Treatment of patients with stage I nonseminomal germ cell testicular tumors

Three different approaches to treatment of non-seminomal germinogenic testicular tumors (NSGTT) of stage I after orchidofuniculectomy: preventive retroperitoneal lymphadenectomy, preventive chemotherapy, expectant treatment. Recurrences, 5-year recurrence-free and overall survivals reached 17.4, 81.8 and 95.4%; 6.3, 93.8 and 100%; 33.3, 66.4 and 83.5%, respectively. Progression occurred more frequently in patients having invasion of tumor cells in lymphatic and blood vessels in the primary tumor. The authors conclude on preferable use of preventive chemotherapy after removal of the primary tumor.     

Primary testicular lesions are associated with testicular germ cell tumors of adult men

The present study aims to establish the nature and frequency of testicular lesions in the parenchyma adjacent to testicular germ cell tumors (TGCT) to improve understanding of the factors involved in the development of testicular cancer. Fifty-three cases of TGCT that were fixed in both neutral-buffered formalin and Bouin solution, allowing for the nuclear characterization of Sertoli cells (SCs), were included in this study. In each case, at least 3 sections of different areas of preserved parenchyma surrounding the TGCT were studied. We found Leydig cell hyperplasia, microlithiasis, angiopathy, adenomatous hyperplasia of the rete testis, SC nodules, SC dysgenesis and involution, SC-only tubules, tubular atrophy, adluminal compartment lesions, hypospermatogenesis associated with spermatocyte sloughing, spermatogonial maturation arrest, and hypertrophic and multinucleated spermatogonia. These lesions were found in regions both adjacent and far away from the tumoral mass, and abnormal seminiferous tubules were found intermingled with those showing complete spermatogenesis, suggesting that these lesions are primary and existed before the development of the tumor. Our study suggests that SCs might play a more important role in the development of testicular tumors than previously thought. Our data supports the hypothesis that there is an abnormal differentiation of SCs, caused either by genetic anomalies or by environmental agents during fetal life. This abnormal SC differentiation may cause not only primary spermatogenesis failure and spermatogenesis arrest at different levels, but may also contribute to the poor differentiation of gonocytes into spermatogonia. The abnormal gonocyte differentiation might favor the development of dysplastic germ cells that may later transform into intratubular germ cell neoplasia, unclassified type.     

Susceptibility alleles for testicular germ cell tumour: a review

Family history is among the strongest and most consistent of the risk factors for testicular germ cell tumour (TGCT). Brothers of affected cases have an 8- to10-fold relative risk and fathers/sons have a risk between four and sixfold. The familial relative risk of TGCT is higher than for most other cancer types, which rarely exceeds four. The high relative risk suggests that inherited susceptibility to TGCT may account for a substantial fraction of TGCT cases. The search for TGCT susceptibility genes has proven difficult and a recent genome-wide linkage study for TGCT susceptibility loci demonstrated no statistically significant regions of linkage with all LOD scores less than two. Moreover, a previous report of linkage to a region on Xq27 was not replicated. The results from genetic linkage analysis demonstrate that TGCT susceptibility is likely to be due to several genes, each with a modest effect on disease risk. The Y chromosome, which cannot be analysed by genetic linkage, carries a number of testis- and germ cell-specific genes. We recently demonstrated that a deletion on the Y chromosome known as 'gr/gr' is a rare, low-penetrance allele that is associated with susceptibility to TGCT. Based on the evidence from the linkage search the 'gr/gr' deletion represents one of possibly many TGCT susceptibility alleles, and new and emerging technologies will be employed in future work to identify these genes.     

Identification of new biomarkers in immune microenvironment of testicular germ cell tumour

To seek novel prognostic biomarkers for testicular germ cell tumour (TGCT) and investigate the tumour immune microenvironment, we identified critical differentially expressed genes (DEGs) by overlapping GSE1818 dataset from Gene Expression Omnibus (GEO). Protein–protein interaction (PPI) network was used to investigate key modules and hub genes. Functional enrichment analysis was performed to investigate the underlying molecular functions of the DEGs in TGCT development and progression. The following survival analysis based on The Cancer Genome Atlas (TCGA) TGCT dataset indicated that AKAP4, SPA17 and TNP1 are correlated with TGCT prognosis. Immunohistochemistry and quantitative real-time polymerase chain reaction verified the down-regulation of the 3 hub genes in TGCT. Gene set enrichment analysis was conducted to further explore the role of the 3 hub genes in TGCT respectively. In addition, TGCT samples had high infiltration of CD8+ T cells, M0 and M1 macrophage cells, and resting myeloid dendritic cells in immune microenvironment. We also constructed the microRNA-gene regulatory networks to identify the key upstream microRNAs in TGCT. In conclusion, our findings indicated that AKAP4, SPA17 and TNP1 are promising biomarkers of TGCT. AKAP4 and TNP1 might regulate immune cells infiltration in immune microenvironment.     

Management of clinical stage I nonseminomatous germ cell testicular cancer

The optimal management of patients who have clinical stage I nonseminomatous germ cell tumors remains controversial. Surveillance, retroperitoneal lymph node dissection (RPLND), and chemotherapy with two cycles of bleomycin-etoposide-cisplatin are established treatment options and all are associated with long-term cancer control rates of 97% or greater. Studies have consistently identified the presence of lymphovascular invasion and a predominant component of embryonal carcinoma in the primary tumor as risk factors for occult metastatic disease in these patients. Patients who do not have these risk factors are optimally managed by active surveillance given the low risk for relapse. For patients at high risk for relapse and who are not candidates for surveillance, we believe the evidence supports RPLND over primary chemotherapy.     

Metastatic testicular germ cell tumour: The role of salvage surgery

To assess the clinical characteristics of metastatic testicular germ cell tumour, response to chemotherapy and outcome of salvage surgery for residual mass were analyzed. Patients with complete response were carefully watched. Salvage surgery was performed in 14 patients after chemotherapy. Resected specimens showed 7 necrosis/fibrosis, 5 teratoma, 1 cancer, and 1 benign schwannoma. Only necrosis/fibrosis was found in cases without teratoma in the primary tumour. Existence of teratomatous elements in a primary tumour suggests that cancer or teratoma is present in the residual tumour. Furthermore, tumour reduction rate could not predict their presence in resected specimens.     

Interdisciplinary cooperation in the treatment of complex patients with advanced testicular germ cell tumor

Testicular germ cell tumors represent the classic example of a curable solid cancer even in the metastatic stage. Cure rates are as high as 95% and 80-85% in patients with good and intermediate prognosis; even in patients with poor prognosis cure rates of 50% have been achieved by interdisciplinary collaboration of all specialties involved in the management of testis cancer. Standardization of diagnosis and therapy should be further optimized due to the recently published interdisciplinary national and European guidelines. Besides realization of standardized guidelines, treatment of patients with extensive primary disease or recurrent germ cell tumors following standard therapy requires comprehensive knowledge in conservative and surgical management, which is basically only available at specialized cancer centers.Patients with complex findings, especially if associated with a poor prognosis according to IGCCCG, should be referred to specialized tertiary referral centers at a very early stage, since the cure rates depend not only on the consideration of guidelines but also on the expertise of the attending oncologist and surgeon. When treating these patients, one has to consider that inadequately administered chemotherapy (dosage, length of cycles, number of cycles) cannot be compensated for by surgery and that inadequately performed retroperitoneal lymphadenectomy or residual tumor resection cannot be compensated for by chemotherapy. In any case, suboptimal primary therapy will result in inferior cure rates and an unnecessarily increased mortality rate.     

Ultrasonographic findings of testicular microlithiasis associated with intratubular germ cell neoplasia.

Testicular microlithiasis is an uncommon condition in which calcified concretions fill the lumina of seminiferous tubules. We report the case of a twenty-three-year-old white man with a metastatic germ cell tumor and normal findings on testicular physical examination, but abnormal ultrasonography of the right testis. Orchiectomy revealed intratubular germ cell neoplasia with testicular microlithiasis. Multiple circular echogenic foci on ultrasound correlated with the histologic finding of testicular microlithiasis. Further studies are indicated for assessing ultrasonography as an adjunct for screening the population at risk for intratubular germ cell neoplasia.     

Repeat retroperitoneal lymph-node dissection after chemotherapy for metastatic testicular germ cell tumour

OBJECTIVES: To examine the operative findings, histopathology and clinical outcome of patients undergoing repeat retroperitoneal lymph node dissection (RPLND) after initial chemotherapy and RPLND (PC-RPLND) for metastatic testicular germ cell tumour (GCT), as a small proportion relapse or have residual disease after incomplete resection in the lung, retrocrural or pelvic nodes, and retroperitoneum. PATIENTS AND METHODS: Between September 1992 and May 2006, 359 patients had PC-RPLND under the care of one surgeon, 54 of which were repeat procedures. We compared the long-term outcome between those having primary and those having repeat PC-RPLND. RESULTS: The median (range) time from original to repeat surgery was 2.4 (0.25-26.5) years, and the median follow-up after the repeat procedure was 5.8 (0.08-12.9) years. There was no difference in survival between patients requiring only one PC-RPLND and those having a repeat procedure (P = 0.592). The most frequent sites of recurrent disease were: behind the great vessels/para-aortic areas (38, 46%), in the suprahilar region (18, 18%), in the retrocrural area (16, 19%), in the pelvic nodes (10, 12%) and in the lung (one, 1%). The most common pathological findings in the repeat PC-RPLNDs were differentiated teratoma (19, 35%), malignant teratoma undifferentiated (nine, 17%), adenocarcinoma (eight, 15%) and necrotic tissue (five, 9.2%). CONCLUSION: Although a small proportion of patients with metastatic GCT might require repeat PC-RPLND, there is no difference in survival between this group and those having one PC-RPLND. However, to avoid cancer recurrence and reoperation, it is crucial that the first PC-RPLND is careful and complete, preferably done in a centre with expertise in this procedure.     

The role of tumour markers in diagnosis and management of testicular germ cell tumours

Alpha-fetoprotein (AFP), human choriogonadotropin (hCG) and lactate dehydrogenase (LDH) are established tumour markers of testicular germ cell tumours (TGCT) which are used according to the guidelines for primary diagnosis, staging, monitoring of therapeutic response and follow-up. Placental alkaline phosphatase and neurone-specific enolase play no role at all in the diagnosis and management of TGCT. Metastasized TGCT are classified according to the IGCCCG classification system into tumours with good, intermediate and poor prognosis depending on their serum concentration. The risk classification has a direct impact on therapy and determines the intensity of chemotherapy. In rare cases AFP and hCG might be elevated due to non-testicular reasons which have to be taken into consideration for the differential diagnosis especially if marker concentration and clinical presentation do not match. Response to chemotherapy is monitored with AFP and hCG which are determined the day before initiation of the next treatment cycle. Marker increases during or shortly after discontinuation of chemotherapy indicate a poor prognosis and make the immediate initiation of salvage treatment regimes necessary. Only 40?C50% and 30% of relapses in patients under active surveillance for clinical stage I disease and after systemic chemotherapy are associated with marker increases. The remainder will be diagnosed by imaging studies or clinical symptoms. Marker increases have to be validated by imaging studies. However, about 10% of all relapsing patients have marker increases only without any imaging evidence of metastatic disease. Residual masses of any size and location have to be treated by postchemotherapy resection once the marker concentration is normalized or once it has reached a stable plateau. So-called desperation surgery in the presence of rising tumour markers is only indicated if no curative chemotherapy is available, all residual masses are completely resectable and no hCG elevation are observed. For follow-up, AFP, hCG and LDH should be evaluated for advanced TGCT and clinical stage I nonseminomas, whereas clinical stage I seminomas should be monitored without any markers.