Bilateral Testicular Germ Cell Tumorsin Turkey: Increase in Incidence in LastDecade and Evaluation of Risk Factors in 30 PatientsAkdogan Bulent, Divrik Rauf Taner, Tombul Tolga, Yazici Sertac, Tasar Celik, Zorlu Ferruhand Ozen Haluk*From the Departments of Urology, Hacettepe University, School of Medicine, Ankara and Tepecik Research and Training Hospital(DRT, ZF), Izmir, Turkey

Purpose: The relative risk of germ cell testicular tumor is significantly higher in patients with a testicular tumor history.We reviewed histological and clinical features in 30 patients with bilateral tumors treated at 2 academic centers in Turkey.Materials and Methods: Of 987 patients with testicular germ cell tumors 30 (3.0%) were diagnosed with bilateral disease.Data on clinical information, histopathology and followup records were reevaluated. Contralateral testis biopsy was notperformed in any patient at initial orchiectomy.Results: Of 30 patients 24 had sequential tumors at a median interval of 75 months (range 3 to 260) and 6 (20.0%) hadsynchronous tumors. Mean age at presentation was 32.3 and 26.7 years, respectively. The second tumor occurred within 2 and5 years in 20.8% and 41.7% of patients, respectively. Patients with seminoma were at significantly higher risk for bilateraldisease (4.5% vs 2.3%), whereas patients with nonseminoma had more advanced disease at presentation. Synchronoustumors had similar tumor histology on each side and more advanced stage at presentation than metachronous tumors. Mostpatients with metachronous tumors had stage 1 disease, including 81% originally and 95.2% subsequently. Primary tumorswere significantly larger than secondary tumors (4.78 vs 2.59 cm). Median time after the first and second germ cell tumorswas 128 and 47 months, respectively. At last followup all patients had no evidence of disease.Conclusions: The risk of contralateral testicular germ cell tumor in patients with seminoma was 2 times higher than inthose without a history of tumor. Synchronous tumors present at advanced stage and have similar histology on each side.Clinical outcome is excellent with appropriate treatment. Contralateral testis biopsy at initial diagnosis is not mandatory.

Key Words: testis; testicular neoplasms; neoplasms, germ cell and embryonal; seminoma; risk

Epidemiological studies have revealed an increased in-cidence of testis cancer in the United States1 and inalmost all developed countries during the last 2 de-

cades.2 Although mean patient age at presentation seems tobe decreasing in the United States and the survival of pa-tients with unilateral tumors has improved,3 the incidenceof bilateral TGCTs is expected to increase.

We have also noted an increase in the incidence of bilat-eral TGCT in our patient population in the last decade. Wedefined the incidence, risk factors and treatment outcome inpatients with bilateral TGCT who were treated and followedat 2 academic tertiary referral centers in Turkey.

MATERIALS AND METHODS

Data on 22 and 8 patients were gathered from 2 large urol-ogy departments in Turkey, including Hacettepe UniversitySchool of Medicine, Ankara, and Tepecik Research andTraining Hospital, Izmir, respectively, between 1980 and2005 for this retrospective study. During the study years atotal of 987 patients with TGCT were treated at these cen-

Submitted for publication November 5, 2006.* Correspondence: Kuleli Sokak 9/2, Gazi Osman Pasa, Ankara

06700, Turkey (telephone: �90 312 4424042; FAX: �90 3124424136; e-mail: ho02-k@tr.net).

0022-5347/07/1781-0129/0THE JOURNAL OF UROLOGY®

Copyright © 2007 by AMERICAN UROLOGICAL ASSOCIATION

129

ters, of whom 30 (3.0%) had bilateral disease. Clinical char-acteristics, histopathology and followup data were obtainedfrom patient medical records and special followup files.

All patients underwent radical inguinal orchiectomy af-ter diagnostic procedures, as described previously.4 How-ever, only 1 patient underwent TSS, which was done forright metachronous testicular tumor. He subsequently un-derwent right orchiectomy due to tumor recurrence in theremaining testis parenchyma. On the other hand, contralat-eral testis biopsy was not performed routinely. The RoyalMarsden Hospital Staging System was used for surgicalstaging.5 According to histopathology results all cases wereclassified into 2 groups as seminomatous if histopathologyrevealed pure seminoma, and as NSGCT.

The choice of treatment modality was based on histo-logical type, clinical tumor stage and earlier treatmentmodalities, as defined previously.4 Patients with stage 1,2A seminoma received radiotherapy focused on the retro-peritoneum. Patients with metachronous stage 1 seminomawho had received radiotherapy initially and those with stage1 NSGCT were included in the surveillance protocol. Allother patients with metastasis received chemotherapy.

Indications for surgery following chemotherapy were nor-malization of markers (�-fetoprotein and/or �-humanchronic gonadotropin) and partial remission of metastatic

disease. Only 3 patients received testosterone gel since tes-

Vol. 178, 129-133, July 2007Printed in U.S.A.

DOI:10.1016/j.juro.2007.03.027

BILATERAL TESTICULAR GERM CELL TUMORS IN TURKEY130

tosterone gel is available in Turkey only recently (50 mgtestosterone daily). All other patients received testosteronedepot injections (200 to 250 mg testosterone enanthate every3 weeks) as androgen replacement therapy.

RESULTS

The prevalence of bilateral TGCT was 2% in 552 patients in1998,4 which increased to 3.1% (22 of 718) for this particularseries at the Department of Urology, Hacettepe UniversitySchool of Medicine.

Bilateral disease developed in 30 of the 987 patients(3.04%) with TGCT who were treated at these 2 centers(table 1). Three patients had a history of cryptorchidism,which was bilateral in 1, and 4 had an atrophic testis. Of 30patients 24 had sequential tumors occurring within a me-dian interval of 75 months (range 3 to 260) and 6 (20.0%) hadsynchronous tumors. Mean � SD age at presentation was32.3 � 8.6 (median 31.5) and 26.7 � 6.3 years (median 26) inpatients presenting with synchronous and metachronoustumors, respectively (p � 0.191). Of 24 patients with metach-ronous tumors the second tumor occurred within 2 years in5 (20.8%) and within 5 years in 10 (41.7%). In patients withnonseminomatous primary tumors the secondary tumor de-veloped in a shorter mean interval than in those with semi-nomatous tumors without attaining statistically significantvalue (62.9 vs 102.4 months, p � 0.152). Most of the secondtumors had already been detected by self-examination. Self-examination was strongly recommended for followup.

Seminoma vs NonseminomaPatients with seminoma were at significantly higher riskfor bilateral disease than those with NSGCT (4.5% vs2.3%, p � 0.048). Of all patients with seminoma only 2with synchronous tumors had metastatic disease. Ad-vanced stage at initial presentation and subsequently wasmore common in patients with NSGCT compared withthose who had seminoma (initial and secondary tumor

TABLE 1. Synchronous and metachronous tumorhistopathological features

Tumor Histology 1/2 No. Pts (%)

Synchronous:Seminoma/seminoma 1 (16.7)Seminoma/seminoma � ECa 1 (16.7)

Seminoma subtotal 2 (33.4)Teratoma/teratoma 1 (16.7)Mixed GCT/mixed GCT 3 (50)

Total No. 6Metachronous:

Seminoma/seminoma 10 (41.7)Seminoma/seminoma � ECa 1 (4.2)Seminoma/teratoma 1 (4.2)Seminoma/yolk sac tumor 1 (4.2)

Seminoma subtotal 13 (54.2)ECa/ECa 3 (12.5)ECa/ECa � teratoma 1 (4.2)ECa/seminoma 1 (4.2)

ECa subtotal 5 (20.8)Teratoma/seminoma 3 (12.5)Mixed GCT/seminoma 1 (4.2)Mixed GCT/ECa 1 (4.2)Mixed GCT/seminoma � ECa 1 (4.2)

Mixed GCT subtotal 3 (12.5)

Total No. 24

66.3% vs 13.3%, p � 0.007 and 42.9% vs 6.3%, p � 0.018,respectively).

Synchronous TumorsAll 6 patients with synchronous tumors had similar tumorhistology on the 2 sides and metastatic disease at presenta-tion. In addition, synchronous tumors carried significantlymore risk since they presented at advanced stage comparedwith metachronous tumors (100.0% vs 25.0%, p � 0.001).Four of 6 patients had nonseminomatous histology and theremaining 2 had seminoma. Furthermore, increased serumtumor markers were observed in 66.7% of the patients withsynchronous tumors.

Metachronous TumorsOf 24 patients with metachronous tumors the initial tumorwas seminoma in 13 and NSGCT in 11. Ten patients withinitial seminoma had a second seminoma and 6 of the 11who presented with NSGCT as the initial tumor had asecondary NSGCT. Disease was stage 1 in 75% of theoriginal lesions and in 95.8% of the subsequent tumors(p � 0.077, table 2). In addition, primary tumors weresignificantly larger than secondary tumors (mean largestdiameter 4.78 � 1.76 vs 2.59 � 1.62 cm, p � 0.001). Seven ofthe 24 patients (29.2%) with metachronous tumor had ECacomponents at initial presentation, of whom 6 (85.7%) alsohad ECa components at subsequent presentation (p �0.001).Considering metachronous tumors, �-fetoprotein and/or�-human chronic gonadotropin were increased in 13 (54.2%)and 7 patients (29.2%) at initial and subsequent presenta-tion, respectively (p � 0.047). Secondary tumors receivedsignificantly less adjuvant radiotherapy but more surveil-lance policy compared to initial treatment (table 2).

TreatmentOf the 24 metachronous tumors 13 (54.2%) received radio-therapy to the retroperitoneum, 6 (25%) received chemother-apy and 5 (20.8%) received surveillance as initial therapy.However, only 1 patient needed surgery after chemotherapy.Radiotherapy, chemotherapy and surveillance were done in20.8%, 16.7% and 62.5% of patients, respectively, for subse-quent tumors. Only 1 of the 24 patients (4.2%) with me-tachronous tumor had metastasis at second orchiectomy.Serum markers remained high in 2 patients with stage 1disease, who received chemotherapy.

All synchronous tumors were associated with metastaticdiseases at presentation. All patients with metastatic dis-ease responded well to chemotherapy. Three patients withsynchronous tumors underwent surgery after chemotherapydue to partial remission. Median followup after the first andsecond TGCTs was 128 (range 41 to 348) and 47 months(range 12 to 204), respectively. All patients had no evidenceof disease at last followup.

Testosterone ReplacementLibido and erectile function was satisfactory in most pa-tients with proper testosterone replacement therapy, includ-ing testosterone enanthate injection and testosterone gel.Three patients treated with injections complained of de-creased libido resulting from subtherapeutic androgen atthe end of the dose interval. However, none reported any

symptoms associated with androgen fluctuation or pain

BILATERAL TESTICULAR GERM CELL TUMORS IN TURKEY 131

caused by injection. Furthermore, patients were advised tomodify the suggested interval between injections accordingto libido. With this policy erectile function and libido weremaintained as satisfactory. Two patients experienced a tran-sient increase in hepatic transaminases, which resolved fol-lowing the cessation of injections.

DISCUSSION

Incidence and IntervalYossepowitch and Baniel calculated that the crude incidenceof bilateral TGCT was 1% to 3.6% by analyzing data from 9published series including more than 10,000 patients.6 An-other recent review showed that reported cumulative inci-dence rates increased from 1.2% to 5.2% in 15 years.7 Ourdata correlated well with these rates (3.0%). Only few stud-ies have focused on the increase in the incidence of bilateralcases.8 Although survival in these particular patients hasimproved dramatically during the last 20 years and con-tralateral tumors may develop many years after the firstone, the increase in the incidence is not surprising. Therewas a similar trend at Hacettepe University, where theincidence of bilateral cases increased from 2% to 3.0% in thelast decade.4 On the other hand, an increase was not re-ported in a recent series from Spain.7

RisksAlthough there is controversy about chemotherapy for tes-ticular cancer, chemotherapy for the initial testis tumorcould potentially prevent or delay the development of acontralateral tumor.7 In the current series most patientswith bilateral metachronous tumors had stage 1 disease asthe primary and secondary tumors and, therefore, they didnot need chemotherapy. However, only 25% of the patientswith metachronous tumors received chemotherapy for theinitial tumor in the current series. In the study from Spain50% of patients received chemotherapy and the investiga-tors argued that this observation may have been a causativefactor.7 On the other hand, chemotherapy did not affect therate of secondary tumor development in a series reported byPamenter et al,9 while Thompson et al reported the con-trary.10

Genetic and molecular mechanisms have been speculatedabout as potential carcinogenic factors for increasing therisk of bilateral testicular cancer. Most adult TGCTs have a

TABLE 2. Metachronous tumor clinical andhistopathological features

Initial Tumor Second Tumor p Value

Mean � SD age at diagnosis 27.1 � 6.5Mean mos followup (range) 128 (41–348) 47 (12–204) —% Seminoma histology 54.2 62.5 0.113% ECa 29.2 29.2 �0.001*% Vascular invasion 26.7 13.3 0.423% Increased serum markers 54.2 29.2 0.047*Mean � SD tumor size (cm) 4.78 � 1.76 2.59 � 1.62 0.001*% Stage 1 disease 75.0 95.8 0.077% Chemotherapy 25 16.7 1.0% Radiotherapy 54.2 20.8 0.006*% Surveillance 20.8 62.5 0.027*

* Statistically significant.

characteristic isochromosome 12p (telomeric region of long

arm of chromosome 12).11 In addition, familial clusteringand bilateral tumors favor the influence of genetic factors asa potential etiological factor. It was proposed that 25% to33% of all patients with TGCT have a genetic predisposi-tion.12 Furthermore, patients in TGCT prone families areyounger at diagnosis compared with patients with a sporadicTGCT and the tumors tend to be bilateral more frequently(15% vs 5%). However, studies of bilateral testicular tumors,including the current study, show that patients with bilat-eral TGCT are the same age at clinical presentation aspatients with familial disease. In addition, a series showed ahigh prevalence of androgen receptor gene mutations inpatients with TGCT and the investigators suggested thatsome CAG/GGC combinations might be more frequently as-sociated with an increased risk of testicular cancer.13 Con-sequently animal models would probably better define thisissue in the near future by testing various hypotheses inetiopathogenetic and genetic studies.

Tumor HistologyTumor histology is a major risk factor for contralateralTGCT recurrence.3,14 In the current series patients withseminoma were at significantly higher risk for bilateral dis-ease than patients with NSGCT (4.5% vs 2.3%, p � 0.048).Similarly Che et al reported that the contralateral testistumor risk was 1.8% in patients with seminoma and 0.6% inthose with NSGCT.3 Moreover, a higher risk in patientswith seminoma was also reported in other series.15,16 On thecontrary, 2 reports showed a higher incidence of bilateralcases in patients with NSGCT compared to those with sem-inoma (8.4% vs 3.6%).8,14 Tabernero et al failed to observe aneffect of tumor histology on tumor bilaterality.7 It should beemphasized that this conclusion was reached with only 6patients in that study.

For secondary tumors the incidence of patients with clin-ical stage 1 is 44% to 91%.8,17 However, to our knowledge thestage distribution of seminoma and NSGCT at presentationhas not been previously analyzed in detail. In the currentstudy we noted that advanced stage at initial presentationand subsequently at presentation was significantly morecommon in NSGCT than that in seminoma cases. Parallel tothe literature findings, synchronous tumors were metastaticat presentation and they had similar histology on the 2sides. The exception is the study by Holzbeierlein et al, whoreported that most patients in the synchronous and meta-chronous tumor groups presented with low stage disease ina series of 58 with bilateral TGCT.18

Self-Examination vs CTBThe current study demonstrates that regular self-examina-tion of the testis was extremely important for leading pa-tients to seek medical advice and, thus, for early referral anddiagnosis. Of presented patients 95.2% had stage 1 diseaseat secondary tumor diagnosis. Furthermore, secondary tu-mors were significantly smaller than primary tumors (4.78vs 2.59 cm). All of these patients were diagnosed by self-examination or at routine followup examination by the cli-nician. Two recent published series also demonstrated thesmall size of secondary tumors (mean 1.5 and 3.0 cm, re-spectively).3,15 Similarly Albers et al reported that 25 of 30patients with bilateral tumors were detected by self-exami-

nation, of whom 83% had stage 1 disease at presentation.19

BILATERAL TESTICULAR GERM CELL TUMORS IN TURKEY132

All of our patients were in a disease-free state at the time ofthis report. Similarly in a recently reported series none ofthe 47 patients with bilateral testicular tumors died of tes-ticular cancer. However, capitalizing on the excellent sur-vival rates, routine CTB is usually not recommended.20 Inaddition, none of our patients underwent routine biopsy atinitial presentation. Although a few of them presented withmetastatic disease, all were cured by appropriate treatmentmodalities.

TSSTo maintain adequate testosterone in patients with bilateraltumors TSS may be done. However, a main problem of TSSis the concern for carcinoma in situ foci adjacent to thetumor, which was reported to be present in 82% of 73 pa-tients with bilateral or solitary tumor treated with TSS.Nevertheless, the German Testicular Cancer Study Groupreported no local relapse following primary TSS with adju-vant radiotherapy (18 Gy) and 85% of patients had normaltestosterone at long-term followup.15 Even tumor enucle-ation might be considered as an alternative approach undercertain conditions, including cold ischemia, organ con-fined tumor (less than 20 mm), multiple negative biopsiesof the tumor bed and adjuvant local irradiation postoper-atively to avoid local recurrence. Furthermore, secondarytumors have had more favorable disease stage with sig-nificantly smaller size, as reported in the current seriesand others.3,15 These features make these patients ame-nable to this management policy. TSS might be morewidely accepted in the future based on more studies withlong-term data, as reported by Hentrich et al.20 However,TSS necessitates close followup and high patient compli-ance, which could prove to be difficult due to cultural,economic and geographic reasons.

CONCLUSIONS

Randomized studies are impracticable for drawing certainconclusions about bilateral testis cancer. Our large seriesshowed an incidence of 3.0% for bilateral TGCT, parallel tothe literature. As suggested in our study, patients withinitial seminoma were at higher risk for disease recur-rence on the other side and they had more favorabledisease stage compared to those with NSGCT. Seminomais the most common histology in bilateral testicular can-cer. Although they are infrequently detected, synchronoustumors presented at more advanced stage with similarhistology on the 2 sides. Treatment for the first and secondtesticular tumor should be based on primary tumor his-tology and stage.

Patients with a history of TGCT require careful fol-lowup and self-examination of the contralateral testicledue to the risk of bilateral disease and the potentially longlatent period for a second tumor. Since long-term survivalis excellent with appropriate management and followup,CTB at initial orchiectomy is generally not recommended.TSS might be more widely accepted in the future based onmore studies with long-term data, as reported by Hentrich

et al.20

Abbreviations and Acronyms

CTB � contralateral testicular biopsyECa � embryonal carcinomaGCT � germ cell tumor

NSGCT � nonseminomatous GCTTGCT � testicular GCT

TSS � testis sparing surgery

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2. Huyghe E, Matsuda T and Thonneau P: Increasing incidence oftesticular cancer worldwide: a review. J Urol 2003; 170: 5.

3. Che M, Tamboli P, Ro JY, Park DS, Ro JS, Amato RJ et al:Bilateral testicular germ cell tumors: 20 year experience atM. D. Anderson Cancer Center. Cancer 2002; 95: 1228.

4. Tekin A, Aygun YC, Aki FT and Ozen H: Bilateral germ cellcancer of the testis: a report of 11 patients with a long termfollowup. BJU Int 2000; 85: 864.

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6. Yossepowitch O and Baniel J: Role of organ-sparing surgery ingerm cell tumors of the testis. Urology 2004; 63: 421.

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10. Thompson J, Williams CJ, Whitehouse JMA and Mead GM:Bilateral testicular germ cell tumours. An increasing inci-dence and prevention by chemotherapy. Br J Urol 1988; 62:374.

11. van Echten J, Oosterhuis JW, Looijenga LHJ, van de Pol M,Wiersema J, te Meerman GJ et al: No recurrent structuralabnormalities apart from i(12p) in primary germ cell tu-mors of the adult testis. Genes Chromosomes Cancer 1995;14: 133.

12. Nicholson PW and Harland SJ: Inheritance and testicularcancer. Br J Cancer 1995; 71: 421.

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15. Heidenreich A, Weissbach L, Holtl W, Albers P, Kliesch S,Köhrmann KU et al: Organ sparing surgery for malignantgerm cell tumors of the testis. J Urol 2001; 166: 2161.

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EDITORIAL COMMENT

Bilateral testis cancers are rare. These authors present ex-perience with 30 patients at 2 institutions during 25 years.The largest series were reported by groups from Memorial-Sloan Kettering Cancer Center (reference 18 in article) andHungary.1

Take-home points for practicing urologists, who may see

1 case in a lifetime, urology residents in training and those

at academic centers with a large volume of testis cancerare 1) long-term followup and self-examination are needed,2) seminoma is the most common histology in bilateral tes-ticular cancer, 3) treatment for the first and second testicu-lar tumors should be based on primary tumor histology andstage, 4) TSS might be more widely accepted based on thelong-term followup, as reported by Hentrich et al (reference20 in article), and 5) biopsy of the contralateral testis atinitial orchiectomy is generally not recommended.

W. Bedford WatersDivision of Urology

University of Tennessee Medical CenterKnoxville, Tennessee

1. Geczi L, Gomez F, Bak M and Bodrogi I: The incidence, prog-nosis, clinical and histological characteristics, treatment,and outcome of patients with bilateral germ cell testicular

cancer in Hungary. J Cancer Res Clin Oncol 2003; 129: 309.