Surveillance for stage I testicular germ cell tumours: results and cost benefit analysis of management options

Between 1979 and 1996 303 men with stage I testicular germ cell tumours (120 seminoma and 183 non-seminomatous germ cell tumours (NSGCT)) were enrolled onto a programme of surveillance. In our institutions the frequency of computed tomography (CT) scans is reduced compared with other centres. For all 303 men, the median follow-up is 5.1 years (range: 0.1-21.7 years) and there have only been 3 deaths (1 from disease, 1 from neutropenic sepsis and 1 from secondary leukaemia). 52/183 (28%) patients with NSGCT and 18/120 (15%) patients with seminoma have relapsed. The relapse-free survival at 5 years is 82% for seminoma and 69% for NSGCT (Logrank P=0.004). All men who relapsed, except 1 man with NSGCT, were in the International Germ Cell Cancer Collaborative Group good or intermediate prognosis group at relapse. Half of the seminoma relapses presented with symptoms and 31% of the NSGCT relapses. The remaining relapses were detected serologically or radiologically by the surveillance programme. 5 men (2%) on surveillance, 3 with initial diagnosis of seminoma and 2 with NSGCT, have developed second contralateral testis tumours (all stage I seminomas). In a well motivated centre a policy of surveillance for stage I testicular germ cell tumours (both NSGCT and seminoma) is associated with a low mortality rate (3/303, 1%) and may have the advantage of sparing overtreatment with potentially toxic therapies in this group of young men.     

Long-term morbidity of adjuvant infradiaphragmatic irradiation in patients with testicular cancer and implications for the treatment of stage I seminoma

Long-term abdominal or urological morbidity and second malignancies in 289 surviving patients with infradiaphragmatic adjuvant radiotherapy (RT) for testicular cancer between 1950 and 1988 are analysed by retrospective chart review. After RT with single doses between 1.5 and 2.0 Gy and a total dose between 30 and 35 Gy, we did not observe any peptic ulcer nor other abdominal or urological long-term morbidity, except second tumours. The cumulative incidence of 16 second extratesticular malignancy was (in years after RT): 0.4% (4 years), 1.3% (9 years), 4.5% (14 years), 6.3% (19 years), 7.5% (24 years), 15.6% (29 years) and 23.6% (35 years). The ratio of observed to expected incidence of extratesticular malignancies did not differ significantly from unity; only the frequency of penile cancer (n = 2) was somewhat higher than expected. The cumulative risk of bilateral testicular cancer was 4.8% with no difference between patients with seminoma or non-seminomatous germ cell tumours. In a recent group of 128 patients with a stage I seminoma staged and treated between 1978 and 1988 by modern standard, there was no recurrence.     

The management and outcome of patients with germ-cell tumours treated in the Edinburgh Cancer Centre between 1988 and 2002

AimsThe aim of this retrospective analysis was to review the outcome of patients with germ-cell tumours treated in the Edinburgh Cancer Centre over the past 15 years, and to see whether there had been any changes over three 5-year cohorts.Materials and methodsPatients referred with gonadal and extra-gonadal primary germ-cell tumours, between 1988 and 2002, were identified from the departmental database, and survival by stage and prognostic group was analysed.Results and conclusionsThe proportion of patients with stage I seminoma has significantly increased. The good prognosis of patients with early stage disease is confirmed, with the outcome for some groups of patients being better than expected. There is a non-significant trend to improved results over the three 5-year cohorts. The outcome for patients with stage IV seminoma is worse than would be expected, but numbers are small. The poor prognosis of patients with non-seminomatous germ-cell tumours who fall into the International Germ Cell Consensus Classification (IGCCC) poor-prognostic group is confirmed. Failure of patients with metastatic non-seminomatous germ-cell tumours to achieve a complete response to initial therapy is shown to be a poor prognostic indicator.     

Germ cell tumours in uncorrected cryptorchid testis at Institute Rotary Cancer Hospital, New Delhi.

Twenty-four out of 164 (14%) adult patients with primary germ cell tumours of testis seen over the last 6 years at the Institute Rotary Cancer Hospital (IRCH) of the All India Institute of Medical Sciences (AIIMS), New Delhi, were found to have cryptorchidism. Only one patient had undergone correction. As a result the testes were intra-abdominal in the vast majority, and patients presented late. Twenty-two patients presented with stage IIb or more advanced disease. Twelve patients had seminoma and the others had mixed or non-seminomatous germ cell tumour (NSGCT), i.e. 50% each. The earlier patients were managed by initial resection followed by radiation and/or chemotherapy. As experience grew the seven patients who presented late were given initial chemotherapy followed by resection in those with residual tumours. The probability of overall survival was 0.65 at 36 months and, was not significantly different from survival in 114 patients with tumours of normally descended testis. Early orchipexy facilitates the detection, but whether it reduces the incidence of tumours is controversial. Uncorrected cryptorchidism is now rarely seen in the West, but in India and many other developing countries tumours of uncorrected cryptorchid testes continue to be seen.     

Cytogenetics, ploidy and differentiation of human testicular, ovarian and extragonadal germ cell tumours

Data from cytogenetics of testicular, ovarian and extragonadal germ cell tumours indicate that the group of germ cell tumours for which Skakkebaek proposed the name gonocytoma (seminoma, dysgerminoma and germinoma) is characterized by the presence of isochromosome 12p. The (dysplastic) gonocytes from which these tumours are derived are prone to polyploidization, especially in the gonads. There is evidence that non-seminomatous germ cell tumours in the testis may evolve through a (subclinical?) gonocytoma stage by loss of chromosomes. Since gonocytomas have already acquired the i(12p) marker, evolution of non-seminomatous germ cell tumours from gonocytomas would explain the presence of i(12p) in non-seminomatous germ cell tumours of the adult testis. A similar evolution may account for the presence of i(12p) in testicular type non-seminomatous germ cell tumours occurring in the ovary and extragonadally.     

Positive expressions of N-acetylglucosaminyltransferase-V (GnT-V) and beta1-6 branching N-linked oligosaccharides in human testicular germ cells diminish during malignant transformation and progression

N-acetylglucosaminyltransferase-V (GnT-V) is an enzyme that catalyzes beta1-6 branching of N-acetylglucosamine on asparagines (N)-linked oligosaccharides of cell proteins. We examined the implication of GnT-V and beta1-6 branching N-linked oligosaccharide expression in human testicular germ cells during malignant transformation and cancer progression. We analyzed immuhistochemically orchiectomy specimens of 130 patients with testicular germ cell tumors (TGCT) using anti-GnT-V monoclonal antibody, and compared GnT-V expression with clinicopathological features. N-linked oligosaccharide structural analysis was also performed to confirm the oligosaccharide profile produced by GnT-V. GnT-V was positive in all normal testis samples. This positive incidence declined in TGCT according to clinical stage; 16/71 (22.5%) in stage I, and 3/59 (5.1%) in stage II/III (p=0.015, chi(2) test). When divided into pathological subtypes, GnT-V positive incidences in stage I seminoma, stage II/III seminoma, stage I non-seminomatous germ cell tumor (NSGCT), and stage II/III NSGCT were 3/43 (7%), 0/22 (0%), 13/28 (46.4%), and 3/37 (8.1%), respectively. In stage I NSGCT, patients with GnT-V-negative tumor samples were at a significantly higher risk of recurrence than those with GnT-V-positive tumors (p=0.015, log-rank test). N-linked oligosaccharide structural analysis revealed that a normal testis has three kinds of beta1-6 branching N-linked oligosaccharides, all of which are downregulated in TGCT tissues. These results suggest that GnT-V and beta1-6 branching N-linked oligosaccharide expressions are downregulated during carcinogenesis and progression of human TGCT. GnT-V may be a promising recurrence predictor for stage I NSGCT.     

Non-Seminomatous Testicular Germ Cell Tumours in Denmark 1976-1980 Results of Treatment

Over a 5-year period (1976-1980) 499 patients with non-seminomatous testicular germ cell tumours were included in the Danish Testicular Carcinoma Study (DATECA). The 3-year crude survival for patients in clinical stages I, II and III was 91, 77 and 45 per cent, respectively. In stage I the relapse-free survival for patients given radiation combined with bleomycin and vincristine was significantly higher than that for patients given radiation alone. No difference in the crude survival was observed. For stage II patients maintenance chemotherapy following radiation combined with bleomycin and vincristine did not improve relapse-free or crude survival. The survival of patients with non-seminomatous tumours improved significantly during the 5-year period. This improvement was probably due to the introduction of cis-platinum in the treatment.     

睾丸生殖细胞肿瘤综合治疗的长期疗效

目的 分析睾丸生殖细胞肿瘤(TGCTs)患者的临床特征、综合治疗疗效、生存率以及与预后有关的因素。方法 对107例行高位睾丸切除 精索静脉结扎术、术后均行化疗的TGCTs患者进行回顾性分析。近期疗效比较采用χ^2检验;生存率的计算采用Kaplan-Meiel生存曲线;生存率的比较采用Log rank检验。结果 107例患者中位年龄32岁。精原细胞瘤33例(30．8％),其中Ⅰ期14例,占42．4％;非精原细胞瘤74例(69．2％),其中I期21例,占28．4％。临床分期和病理类型是影响患者预后的主要因素。患者总的3,5,10年生存率分别为75．8％、73．5％和73．5％。精原细胞瘤患者3,5,10年生存率分别为100％、96．8％和96．8％;非精原细胞瘤患者3,5,10年生存率分别为63、5％、61．7％和61．7％。64例患者可评价疗效,单用化疗的患者中,17例(26,6％)达CR,另有8例(12．5％)化疗加放疗或解救手术后达CR。获CR与未获CR者5年生存率分别为91．7％和26．2％。结论 Ⅰ期TGCTs预后好。采用以化疗为主的综合治疗可明显提高转移性TGCTs患者的疗效和生存率。     

Clinical profile and problems of management of 108 cases of germ cell tumours of testis at Institute Rotary Cancer Hospital, All India Institute of Medical Sciences New Delhi 1985-1990.

A retrospective analysis of 108 cases of primary germ cell tumours of testis seen over a 6 year period at Institute Rotary Cancer Hospital of All India Institute of Medical Sciences, New Delhi is presented. There were 45 (42%) cases of seminoma and 63 (48%) of non-seminomatous germ cell tumours (NSGCT). The median age at presentation was 35 and 30 years respectively. Almost half (56) patients presented in advanced stage (stages IIc-IV). Tumours in undescended testis formed an important subgroup (14%). The standard approach of treatment was radiotherapy in stages I & II seminomas and chemotherapy in bulky seminomas and metastatic NSGCT. Chemotherapy protocols used were VAB-6 and PVB. Although a policy of surveillance has been practised for stage I NSGCT, it is debatable whether it is universally suitable for our patients. The results of treatment in low volume disease are comparable to that in the west but the management of bulky disease requires a more aggressive approach. Unfortunately only 74 out of 108 (68.5%) patients were able to complete the treatment prescribed. Most of the defaulters were from the chemotherapy group because of inability to afford the drugs. The probability of survival of those who completed treatment was 0.77 at 4 years. Since testicular tumours are largely curable, a more vigorous policy of detection, follow up and treatment needs to be pursued. Better screening of children with undescended testis will reduce cancer in this group. Failure to provide chemotherapy to all patients is particularly unfortunate for a curable disease like testis cancer.     

Glutathione S-transferase expression in the human testis and testicular germ cell neoplasia.

Glutathione S-transferase (GST) isoenzyme expression is altered in a variety of neoplasms and the enzymes are implicated in metabolism of carcinogens and resistance to drugs, including cisplatin. We have studied GST Alpha, Pi, Mu and microsomal isoenzyme expression by immunohistochemistry in normal and cryptorchid testes, intratubal germ cell neoplasia (ITGCN), seminoma and non-seminomatous germ cell tumours. In 16 stage II-IV malignant teratoma intermediate (MTI) both orchidectomy and post-treatment residual surgical masses were studied. All four isoenzymes were strongly expressed in Leydig and Sertoli cells. GST Pi was absent from normal spermatogonia but strongly expressed by the neoplastic germ cells of ITGCN and seminoma. GST Pi was strongly expressed in all elements of teratoma, irrespective of differentiation. There were no qualitative differences in expression between primary and post-chemotherapy metastases. GST Alpha expression in teratoma correlated with epithelial differentiation. GSTs may be important in normal spermatogenesis and protection of germ cells from teratogens and carcinogens. They may have a role in testicular tumour drug resistance but this role is not well defined. GST Pi is a new marker for ITGCN.     

Multimodality treatment of malignant germ cell tumours of the mediastinum

Of 15 patients with malignant germ cell tumours of the mediastinum, 9 patients had pure seminomas and 6 had non-seminomas. Resection was radical in only 4 non-seminomas, 1 of which was resected after chemotherapy; radiotherapy was delivered to all seminoma patients as sole therapy (2 patients) or as part of combined modality therapy. All patients with non-seminomatous tumours underwent chemotherapy (cisplatin-based combination). Therapy was generally well tolerated, but 1 seminoma patient died of sepsis. Chemotherapy achieved a 71% complete response rate in pure seminoma patients and a 33% complete response rate in non-seminoma patients. 53% of patients are alive and free of disease beyond 36 months from start of any treatment. Pure seminoma patients survived longer than non-seminoma patients (3 and 5 year survivals were 67% and 33%, respectively). Although cisplatin-based chemotherapy is highly effective in pure seminomas and also in non-seminomas, a better therapeutic approach is needed in non-seminomas.     

Treatment and outcome of patients with extragonadal germ cell tumours--the Norwegian Radium Hospital's experience 1979-94.

This report reviews 48 patients who from 1979 to 1994 were treated at the Norwegian Radium Hospital for newly diagnosed noncerebral extragonadal malignant germ cell tumour (EGGCT). Based on histology and/or serum tumour markers, 12 patients had a seminoma and 36 a non-seminoma. At diagnosis, 33 and 15 patients were classified as having abdominal and mediastinal EGGCT respectively. At the time of diagnosis 13 patients, all with non-seminomatous tumours, had metastases to bone, liver or brain. One patient with abdominal seminoma was cured by radiotherapy alone, whereas cisplatin-based chemotherapy (with or without surgery) was planned in the 47 remaining patients. Twenty-seven out of 42 patients receiving four or more chemotherapy cycles were rendered tumour free by induction chemotherapy, including 5 of the 13 patients with extralymphatic non-pulmonal disease. An additional tumour-free patient died of septicaemia after only two cycles of chemotherapy. Late relapses (after > 2 years) were observed in three patients, and a testicular primary was diagnosed during follow-up in three cases. Seven patients died of treatment-related complications, five of these because of neutropenic septicaemia. The median age of these patients was 52 years compared with 35 years in the remaining 41 patients (P < 0.05). The 5-year overall survival for all 48 patients was 60% (95% CI 46-74%) [cancer-specific 5-year survival 71% (95% CI 50-92%)]. EGGCT is a potentially curable disease, even in patients with very advanced disease. Special attention should, however, be devoted to patients above the age of 40 years because of an increased risk of treatment-related side-effects. Late relapses and the subsequent development of testicular tumours indicate the need for long-term follow-up.     

Surveillance following orchidectomy for stage I testicular seminoma.

An analysis of the primary tumour histopathology was performed on 103 patients managed by orchidectomy and surveillance for stage I seminoma. Patients have been followed for 14-141 months (median 62 months) after orchidectomy. Seventeen patients relapsed, the probability of remaining relapse free at 5 years being 82% (95% confidence intervals, 74%-88%). No patients died of progressive germ cell tumours. The only significant histological factor predicting relapse was the presence of lymphatic and vascular invasion. Four of 42 patients with neither lymphatic or vascular invasion recurred, nine of 53 patients with either lymphatic or vascular invasion recurred and three of eight cases with both lymphatic and vascular invasion recurred (P = 0.05-trend). Though initial recurrence was usually of moderate volume and confined to para-aortic nodes, eight patients were treated with chemotherapy either because of the extent of their initial relapse (four cases), or because of subsequent relapse (four cases). In view of the difficulties of identifying patients at risk and of detecting early relapse, surveillance for stage I seminoma should remain a research protocol.     

Testicular Carcinoma in Denmark 1976-1980 Stage and Selected Clinical Parameters at Presentation

Since Jan. 1, 1976 practically all new cases of germ cell tumours of the testis in Denmark have been included in the Danish Testicular Carcinoma Study (DATECA), permitting detailed registration of data concerning histology and stage at the time of diagnosis. The incidence of carcinoma of the testis in Denmark continues to be high with a crude rate of 8 to 9/100000 males per year. During the past 5 years the size of the primary tumours has decreased. Parallel to this, the rate of metastatic spread has decreased for seminoma, while no such change has been observed for non-seminomatous tumours. Data are presented on histology and stage for 1058 consecutive patients.     

Referral patterns within Scotland to specialist oncology centres for patients with testicular germ cell tumours. The Scottish Radiological Society and the Scottish Standing Committee of the Royal College of Radiologists.

Details of 1123 patients registered in Scotland between 1983 and 1990 for testicular cancer under the Scottish Cancer Registration Scheme were obtained and compared with registrations within the five Scottish oncology centres. Some registration discrepancies were identified. Twenty-eight cancer registrations (2.5%) were coded to the wrong site, 29 patients seen at oncology centres had no cancer registration and 14 cancer registrations had the wrong histology. Five hundred and twenty-seven patients with testicular non-seminomatous germ cell tumours (NSGCT) and 567 with testicular seminoma were identified. Referral rates to specialist oncology centres for testicular germ cell tumours were measured by period and health board area of residence. For the whole study period 92% of NSGCT and 93% of seminoma patients were referred to specialist centres for treatment. Referral rates for different health board areas of residence were not significantly different. This study shows that within Scotland the majority of patients with testicular NSGCT and seminoma are referred to specialist centres, and suggests referral rates of around 92% are underestimates. Access is not related to area of residence.     

Frequent epigenetic inactivation of the RASSF1A tumour suppressor gene in testicular tumours and distinct methylation profiles of seminoma and nonseminoma testicular germ cell tumours

Testicular germ cell tumours (TGCTs) are histologically heterogeneous neoplasms with variable malignant potential. Previously, we demonstrated frequent 3p allele loss in TGCTs, and recently we and others have shown that the 3p21.3 RASSF1A tumour suppressor gene (TSG) is frequently inactivated by promoter hypermethylation in a wide range of cancers including lung, breast, kidney and neuroblastoma. In order to investigate the role of epigenetic events in the pathogenesis of TGCTs, we analysed the promoter methylation status of RASSF1A and nine other genes that may be epigenetically inactivated in cancer (p16(INK4A), APC, MGMT, GSTP1, DAPK, CDH1, CDH13, RARbeta and FHIT) in 24 primary TGCTs (28 histologically distinct components). RASSF1A methylation was detected in four of 10 (40%) seminomas and 15 of 18 (83%) nonseminoma TGCT (NSTGCT) components (P=0.0346). None of the other nine candidate genes were methylated in seminomas, but MGMT (44%), APC (29%) and FHIT (29%) were frequently methylated in NSTGCTs. Furthermore, in two mixed germ cell tumours, the NSTGCT component for one demonstrated RASSF1A, APC and CDH13 promoter methylation, but the seminoma component was unmethylated for all genes analysed. In the second mixed germ cell tumour, the NSTGCT component was methylated for RASSF1A and MGMT, while the seminoma component was methylated only for RASSF1A. In all, 61% NSTGCT components but no seminoma samples demonstrated promoter methylation at two or more genes (P=0.0016). These findings are consistent with a multistep model for TGCT pathogenesis in which RASSF1A methylation occurs early in tumorigenesis and additional epigenetic events characterize progression from seminoma to NSTGCTs.     

Allelic losses in carcinoma in situ and testicular germ cell tumours of adolescents and adults: evidence suggestive of the linear progression model

Testicular germ cell tumours (TGCTs) may arise through a process of multi-step carcinogenesis, and loss of heterozygosity (LOH) at specific loci is likely to be an important early event, although this has not been studied in detail. In order to explore the pathogenetic relationships among TGCTs, we investigated the genetic changes in testicular tumours that exhibit a disease continuum through the precursor carcinoma in situ (CIS) to either seminoma (SE) and/or non-seminomatous germ cell tumour (NSGCT). Universal amplification has been performed on 87 TGCT specimens and 36 samples of CIS cells microdissected from single paraffin-embedded tumour sections from 40 patients, including multiple specimens of CIS and TGCT cells of varied histology microdissected from 24 individual patients. Seventy-seven microsatellite markers were used to assay these samples for LOH at candidate regions selected from the literature, mapping to 3q, 5q, 9p, 11p, 11q, 12q, 17p and 18q. Construction of deletion maps for each of these regions identified common sites of deletion at 3q27-q28, 5q31, 5q34-q35, 9p22-p21 and 12q22, which correlate with allelic losses we have also observed in the precursor CIS cells. Evidence for allelic loss at 3q27-q28 was observed in all of the embryonal carcinoma samples analysed. We conclude that inactivation of gene(s) within these regions are likely to be early events in the development and progression of TGCTs. These results also provide molecular evidence in support of the hypothesis that SE is an intermediate stage of development within a single neoplastic pathway of progression from CIS precursor cells to NSGCT.     

The prognostic significance of the tumour infiltrating lymphocyte count in stage I testicular seminoma managed by surveillance

The degree of lymphocytic infiltration is a significant determinant of outcome for a variety of malignancies, but its role in seminoma is unknown. 150 men with stage I testicular seminoma presenting between 1981 and 1993 were managed by surveillance following orchidectomy. The presence of tumour infiltrating lymphocytes (TILs) in each case was classified as high, intermediate or low. At a median follow-up of 9.4 years, 30 of the 150 men developed recurrent seminoma. On univariate analysis, the risk of relapse was associated with age < or =33 years (P=0.002), tumour diameter >6 cm (P=0.03), lymphatic or vascular invasion (P=0.04), tumour invasion of rete testis (P=0.05), and lower TIL count (P=0.02). On multivariate analysis, statistically significant predictors of risk of relapse were age < or =33 years (hazard ratio (HR) 4.6 (95% confidence intervals (CI): 1.7-12.2)) and tumour diameter >6 cm (HR 2.8 (CI: 1.2-6.5)). Lower TIL count was of borderline statistical significance (HR 1.8 (CI: 0.96-3.44)). The functional role of the lymphocytic infiltrate in testicular seminoma warrants further study.     

Lactate dehydrogenase as a marker for testicular germ-cell tumours

One hundred and eighty-four patients with testicular germ-cell tumours, 92 with seminoma and 92 with non-seminomatous germ-cell tumours (NSGCT) had total lactate dehydrogenase (LD) assay performed of the time of initial staging following archidectomy. The proportion of patients with elevated plasma LD and the mean plasma LD increased with advancing stage and increasing tumour bulk for both seminoma and NSGCT. Of patients receiving cytotoxic chemotherapy, 87.5% with seminoma and 63% with NSGCT had elevated plasma LD with subsequent levels reflecting regression or progression of disease. Elevated plasma LD levels were seen in four of seven seminoma, and in 18 of 30 NSGCT patients relapsing after primary treatment.The LD assay provides useful information, and complements the routine measurement of alphafetoprotein (AFP) and beta human chorionic gonadotrophin (βhCG) in the management of patients with testicular germ-cell tumours.     

Has lymphography a role in early stage testicular germ cell tumours?

A retrospective study was performed of 183 newly diagnosed seminoma cases and 73 newly diagnosed non-seminomatous germ cell tumours (NSGCT) presenting from 1985 to 1989 to a tertiary referral cancer hospital. The purpose was to assess the contribution of bipedal lymphography (LG) to the management of these patients. As the main value of LG is in detecting small retroperitoneal lymph node (LN) metastases, analysis concentrated upon early stage disease, specifically N₀ and N_1a LN disease. Comparison between LG results, abdominopelvic computed tomography (APCT), final clinical stage and treatment outcome was performed. We found that with the LG and APCT criteria used (filling defects > 2 mm and LN diameter >20 mm, respectively), LG was much more sensitive in disease detection. However, with modem techniques APCT can reliably detect disease 10 mm or greater. In addition, tumour marker status, primary tumour vascular invasion status and initial clinical examination were each more important in staging NSGCT disease than LG alone. Thus, LG is now rarely used in our institution but we will have to monitor our excellent survival data to confirm that this change in policy is warranted.