The existence of a true mixed germ cell-sex cord stromal tumor (MGSCT) of the testis remains controversial. Based on our experience with rare testicular tumors in this spectrum, we sought to perform a detailed clinicopathologic and molecular study of MGCSCT. Eight cases of testicular MGSCT were morphologically reviewed, screened for chromosomal aberrations (using array comparative genomic hybridization (aCGH) and low pass genomic sequencing), and analyzed by next generation sequencing (The Illumina TruSight Tumor 170). Immunohistochemistry for OCT3/4, Nanog, SALL4, DMRT1, and inhibin was performed on the cohort. Clinical data and follow-up were assessed by medical record review. All patients were karyotypically normal men aged 27-74 years (median 41). All tumors had a similar biphasic morphology characterized by various proportions of the sex cord component resembling granulosa cell tumor of adult type and the germ cell component cytomorphologically akin to spermatocytic tumor. Germ cells were haphazardly scattered throughout the tumor or arranged in larger groups, without tubular formation. In 4 cases, atypical mitoses were found within the germ cells. Additionally, in 2 cases there was invasion into the spermatic cord, adjacent hilar soft tissue and into the tumor capsule, which contained both tumor components. Immunohistochemically, focal nuclear expression of DMRT1 was found in the germ cell component in 7/7 analyzable tumors, while SALL4 was positive in 6 cases and negative in one case. All tumors were negative with OCT3/4 and Nanog. The sex cord stromal component had immunoreactivity for inhibin in 7/7 analyzable cases. Four of 8 cases were cytogenetically analyzable: 4/8 by low pass genomic sequencing and 2/8 by aCGH. The results of both methods correlated well, revealing mostly multiple chromosomal losses and gains. One case revealed loss of chromosome 21; 1 case had loss of chromosomes 21 and 22 and partial gain of 22; 1 case had loss of chromosomes 22 and Y, partial loss of X, and gain of chromosomes 20, 5, 8, 9, 12, and 13; and the remaining one gain of chromosomes 20, 3, 6, 8, 2x(9), 11, 2x(12), 13, 14, 18, and 19. Three cases were analyzable by NGS; clinically significant activating mutations of either FGFR3 or HRAS were not detected in any case. Follow-up was available for 4 patients (12, 24, 84, and 288 months) and was uneventful in all 4 cases. The identification of extratesticular invasion of both the germ cell and sex cord stromal components, the DMRT1 expression, and the presence of atypical mitoses in germ cells argue for the neoplastic nature of the germ cell component. The molecular genetic study revealing multiple chromosomal losses and gains in a subset of the cases provides the first evidence that molecular abnormalities occur in testicular MGSCT. Multiple chromosomal aneuploidies, namely, recurrent losses of chromosomes 21 and 22 and gains of 8, 9, 12, 13, and 20, indicate that the germ cell component might be related to the morphologically similar spermatocytic tumor, which is characterized by extensive aneuploidies including recurrent gains of chromosomes 9 and 20 and loss of chromosome 7. In summary, our data support that rare examples of true MGSCT of the testis do exist and they represent a distinct tumor entity with admixed adult-type granulosa cell tumor and spermatocytic tumor components.
- MeSH
- aneuploidie * MeSH
- biopsie MeSH
- dospělí MeSH
- fenotyp MeSH
- genetická predispozice k nemoci MeSH
- germinální a embryonální nádory chemie genetika patologie MeSH
- gonadální stromální nádory chemie genetika patologie MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidské chromozomy * MeSH
- nádorové biomarkery analýza genetika MeSH
- senioři MeSH
- srovnávací genomová hybridizace MeSH
- testikulární nádory chemie genetika patologie MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
In the present study, we investigated protein expression of the transcription factors mammalian doublesex and mab-3 related transcription factor 1 (DMRT1), basic helix-loop-helix transcription factor-like 5 (TCLF5), and octamer-binding transcription factor 4 (OCT4) in normal human spermatogenesis, testicular mixed germ cell-sex cord stromal tumor (MGC-SCST), spermatocytic tumor, and seminoma. In normal human spermatogenesis, DMRT1 is expressed in the nuclei of spermatogonia but not in those of more mature germ cells. By way of contrast, TCLF5 is expressed in the nuclei of some clusters of primary spermatocytes that have entered meiosis 1, in secondary spermatocytes, and in round (early) spermatids in the seminiferous tubules of adults during the reproductive years. OCT4 is expressed in primordial germ cells but not in the seminiferous tubules of the normal adult testis during the reproductive years. DMRT1 is expressed in the germ cells of both testicular MGC-SCST and spermatocytic tumor, whereas TCLF5 is not expressed in either neoplasm. These low-grade neoplasms, however, differ histologically in that all the germ cell nuclei of testicular MGC-SCST resemble spermatogonia, whereas in spermatocytic tumor, the nuclei of the medium-sized and large cells resemble those of primary spermatocytes. Both neoplasms lack expression of OCT4. By way of contrast, in seminoma, a fully malignant testicular germ cell tumor, the germ cell nuclei express OCT4 but do not express either DMRT1 or TCLF5.
- MeSH
- biopsie MeSH
- buněčné jádro chemie patologie MeSH
- germinální a embryonální nádory chemie patologie MeSH
- imunohistochemie MeSH
- lidé MeSH
- nádorové biomarkery analýza MeSH
- oktamerní transkripční faktor 3 analýza MeSH
- semenotvorné kanálky chemie patologie MeSH
- seminom chemie patologie MeSH
- spermatocyty chemie patologie MeSH
- spermatogeneze MeSH
- testikulární nádory chemie patologie MeSH
- transkripční faktory bHLH analýza MeSH
- transkripční faktory analýza MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Glypican 3 is a membrane-bound heparan sulfate proteoglycan, which has recently been identified as a marker for liver cancer and germ cell malignancies. Individuals with loss-of-function mutations for the glypican 3 gene exhibit Simpson-Golabi-Behmel syndrome, a rare X-linked overgrowth disorder. Expression of glypican 3 mRNA and protein is normally silenced in most adult organs and may reappear during malignant transformation. In the past few years, immunohistochemical and molecular characteristics of glypican 3 in hepatocellular carcinoma have been elucidated. More recently, glypican 3 has been emerging as a new diagnostic marker for germ cell tumors and especially testicular and ovarian yolk sac tumors. However, in other tumors such as renal cell carcinomas, squamous cell carcinomas, and melanomas, studies disagree on the level of glypican 3 expression. Finally, there is the controversial notion of glypican 3 as a tumor suppressor gene. In this review article, we update current knowledge on glypican 3 expression in normal and neoplastic tissues, evaluate its utility as a tumor marker in clinical practice, and explore its role as a novel oncofetal protein with clinical implications. Our focus is on the diagnostic value of glypican 3 in germ cell tumors and other neoplasms in addition to hepatocellular carcinoma. In conclusion, glypican 3 has been proven to be a useful immunohistochemical marker in distinguishing yolk sac tumors, choriocarcinomas, and Wilms tumors from other malignancies histologically mimicking these primitive tumors. Clinically, we recommend that glypican 3 be used as part of a panel of markers in subtyping testicular germ cell tumors.
- MeSH
- biopsie MeSH
- genetické testování MeSH
- germinální a embryonální nádory krev chemie diagnóza genetika patologie MeSH
- glypikany * analýza krev genetika MeSH
- hepatocelulární karcinom krev chemie diagnóza genetika patologie MeSH
- imunohistochemie MeSH
- lidé MeSH
- nádorové biomarkery * analýza krev genetika MeSH
- nádory jater krev chemie diagnóza genetika patologie MeSH
- nádory vaječníků krev chemie diagnóza genetika patologie MeSH
- prediktivní hodnota testů MeSH
- prognóza MeSH
- testikulární nádory krev chemie diagnóza genetika patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Expression of the p53 oncoprotein was examined in a wide range of primary human testicular germ-cell tumours using a new mouse monoclonal antibody (MAb) BP53-11 raised and characterized in this study, in parallel with a polyclonal rabbit antiserum CM-1. Immunohistochemistry on paraffin sections showed positive nuclear reaction in at least a fraction of malignant cells in 90 (84%) out of 107 cases studied. Aberrant accumulation of the p53 protein was found among testicular tumours of all major histological types, although generally a higher percentage of positive cases and a higher proportion of p53 over-expressing nuclei within individual lesions was observed in embryonal carcinomas when compared with seminomas. The typical heterogeneous staining pattern characteristic of histological specimens was also found in a cultured cell line derived from a human embryonal carcinoma. In contrast to immunohistochemically undetectable levels in normal testes and morphologically normal tissue areas in the tumour-bearing testes, the accumulation of the p53 protein was clearly identified in a high proportion (59% of cases) of the pre-invasive lesions with positive atypical intratubular germ cells often found in the tissue adjacent to invasive tumours. Altered expression of the p53 protein is therefore a unifying feature of the majority of invasive male germ-cell tumours and the change resulting in high levels of p53 appears to be a relatively early step in the human testicular cancer pathogenesis.
- MeSH
- choriokarcinom chemie MeSH
- dysgerminom chemie MeSH
- germinální a embryonální nádory chemie MeSH
- lidé MeSH
- mezonefrom chemie MeSH
- monoklonální protilátky diagnostické užití MeSH
- mutace * genetika MeSH
- nádorový supresorový protein p53 * analýza genetika MeSH
- teratom chemie MeSH
- testikulární nádory * chemie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
