Sperm integrity pre- and post-chemotherapy in men with testicular germ cell cancer.

BACKGROUND: While (partial) recovery of spermatogenesis, observed by means of standard semen analysis, has been seen in testicular cancer patients after chemotherapy with cisplatin, sperm genomic integrity and its implication for the patient's fertility are poorly understood. METHODS: Semen and serum from 22 patients treated for testicular cancer were analysed pre- and post-chemotherapy. Besides routine semen analysis, sperm samples were evaluated by computerized karyometric image analysis (CKIA), chromomycin-A3 assay (CMA3, chromatin condensation) and TdT-mediated dUTP nick-end labelling assay (TUNEL, DNA damage). Serum FSH, LH and testosterone concentrations were measured. RESULTS: Ejaculate volume decreased post-chemotherapy (P<0.05). External sperm characteristics (CKIA morphometry) and sperm counts did not deteriorate after chemotherapy. An improvement in DNA condensation was assessed after chemotherapy (37 versus 50% and 47.5 versus 63.7% for CMA3 and CKIA respectively; both P<0.005); yet a high percentage of TUNEL-positive sperm was found in the samples (21 versus 25% for pre- and post-chemotherapy samples respectively). These values were significantly higher than those of a convenience sample of normozoospermic males attending pre-IVF screening. Serum FSH and LH (IU/l) increased after chemotherapy compared with pretreatment levels (8.1 versus 16.7 and 4.5 vs 6.8; both P<0.05, respectively). CONCLUSIONS: Despite the improvement in sperm chromatin packaging after chemotherapy, an abnormally high percentage of DNA-damaged sperm was found in these samples. As sperm quality does not reach normal levels after treatment, it remains difficult to outline the best strategy and guidance concerning fertility potential of testicular cancer patients.

[Treatment of testicular cancer clinical stage I: watchful waiting, radiotherapy, chemotherapy or surgical intervention]. / Behandeling van testiscarcinoom, klinisch stadium I: waakzaam wachten, radiotherapie, chemotherapie of chirurgisch ingrijpen.

Micrometastasis in the retroperitoneal lymph nodes is seen in 20% of patients with a seminoma in clinical stage I and in 30% of patients with a nonseminoma in clinical stage I. It is not possible to detect micrometastases. Nearly all patients recover from the illness irrespective of the treatment choice. This is based on the patient's wish, the doctor's preference, local expertise and risk factors for dissemination. In the case of a seminoma, treatment consists of regular checks ('watchful waiting'), radiotherapy or chemotherapy. In the case of a non-seminoma in clinical stage I without vascular impingement the risk of micrometastases in the retroperitoneal nodes is 15%. Standard treatment consists of watchful waiting. The options 'retroperitoneal lymph node dissection with, in the case of positive nodes, chemotherapy' and 'primary chemotherapy' result in more excessive treatment, but less uncertainty in patients. In the case of a non-seminoma in clinical stage I with vascular impingement, the risk of micrometastases is 50%. Standard treatment in this case consists of watchful waiting or retroperitoneal lymph node dissection with chemotherapy, if necessary, in case of positive lymph nodes. Another option is primary chemotherapy.

Efficacy of routine follow-up after first-line treatment for testicular cancer.

To define guidelines for the follow-up management of patients treated for testicular germ cell tumor this study assessed characteristics of patients with recurrent disease. The charts of 505 patients with testicular cancer treated and followed-up at the University Medical Centre Nijmegen between 1982-2000 were reviewed retrospectively. In 42 patients disease recurrence was found during routine follow-up. In a subset of patients no recurrences were seen after first-line treatment: (a) pathological stage IIa nonseminoma patients who were adjuvantly treated with chemotherapy and (b) histologically confirmed complete responders after primary chemotherapy. Furthermore, in low-stage disease no intra-abdominal recurrences were seen in (a) pathological stage I nonseminoma patients and (b) low-stage seminoma patients who received radiotherapy. The risk of recurrent testicular cancer depends on primary therapy and efficacy of it; these results indicate a limited role for follow-up in pathological stage II nonseminoma patients adjuvantly treated with chemotherapy and in histologically confirmed complete responders after chemotherapy. Abdominal computed tomography does not appear necessary in routine follow-up of patients treated for low-stage testicular cancer.

Solitary skull recurrence from stage I seminomatous germ cell tumor of testis.

We describe a 35-year-old man who was initially treated with standard inguinal orchiectomy and prophylactic radiotherapy for Stage I seminomatous germ cell tumor of the testis. We report the case because of the unique nature of the later disease recurrence, which was a solitary cranial bony recurrence that extended both intracranially and extracranially. The patient had complete remission after combined cisplatin-based chemotherapy.

Difference in stage and morphology-adjusted survival between young and elderly patients with a testicular germ cell tumor.

OBJECTIVES: To compare the relative survival in men younger and older than 50 years with a testicular germ cell tumor. METHODS: Data on patients with testicular cancer diagnosed between 1973 and 1997 and registered by one of the nine population-based Surveillance, Epidemiology, and End Results (SEER) cancer registries in the United States were obtained from the National Cancer Institute public domain SEER*Stat 3.0 package. Survival rates adjusted for mortality owing to other causes (ie, relative survival) were calculated for men within each category of the American Joint Committee on Cancer staging system. RESULTS: Patients who developed a germ cell tumor before the age of 50 years had better 10-year relative survival (90.8%, 95% confidence interval 90.6% to 91.0%) than those who developed one after the age of 50 years (84.0%, 95% confidence interval 81.9% to 86.1%). This difference remained after stratification by histologic type and stage, except for patients with localized seminomatous disease (97.9% versus 98.0% for men younger and older than 50 years, respectively). The largest difference in 10-year relative survival was found in men with metastasized disease: seminomatous disease, 89.7% versus 69.6%, and nonseminomatous disease, 76.9% versus 57.0%, for men younger and older than 50 years, respectively. CONCLUSIONS: Lower stage and morphology-adjusted relative survival rate was observed among patients older than 50 years of age with testicular cancer. This difference was more evident in metastasized disease. Whether the worse prognosis in testicular cancer can be explained by a lower tolerance to chemotherapy and/or to suboptimal treatment in the elderly has to be established.

Comparison of surveillance and retroperitoneal lymph node dissection in Stage I nonseminomatous germ cell tumors.

OBJECTIVES: To compare retrospectively the treatment results of surveillance and primary retroperitoneal lymph node dissection (RPLND) of patients with clinical Stage I nonseminomatous germ cell tumors of the testis (NSGCT) in two institutions in The Netherlands. METHODS: From 1982 to 1994, 90 consecutive patients with clinical Stage I NSGCT were prospectively entered in a surveillance protocol in Amsterdam (group 1). In the same period, 101 patients with clinical Stage I NSGCT underwent primary RPLND in Nijmegen (group 2). Both patient populations were comparable for patient age, presence of vascular invasion, and embryonal cell components in the primary tumor. All patients in group 1 with relapse, except for 2, were treated with cisplatin-based chemotherapy. All patients in group 2 with vital tumor in the RPLND specimen were treated with two adjuvant courses of combined chemotherapy (cisplatin, etoposide, and bleomycin). RESULTS: In group 1, at a median follow-up of 7.7 years, 23 patients (26%) had relapse. The median time to relapse was 12 months. Relapses were located retroperitoneally (n = 18, 78%), in the lung (n = 3, 13%), scrotally (n = 1, 4%), and combined in the liver, lung, and pleura (n = 1, 4%). After treatment of relapses (chemotherapy in 21 and/or surgery in 11), only 1 patient died of disseminated disease. A disease-free survival rate of 98.5% was achieved at the median follow-up. The main toxicities consisted of short-lasting leukopenia, accompanied by infection (13%). Four patients reported cardiovascular and four neuropathy complaints. In group 2, the median follow-up was 6.9 years. In 31 patients (30.7%), vital tumor was found retroperitoneally; after two courses of combined chemotherapy, none of them had a relapse. Seven patients with pathologic Stage I disease (6.4%) had a pulmonary relapse within 1 year after surgery. No retroperitoneal relapses were found. After chemotherapy, 6 patients with relapse were salvaged, and 1 died of disseminated disease. The disease-specific survival rate in group 2 was 98% at the median follow-up. The most frequent surgical complications were lymphocele (n = 3), small bowel obstruction (n = 3), and abdominal pain (n = 3). The antegrade ejaculation rate was 94%. CONCLUSIONS: Excellent treatment results in terms of disease-free survival can be achieved in Stage I NSGCT with both surveillance and primary RPLND. Patients with pathologic Stage II disease adjuvantly treated with chemotherapy did not have any relapse and consequently all survived. Most complications after both treatment strategies are reversible. The choice of treatment should be based on balanced information and not on dogmatic principles.

The role of (18)fluoro-2-deoxyglucose positron emission tomography in initial staging and re-staging after chemotherapy for testicular germ cell tumours.

OBJECTIVE: To investigate the role of 18fluoro-2-deoxyglucose positron emission tomography (FDG-PET) in the initial staging of clinical stage I and II nonseminomatous germ cell tumours (NSGCTs) and in re-staging (non)seminomatous GCTs after chemotherapy. PATIENTS AND METHODS: FDG-PET studies were undertaken in 50 patients. FDG uptake was interpreted visually and when possible the standardized uptake value was determined. A FDG-PET scan was taken in five patients with clinical stage I and in seven with stage II NSGCT. The scans were validated by histology. Stage I patients underwent a retroperitoneal lymph node dissection because of vascular invasion in the primary tumour. Thirty-eight scans were taken after completing chemotherapy (28 NSGCTs and 10 seminomatous GCTs), and validated by histology or clinical follow-up. RESULTS: In stage I NSGCT, FDG-PET staging was equivalent to computed tomography (CT) staging. One small lesion, consisting of mature teratoma, was missed by both FDG-PET and CT. In stage II NSGCT, FDG-PET missed two lesions (mature teratoma and retroperitoneal mass with a small component of embryonal cell carcinoma) whereas CT correctly classified all. In 20 of 28 patients with NSGCT, histology was obtained after chemotherapy. In one of three patients with viable tumorous residual mass the FDG-PET scan was clearly positive; in four of 12 with mature teratoma and inflammation components retroperitoneally, the FDG-PET was also positive. In contrast, eight patients with solitary mature teratoma had a negative PET result. In four of five patients with necrosis after chemotherapy the PET result was correctly negative. All eight patients on surveillance had a negative PET scan and were free of disease at median (range) of 14 (8-18) months. Interestingly, of the 12 patients with a correct negative PET result, 11 had no mature teratoma in their primary tumour. Nine of 10 patients with SGCT were correctly staged. Two FDG-PET studies showed increased uptake; in one, a viable seminomatous mass was found and in the other there was inflammation in the residual mass. In all other patients the FDG-PET scan correctly predicted absence of viability in the residual mass. CONCLUSIONS: In primary staging, FDG-PET has no benefit over CT. In re-staging, a negative FDG-PET result predicts fibrotic residual mass in seminomatous GCT. Moreover, it could be useful to predict fibrotic residual mass in NSGCT in those patients with no teratoma component in their primary tumour.

alpha-Catenin expression pattern and DNA image-analysis cytometry have no additional value over primary histology in clinical stage I nonseminomatous testicular cancer.

OBJECTIVE: To determine whether the alpha-catenin expression pattern and DNA content have additional value over primary tumour histology, including information on vascular invasion and tunica albuginea invasion, in detecting occult metastasis in patients with clinical stage I nonseminomatous germ cell tumours of the testis (NSGCT). PATIENTS AND METHODS: Fifty consecutive patients with clinical stage I NSGCT underwent retroperitoneal lymphadenectomy (RPLND) between 1986 and 1992. The orchidectomy specimens were histopathologically reviewed and immunohistochemically stained with mouse monoclonal anti-alpha-catenin antibody. The presence of an aberrant or negative staining in >10% of the malignant cells was defined as abnormal; in all other cases tumours were classified as normal. Furthermore, intact nuclei were isolated from 50 microm thick paraffin sections of the primary tumour, Feulgen stained, and analysed with an image-analysis system. RESULTS: Of the 50 patients, 14 had positive retroperitoneal nodes (stage IIa, 28%), one pathologically staged I patient developed a lung metastasis (stage IV) within 3 months of RPLND. Univariate analysis showed that the presence of embryonal cell carcinoma, vascular invasion and tunica albuginea invasion were predictive for occult metastases. In multivariate logistic regression analysis only vascular and tunica albuginea invasion were significant. All 11 patients with no embryonal cell carcinoma in the primary tumour were classified as having pathological stage I disease. Also, the tumours which were DNA-diploid (three) or DNA-polyploid (two) were pathologically stage I. In screening for occult metastases the DNA content and the alpha-catenin expression pattern had no additional value. CONCLUSION: Vascular and tunica albuginea invasion have prognostic value in identifying patients with clinical stage I NSGCT at high risk for occult retroperitoneal disease. In contrast, the absence of embryonal cell carcinoma could predict all patients at low risk for metastasis. The DNA-ploidy also identified patients at low risk. Other DNA-analyses and the alpha-catenin expression pattern provided no additional information. Further studies are recommended to identify patients who are at low or high risk for metastasis.

Prognostic factors in clinical stage 1 non-seminomatous testicular tumours.

For patients with a clinical stage 1 non-seminomatous germ cell tumour of the testis cure rates should be close to 100%, whether surveillance, primary surgery, primary chemotherapy or a combination is chosen. The identification of patients with microscopic metastases is difficult. Even with the best predictive factors currently available (vascular invasion and percentage embryonal cell carcinoma in the primary tumour), the identification of micro-metastases is no better than the flip of a coin. Several additional prognostic factors have been studied, but none is yet applicable in daily practice.

Cancer incidence in relatives of patients with testicular cancer in the eastern part of The Netherlands.

OBJECTIVES: To investigate the incidence of malignant tumors in first-degree relatives of patients with testicular cancer. METHODS: Information about the occurrence of cancer in relatives of patients treated for testicular germ cell cancer (TC) at the Department of Urology of the University Medical Centre Nijmegen from 1986 to 1997 was collected using postal questionnaires from 379 (72%) of 524 patients. The expected numbers of cancers in relatives were computed from age- and sex-specific incidence data in the Netherlands Cancer Registry. The observed/expected (O/E) ratios with 95% confidence intervals (CIs) were calculated using Byar's approximation of the exact Poisson test. RESULTS: The O/E ratio for developing cancer in the families of patients with TC was 1.2 (95% CI 1.0 to 1.3). Among first-degree relatives of patients with TC, more TC was observed than expected (O/E 3.3; 95% CI 1.4 to 6.9). The risk for brothers of patients with TC increased 5.9-fold (95% CI 2.2 to 12.8). Both the risk of developing lung cancer (O/E 1.5) and malignancy of the female genital tract in sisters (O/E 2.8) was slightly increased. In contrast, the risk of urinary tract malignancies (O/E 0.3) and other and unknown primary tumors (O/E 0.2) had a lower incidence among relatives. However, both the increased and decreased risk of nontesticular cancer for first-degree relatives may have been caused by misclassification. CONCLUSIONS: TC clusters in families were more pronounced among brothers than among fathers and sons. This study supports previous reports that families of patients with TC do not seem to be prone to nontesticular cancer. Additional investigations in families with TC are recommended to map candidate genes for TC.