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      Extragonadal germ cell tumors: Not just a matter of location. A review about clinical, molecular and pathological features

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          Abstract

          Extragonadal germ cell tumors (EGGCTs) are uncommon neoplasms, which arise in anatomical locations other than gonads. The pathogenesis of these neoplasms is still poorly understood and it is a matter of debate if they really represent extragondal primary neoplasms or rather extragondal metastasis from occult gonadal neoplasms. The actual observations suggest that EGGCTs represent a unique entity, so their biology and behavior are substantially different from gonadal counterparts. The diagnosis of EGGCTs is often challenging, and differential diagnosis is particularly wide. Nevertheless, a correct diagnosis is essential for the correct management of the patient. We summarize the state of art about EGGCTs, with particular emphasis on diagnosis and prognosis.

          Abstract

          Extragonadal germ cell tumors (EGGCTs) are uncommon neoplasms with peculiar molecular and pathological features; the diagnosis of these neoplasms may be challenging, due to wide differential diagnosis depending to the variable anatomical location. The authors summarize the state of art about EGGCTs, with particular emphasis on diagnosis and prognosis.

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          Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors.

          J. Sperger, X. Chen, J. Draper … (2011)
          Remarkably little is known about the transcriptional profiles of human embryonic stem (ES) cells or the molecular mechanisms that underlie their pluripotency. To identify commonalties among the transcriptional profiles of different human pluripotent cells and to search for clues into the genesis of human germ cell tumors, we compared the expression profiles of human ES cell lines, human germ cell tumor cell lines and tumor samples, somatic cell lines, and testicular tissue samples by using cDNA microarray analysis. Hierarchical cluster analysis of gene expression profiles showed that the five independent human ES cell lines clustered tightly together, reflecting highly similar expression profiles. The gene expression patterns of human ES cell lines showed many similarities with the human embryonal carcinoma cell samples and more distantly with the seminoma samples. We identified 895 genes that were expressed at significantly greater levels in human ES and embryonal carcinoma cell lines than in control samples. These genes are candidates for involvement in the maintenance of a pluripotent, undifferentiated phenotype.
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            Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis.

            Jörg Beyer, A. Gerl, Lothar Kanz … (2002)
            To characterize the clinical and biologic features of extragonadal germ cell tumor (EGCT) and to determine the overall outcome with currently available treatment strategies. Of an unselected population of 635 consecutive patients treated from 1975 through 1996 at 11 cancer centers, 341 patients (54%) had primary mediastinal EGCT, and 283 patients (45%) had retroperitoneal EGCT. Five hundred twenty-four patients (83%) had a nonseminomatous germ cell tumor (GCT), and 104 patients (16%) had a seminomatous histology. After platinum-based induction chemotherapy with or without secondary surgery, 141 patients (49%) with mediastinal nonseminomas (median follow-up, 19 months; range, 1 to 178 months) and 144 patients (63%) with retroperitoneal nonseminoma (median follow-up, 29 months; range, 1 to 203 months) are alive (P =.0006). In contrast, the overall survival rate for patients with a seminomatous EGCT is 88%, with no difference between patients with mediastinal or retroperitoneal tumor location (median follow-up, 49 months; range, 4 to 193 months; respective 70 months; range, 1 to 211 months). A significantly lower progression-free survival rate was found in seminoma patients treated with initial radiotherapy alone compared with chemotherapy. Nonseminomatous histology, presence of nonpulmonary visceral metastases, primary mediastinal GCT location, and elevated beta-human chorionic gonadotropin were independent prognostic factors for shorter survival. Hematologic malignancies (n = 17) occurred without exception in patients with primary mediastinal nonseminoma. Sixteen patients developed a metachronous testicular cancer despite the use of platinum-based chemotherapy. Whereas patients with pure seminomatous EGCT histology have a long-term chance of cure of almost 90% irrespective of the primary tumor site, 45% of patients with mediastinal nonseminomas are alive at 5 years. This outcome is clearly inferior compared with patients with nonseminomatous retroperitoneal primary tumors.
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              POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors.

              J Kononen, H Dekken, Jan Oirschot … (2003)
              Human germ cell tumors (GCTs) may have variable histology and clinical behavior, depending on factors such as sex of the patient, age at clinical diagnosis, and anatomical site of the tumor. Some types of GCT, i.e., the seminomas/germinomas/dysgerminomas and embryonal carcinomas (the stem cell component of nonseminomas), have pluripotent potential, which is demonstrated by their capacity to differentiate into somatic and/or extraembryonic elements. Although embryonal carcinoma cells are intrinsically pluripotent, seminoma/germinoma/dysgerminoma cells, as well as their precursor carcinoma in situ/gonadoblastoma cells, have the phenotype of early germ cells that can be activated to pluripotency. The other types of GCT (teratomas and yolk sac tumors of infants and newborn, dermoid cyst of the ovary, and spermatocytic seminoma of elderly) are composed of (fully) differentiated tissues and lack the appearance of undifferentiated and pluripotent stem cells. OCT3/4, a transcription factor also known as OTF3 and POU5F1, is involved in regulation of pluripotency during normal development and is detectable in embryonic stem and germ cells. We analyzed the presence of POU5F1 in GCT and other tumor types using immunohistochemistry. The protein was consistently detected in carcinoma in situ/gonadoblastoma, seminomas/germinoma/dysgerminoma, and embryonal carcinoma but not in the various types of differentiated nonseminomas. Multitumor tissue microarray analysis covering >100 different tumor categories and 3600 individual cancers verified that POU5F1 expression is specific for particular subtypes of GCT of adults. No protein was observed in GCT of newborn and infants, spermatocytic seminomas, and the various tumors of nongerm cell origin. In addition, no difference in staining pattern was found in chemosensitive and chemoresistant GCT of adults. These results indicate preservation of the link between POU5F1 and pluripotency, as reported during normal development, after malignant transformation. Therefore, POU5F1 immunohistochemistry is an informative diagnostic tool for pluripotent GCT and offers new insights into the histological heterogeneity of this cancer.
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                Author and article information

                Contributors
                Renato Franco:
                ORCID: https://orcid.org/0000-0002-8340-3184
                renato.franco@unicampania.it
                Journal
                Journal ID (nlm-ta): Cancer Med
                Journal ID (iso-abbrev): Cancer Med
                Journal ID (doi): 10.1002/(ISSN)2045-7634
                Journal ID (publisher-id): CAM4
                Title: Cancer Medicine
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2045-7634
                Publication date (Electronic): 30 September 2019
                Publication date Collection: November 2019
                Volume: 8
                Issue: 16 ( doiID: 10.1002/cam4.v8.16 )
                Pages: 6832-6840
                Affiliations
                [ 1 ] Pathology Unit Department of Mental and Physical Health and Preventive Medicine University of Campania “L. Vanvitelli” Naples Italy
                [ 2 ] Department of Psychology University of Campania “L. Vanvitelli” Caserta Italy
                [ 3 ] Uro‐Andrologic Oncology Unit Department of Uro‐Gynaecological Oncology Istituto Nazionale Tumori “Fondazione G. Pascale”—IRCCS Naples Italy
                Author notes
                [*] [* ] Correspondence

                Renato Franco, Pathology Unit, Department of Mental and Physical Healt and Preventive Medicine, University of Campania “Luigi Vanvitelli,” Via Luciano Armanni 20, 80100 Naples, Italy.

                Email: renato.franco@ 123456unicampania.it

                Author information
                https://orcid.org/0000-0002-8340-3184
                Article
                Publisher ID: CAM42195
                DOI: 10.1002/cam4.2195
                PMC ID: 6853824
                PubMed ID: 31568647
                SO-VID: a9238dac-0c9c-4db5-8575-6c706fe84aa9
                Copyright © © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 02 November 2018
                Date revision received : 25 March 2019
                Date accepted : 10 April 2019
                Page count
                Figures: 4, Tables: 1, Pages: 9, Words: 6004
                Funding
                Funded by: Progetto ONCONET 2.0—Linea progettuale 14 per l'implementazione della prevenzione e diagnosi precoce del tumore alla prostata e testicolo—Regione Campania, Italy
                Categories
                Subject: Review
                Subject: Clinical Cancer Research
                Subject: Reviews
                Custom metadata
                source-schema-version-number 2.0
                cover-date November 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.2 mode:remove_FC converted:05.12.2019

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: choriocarcinoma,chromosome 12p,embryonal carcinoma,extragonadal germ cell tumors,sall4,seminoma,sox2,teratoma,yolk sac tumor
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: choriocarcinoma, chromosome 12p, embryonal carcinoma, extragonadal germ cell tumors, sall4, seminoma, sox2, teratoma, yolk sac tumor

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