Unilateral Testicular Germ Cell Tumor Research Articles

Analysis of clinical characteristics, treatment patterns, and outcome of patients with bilateral testicular germ cell tumors

IntroductionBilateral testicular germ cell tumor (BGCT) is a rare disease, occasionally considered to be more aggressive than unilateral germ cell tumors (GCT) in some reports. Among BGCT, a synchronous disease might be diagnosed at a higher stage than a metachronous disease, resulting in lower cancer-specific survival. Hence, our study aimed to perform a comparative analysis between unilateral testicular GCT, bilateral synchronous GCT, and bilateral metachronous GCT, aiming to verify the possibility that BGCT is diagnosed with a higher stage and may require more aggressive management.Material and methodsIn our multicenter retrospective study we reviewed medical records of 40 patients with BGCT (24 metachronous and 16 synchronous). Clinical characteristics, pathological features of the primary and secondary tumors, adjuvant treatments (chemotherapy and radiotherapy)and sperm quality were evaluated as well as cancer-specific survival and overall survival. A cohort of one-to-one matched patients with unilateral GCT were used to determine risk factors for developing BGCT.ResultsPatients with BGCT were slightly younger compared to those with unilateral GCT and had more advanced disease. Despite similar T-stage distribution between the two groups, nodal involvement was nearly twofold more frequent in patients with BGCT disease (42% vs 22%, p = 0.056). Additionally, although similar histological subtypes distribution at presentation among the two groups, the synchronous disease was diagnosed with a higher local T-stage (OR = 3.4), higher proportions of patients with elevated serum BHCG levels, and more frequent nodal involvement (OR = 2.2). This was later translated into an 18% higher disease-specific mortality rate. The median time to develop a contralateral tumor was 92 months. Pathological local T-stage (T2–T3) of the primary tumor predicted a shorter time interval to a diagnosis of a second contralateral tumor (HR 0.92, P < 0.05).ConclusionBGCT presents at a younger age and potentially with more advanced disease. Synchronous BGCT is diagnosed at a later stage compared to metachronous BGCT and has higher disease-specific mortality. Metachronous tumors might have a long time interval for the development of a contralateral neoplasm. The main predictor of developing an early metachronous disease is a high primary T stage.

Sperm Concentration, Testicular Volume and Age Predict Risk of Carcinoma In Situ in Contralateral Testis of Men with Testicular Germ Cell Cancer

We investigated whether semen quality or some easily attainable clinical parameters might be used to estimate the risk of contralateral carcinoma in situ in patients with unilateral testicular germ cell tumors. A total of 264 Danish patients with testicular germ cell tumor with or without contralateral testicular carcinoma in situ were retrospectively investigated. Clinical data included andrological history, physical examination, testis ultrasonography, semen quality and testis histology. Study groups were compared by univariate linear regression analysis and the chi-square test. Associations between contralateral carcinoma in situ and risk factors were modeled in 2 stages: Bayes rule was used to assess the probability of carcinoma in situ; the terms in Bayes rule were estimated using regression models. Significant characteristics of patients with contralateral carcinoma insitu were lower sperm concentration, smaller contralateral testis volume, irregular ultrasonic echo pattern of the contralateral testis and younger age. Cutoff values of sperm concentration and testicular volume were defined. However, according to these only a minority of the noncarcinoma in situ cases could potentially have been spared a diagnostic testicular biopsy. Combining information on age and sperm concentration, secondly age and testis volume resulted in models of the estimated contralateral carcinoma in situ risk, from which patients at particular high risk of carcinoma in situ could be identified. The combined information on sperm concentration, age and contralateral testis volume predict the risk of contralateral carcinoma in situ in patients with unilateral testicular germ cell tumor. The proposed models may facilitate selection of patients with testicular germ cell tumor for contralateral testicular biopsy at the time of orchiectomy if this is not routinely done.

Testicular microlithiasis in Japanese male infertility patients: Clinical implications for predicting future testicular malignancy.

e15579 Background: Testicular microlithiasis (TM) is commonly diagnosed by scrotal ultrasonography (US) in which it appears as multiple, small, uniform, echogenic foci without shadowing, scattered randomly throughout the testicular parenchyma. It is also prevalent in several urologic diseases including subfertility and testicular germ cell tumor. TM has been reported to be associated with carcinoma in situ (CIS) and the development of second testicular germ cell tumor (TGCT) after contralateral orchiectomy treatment for primary TGCT; however, no prospective studies have investigated the relationship between the detection of TM in patients without TGCT and future development of TGCT. In the present study, therefore, we investigated the prevalence of TM in the testes of male infertility patients and unilateral TGCT patients to determine if TM could be a predictor of future germ cell tumor in such patients. Methods: A total of 1,139 subfertile patients (296 with nonobstructive azoospermia, 58 with obstructive azoospermia, and 785 with oligozoospermia) and 22 unilateral testicular germ cell tumor patients were enrolled in the study. Prevalence of testicular microlithiasis according to testicular ultrasonography was compared between patients, and development of testicular germ cell tumors was monitored for at least 3 years. All patients were fully informed about the study, and their prior consent was obtained according to the recommendation of the institutional ethics committee. Results: The prevalence of TM was significantly higher in unilateral TGCT patients (40.9%) than in subfertile men (8.6%). No infertile patients without TM developed TGCT but one infertile patient with TM developed TGCT (seminoma) during follow up. One seminoma patient with TM in his remaining testis went on to developed testicular seminoma 3years after primary surgery. Conclusions: Testicular microlithiasis is more common in testicular germ cell tumor patients than in subfertile men. Since TM could be a surrogate marker for future TGCT in both patient populations, TM patients are recommended to perform careful self-checking of the testes and periodical testicular ultrasonography.

Risk of metachronous contralateral testicular germ cell tumors: A population‐based study of 7,102 Norwegian patients (1953–2007)

The purpose of the study was to identify overall incidence and risk of developing a metachronous contralateral testicular germ cell tumor (TGCT) and compare the risk for patients treated before and after 1980 (cisplatin became available for patients with metastatic TGCT). Our hypothesis was that the risk of metachronous TCGT would be reduced for patients with metastatic disease diagnosed after 1980. We included 7,102 men with unilateral TGCT, recorded in the Cancer Registry of Norway. Allowing for competing risk, cumulative incidence and adjusted hazard ratio (HR) were estimated for different subgroups, and the diagnostic periods 1953-1979 (I) and 1980-2007 (II). Relative risks were assessed by standardized incidence ratio (SIR). In Period I and Period II, 38 and 137 males, respectively, were diagnosed with metachronous contralateral TGCT. Corresponding 20-year cumulative incidences were 1.9% and 3.9%. In Period II, risk of a second TGCT was halved [HR = 0.5, 95% confidence interval (95% CI) = 0.33-0.77] for patients with metastatic compared to localized disease. For patients presenting with localized and metastatic disease, the SIRs for Period I were 14.6 (95% CI = 9.6-21.2) and 25.3 (95% CI = 12.1-46.5), respectively. In Period II, the corresponding numbers were 19.0 (95% CI = 15.6-22.9) and 9.8 (95% CI = 6.4-14.5). In conclusion, the risk of metachronous contralateral TGCT was halved for patients with metastatic compared to localized disease in Period II, whereas this protective effect of extent of disease lacked significance for Period I. These findings support our hypothesis that cisplatin-based chemotherapy reduced the risk of a second TGCT for patients with metastatic TGCT diagnosed after 1980.

Management and outcome of bilateral testicular germ cell tumors: A 25‐year single center experience

To analyze risk factors, management, histology, and outcome of bilateral testicular germ cell tumors (TGCT) based on a 25-year single center experience. Out of 612 patients treated for TGCT between 1982 and 2007, 17 (3%) were found to have bilateral disease. Data of these patients were reviewed and analyzed. Eleven patients (65%) were identified with metachronous and 6 (35%) with synchronous bilateral TGCT. One patient had a cryptorchism in childhood. Patients with metachronous bilateral disease presented at lower stages than those with synchronous bilateral disease (stage I: 82% vs 33%, P = 0.02). In metachronous bilateral TGCT, the interval between the tumors ranged from 4 months to 25 years with a median of 47 months. The risk of developing a TGCT in the contralateral testicle was 26-fold higher than the a-priori risk for a healthy individual to develop TGCT. Overall, 74% of the bilateral tumors were seminomas and >50% of the patients had similar histology on both sides. After a median follow up of 121 months for patients with synchronous and 95 months for patients with metachronous bilateral TGCT, all patients were alive with no evidence of disease. Most bilateral TGCT develop metachronously and are seminomas. Although patients with synchronous bilateral disease present at higher stages, both synchronous and metachronous bilateral TGCT carry a similar, excellent prognosis. Patients with unilateral TGCT require careful long-term monitoring of the remaining testicle due to a 26-fold increased risk of contralateral disease and a potentially long risk interval of up to 25 years.

Somatic KIT mutations occur predominantly in seminoma germ cell tumors and are not predictive of bilateral disease: Report of 220 tumors and review of literature

Mutations in the KIT gene occur in approximately 8% of all testicular germ cell tumors (TGCT) and KIT is the most frequently mutated known cancer gene. One report has shown that 93% of patients with bilateral disease have a mutation at codon 816 of the KIT gene. Importantly, this suggests that the identification of a mutation in KIT is predictive of the development of a contralateral TGCT. We investigated the frequency and type of mutations in KIT in a series of 220 tumors from 211 patients with TGCTs and extragonadal germ cell tumors. In 170 patients with unilateral TGCT and no additional germ cell tumour, we identified one exon 11 mutation in a patient with unilateral TGCT and eight activating KIT mutations in exon 17 (9/175, 5.1%). In 32 patients with bilateral TGCT, one patient had an activating KIT mutation in exon 17 (3.1%). The incidence of activating KIT mutations in sporadic TGCT vs. familial TGCT was not significantly different. All mutations were identified in seminomas. Three extragonadal primary germ cell tumors were examined and in one tumor an activating KIT mutation was demonstrated in the pineal germinoma. Interestingly, this mutation was also seen in the patient's testicular seminoma. We find no evidence for an increased frequency of KIT mutations in bilateral TGCT.

Testicular microlithiasis identified ultrasonographically in Japanese adult patients: Prevalence and associated conditions

Objectives To determine the prevalence of testicular microlithiasis (TM) seen by testicular ultrasonography (US) in Japanese adult men referred for andrologic symptoms and evaluate associations of TM with pathologic conditions. Methods For 7 years, US was performed in 969 patients (mean age 40.9 years) at one institution. The patients were divided into groups with infertility (n = 550), unilateral testicular tumor (n = 46), or other andrologic conditions (n = 373). TM was identified as multiple small hyperechogenic foci. In the tumor group, only images of the tumor-free testis were reviewed. Patients with TM accompanying tumor or infertility completed follow-up questionnaires and US examinations. Results TM was diagnosed in 46 patients (mean age 38.5 years, range 23 to 75). The prevalence of TM was 17.4% in the tumor group, 5.6% in the infertility group, and 1.9% in the other-conditions group. TM was associated with testicular tumor and infertility, but not with other conditions. In patients with unilateral testicular germ cell tumor, the prevalence of carcinoma in situ in the contralateral testis was greater when TM was present in that testis (2 of 8 patients) than when TM was absent (0 of 32, P = 0.0037). No new testicular tumor developed subsequently. In the infertility group, the 31 patients with TM showed no subsequent testicular tumor development, and neither patient undergoing testicular biopsy had carcinoma in situ. Conclusions TM, as demonstrated by US, was associated with infertility, as well as testicular tumor. TM in a testis contralateral to a unilateral testicular germ cell tumor may increase the risk of carcinoma in situ.

Testicular cancer susceptibility in the 129.MOLF-Chr19 mouse strain: additive effects, gene interactions and epigenetic modifications.

Testicular germ cell tumors (TGCTs) are the most common solid cancers affecting young men. Although the evidence for genetic predisposition to TGCTs in humans is compelling, the genetic control of susceptibility is poorly understood. The 129S1/SvImJ (129/Sv) inbred strain of mice is an excellent model for studying TGCT susceptibility. We previously reported a new mouse strain, the 129.MOLF-Chr19 chromosome substitution strain, which develops spontaneous TGCTs at a high frequency (70-80%) as compared with the much lower rate in the 129/Sv strain (5%). To characterize the genetic control of TGCT susceptibility, we created a panel of single- and double-congenic strains derived from 129.MOLF-Chr19. The frequency of TGCTs in these strains suggests that several genes with additive and epistatic effects located at distinct sites on chromosome 19 control susceptibility. However, an alternative interpretation involving epigenesis is based on a striking correlation between TGCT frequency and the length of the MOLF-derived congenic segment, regardless of their chromosomal location on Chr 19 in each congenic strain. We also show that bilateral TGCT cases result from the coincidental co-occurrence of unilateral TGCTs rather than from the action of distinct genes that control susceptibility to bilateral versus unilateral TGCT cases. Finally, we propose that these TGCTs result from disrupted testicular and spermatogenic developmental programs.

Contralateral testicular biopsy procedure in patients with unilateral testis cancer: is it indicated?

About 5% of all patients with unilateral testis cancer harbor testicular intraepithelial neoplasia (TIN) in their contralateral testicle, which will progress into an invasive germ-cell tumor over time. Accurate diagnosis of TIN by a random surgical testis biopsy examination and effective therapy by local radiation has led to the concept of a contralateral screening biopsy procedure in all testis cancer patients. Screening and preventive treatment, however, only are indicated if (1) therapeutic outcome of the screened population is improved and (2) physiologic function of the affected organ might be maintained. Based on a critical review of the literature, some drawbacks of this policy have to be considered and the routine indication for contralateral testis biopsy procedure has to be questioned: (1) all TIN-negative patients still have to undergo meticulous follow-up evaluation for metachronous testis cancer owing to a false-negative biopsy diagnosis rate of 0.3%; (2) testis biopsy procedure is associated with a 15% to 20% complication rate, which might a negative impact on endocrine and exocrine testicular function; (3) local radiation of TIN results in irreversible infertility owing to eradication of spermatogenesis; (4) local radiation of TIN results in an impairment of endocrine Leydig cell function in 25% of patients; (5) therapeutic outcome and prognosis will not be improved in irradiated patients as compared with patients on surveillance; (6) local tumor resection for the management of metachronous testicular cancer represents an effective and viable option. The current literature does not support the strategy to perform contralateral testis biopsy procedures in all patients with unilateral testicular germ-cell tumors. Testis biopsy procedures might, however, be offered to high-risk (34%) patients for contralateral TIN with a testicular volume less than 12 mL, a history of cryptorchidism, and an age less than 30 years.

Prevalence of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell neoplasms.

Testicular intraepithelial neoplasia ([TIN], so-called carcinoma in situ of the testis) is hypothesized to be the precursor of testicular germ cell neoplasms. According to previous studies, it can be detected by testicular biopsy. Since patients with a unilateral testicular tumor are at high risk of a second testicular tumor, it seemed feasible to examine the prevalence of contralateral TIN in patients with testicular germ cell cancer and correlate it with the known prevalence of bilateral testicular tumors. The aim was to provide more evidence for the role of TIN as the preinvasive stage of testicular cancer. Nineteen hundred fifty-four consecutive patients with a unilateral testicular germ cell tumor underwent contralateral biopsy. All specimens were examined immunohistologically. TIN was observed in 4.9% (95% confidence interval [CI], 3.95% to 5.91%). Testicular atrophy and a history of undescended testis were more frequently observed in patients with contralateral TIN, but only atrophy was shown to be independently associated by multivariate analysis. Patients with testicular atrophy have a 4.3-fold increased risk of having contralateral TIN. Sixty-four percent of TIN cases were found in normal testes. Patients with TIN were significantly younger than those without (P < .0017). Three patients developed a second testicular tumor despite a negative biopsy for TIN. The prevalence of contralateral TIN corresponds well to the known prevalence of bilateral testicular tumors. Testicular atrophy is a strong indicator for the presence of TIN, but approximately 60% of TIN cases occur without atrophy. The present data are in accordance with the theory that TIN is an early step in the histogenesis of testicular germ cell neoplasms.

Low-dose radiation therapy for testicular intraepithelial neoplasia.

Four patients with unilateral testicular germ-cell tumor and biopsy-proven contralateral testicular intraepithelial neoplasia (TIN; so-called carcinoma in situ) received localized low-dose radiation therapy (18-20 Gy) of the testis with TIN. Repeated biopsies disclosed the disappearance of TIN and germ cells. No recurrence of TIN or germ cells was observed after a follow-up of 18-42 months. All patients reported a normal sex life without need of androgen supplementation. Serum follicle-stimulating hormone increased significantly immediately after radiation treatment and started to decline after 24 months. Serum luteinizing hormone increased slightly but not significantly. A decline after 24 months was observed in only one of three patients. Serum testosterone decreased significantly in all patients after 1 year but never became subnormal. Low-dose radiation treatment is efficacious in eradicating testicular intraepithelial neoplasia without destroying Leydig cells or stromal cells of the testis. Thus, a patient otherwise destined to develop a second testicular tumor can be spared orchiectomy and life-long hormonal replacement.