A guide to the investigation and treatment of patients with AIDS and AIDS-related disorders.

In 1977 the rate of death from testicular cancer in Ontario began to decline following a long period of relative stability. This coincided with the addition of cisplatin to the chemotherapeutic regimens used in the treatment of disseminated germ-cell testicular cancer. A study was carried out to determine whether the decline has been similar for the two major histologic subgroups, seminoma and nonseminoma. By means of Ontario Cancer Registry data, histologic type was determined for all testicular cancers causing death in Ontario residents between 1964 and 1982, and death rates were calculated for seminoma and nonseminoma germ-cell testicular cancer. The rates of death from nonseminoma exceeded those from seminoma for the entire study period. Although the death rates for both subgroups declined by about 50% after 1976, the reduction in the overall rate of death from testicular cancer is primarily attributable to the decline in the rate for nonseminoma germ-cell testicular cancer. The increased overall rate of death from testicular cancer (all types) between 1980 and 1984 is cause for concern and indicates the need for continued monitoring of the trends in rates of death from this disease.     

Survival after a diagnosis of testicular germ cell cancers in Germany and the United States, 2002–2006: A high resolution study by histology and age

Introduction: The aim of this study was to provide detailed age-specific (5-year age groups) and histology-specific (histologic subtypes of seminoma and nonseminoma) relative survival estimates of testicular germ cell cancer patients in Germany and the United States (U.S.) for the years 2002–2006 and to compare these estimates between countries. Methods: We pooled data from 11 cancer registries of Germany and used data from the U.S. (SEER-13 database) including 11,508 and 10,774 newly diagnosed cases (1997–2006) in Germany and the U.S., respectively. We estimated 5-year relative survival (5-year-RS) by histology and age based on period analysis. Results: 5-year-RS for testicular germ cell tumors was 96.7% and 96.3% in Germany and the U.S., respectively. 5-Year-RS for spermatocytic seminoma was close to 100% in both countries. 5-Year-RS for nonseminoma was lower than for classical seminoma in Germany (93.3% versus 97.6%) and the U.S. (91.0% versus 98.2%). Among nonseminomas, choriocarcinomas provided the lowest 5-year-RS in both countries (Germany 80.1%, U.S. 79.6%). Age-specific 5-year-RS for seminoma showed only little variation by age. 5-Year-RS for nonseminomas tended to be lower at higher ages, especially for malignant teratoma. Discussion: This is the first study that provides up-to-date survival estimates for testicular cancer by histology and age in Germany and the U.S. Survival after a diagnosis of testicular cancer is very comparable between Germany and the U.S. 5-Year-RS for spermatocytic seminoma was close to 100% and the lowest 5-year-RS occurred among choriocarcinoma. Higher age at diagnosis is associated with a poorer prognosis among nonseminoma patients.     

Bilateral germ cell testicular tumors

PURPOSE: To study the clinical characteristics of bilateral testicular tumors in the cisplatin era. PATIENTS AND METHODS: Between November 1988 and November 1998 2386 testicular cancer patients were treated in our Department and 72 bilateral germ cell testicular cancer patients were retrospectively explored (3%). The incidence, the clinical and histological characteristics and, in the case of asynchronous tumor, the interval between the two tumors were analyzed. RESULTS: During the 10 years 19 synchronous (26.4%) and 53 asynchronous bilateral germ cell testicular cancers (73.6%) were treated. The incidence of bilateral synchronous seminoma was 68.4%. Among the asynchronous tumors 9 concordant seminomas and 9 concordant nonseminomas were detected. In the first, second and third 5-year follow-up period 39.6, 30.2, and 28.2% of asynchronous tumors were diagnosed. The incidence of seminoma after the first castration in the 5, 10 and 15 years was 19, 37.5, and 60%, respectively. The overall survival rates of synchronous and asynchronous testicular cancer were 84 and 93%. In cases of asynchronous tumor the prevalence of stage I cancer was significantly greater in a regularly controlled population (p=0.014) than in the not regularly followed population, but the survival rate was good in both groups. Nonseminoma showed up earlier as first and second tumor than seminoma (p=0.05, p=0.045). The interval between the two asynchronous tumors was shorter in the case of nonseminoma than in the case of seminoma (p=0.002). CONCLUSION: The prognosis of bilateral germ cell testicular cancer is good because of the high incidence rate of seminoma and the effective treatment. With regular follow-up the early diagnosis of second testicular tumors is probable. The interval between the tumors depends on the patients' age and the histology of the second tumor, in the case of seminoma it is longer. The effect of the previous treatment on the incidence of seminoma and the interval between the two asynchronous tumors requires further investigations.     

GPR30, the non-classical membrane G protein related estrogen receptor, is overexpressed in human seminoma and promotes seminoma cell proliferation

Background

Testicular germ cell tumours are the most frequent cancer of young men with an increasing incidence all over the world. Pathogenesis and reasons of this increase remain unknown but epidemiological and clinical data have suggested that fetal exposure to environmental endocrine disruptors (EEDs) with estrogenic effects, could participate to testicular germ cell carcinogenesis. However, these EEDs (like bisphenol A) are often weak ligands for classical nuclear estrogen receptors. Several research groups recently showed that the non classical membrane G-protein coupled estrogen receptor (GPER/GPR30) mediates the effects of estrogens and several xenoestrogens through rapid non genomic activation of signal transduction pathways in various human estrogen dependent cancer cells (breast, ovary, endometrium). The aim of this study was to demonstrate that GPER was overexpressed in testicular tumours and was able to trigger JKT-1 seminoma cell proliferation.

Results

We report here for the first time a complete morphological and functional characterization of GPER in normal and malignant human testicular germ cells. In normal adult human testes, GPER was expressed by somatic (Sertoli cells) and germ cells (spermatogonia and spermatocytes). GPER was exclusively overexpressed in seminomas, the most frequent testicular germ cell cancer, localized at the cell membrane and triggered a proliferative effect on JKT-1 cells in vitro, which was completely abolished by G15 (a GPER selective antagonist) and by siRNA invalidation.

Conclusion

These results demonstrate that GPER is expressed by human normal adult testicular germ cells, specifically overexpressed in seminoma tumours and able to trigger seminoma cell proliferation in vitro. It should therefore be considered rather than classical ERs when xeno-estrogens or other endocrine disruptors are assessed in testicular germ cell cancers. It may also represent a prognosis marker and/or a therapeutic target for seminomas.     

Prolactin secretion in testicular cancer patients

The role of prolactin (PRL) in testicular function and in its disorders is still obscure. To draw some preliminary conclusions on the relation between the PRL and testis cancer, we assessed the PRL response to thyrotropin-releasing hormone (THR) in 15 patients with testicular cancer (8 seminoma; 6 nonseminoma; 1 leydigioma), and in 11 healthy male subjects as controls. The results showed that 5/15 cancer patients gave no PRL response to TRH; 4 of them had a nonseminoma and the fifth a seminomatous testis carcinoma. Patients with nonseminoma had significantly lower mean peak values of PRL after TRH than controls or patients with seminoma. The biological significance of the altered PRL response to TRH in testicular carcinoma has still to be established.     

Le cancer à cellules germinales du testicule, élément constitutif du Syndrome de Dysgénésie Testiculaire: rôle des facteurs environnementaux et de la susceptibilité génétique

The incidence of testicular germ cell cancer has been increasing over recent decades in many countries of the world. Many studies over recent years have reported adverse trends in other aspects of male reproductive health, such as high and possibly increasing frequencies of undescended testis and hypospadias, declining semen quality, and an apparently growing demand for assisted reproduction due to male infertility. This article summarises the available evidence supporting a new concept that these male reproductive abnormalities may be signs of a single underlying entity: testicular dysgenesis syndrome (TDS). This syndrome, caused by nonspecific delays and aberrations of early testicular development, may be increasingly common because of deteriorating environmental and life-style factors that impair gonadal development. Geographical and ethnic differences in the incidence of various forms of TDS could be explained either by differences in exposure to adverse factors or by differences in genetic susceptibility to these factors.     

Fetal radiation exposure induces testicular cancer in genetically susceptible mice

The prevalence of testicular germ cell tumors (TGCT), a common solid tissue malignancy in young men, has been annually increasing at an alarming rate of 3%. Since the majority of testicular cancers are derived from germ cells at the stage of transformation of primordial germ cell (PGC) into gonocytes, the increase has been attributed to maternal/fetal exposures to environmental factors. We examined the effects of an estrogen (diethylstilbestrol, DES), an antiandrogen (flutamide), or radiation on the incidence of testicular germ cell tumors in genetically predisposed 129.MOLF-L1 (L1) congenic mice by exposing them to these agents on days 10.5 and 11.5 of pregnancy. Neither flutamide nor DES produced noticeable increases in testis cancer incidence at 4 weeks of age. In contrast, two doses of 0.8-Gy radiation increased the incidence of TGCT from 45% to 100% in the offspring. The percentage of mice with bilateral tumors, weights of testes with TGCT, and the percentage of tumors that were clearly teratomas were higher in the irradiated mice than in controls, indicating that irradiation induced more aggressive tumors and/or more foci of initiation sites in each testis. This radiation dose did not disrupt spermatogenesis, which was qualitatively normal in tumor-free testes although they were reduced in size. This is the first proof of induction of testicular cancer by an environmental agent and suggests that the male fetus of women exposed to radiation at about 5-6 weeks of pregnancy might have an increased risk of developing testicular cancer. Furthermore, it provides a novel tool for studying the molecular and cellular events of testicular cancer pathogenesis.     

Time trends in testicular cancer in Croatia 1983-2007: rapid increases in incidence, no declines in mortality

Testicular cancer, although a rare malignancy, represents the most common cancer in young male populations of Western origin. While increasing incidence trends of testicular cancer have been reported, mortality is declining in many high-resource settings. Using national data from the Croatian National Cancer Registry for the period 1983-2007, time trends were analysed by joinpoint regression and Age-Period-Cohort models. The present study is the first to analyse the testicular cancer trends in the Croatian population. Over the 25-year period, a mean number of 89 incident cases and 13 deaths were reported annually. The observed mean annual increases in age-standardised rates were 7.0% for incidence and 1.6% for mortality, with no abrupt linear changes (joinpoints) identified. The incidence rates of testicular cancer incidence have been steeply increasing in successive cohorts born since the mid-1930s. The rapid rise in testicular cancer incidence in the Croatian population appears to be one of the highest rates of increase recorded in Europe and worldwide. The lack of decline in the mortality rates over time, while based on relatively few deaths, highlights a need for improvements in diagnostics and management of therapy in Croatia in order to improve the survival and quality-of-life of testicular cancer patients.     

Évolution du cancer du testicule en France

As in many countries, the mortality rate of testicular cancer in France has decreased from 0.75 in 1978 to 0.25 per 100,000 in 2000 (standardized on world population). Over the same period, the incidence rate increased from 3.17 in 1978 to 4.82 per 100,000 in 2000 (standardized on world population). However, although the incidence of seminoma has increased continually with all birth cohorts, the incidence of non-seminomas first decreased for the men born between the first and second world wars and then increased at the same rate as the seminoma rate. No explanation for this pattern has yet been provided, but it does not appear to be simply an artefact. A North/South and East/West gradient has been observed, as the incidence varies from 4.0 in the South West to 8.0 in the North East. There is an estimated 1,500 new cases of testicular cancer each year in France, including 960 new cases for men between the ages of 15 and 40.     

Testicular germ cell tumors. Classification based on fine needle aspiration biopsy

Fine needle aspiration (FNA) biopsy was performed preoperatively on 13 patients with testicular germ cell tumors. The cytologic typing of the tumors was based on the presence or absence of seminoma, embryonal carcinoma, yolk-sac tumor, choriocarcinoma and teratoma in the aspirate. The cytologic findings showed good agreement with the histologic findings. Only four cases showed a single type of tumor; the other nine cases showed as many as four different tumor components. A few characteristic cytologic features proved to be sufficient for tumor typing; this suggests that FNA biopsy cytology can also be useful in identifying metastatic germ cell tumors in extra-gonadal sites.     

Helicobacter species are associated with possible increase in risk of biliary lithiasis and benign biliary diseases

Background

Late relapses of testicular germ cell tumor are uncommon. We report a case of cervical mature teratoma appeared 17 years after treatment of testicular teratocarcinoma.

Case presentation

A 20- year- old patient underwent left sided orchiectomy followed by systemic therapy and retroperitoneal residual mass resection in 1989. He remained in complete remission for 200 months. In 2005 a huge left supraclavicular neck mass with extension to anterior mediastinum appeared. Radical surgical resection of the mass was performed and pathologic examination revealed mature teratoma.

Conclusion

This is one of the longest long-term reported intervals of a mature teratoma after treatment of a testicular nonseminoma germ cell tumor. This case emphasizes the necessity for follow up of testicular cancer throughout the patient's life.     

The rising incidence of testicular cancer among young men in Canada,data from 1971–2015

BackgroundTesticular cancer is the most common malignancy among young men aged 15–44 in Canada. The goal of this analysis was to examine age-period-cohort effects of testicular cancer incidence between 1971 and 2015.MethodsData were collected from the National Cancer Incidence Reporting System and the Canadian Cancer Registry. Birth cohort models were fit using the National Cancer Institute’s web tool. Incidence annual percent changes were estimated using NCI’s Joinpoint Regression Program.ResultsIncidence of testicular cancer in Canada has increased steadily since 1971. A birth cohort effect was observed for men born in the years after 1945. The rate of testicular cancer peaks at age 35 and drops off with increasing age.ConclusionIncidence of testicular cancer has risen dramatically in Canada in recent decades and the cohort effect indicates the need to investigate exposures that have increased since 1945 and that may affect development in young men.     

Risk of testicular cancer in subfertile men: case-control study

ObjectiveTo evaluate the association between subfertility in men and the subsequent risk of testicular cancer.DesignPopulation based case-control study.SettingThe Danish population.ParticipantsCases were identified in the Danish Cancer Registry; controls were randomly selected from the Danish population with the computerised Danish Central Population Register. Men were interviewed by telephone; 514 men with cancer and 720 controls participated.ResultsA reduced risk of testicular cancer was associated with paternity (relative risk 0.63; 95% confidence interval 0.47 to 0.85). In men who before the diagnosis of testicular cancer had a lower number of children than expected on the basis of their age, the relative risk was 1.98 (1.43 to 2.75). There was no corresponding protective effect associated with a higher number of children than expected. The associations were similar for seminoma and non-seminoma and were not influenced by adjustment for potential confounding factors.ConclusionThese data are consistent with the hypothesis that male subfertility and testicular cancer share important aetiological factors.

Key messages

• The incidence of testicular cancer has increased in the past 50 years, and there is some evidence to suggest that sperm quality has decreased in the same period
• It has been hypothesised that common aetiological factors may exist for testicular cancer and for male subfertility
• The association between male subfertility and subsequent risk of testicular cancer is strong and consistent with the hypothesis of a common aetiology
• The association is similar for seminoma and non-seminoma, and it persists when several potentially confounding factors are taken into account

     

Mutations in LRRC50 Predispose Zebrafish and Humans to Seminomas

Seminoma is a subclass of human testicular germ cell tumors (TGCT), the most frequently observed cancer in young men with a rising incidence. Here we describe the identification of a novel gene predisposing specifically to seminoma formation in a vertebrate model organism. Zebrafish carrying a heterozygous nonsense mutation in Leucine-Rich Repeat Containing protein 50 (lrrc50 also called dnaaf1), associated previously with ciliary function, are found to be highly susceptible to the formation of seminomas. Genotyping of these zebrafish tumors shows loss of heterozygosity (LOH) of the wild-type lrrc50 allele in 44.4% of tumor samples, correlating with tumor progression. In humans we identified heterozygous germline LRRC50 mutations in two different pedigrees with a family history of seminomas, resulting in a nonsense Arg488* change and a missense Thr590Met change, which show reduced expression of the wild-type allele in seminomas. Zebrafish in vivo complementation studies indicate the Thr590Met to be a loss-of-function mutation. Moreover, we show that a pathogenic Gln307Glu change is significantly enriched in individuals with seminoma tumors (13% of our cohort). Together, our study introduces an animal model for seminoma and suggests LRRC50 to be a novel tumor suppressor implicated in human seminoma pathogenesis.     

Le carcinome in situ du testicule — un précurseur du cancer à cellule germinale. Revue de la pathogenèse et aspects cliniques

Testicular germ cell tumors are different than other solid tumours with regard to their epidemiology and certain biological aspects. Pathogenesis of this malignancy remains unknown with the exception that all types of germ cell tumours in young adults originate from a common precursor:carcinoma in situ (CIS) cell. A recent dramatic increase in the incidence of testicular cancer suggests that environmental factors, especially those acting during development, may play a role. This review summarises the most important biological features of testicular CIS and discusses clinical management.     

The Amoroso Lecture. The human spermatozoon--a cell in crisis?

A great deal of evidence has accumulated in recent years to suggest that there has been a gradual increase in male reproductive pathology over the past 30-40 years, as evidenced by increased rates of testicular cancer and declining semen quality. The hypothesis is advanced that this phenomenon is causally related to the ability of male germ cells to generate reactive oxygen metabolites. When produced in low levels, such metabolites are thought to enhance sperm function by stimulating DNA compaction and promoting a redox-regulated cAMP-mediated pathway that is central to the induction of sperm capacitation. When produced in excessive amounts, the same metabolites stimulate DNA fragmentation and a loss of sperm function associated with peroxidative damage to the sperm plasma membrane. Free radical-induced mutations in the male germ line may also be involved in the aetiology of childhood cancer and recent increases in the incidence of seminoma. In light of these considerations, establishing the mechanisms for free radical generation by the male germ line and determining the factors that influence this activity are important objectives for future research in this area.     

Augmentation de l’incidence du cancer du testicule: état de la question

Although germ cell cancer is rare (about 1% of cancers in male), it is the commonest cancer in young man. Many studies in Europe, Northern America and Australia show that incidence rates of testis cancer are climbing. In Northern Europe and America, where cancer registration exist since the fifties, it is showed that overall age-adjusted incidence rate of testis cancer has increased more than 3 fold during the past 50 years. This increase affect particularly teenagers and young men. The increase of incidence rates is less documented in under developed countries but recent studies seem to confirm an increase of incidence rates in many parts of the world, even if testis cancer remain rarer in non Caucasian populations. Etiologies of a such increase are still unknown, but arguments point in view a possible relation between environmental hormone disrupters and many hormonodependent cancers, such as testicular neoplasm, the cancer of the breast or even prostate cancer. Epidemiological studies with large sample size are needed to identify risk factors responsible for the increase of incidence rates of testis cancer.     

The incidence of male genital tumors: a cellular model for the age dependence.

Most human tumors, including most male genital tumors, exhibit an exponential increase in incidence with advancing age of the host. This exponential age-incidence pattern can be explained by the accumulation of mutations in the stem cells of the tissues of tumor origin. The age-incidence pattern for testicular tumors, however, is unique with a large linear increase in incidence from age 14 to 30 and a linear decline in incidence from age 30 to 60. After age 60, the incidence of testicular tumors remains low and constant. The probability of testicular tumorigenesis is determined by the susceptibility of male germ cells to neoplastic mutation and/or the neoplastic mutagenicity of the male germ cell environment. Since there is no evidence for an environmental mutagen which is specific for male germ cells, and since male germ cells are unusually susceptible to mutation, we interpret the variation in testicular tumor incidence with age as a reflection of the susceptibility of male germ cells to neoplastic mutation. Cell are most susceptible to mutation during genome replication and we propose a model for testicular tumorigenesis which is consistent with the available data on male germ cell proliferation and with the data on testicular tumor incidence.     

Incidence trends in oesophageal cancer by histological type: An updated analysis in Sweden

BackgroundWe aimed to update incidence trends of oesophageal cancer by histological type in Sweden.MethodsUsing data from the Swedish Cancer Registry, we examined incidence trends of oesophageal cancer by histological types in individuals aged ≥50 years in 1970–2014 using log-linear joinpoint regressions.ResultsThe age-standardised incidence rate of oesophageal adenocarcinoma in men increased on average by 3.0% per year in 1970–1994, followed by a more rapid increase of 13.7% per year in 1994–2000, and a slower increase of 2.6% per year in 2010–2014. The rate of oesophageal adenocarcinoma in women increased on average by 4.2% per year during the entire period. The rate of squamous cell carcinoma generally decreased over the past 2–3 decades in both sexes.ConclusionsThe incidence of oesophageal adenocarcinoma continues to rise in Sweden, although the increase seems to have slowed down in men since 2000. The incidence of oesophageal squamous cell carcinoma is decreasing.     

Nuclear DNA content and proliferative potential of human carcinoma in situ cells in testes of intersex children

Gonocytes, fetal germ cells, when persisted beyond infantile period of life are considered as preinvasive testicular germ cell cancer (carcinoma in situ--CIS). The aim of the study was to investigate nuclear DNA content and proliferative potential of CIS cells together with the expression of placental-like alkaline phosphatase (PLAP), a marker of CIS and germ cell cancer. In dysgenetic testes of 4 intersex children proliferating cell nuclear antigen (PCNA) and PLAP were examined immunohistochemically. DNA content was assessed by densitometry of nucleus in Feulgen stained histologic sections. High incidence of aneuploidy (95.1-97.6% of CIS cells with 2.6-6.8c) was found with the predominant DNA pattern of tri- and tetraploidy in children aged 1 to 3 years. The incidence of triploidy (65-78.1% of cells) was similar to the incidence of the expression of PCNA (53.4-62%), what indicates that part of hyperploid germ cells might represent phase S of cell cycle, but the rest of hyperploid cells might represent neoplastic transformation. In turn, germ cells of 8-months-old patient were predominantly diploid with low incidence of PCNA positive cells which indicate that proliferation/neoplastic transformation of abnormal germ cells is significant mostly after 1 year of age in intersex children. The frequency of PLAP expression in CIS cells (3.1-27% of cells) was weakly related to the frequency of aneuploidy what limits the usefulness of PLAP reaction for the detection of CIS cells.