Testicular Germ Cell Carcinoma Research Articles

Risk for testicular germ cell tumors and spermatogenesis failure in post-pubertal undescended testes.

Cryptorchidism is a well-defined risk factor for testicular germ cell tumors, whereas the underlying mechanisms have not been fully elucidated. Surgical procedures to reposition undescended testicles into the scrotum (orchidopexy) in early childhood are recommended both to increase fertility potential and to reduce the risk of developing testicular tumors. However, treatment in the post-pubertal period is controversial. The aim of this study is to review the histopathology of orchiectomy specimens and determination of spermatogenesis in post-pubertal patients with non-treated cryptorchidism. Retrospective chart review was performed to assess the occurrence of TGCTs and determine spermatogenesis in post-pubertal individuals who underwent inguinal orchiectomy for undescended testis between January 2010 and December 2019. Age at the time of surgery, laterality, location of theundescended testis and pathology results were evaluated. All pathology specimens were reviewed by a blinded pathologist. There were 23 patients in the cohort with a mean age of 21years (range 13-46years). All testes were in the inguinal canal. Our results indicated that 1 patient had seminoma. In the histological evaluation of the remaining 22 patients in whom no tumor was detected, normal spermatogenesis was not observed in any patient. Further, seminiferous tubules were not found in 19 patients. Maturation arrest was detected in the remaining 3 patients. Testicular germ cell carcinoma was found in 4% of the patients who underwent post-pubertal orchiectomy. In addition, none of the undescended testes had normal spermatogenetic activity. Thus, orchiectomy should be considered in post-pubertal males with unilateral undescended testis that do not need the endocrinological activity of the testis.

Comprehensive in silico analysis of glycosylphosphatidylinositol- anchored protein (GPI-AP) related genes expression profiles in human normal and cancer tissues.

In human cells, there are more than 146 glycosylphosphatidylinositol-anchored proteins (GPI-APs), including receptors, ligands, adhesion molecules and enzymes. The proteins are associated with membrane microdomains called lipid rafts through GPI, and plays a variety of important biological functions. At present, plenty of studies have been carried out on the biosynthesis of GPI-APs. The biosynthesis of GPI-APs requires at least 20 steps, and more than 40 GPI biosynthetic genes have been identified. However, it remains unclear how expression of GPI-AP related genes is regulated in normal and cancer tissues. In this study, we utilized gene expression data from both the TCGA database and GTEx portal to analysis the gene expression involved in GPI-AP biosynthesis and encoding GPI-APs in normal and cancer tissues. In order to perform a comprehensive analysis, we employed the GlycoMaple, a tool that is specifically designed to analyze glycosylation pathways. The results showed that compared with normal tissues, the expression of genes involved in GPI-AP biosynthesis in cancer tissues such as early glioma, glioblastoma multiforme, pancreatic cancer, testicular germ cell carcinoma, skin primary cutaneous melanoma and skin metastatic cutaneous melanoma, was changed significantly. Particularly, the expression of PIGY in these six cancers was increased. In addition, the expression of CD14, a GPI-AP gene, was increased in these six cancers. The expression of GAS1, GPC2 and GPC4 was increased only in early glioma and glioblastoma multiforme indicating that some GPI-APs such as GAS1 can be used as biomarkers of glioma. This study provides new insights into the expression of GPI-AP related genes in normal and cancer tissues, and lays a solid foundation for the development of GPI-APs as biomarkers.

Changes in skeletal muscle and adipose tissue during cytotoxic chemotherapy for testicular germ cell carcinoma and associations with adverse events.

To quantify changes in body composition during cytotoxic chemotherapy for germ cell carcinoma of the testis (GCT) and evaluate associations between change in skeletal muscle and adipose tissue and chemotherapy-associated adverse events. This retrospective single-institution study evaluated men with GCT treated with cytotoxic chemotherapy from 2005 to 2018. We measured skeletal muscle index (SMI [cm2/m2]), skeletal muscle density (SMD [Hounsfield Units (HU)]), skeletal muscle gauge (SMG [cm²*HU/m²]), fat mass index (FMI [kg/m2]), visceral adipose index (VAI [cm2/m2]), and subcutaneous adipose index (SAI [cm2/m2]) on axial computed tomography images at the level of the third lumbar vertebra within 75 days before and after chemotherapy. Chemotherapy-associated adverse events (AE) were graded based on the Common Terminology Criteria for Adverse Events (CTCAE v5.0.) Changes in body composition were quantified. Predictors of change in body composition were evaluated with multivariable linear regression. Associations between baseline or change in body composition and AEs were estimated with multivariable logistic regression adjusting for age, comorbidity, performance status, stage, and number/type of chemotherapy cycles. 141 patients (median age, 30 years [IQR 25-39]) including 86 patients (61%) with non-seminomatous GCT were included. Patients received a median of 3 cycles of cisplatin-based chemotherapy, and 124 patients (88%) completed planned chemotherapy. Median observed changes in SMI, SMD, and SMG were -6% (P<0.0001), -2% (P=0.07), and -7% (P<0.0001), respectively, while FMI increased 5.3% (P<0.0001). Overall, 120 patients (85%) experienced at least one AE including one or more ≥grade 3 AE in 57 patients (48%). Decrease in SMI (OR: 0.89, P=0.02), decrease in SMG (OR: 0.88, P=0.01,) and post-chemotherapy SMG (OR: 0.94, P=0.05) were independently associated with higher incidence of AEs, while pre-chemotherapy skeletal muscle parameters and post-chemotherapy SMI and SMD were not associated with AEs (P>0.05 for all). Preoperative adipose tissue or change in adiposity was not associated with incidence of AEs. In men with GCT receiving cytotoxic chemotherapy, a decrease in skeletal muscle mass and quality during chemotherapy were associated with a higher incidence of chemotherapy-associated AEs. Adipose tissue was not associated with the incidence of AEs.

Conditional survival of patients with metastatic testicular germ-cell carcinoma (MT-GCT) treated with first-line curative therapy.

Conditional survival of patients with metastatic testicular germ-cell carcinoma (MT-GCT) treated with first-line curative therapy.

A case of testicular germ cell carcinoma identified five years after lung metastasis resection

A 33 year-old man was referred to our center with swelling of the left scrotum. He underwent resection of the left testis,and pathological diagnosis indicated a germ cell tumor of that testis. His past history included lung cancer resection 5 yearsbefore the testicular surgery. Precise pathological reevaluation of the lung cancer using immunohistochemical methodsindicated that the tumor originally diagnosed as lung cancer was a metastasis of the germ cell tumor of the left testis.

Testicular germ-cell tumors - epidemiology and etiology

Testicular cancer is one of the most common malignancies among young men in the age group 15-40 with peak of incidence in the third decade. Testicular germ cell carcinoma accounts for about 95-97 % of all malignant testicular cancers. Around half of this group is presented by seminomas and the other half is mixed group named as nonseminomas including choriocarcinomas, teratomas, embryonal cell carcinoma, tumor yolk sac. This group of tumors is not evenly spread around the world. It has highest density in North Europe and Denmark and Slovenia in particular. Many risk factors have been blamed to be responsible for cancerogenesis in this group but for the time being there are few proven theories. Along with the epidemiological statistic data new scientific revelations shown and proved heredity of testicular carcinoma in specific genetic lines. In other studies indirect evidence supports that hormonal misbalance even "in utero" can cause conditions for developing malignant cells in the testicular parenchyma. There is still an open issue the reason for deference in density among different countries shearing neighbor territories. SSM, 2012;44(1):57-66

Therapeutic Potential of SOX2 Inhibition for Embryonal Carcinoma

Some nonseminomatous germ cell tumors are resistant to any type of chemotherapy. Control of embryonal carcinoma cells is crucial to manage nonseminomatous germ cell tumors. We established SOX2 targeting therapy in an embryonal carcinoma model. SOX2 expression was evaluated in a series of testicular germ cell tumor tissue samples. The antitumor effect of SOX2 knockdown was analyzed in vitro and in vivo using an embryonal carcinoma model. In testicular germ cell tumor tissue SOX2 was expressed in the foci of embryonal carcinoma but negative in seminoma and yolk sac tumors. In an embryonal carcinoma model SOX2-siRNA induced apoptotic cell death in vitro and significant growth suppression in vivo. This study shows the therapeutic potential of SOX2 silencing for embryonal carcinoma. However, further improvements are needed in SOX2-siRNA delivery to the tumor.

Abstract B127: Alcohol consumption and risk of testicular germ cell carcinoma

Abstract B127 The incidence of testicular germ cell carcinoma (TGCC), the most common malignancy among men aged 20-34, has increased several-fold during the past several decades. The etiology of TGCC is poorly understood and the cause of the increased incidence is unknown. Established risk factors include age, race, personal history of undescended testes, and family history of TGCC, none of which is modifiable. Alcohol is an established testicular toxicant, causing testicular atrophy, gynecomastia, and disrupted sexual function in alcoholic men. In both alcoholics and non-alcoholic men with moderate intake, alcohol depresses levels of circulating testosterone and luteinizing hormone. We hypothesized that alcohol consumption, particularly during adolescence, increases the risk of TGCC. A single previous epidemiologic analysis of alcohol intake and TGCC found no association. We conducted a population-based case-control study among 18-44 year-old male residents of three Washington State counties. Cases (n=400) were diagnosed during 1999-2006 with a first, primary TGCC. Controls (n=1,020) were men of similar age with no history of TGCC from the same population identified through random-digit telephone dialing. Questionnaires elicited information on demographic, medical, and lifestyle factors, including usual consumption of beer, wine, and liquor during the 5 years prior to reference date and during grades 7-12. We used logistic regression models to compute odds ratio (OR) estimates and 95% confidence intervals (CI) for TGCC in men that consumed 1-6, 7-13, and 14+ alcoholic beverages per week compared to those that consumed none, adjusting for age, education, smoking, and current marijuana use. A higher proportion of cases than controls (73% vs. 66%) reported drinking 1 or more alcoholic beverages per week during the five years prior to reference date, and during grades 9-12 (44% vs. 37%). Consumption of 14+ alcoholic drinks/week was associated with an approximately 60% increased risk of TGCC (OR=1.62; 95% CI: 1.02-2.58) for consumption during the 5 years prior to reference date, and for consumption during grades 9-12 (OR=1.56; 95% CI: 0.99-2.47). The risk of TGCC appeared to be similar for consumption of beer, wine, or liquor, and for consumption of alcoholic beverages during adolescence versus consumption during adulthood. The risk of TGCC associated with 14+ alcoholic drinks/week was higher among men diagnosed with nonseminomas (OR=2.28; 95% CI: 1.08-4.82) than among men diagnosed with seminomas (OR=1.40 95%CI: 0.80-2.42). Our results indicate that consumption of 14 or more alcoholic beverages per week during adolescence or adulthood may be associated with a doubling of the risk of non-seminomatous TGCC. This is the first study to report an association between alcohol consumption and an increased risk of TGCC. Additional studies are needed to clarify the relationship between alcohol intake and TGCC. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B127.

Improved Systemic Chemotherapy for Metastatic Testicular Choriocarcinoma Can Result in Excellent Prognosis for Life and Vision

Although testicular germ cell carcinoma is rare, it is the most common malignant neoplasm in men between the ages of 15 and 35 years. We report a case of metastatic choriocarcinoma involving the choroid that was effectively treated with chemotherapy and had an excellent visual outcome.

Sequence variation in the human transcription factor gene POU5F1

BackgroundPOU5F1 expression is required to maintain stem cell pluripotency and for primordial germ cells to retain proliferative capability in embryonic development. Recent evidence suggests that POU5F1 may also be a testicular germ cell carcinoma (TGCC) oncogene, and POU5F1 variation may influence TGCC risk. As an important first step to a genetic association study, we sought to identify all common sequence variants in an 11.3 kb region containing POU5F1, and to describe the linkage disequilibrium patterns, using DNA from individuals of African-descent (AD) and European-descent (ED).ResultsA higher number of polymorphisms was observed in the AD (n = 102) versus ED (n = 82) population. Among the 41 observed haplotypes, 21 (51%) and 12 (29%) were unique to the AD and ED populations, respectively, while 8 (20%) were observed in both. The number of tagging polymorphisms necessary to explain at least 80% of common variation (minor allele frequency ≥ 0.10) due to the remaining untyped polymorphisms was 17 for an AD and 10 for an ED population, providing a 4.0- and 7.0-fold gain in genotyping efficiency for characterizing nucleotide variation, respectively.ConclusionPOU5F1 is highly polymorphic, however a smaller subset of polymorphisms can tag the observed genetic variation with little loss of information.

Risk of Testicular Germ Cell Cancer in Relation to Variation in Maternal and Offspring CytochromeP450 Genes Involved in Catechol Estrogen Metabolism

The incidence of testicular germ cell carcinoma (TGCC) is highest among men ages 20 to 44 years. Exposure to relatively high circulating maternal estrogen levels during pregnancy has long been suspected as being a risk factor for TGCC. Catechol (hydroxylated) estrogens have carcinogenic potential, thought to arise from reactive catechol intermediates with enhanced capability of forming mutation-inducing DNA adducts. Polymorphisms in maternal or offspring genes encoding estrogen-metabolizing enzymes may influence prenatal catechol estrogen levels and could therefore be biomarkers of TGCC risk. We conducted a population-based, case-parent triad study to evaluate TGCC risk in relation to maternal and/or offspring polymorphisms in CYP1A2, CYP1B1, CYP3A4, and CYP3A5. We identified 18- to 44-year-old men diagnosed with invasive TGCC from 1999 to 2004 through a population-based cancer registry in Washington State and recruited cases and their parents (110 case-parent triads, 50 case-parent dyads). Maternal or offspring carriage of CYP1A2 -163A was associated with reduced risk of TGCC [maternal heterozygote relative risk (RR), 0.6; 95% confidence interval (95% CI), 0.2-1.7; offspring heterozygote RR, 0.7; 95% CI, 0.3-1.5)]. Maternal CYP1B1 (48)Gly homozygosity was associated with a 2.7-fold increased risk of TGCC (95% CI, 0.9-7.9), with little evidence that Leu(432)Val or Asn(453)Ser genotypes were related to risk. Men were also at increased risk of TGCC if they carried the CYP3A4 -392G (RR, 7.0; 95% CI, 1.6-31) or CYP3A5 6986G (RR, 2.4; 95% CI, 1.1-5.6) alleles. These results support the hypothesis that maternal and/or offspring catechol estrogen activity may influence sons' risk of TGCC.

Factors that influence the results of salvage surgery in patients with chemorefractory germ cell carcinomas with elevated tumor markers: Habuchi T, Kamoto T, Hara I, Kawai K, Nakao M, Nonomura N, Kobayashi T, Ogawa O, Kamidono S, Akaza H, Okuyama A, Kato T, Miki T, Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Cancer 2003;98:1635–42 Background A standard concept for the integration of surgery into the chemotherapy-based treatment of patients with advanced germ cell carcinoma has been that surgery should be avoided in patients with serum tumor markers (alpha-fetoprotein [AFP] and human chorionic gonadotropin [HCG]) that remain elevated. However, some patients may benefit from resection under such chemorefractory conditions. The objective of this retrospective study was to clarify the outcome and clinical prognostic variables of salvage surgery in patients with disseminated (AJCC Stage II or III) testicular germ cell carcinoma or extragonadal germ cell carcinoma who had elevated serum markers. Methods The authors reviewed the clinical records of 24 patients who underwent salvage surgery with elevated serum AFP and/or HCG levels after at least 3 courses of cisplatin-based, systemic chemotherapy between January, 1985 and December, 2000. The survival rates were compared between the subgroups with regard to preoperative and postoperative clinical parameters using the Kaplan-Meier method and a Cox proportional hazards model. Results Ten of 24 patients (41.7%) were rendered free of disease and alive without disease after the surgery with or without adjuvant therapy at a median follow-up of 74 months (range, 24–207 months). Among the preoperative parameters, high HCG levels were associated with significantly poorer survival (hazard ratio [HR], 8.321; 95% confidence interval [95% CI], 1.0753–64.553; P = 0.043 and P = 0.016, respectively; log-rank test). In addition, patients who had visceral lesions at resection had a significantly poorer prognosis compared with patients who had retroperitoneal and/or mediastinal lymph node lesions ( P = 0.038; log-rank test). Among postoperative parameters, incomplete resection and persistently high HCG levels were associated significantly with poor survival, with a risk of death from disease of 12.516-fold (95% CI, 1.786–87.781) and 9.311-fold (95% CI, 1.796–48.256), respectively. Conclusions Salvage surgery in patients with high serum tumors markers resulted in long-term disease free status in approximately 40% of patients in a small subset with advanced germ cell carcinoma. Patients with elevated AFP levels alone (i.e., normal HCG levels) or with lymph node lesions alone seem to be good candidates for such surgery. Complete resection of target lesions and normalization of HCG levels after surgery are mandatory to achieve long-term disease free status.

The impact of testicular carcinoma and its treatment on sperm DNA integrity

In patients with testicular germ cell carcinoma (TGCC), spermatogenesis and fertility are impaired. Intracytoplasmic sperm injection has improved their possibility of fatherhood, but might also impose a risk of transmitting DNA defects to the offspring. The aim of the current study was to evaluate the impact of chemotherapy and irradiation on sperm DNA integrity. The study included 74 patients with TGCC. Semen samples were collected before and at specific time points after patients received therapy. Sperm DNA integrity was assessed by the sperm chromatin structure assay. Controls comprised 278 military conscripts. There was no significant difference in the fraction of sperm with fragmented DNA (DNA fragmentation index [DFI]) between controls and patients with TGCC before postoperative cancer treatment (11% vs. 13%). Men treated with adjuvant radiotherapy had a transiently (up to 2 years) higher DFI than nontreated patients (18% vs. 13%; P = 0.03). Patients who received 1-2 cycles of adjuvant chemotherapy had a significantly lower DFI 6 months after treatment than after 1-2 years (9.1% vs. 13%; P = 0.004). Higher doses of chemotherapy among patients resulted in a significantly lower DFI compared with controls (7.3% vs. 11%; P = 0.028), which persisted throughout the 5 years of follow-up. Postorchiectomy, the DFI in sperm samples from patients with testicular carcinoma was at the level of controls. Radiotherapy caused a transient increase in the proportion of DFI, whereas this value decreased after chemotherapy. The biologic implications of such changes in sperm DNA after cancer therapy need to be elucidated.

Factors that influence the results of salvage surgery in patients with chemorefractory germ cell carcinomas with elevated tumor markers.

A standard concept for the integration of surgery into the chemotherapy-based treatment of patients with advanced germ cell carcinoma has been that surgery should be avoided in patients with serum tumor markers (alpha-fetoprotein [AFP] and human chorionic gonadotropin [HCG]) that remain elevated. However, some patients may benefit from resection under such chemorefractory conditions. The objective of this retrospective study was to clarify the outcome and clinical prognostic variables of salvage surgery in patients with disseminated (AJCC Stage II or III) testicular germ cell carcinoma or extragonadal germ cell carcinoma who had elevated serum markers. The authors reviewed the clinical records of 24 patients who underwent salvage surgery with elevated serum AFP and/or HCG levels after at least 3 courses of cisplatin-based, systemic chemotherapy between January, 1985 and December, 2000. The survival rates were compared between the subgroups with regard to preoperative and postoperative clinical parameters using the Kaplan-Meier method and a Cox proportional hazards model. Ten of 24 patients (41.7%) were rendered free of disease and alive without disease after the surgery with or without adjuvant therapy at a median follow-up of 74 months (range, 24-207 months). Among the preoperative parameters, high HCG levels were associated with significantly poorer survival (hazard ratio [HR], 8.321; 95% confidence interval [95% CI], 1.0753-64.553; P = 0.043 and P = 0.016, respectively; log-rank test). In addition, patients who had visceral lesions at resection had a significantly poorer prognosis compared with patients who had retroperitoneal and/or mediastinal lymph node lesions (P = 0.038; log-rank test). Among postoperative parameters, incomplete resection and persistently high HCG levels were associated significantly with poor survival, with a risk of death from disease of 12.516-fold (95% CI, 1.786-87.781) and 9.311-fold (95% CI, 1.796-48.256), respectively. Salvage surgery in patients with high serum tumors markers resulted in long-term disease free status in approximately 40% of patients in a small subset with advanced germ cell carcinoma. Patients with elevated AFP levels alone (i.e., normal HCG levels) or with lymph node lesions alone seem to be good candidates for such surgery. Complete resection of target lesions and normalization of HCG levels after surgery are mandatory to achieve long-term disease free status.

Improved long term survival of patients with metastatic nonseminomatous testicular germ cell carcinoma in relation to prognostic classification systems during the cisplatin era

Improved long term survival of patients with metastatic nonseminomatous testicular germ cell carcinoma in relation to prognostic classification systems during the cisplatin era

Improved long term survival of patients with metastatic nonseminomatous testicular germ cell carcinoma in relation to prognostic classification systems during the cisplatin era

The current study reviews chronologic changes in the long term outcome of patients with metastatic nonseminomatous testicular germ cell tumors (NSTGCT) who were treated at a single institution during the past two decades. The 10-year survival of prognostic subgroups according to the classification of the International Germ Cell Consensus Classification Group (IGCCCG) and various other prognostic classifications is examined in time to evaluate whether cumulative experience has led to an improved outcome of patients with metastatic NSTGCT and to explore differences in outcome of prognostic subgroups. Two hundred ninety-nine patients with metastatic NSTGCT who were treated with cisplatin-based polychemotherapy during the period from 1977 to 1996 were staged retrospectively according to the Royal Marsden (RM) classification and the following prognostic classifications: IGCCCG, Indiana, Medical Research Council (MRC), and European Organization for Research and Treatment of Cancer (EORTC). The numbers of patients who were treated during the periods 1977-1986 and 1987-1996 were 146 and 153, respectively. Survival curves were constructed using the Kaplan-Meier method, and disease specific 10-year survival rates of prognostic subgroups treated during the two consecutive 10-year periods were compared using the log rank test. The median follow-up of surviving patients during the periods 1977-1986 and 1987-1996 was 14.7 years (range, 0.2-20.6 years) and 7.0 years (range, 0.4-11.4 years), respectively. The actuarial disease specific 10-year survival rate of patients with metastatic NSTGCT increased from 76% during the period 1977-1986 to 88% during the period 1987-1996 (relative risk [RR], 0.51; 95% confidence interval [95% CI], 0.29-0.89; P < 0.05). The 10-year survival rates of patients with good, intermediate, and poor prognoses according to the IGCCCG classification were 95%, 74%, and 37%, respectively, during the period 1977-1986 and 94%, 87%, and 66%, respectively, during the period 1987-1996. Patients with a poor prognosis according to the IGCCCG classification showed the greatest increase in 10-year survival (RR, 0.43; 95% CI, 0.18-1.04; P = 0.06). Analysis using the RM, Indiana, and EORTC classifications also showed an improved 10-year survival rate of patients with a poor prognosis who were treated during 1987-1996 compared with those who were treated during 1977-1986. The 10-year survival rate of patients with metastatic NSTGCT who were treated with cisplatin-based chemotherapy significantly increased from 76% during the period 1977-1986 to 88% during the period 1987-1996. This improvement during the cisplatin era resulted mainly from an increase in the survival of patients with metastatic disease who had a poor prognosis. These results indicate that the management of patients with NSTGCT is still improving.

High-resolution HLA-DRB1 and DQB1 genotyping in Japanese patients with testicular germ cell carcinoma.

We report for the first time the frequency distributions of HLA-DRB1 and -DQB1 genes in 55 patients with testicular germ cell carcinoma (TGC) using the modified PCR-RFLP method and compare the results with those for 1216 healthy Japanese control subjects. The modified PCR-RFLP method produced accurate, reproducible cleavage patterns that are easily discriminated. HLA-DRB1*0410 was the susceptibility allele (RR = 3.26, P = 0.006) and DQB1*0602 appears to be a candidate protective allele (RR = 0.26, P = 0.02) for TGC in the Japanese. None of the HLA-DRB1 and -DQB1 alleles showed a specific tendency for histological type or clinical stage of the tumours. Previous studies based on serotyping methods failed to show these allelic associations. High-resolution genotyping is essential because the peptide-binding domain of MHC class II molecules is determined more precisely by their genotypes than by their serotypes. In addition, inherent technical difficulties and typing errors of up to 25% make serotyping inefficient. Our results suggest that high-resolution genotyping is a useful genetic marker to determine risk for TGC.

The significance of the nuclear and cytoplasmic localization of metallothionein in human liver and tumor cells.

Metallothioneins are a group of low-molecular-weight intracellular proteins present in high levels in fetal mammalian livers, bound to zinc and copper. They are also present in two major isoforms in low basal levels in various organs of adults in several species. Although a number of functions have been proposed for metallothioneins, their major biological roles may be in the storage of zinc and copper during rapid growth and development, and also in the detoxification of certain toxic metals. In adult liver, metallothionein is mainly localized in the cytoplasm, it is localized also in the hepatocyte nuclei in human fetal liver and fetal and neonatal rat liver, as determined by immunohistochemical staining with a specific metallothionein antibody. Because of its high expression in fetal development, the potential role of metallothioneins in human tumors was investigated. The cellular localization of metallothionein was demonstrated in various human tumors such as thyroid tumors, testicular germ cell carcinoma, bladder transitional cell carcinomas, and salivary gland tumors. In most of these tumor tissues, metallothioneins were found in high levels in nucleus and cytoplasm in both benign and malignant tumors, although the proliferating edge of the malignant tumors showed most intense metallothionein staining. The expression of metallothionein is not universal to all tumor growth; its presence may depend on various factors, such as the type of tumor, cellular origin, morphological heterogeneity, or stage of growth. Human testicular seminomas, which are well differentiated, showed little expression of metallothionein irrespective of the staging, as compared to less well-differentiated embryonal carcinomas.(ABSTRACT TRUNCATED AT 250 WORDS)