of 24 patients had metachronous tumors, and 4 patients had synchronous tumors. The major clinical and histologic features of the bilateral germ cell tumors are summarized in Tables 1 and 2, respectively. None of the 24 patients had a history of cryptorchidism. There was a statistically significant difference (P ) in the incidence of bilateral germ cell tumors between patients who presented with seminoma and patients who presented with NSGCT. Among the 776 patients with seminoma who were treated at The University of Texas M. D. Cancer Center during this period, 14 patients (1.8%) had bilateral germ cell tumors. But, only 10 of 1655 patients (0.6%) with NSGCT developed bilateral tumors. The incidence of bilateral germ cell tumors in patients with seminoma was influenced markedly by patient age at the time of initial presentation (Table 3). Although seminoma was most common in the group of patients age years, the patients with seminoma at a younger age ( 30 years) had a greater risk

3 1230 CANCER September 15, 2002 / Volume 95 / Number 6 TABLE 1 Clinical and Histologic Features of 20 Patients with Metachronous Bilateral Germ Cell Tumors Patient Age at first tumor (yrs) Histology First germ cell tumor TNM stage Postorchiectomy management Interval between tumors (months) Histology Second germ cell tumor TNM stage Postorchiectomy management Follow-up (months) Outcome 1 18 Seminoma I XRT 180 Seminoma II RPLND, ChRx 108 NED 2 a 46 Seminoma I XRT 145 Mixed NSGCT II RPLND, ChRx 102 NED 3 36 Seminoma II ChRx, XRT 128 Seminoma I Surveillance 23 NED 4 29 Seminoma II XRT 118 Seminoma III ChRx 69 NED 5 26 Seminoma I XRT 60 Mixed NSGCT I Surveillance 62 NED 6 29 Seminoma I XRT 49 Seminoma I Surveillance 20 NED 7 22 Seminoma I XRT 34 Seminoma I Surveillance 72 NED 8 23 Seminoma II XRT, ChRx 29 Seminoma I Surveillance 173 NED 9 a 30 Seminoma I XRT 28 Seminoma I Surveillance 14 NED Seminoma II ChRx 24 Seminoma I Surveillance 7 NED Embryonal Ca. III RPLND, ChRx 142 Seminoma I Surveillance 33 NED Embryonal Ca. II ChRx 44 Mixed NSGCT III ChRx 87 NED Embryonal Ca. III ChRx 19 Seminoma I Surveillance 63 NED Mixed NSGCT I RPLND, ChRx 116 Mixed NSGCT I Surveillance 130 NED 15 b 31 Mixed NSGCT I XRT 40 Mixed NSGCT I Surveillance 36 NED Mixed NSGCT I ChRx 38 Seminoma I XRT 48 NED Mixed NSGCT I RPLND, ChRx 28 Teratoma I Surveillance 46 NED Mixed NSGCT I ChRx 28 Seminoma I Surveillance 24 NED Mixed NSGCT I ChRx 21 Mixed NSGCT I Surveillance 10 NED Mixed NSGCT II RPLND, XRT 14 Mixed NSGCT III ChRx 245 NED XRT: radiation therapy; RPLND: retroperitoneal lymph node dissection; ChRx: chemotherapy; NED: no evidence of disease; NSGCT: nonseminamatous germ cell tumor; Ca.: carcinoma. a These two patients developed retroperitoneal lymph node metastasis (mature teratoma in Patient 2 and seminoma in Patient 9) after treatment for the second germ cell tumor. b This patient was diagnosed with and treated for seminoma initially at an outside institution, and a minor component of yolk sac tumor was identified upon review of the pathology slides at M. D. Anderson Cancer Center. The patient also developed left inguinal lymph node metastasis (embryonal carcinoma) after treatment for the second germ cell tumor. TABLE 2 Clinical and Histologic Features of Four Patients with Synchronous Bilateral Germ Cell Tumors Patient Patient age (yrs) Histology of bilateral tumors TNM stage Postorchiectomy management Follow-up (months) Outcome 1 30 Seminoma Seminoma I XRT 27 NED 2 47 Seminoma Seminoma I XRT 27 NED 3 23 Seminoma Seminoma I XRT 18 NED 4 30 Seminoma Embryonal Ca. III ChRx 41 DOD XRT: radiation therapy; NED: no evidence of disease; Ca.: carcinoma; ChRx: chemotherapy; DOD: died of disease. of developing a germ cell tumor in the contralateral testis (P ). NSGCT was most common in the group of patients age years. There was no significant difference in the incidence of bilateral germ cell tumors between these patients in the different age groups (all 1%) (Table 4). Intervals between the First and Second Germ Cell Tumors Of 20 patients with metachronous tumors, the second tumor occurred within 5 years in 14 patients (70%) and between years in the other 6 patients (30%) (Fig 1). Pathologic Features of Bilateral Germ Cell Tumors Seminoma was the predominant histologic type of synchronous tumor. In three of four patients with synchronous bilateral tumor, both tumors were seminomas. In the fourth patient, there was seminoma on one side and an embryonal carcinoma on the opposite side. In 20 men with metachronous tumors, the initial tumor was seminoma in 10 patients and NSGCT in 10

4 Bilateral Testicular Germ Cell Tumors/Che et al TABLE 3 Age Specific Incidence of Bilateral Germ Cell Tumors in Patients with Seminoma Age group (yrs) All patients with seminoma Patients with bilateral GCT No. % P value a GCT: germ cell tumor. a Chi-square test. TABLE 4 Age Specific Incidence of Bilateral Germ Cell Tumors in Patients with Nonseminomatous Germ Cell Tumors Age group (years) All patients with NSGCT Patients with bilateral GCT No. % P value a GCT: germ cell tumor; NSGCT: nonseminomatous GCT. a Chi-square test. FIGURE 1. Time intervals between first and second tumors in the 20 patients with metachronous bilateral testicular germ cell tumors. patients. Of 10 patients with initial seminomas, 8 patients developed a second seminoma, whereas the other 2 patients had NSGCT as their second tumor. Of 10 patients who presented with NSGCT as their initial tumor, 6 patients had a second NSGCT, whereas 4 patients developed seminoma as their second tumor. However, there was no significant correlation of histologic type between the first and second tumors in men with metachronous tumors (P 0.064). There was no substantial difference in the TNM stage of the first tumor between patients with seminoma and patients with NSGCT (Tables 1, 2). The size of the first tumor ranged from 0.5 cm to 13 cm (mean 4.7 cm; median, 3.6 cm), and the size of the second tumor ranged from 0.4 cm to 13 cm (mean, 3.0 cm; median, 2.2 cm). Outcome The median follow-up after the second germ cell tumor was 43.5 months (range, months). The prognosis of patients with bilateral germ cell tumors was excellent. Three of 20 patients with metachronous tumors developed retroperitoneal lymph node metastasis at 6 months, 14 months, and 58 months, respectively, after treatment of the second tumor, and all 3 patients responded well to further treatment. One of four patients with synchronous tumors developed metastatic embryonal carcinoma in the lung 10 months after treatment for bilateral tumors. He responded poorly to further treatment and died of recurrent lung metastasis. None of the remaining patients with bilateral tumors had any evidence of disease at the most recent follow-up. DISCUSSION It is known that having a testicular germ cell tumor predisposes men to a second germ cell tumor in the contralateral testis, with the second tumor occurring in 1 5% of such patients One of the earliest series on bilateral testicular germ cell tumors was the study by Gilbert and Hamilton 13 in Those authors included 1466 consecutive patients with primary testicular tumors and found that 1.6% of patients had bilateral testicular tumors. In 1978, Aristizabal et al. 12 reviewed the literature over a period of two decades and found 4864 patients with testicular neoplasms, for an overall incidence of 1.56% bilateral tumors. In the current study, we included 2431 patients with testicular germ cell tumors who were treated at The University of Texas M. D. Anderson Cancer Center between 1978 and Twenty-four of these patients had bilateral testicular germ cell tumors, for an overall incidence of 1%. It may be possible that the incidence of bilateral germ cell tumors may increase in the future due to the long-term survival of patients after they receive effective treatment for their first tumor. Our study partially supports this premise, because, even though 14 of 20 patients developed their second tumor within the first 5 years, the remaining 6 patients developed the sec-

5 1232 CANCER September 15, 2002 / Volume 95 / Number 6 ond tumor between years after the sentinel event (see Fig. 1). It has been reported that the incidence of bilateral germ cell tumors is significantly different in patients who have seminoma compared with patients who have NSGCT. 5,9 In a study of 2850 patients, Osterlind et al. reported that the incidence of bilateral germ cell tumors was greater in patients who had NSGCT (8.4%) compared with patients who had seminoma (3.6%). 5 In the current study, however, the reverse was true, with the incidence of bilateral tumors 1.8% being in patients with seminoma compared with 0.6% in patients with NSGCT. A similar finding was observed by Bokemeyer et al., 9 who found that 4.8% of men with seminoma had bilateral testicular tumors compared with 1.8% of men with NSGCT. Therefore, it remains unclear whether the relative risk of developing a second testicular tumor differs in men with seminoma and men with NSGCT. We also found that the incidence of bilateral germ cell tumors in patients with seminoma was influenced by patient age at the time of initial diagnosis. Although seminoma was most common in patients between ages years, the incidence of bilateral germ cell tumors was much greater in patients in the younger age groups. This result suggests that men who have an early onset of seminoma (at age 30 years) may be at greater risk of developing a second tumor. Dieckmann et al. 8 observed that patients with bilateral tumors were younger (mean age, 29 years) compared with men who had a unilateral tumor (mean age, 34 years). However, in that study, patients were not grouped according to histologic tumor type. Our study found that the incidence of bilateral germ cell tumors in patients with NSGCT was not influenced by patient age. Cryptorchidism is a known risk factor for the development of a testicular germ cell tumor. In one study, 8 9.5% of patients with bilateral germ cell tumors had a history of bilateral cryptorchidism compared with 2.2% of patients with unilateral germ cell tumors. However, a greater incidence of cryptorchidism in patients with bilateral germ cell tumors was not observed in another report. 9 In the current study, none of the patients with bilateral germ cell tumors had a history of cryptorchidism. The strategies employed for the management of patients with testicular germ cell tumors were based on the individual patient (Table 1). Treatment decisions for patients with synchronous tumors and metachronous tumors were formulated on the basis of risk stratification, as defined by the International Germ Cell Consensus Classification. 14 Surveillance was the preferred mode of management for patients with lowrisk, clinical Stage I seminoma. For patients with highrisk germ cell tumors, three options would be discussed, i.e., surveillance, retroperitoneal lymph node dissection (RPLND), or two courses of chemotherapy. For patients with seminoma in the group with a good prognosis or the group with an intermediate prognosis, cisplatin chemotherapy would be offered. Patients with NSGCTs in the group with a good prognosis were offered bleomycin and etoposide or carboplatin chemotherapy. Patients with NSGCTs in the intermediate volume or intermediate prognosis group were given chemotherapy with cisplatin, cyclophosphamide, and doxorubicin and with vincristine and bleomycin. All patients were rendered disease free after their specific therapy. The treatment decisions for the second tumor were determined mainly by the clinical and/or pathologic stage of the second tumor and the previous treatment method for the first tumor (Table 1). In general, radiation therapy was not used for treating the second tumor in patients who received irradiation for the first tumor. RPLND after irradiation for the first tumor was performed in two patients with clinical evidence of retroperitoneal lymph node involvement. Posttreatment surveillance of these patients (following both the first tumor and the second tumor) consisted of evaluating serum tumor markers and radiographic studies. The time frame for surveillance was defined by the nature of disease presentation. However, the most common follow-up was evaluation every 3 months during the first year, every 4 months during the second year, every 6 months during the third year, and yearly thereafter. Most of the second tumors were detected during this surveillance period; however, in some of these patients, the second tumor was detected much later through self-examination, physical examination, or ultrasonography. During routine surveillance using radiologic studies, there were no significant changes seen in the retroperitoneal region in any of these patients. Although most of the second germ cell tumors in the contralateral testis occurred within 5 years of the first tumor, in our study, second tumors occurred after 10 years in 6 men; the longest time interval between the first tumor and the second tumors was 15 years. It is interesting to note that another study reported an interval of 32 years. 7 Therefore, patients with germ cell tumors require lifelong follow-up. Monitoring of serum markers ( -fetoprotein and -human chorionic gonadotropin), scrotal sonography, and periodic self-examination are the major modalities for surveillance of these patients. In our experience, patients who had tumors that measured 1 cm, which represents half of our patients with metachronous bilateral testicular tumors, usually

6 Bilateral Testicular Germ Cell Tumors/Che et al had their tumors detected initially by physical examination. For patients with smaller tumors ( 1 cm), ultrasonography is a most sensitive and reliable method for detection. Testicular intratubular germ cell neoplasia has been considered a precursor lesion for developing germ cell tumors. It has been reported that 6.6% of patients with testicular germ cell tumors have intratubular germ cell neoplasia in the contralateral testicular biopsy specimen at the time they undergo orchiectomy. 8 Therefore, it has been suggested that patients with unilateral germ cell tumors should undergo a contralateral testicular biopsy at the time of orchiectomy to evaluate for intratubular germ cell neoplasia and to possibly identify patients who may develop second germ cell tumors. 10 However, biopsies of the contralateral testis were not performed in any of our patients. Our finding of a 1% incidence of bilateral tumors is significantly different compared with the reported incidence of intratubular germ cell neoplasia in the contralateral testis (6.6%). This suggests that intratubular germ cell neoplasia occurs more frequently than bilateral germ cell tumors. At this time, the management of patients with intratubular germ cell neoplasia remains controversial; either surveillance or irradiation of the contralateral testis is the choice. Whether all patients with intratubular germ cell neoplasia should receive irradiation of the contralateral testis, which would result in definite infertility and also may affect Leydig cell function, 10,11,14 16 remains open to debate. The results of our study support the utility of surveillance for the management of these patients, because only 1% of patients who were treated for a testicular germ cell tumor developed a second germ cell tumor. In conclusion, the current study of men who were treated for bilateral germ cell tumors of the testis found the following results: 1) The incidence of bilateral germ cell tumors remained low (1%) despite longer survival time for patients with unilateral germ cell tumors; 2) the incidence of bilateral tumors was greater in patients with seminoma than in patients with NSGCT; 3) patients who developed a seminoma at a younger age had a greater risk of developing a contralateral tumor; 4) there was no significant concordance between the histologic classification of the first tumor and the second tumor; and 5) with proper treatment, the outcome of patients with bilateral germ cell tumors was excellent. REFERENCES 1. Pharris-Ciurej ND, Cook LS, Weiss N. Incidence of testicular cancer in the United States: has the epidemic begun to abate? Am J Epidemiol. 1999;150: Mckiernan JM, Goluboff ET, Liberson GL, Golden R, Fisch H. Rising risk of testicular cancer by birth cohort in the United States from 1973 to J Urol. 1999;162: Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, CA Cancer J Clin. 2001;51: Ulbright TM. Testis risk and prognostic factors. The pathologist s perspective. Urol Clin North Am. 1999;26: Osterlind A, Berthelsen JG, Abildgaard N, et al. Risk of bilateral testicular germ cell cancer in Denmark: J Natl Cancer Inst. 1991,83: Colls BM, Harvey VJ, Skelton L, Thompson PI, Frampton CM. Bilateral germ cell testicular tumors in New Zealand: experience in Auckland and Christchurch J Clin Oncol. 1996; 14: Scheiber K, Ackermann D, Studer UE. Bilateral testicular germ cell tumors: a report of 20 cases. J Urol. 1987;138: Dieckmann KP, Loy V, Buttner P. Prevalence of bilateral testicular germ cell tumors and early detection based on contralateral testicular intra-epithelial neoplasia. Br J Urol. 1993;71: Bokemeyer C, Schmoll HJ, Schoffski P, Harstrick A, Bading M, Poliwoda H. Bilateral testicular tumors: prevalence and clinical implications. Eur J Cancer. 1993;29A: Grigor KM, Rorth M. Should the contralateral testis be biopsied? Round table discussion. Eur Urol. 1993,23: Dieckmann KP, Boeckmann W, Brosig W, Jonas D, Bauer H-W. Bilateral testicular germ cell tumors. Report of nine cases and review of the literature. Cancer. 1986;57: Aristizabal S, Davis JR, Miller RC, Moore MJ, Boone MLM. Bilateral primary germ cell testicular tumors. Report of four cases and review of the literature. Cancer. 1978;42: Gilbert JB, Hamilton JB. Studies in malignant tumor of the testis. IV. Bilateral testicular cancer. Incidence, nature, and bearing upon management of the patient with a single testicular cancer. Cancer Res. 1942;21: International Germ Cell Cancer Collaborative Group. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol. 1997;15: von der Maase H, Giwercman A, Skakkebaek NE. Radiation treatment of carcinoma-in-situ of the testis. Lancet. 1986;1: Dieckmann K-P, Loy V. The value of the biopsy of the contralateral testis in patients with testicular germ cell cancer: the recent German experience. APMIS. 1998;106:13 20.