Expression of Kit and Etv1 in restricted brain regions supports a brain-cell progenitor as an origin for cranial germinomas.

Mismigrating germ-cell progenitors have historically been accepted as the cell of origin for central nervous system (CNS) germinomas. However, an alternative hypothesis suggests that CNS germinomas arise from a brain-cell progenitor. Germinomas often acquire Kit signaling pathway mutations, and there is evidence for an oncogenic relationship between KIT and the ETV1 transcription factor. KIT appears to be necessary to stabilize ETV1, and ETV1 then activates oncogenesis-associated genes. ETV1 expression is not increased by KIT, so ETV1 already needs to be expressed in order for KIT to have an oncogenic function. Therefore, if brain-cell progenitors are the cell of origin for germinomas, those cells would already need to coexpress ETV1 and KIT. We examined Kit and Etv1 in situ hybridization data from the Allen Brain Atlas, for mouse brain tissue at various stages of development. Both Kit and Etv1 were expressed in the regions where germinomas most commonly arise, and in the medulla oblongata. All human cases of germinomas correlated to the regions where ETV1 and KIT are coexpressed. We therefore postulate that germinomas in the brain share a similar mechanism with other KIT-driven cancers, which supports the hypothesis that germinomas arise from a brain-cell progenitor.

Intracranial germinoma in the pineal region arising after subtotal resection of epidermoid cyst: case report.

We present an unusual case of a germinoma of the pineal region arising adjacent to an epidermoid cyst in a 16-year-old male. Initial imaging findings were classic for epidermoid cyst. The patient underwent two partial resections at an outside institution, each specimen demonstrating pure epidermoid cyst. Follow-up imaging over a period of 24 months showed an area of progressive contrast enhancement adjacent to the initial lesion, suggesting the development of a neoplasm. Given the area of contrast enhancement in addition to worsening headaches and visual changes, he underwent a third and final resection at our institution. Pathology revealed a mixed germ cell tumor with prominent germinoma component in addition to a well-differentiated epidermoid cyst. Details of his imaging and pathologic findings are presented, and possible explanations for these findings are explored, the most likely of which is lack of complete resection at the onset failed to identify the whole of the neoplasm. We conclude that pediatric epidermoid cysts of the pineal region should always receive close follow-up, particularly when total resection is not performed.

Germinoma presenting as a fourth cranial nerve palsy in a patient with adenomatous polyposis coli (APC) gene mutation.

A 17-year-old boy with adenomatous polyposis and a history of an adenomatous polyposis coli (APC) gene mutation (IVS13(-2) A>G) presented for evaluation of vertical, binocular diplopia. Examination was suggestive of a fourth (trochlear) nerve palsy. A history of headaches was elicited and led to further investigation with neuroimaging, which identified a germinoma in the tectal plate and secondary hydrocephalus. We report the clinical, radiological, and histopathological findings of this patient, who to our knowledge is the first reported case of a germinoma occurring in association with adenomatous polyposis.

Recurrent pure CNS germinoma with markedly elevated serum and cerebrospinal fluid human chorionic gonadotropin-beta (HCGß).

Controversy continues regarding what level of serum and/or cerebrospinal fluid (CSF) human chorionic gonadotrophin-beta (HCGß) is consistent with pure germinoma of the central nervous system (CNS). We report a 10-year female with biopsy-proven pure germinoma and normal serum and CSF HCGß who experienced subsequent biopsy-proven recurrences of germinoma. At recurrence, serum and CSF HCGß levels were 560 and 3,202 mIU/ml, respectively, although final autopsy demonstrated pure germinoma. This case illustrates the need to re-evaluate the assumption that pathologically pure germinomas may be associated with high levels of HCGß which are unrelated to nongerminomatous germ cell tumor (NGGCT)/choriocarcinomatous elements.

Re-evaluation of the significance of cerebrospinal fluid human chorionic gonadotropin in detecting intracranial ectopic germinomas.

This study was conducted to establish a reference value for cerebrospinal fluid (CSF) human chorionic gonadotropin (hCG) levels. We also evaluated the sensitivity of CSF hCG as a biomarker to detect intracranial ectopic germinomas that arise in rare sites other than the pineal and suprasellar regions. CSF hCG was measured in 201 male patients who had various types of neurological disease (not tumours of germ cell origin or other malignant tumours). A reference value of 1.009 U/L was established, and the CSF hCG level among different age groups was not significantly different. CSF and serum hCG were measured before and after radiotherapy in 14 consecutive patients with intracranial ectopic germinomas. The CSF hCG levels were all above 1.009 U/L before radiotherapy. In male patients, a CSF hCG value above 1.009 U/L suggests abnormal intrathecal hCG secretion. These results demonstrate that the CSF hCG assay is a sensitive method for diagnosing intracranial ectopic germinoma.

Increased risk of testicular germ cell cancer among infertile men.

BACKGROUND: The risk of testicular cancer is thought to be higher among men seeking infertility treatment compared with the general population. Confirmation of this risk in a large US cohort of at-risk patients is lacking. This study explored the association between male infertility and subsequent development of testicular cancer in a US-based cohort. METHODS: A total of 51 461 couples evaluated for infertility from 1967 to 1998 were recruited from 15 California infertility centers. We linked data on 22 562 identified male partners to the California Cancer Registry. The incidence of testicular cancer in this cohort was compared with the incidence in an age-matched sample of men from the general population using the Surveillance Epidemiology and End Results program. We analyzed the risk for testicular cancer in men with and without male factor infertility using a Cox proportional hazards regression model. RESULTS: Thirty-four post-infertility-diagnosis cases of histologically confirmed testicular cancer were identified. Men seeking infertility treatment had an increased risk of subsequently developing testicular cancer (standardized incidence ratio, 1.3; 95% confidence interval, 0.9-1.9), with a markedly higher risk among those with known male factor infertility (2.8; 1.5-4.8). In multivariable analysis, men with male factor infertility were nearly 3 times more likely to develop testicular cancer compared with those without (hazard ratio, 2.8; 95% confidence interval, 1.3-6.0). CONCLUSION: Men with male factor infertility have an increased risk of subsequently developing testicular cancer, suggesting the existence of common etiologic factors for infertility and testicular cancer.

Malignant intracranial germinoma in Smith-Lemli-Opitz syndrome: cholesterol homeostasis possibly connecting morphogenesis and cancer development.

Smith-Lemli-Opitz syndrome is a rare hereditary autosomal recessive disease characterized by deficiency of 7-dehydrocholesterol reductase. Clinical picture encompasses prenatal and postnatal growth abnormalities and multisystemic structural malformations. To date, predisposition for tumor development is not considered a feature associated with this syndrome. Here, we describe a 16-year-old boy with Smith-Lemli-Opitz syndrome who developed cerebral germinoma. To our knowledge, this is the first report of association of this syndrome with malignant intracranial germ-cell tumor.

Anterior mediastinal immature teratoma with precocious puberty in a child with Klinefelter syndrome.

Klinefelter syndrome occurs in approximately 1 in 1000 males. A 4-year-old boy presented with precocious puberty and an anterior mediastinal mass. Serum alpha-fetoprotein and human chorionic gonadotropin levels were mildly increased. Computed tomography revealed a germ cell tumor (GCT) of the mediastinum. Complete resection of the tumor was performed. Histologic analysis revealed an immature teratoma. Males with Klinefelter syndrome develop GCTs at a rate 50 times higher than unaffected males. This case report calls attention to the need to rule out Klinefelter syndrome in boys who present with precocious puberty and a mediastinal GCT.

Maternal hormone levels and risk of cryptorchism among populations at high and low risk of testicular germ cell tumors.

Cryptorchism is one of the few well-described risk factors for testicular cancer. It has been suggested that both conditions are related to increased in utero estrogen exposure. The evidence supporting the "estrogen hypothesis" has been inconsistent, however. An alternative hypothesis suggests that higher in utero androgen exposure may protect against the development of cryptorchism and testicular cancer. In order to examine both hypotheses, we studied maternal hormone levels in two populations at diverse risks of testicular cancer; Black Americans (low-risk) and White Americans (high-risk). The study population of 200 mothers of cryptorchid sons and 200 mothers of noncryptorchid sons was nested within the Collaborative Perinatal Project, a cohort study of pregnant women and their children. Third trimester serum levels of estradiol (total, free, bioavailable), estriol, testosterone (total, free, bioavailable), sex hormone-binding globulin, alpha-fetoprotein, and the ratios of estradiols to testosterones were compared between the case and control mothers. The results found no significant differences in the levels of testosterone (total, free, bioavailable), alpha-fetoprotein, sex hormone-binding globulin, or in the ratios of estrogens to androgens. Total estradiol, however, was significantly lower in the cases versus the controls (P = 0.03) among all mothers and, separately, among White mothers (P = 0.05). Similarly, estriol was significantly lower among all cases (P = 0.05) and among White cases (P = 0.05). These results do not support either the estrogen or the androgen hypothesis. Rather, lower estrogens in case mothers may indicate that a placental defect increases the risk of cryptorchism and, possibly, testicular cancer.

Carcinoma in situ testis, the progenitor of testicular germ cell tumours: a clinical review.

Testicular germ cell tumours (TGCT), including seminomas, embryonal carcinomas, teratomas and yolk sac tumours, have a common precursor, the carcinoma in situ (CIS) cell. Recent gene expression studies displaying close similarity of CIS cells to embryonic stem cells support the longstanding theory that CIS most likely originates in utero from fetal gonocytes. The clinical association between the testicular dysgenesis syndrome components (TGCT, cryptorchidism, genital malformations, some forms of decreased spermatogenesis) also implies a prenatal origin. Despite high cure rates of TGCT, efforts should be made to obtain diagnosis at the CIS stage, as intervention is possible before an invasive tumour develops, thus reducing the necessity for intensive therapy. CIS may be suspected in patients with an assumed extragonadal GCT or cryptorchidism, and in intersex patients and selected cases with infertility (presenting with atrophic testes and ultrasonic microlithiasis). Surgical testicular biopsy seems the only reliable diagnostic method. The management of choice of unilateral CIS is orchidectomy, or localised irradiation in bilateral cases. At least 5% of TGCT patients present with contralateral CIS; therefore, contralateral biopsy is recommended at the time of orchidectomy. Further research is warranted to identify causal factors explaining the increasing incidence of TGCT and to obtain a method of non-invasive CIS detection.

Genetic alteration of poly(ADP-ribose) polymerase-1 in human germ cell tumors.

Accumulated evidence suggests that poly(ADP-ribose) polymerase-1 (PARP-1) is involved in DNA repair, cell-death induction, differentiation and tumorigenesis. Parp-1 deficiency also induces trophoblast differentiation from mouse embryonic stem cells during teratocarcinoma-like tumor formation. To understand the relationship of PARP-1 dysfunction and development of germ cell tumors, we conducted a genetic analysis of the PARP-1 gene in human germ cell tumors. Sixteen surgical specimens of germ cell tumors that developed in the brain and testes were used. Two known single nucleotide polymorphisms (SNPs) (Val762Ala and Lys940Arg), which are listed in the SNP database of the NCBI (National Center for Biotechnology Information), were detected. In both cases, cSNPs encoded amino acids located within peptide stretches in the catalytic domain, which are highly conserved among various animal species. Furthermore, another novel sequence alteration, a base change of ATG to ACG, was identified in a tumor specimen, which would result in the amino acid substitution, Met129Thr. This base change was observed in one allele of both tumor and normal tissues, suggesting that it is either a rare SNP or a germline mutation of the PARP-1 gene. Notably, the amino acid Met129 is located within the second zinc finger domain, which is essential for DNA binding and is conserved among animal species. One SNP in intron 2 and one in the upstream 5'-UTR (untranslated region) were also detected.

Risk of childhood germ cell tumors in association with parental smoking and drinking.

BACKGROUND: The etiology of childhood germ cell tumors (GCT) is not well understood. The Children's Oncology Group conducted the largest case-control study of childhood GCT to investigate whether parental exposures to smoking and alcohol contributed to the disease. METHODS: Cases included 274 children with GCT diagnosed between January 1, 1993 and December 31, 2001 who were age <15 years. Controls (n=421) were selected by random digit dialing and were frequency matched based on gender, age (+/-1 year), and geographic area. Exposure information was collected from subjects' parents using independent telephone interviews and self-administrated questionnaires. RESULTS: No association was found between parental smoking or drinking alcohol and risk of childhood GCT (for smoking: odds ratio [OR]=1.0, 95% confidence interval [95% CI], 0.8-1.3 and OR = 1.2, 95% CI, 0.9-1.5, for mothers and fathers, respectively; for drinking: OR=0.9, 95% CI, 0.7-1.2 and OR=1.0, 95% CI, 0.8-1.3, for mothers and fathers, respectively). No significant trend was observed for length of maternal exposure to passive smoking during the index pregnancy and GCT risk (for total subject: P=0.77; boys: P=0.52; girls: P=0.93). CONCLUSIONS: The authors found no evidence that childhood GCT was related to prenatal exposure to parental cigarette smoking, alcohol drinking, and maternal passive smoking.

Transcription factor AP-2gamma is a developmentally regulated marker of testicular carcinoma in situ and germ cell tumors.

PURPOSE: Transcription factor activator protein-2gamma (TFAP2C, AP-2gamma) was reported previously in extraembryonic ectoderm and breast carcinomas but not in the testis. In our recent gene expression study we detected AP-2gamma in carcinoma in situ testis (CIS, or intratubular germ cell neoplasia), precursor of testicular germ cell tumors. In this study we aimed to investigate the expression pattern of AP-2gamma and to shed light on this factor in germ cell differentiation and the pathogenesis of germ cell neoplasia. EXPERIMENTAL DESIGN: We analyzed expression pattern of AP-2gamma at the RNA and protein level in normal human tissues and a panel of tumors and tumor-derived cell lines. In the gonads, we established the ontogeny of expression of AP-2gamma in normal and dysgenetic samples. We also investigated the regulation of AP-2gamma by steroids and retinoic acid. RESULTS: We detected abundant AP-2gamma in testicular CIS and in testicular germ cell tumors of young adults and confirmed differential expression of AP-2gamma in somatic tumors. We found that AP-2gamma expression was regulated by retinoic acid in an embryonal carcinoma cell line (NT2). The investigation of ontogeny of AP-2gamma protein expression in fetal gonads revealed that it was confined to oogonia/gonocytes and was down-regulated with germ cell differentiation. In some prepubertal intersex cases, AP-2gamma was detected outside of the normal window of expression, probably marking neoplastic transformation of germ cells. CONCLUSIONS: AP-2gamma is developmentally regulated and associated with the undifferentiated phenotype in germ cells. This transcription factor may be involved in self-renewal and survival of immature germ cells and tissue-specific stem cells. AP-2gamma is a novel marker of testicular CIS and CIS-derived tumors.

Involvement of E-cadherin and beta-catenin in germ cell tumours and in normal male fetal germ cell development.

Intercellular contacts, mediated by E-cadherin, are essential for germ cell migration and maturation. Furthermore, it has been suggested that decrease or loss of E-cadherin correlates with tumour progression and invasive behaviour. beta-catenin is involved in a number of different processes, including cell--cell interaction when bound to cadherins, and determination of cell fate in pluripotent cells when activated via the Wnt signal-transduction pathway. To shed more light on the role of these factors in normal fetal germ cell development and the pathogenesis of germ cell tumours (GCTs), the present study investigated the presence and localization of E-cadherin and beta-catenin by immunohistochemistry. E-cadherin was only weakly expressed in or absent from fetal germ cells of the second and third trimesters, and was not expressed in carcinoma in situ/intratubular germ cell neoplasia unclassified (CIS/ITGCNU) and gonadoblastoma, the precursor of an invasive GCT in dysgenetic gonads. In GCTs, it was generally not expressed in seminoma and dysgerminoma, but was found in the vast majority of non-seminoma cells. beta-catenin was found in the cytoplasm of fetal germ cells at all gestational ages and in spermatogenesis in post-pubertal testes. It was also present in CIS/ITGCNU and gonadoblastoma. Whereas seminomas and dysgerminoma were negative, non-seminoma cells were frequently found to express beta-catenin. Expression of both factors therefore reflects the degree of differentiation of these tumours. No differences for either E-cadherin or beta-catenin were observed between samples of tumours resistant or sensitive to chemotherapy, and E-cadherin expression did not correlate with vascular invasion. E-cadherin and beta-catenin therefore play a role in both normal and malignant germ cell development and differentiation that warrants further investigation, but they seem to be of limited value as predictive or prognostic factors in GCTs.

Risk factors in past histories and familial episodes related to development of testicular germ cell tumor.

BACKGROUND: A retrospective study was conducted to examine the host factors of 240 testicular germ cell tumor patients. This study was performed to address a new theory proposed by Skakkebaek called testicular dysgenesis syndrome which claims that cryptorchism, hypospadias, poor semen quality and testicular germ cell tumors are symptoms of an underlying testicular dysgenesis in uterus. METHODS: The past health histories and familial episodes of 240 testicular germ cell tumor patients were examined. The past health histories included cryptorchism, hypospadias, infertility, atrophic testis and inguinal hernia. RESULTS: Of the 240 patients, 13 (5.4%) had a history of cryptorchism or orchidopexy. Two (0.8%) showed existence of hypospadias or had experienced urethroplasty. Among 129 married couples, 104 (80.6%) couples were fertile. Three (1.3%) patients developed testicular tumors after they were diagnosed as infertile or came to the hospital with the complaints of infertility. Four (1.7%) had contralateral atrophic testis. 19 (7.9%) had experienced inguinal herniorrhaphy before age 15. Three (1.3%) had testicular germ cell tumor patients among their family or relatives. CONCLUSIONS: The testicular germ cell tumor patients showed a considerable incidence of complications such as cryptorchism, hypospadias and incomplete closure of processus vaginalis. Cryptorchism, perinatal factors and familial factors could be risks for developing testicular germ cell tumors.

The frequency of intratubular embryonal carcinoma: implications for the pathogenesis of germ cell tumours.

AIMS: To define the frequency and distribution of intratubular embryonal carcinoma (IEC) in an attempt to shed light on the pathogenesis of non-seminomatous germ cell tumours (NSGCTs). Intratubular germ cell neoplasia of unclassified type (IGCNU) is common in NSGCT; however, IEC is rarely described. METHODS AND RESULTS: Sixty-two germ cell tumours were reviewed. Immunochemistry for CD30, placental alkaline phosphatase (PLAP) and c-kit was performed. The distribution, immunohistochemistry and morphology of the intratubular neoplasia were noted. All cases showed widespread IGCNU with PLAP and c-kit staining. CD30 showed strong focal intratubular positivity in 20/31 NSGCTs, 1/29 seminomas and 1/4 mixed seminomas/NSGCTs. In 17 of these cases, the CD30+ tubules were not easily identified as IEC on routine stains. These tubules were scanty in number and c-kit was negative, though some showed patchy PLAP staining. The cells within these tubules differed morphologically from IGCNU. CONCLUSIONS: IEC defined by CD30 positivity is not always easily identified on haematoxylin and eosin staining. We suggest that IEC is a common intermediate step between IGCNU and NSGCTs. The patchy and focal distribution of IEC suggests it may evolve quickly to invasive disease.

Clinical review of 55 cases of malignant ovarian germ cell tumors.

PURPOSE OF INVESTIGATION: A retrospective analysis of 55 cases of malignant germ cell tumors in a 20-year period was done to evaluate the impact of conservative surgery and adjuvant treatment on survival and fertility. METHODS: Fifty-five cases of malignant ovarian germ cell tumors (MOGCTs) were studied. Mean age was 22 years. Dysgerminoma was the most common histotype (45%). RESULTS: Thirty-nine patients (71%) presented with FIGO surgical Stage I disease. Fertility-sparing surgery was performed in 39 (71%) women. Postoperative systemic chemotherapy was administered to 40 women (73%), 27 (68%) had received conservative treatment. One woman developed renal failure after the first cycle of chemotherapy and died a few days thereafter and there was one case of bleomycin-induced death due to pulmonary fibrosis. There were eight (14.5%) clinical recurrences. Overall survival rate for relapsing women was 75% (6/8). The recurrence rate for women treated conservatively was 15%, and it was 13% for those treated radically. With a median follow-up of 129 months the overall survival rate for the entire study-population was 90.9%. Eleven pregnancies occurred in 36 women treated with fertility-sparing surgery who were of child-bearing age. CONCLUSION: The management of MOGCTs with fertility-sparing surgery is a safe, practicable treatment option. The majority of these patients can retain normal ovarian function and reproductive potential after chemotherapy treatment.