Abstract
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.
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References
Michal M, Vanecek T, Sima R, Mukensnabl P, Hes O, Kazakov DV, Matoska J, Zuntova A, Dvorak V, Talerman A (2006) Mixed germ cell sex cord-stromal tumors of the testis and ovary. Morphological, immunohistochemical, and molecular genetic study of seven cases. Virchows Archiv 448:612–622
Arroyo JG, Harris W, Laden SA (1998) Recurrent mixed germ cell-sex cord-stromal tumor of the ovary in an adult. Int J Gynecol Pathol 17:281–283
Talerman A, Roth LM (2007) Recent advances in the pathology and classification of gonadal neoplasms composed of germ cells and sex cord derivatives. Int J Gynecol Pathol 26:313–321
Talerman A (1972) A distinctive gonadal neoplasm related to gonadoblastoma. Cancer. 30:1219–1224
Zuntova A, Motlik K, Horejsi J et al (1992) Mixed germ cell-sex cord stromal tumor with heterologous structures. Int J Gynecol Pathol 11:227–233
Talerman A, van der Harten JJ (1977) Mixed germ cell-sex cord stroma tumor of the ovary associated with isosexual precocious puberty in a normal girl. Cancer. 40:889–894
Ulbright TM, Srigley JR, Reuter VE, Wojno K, Roth LM, Young RH (2000) Sex cord-stromal tumors of the testis with entrapped germ cells: a lesion mimicking unclassified mixed germ cell sex cord-stromal tumors. Am J Surg Pathol 24:535–542
Conlon N, Schultheis AM, Piscuoglio S, Silva A, Guerra E, Tornos C, Reuter VE, Soslow RA, Young RH, Oliva E, Weigelt B (2015) A survey of DICER1 hotspot mutations in ovarian and testicular sex cord-stromal tumors. Mod Pathol 28:1603–1612
Roth LM, Lyu B, Cheng L (2017) Perspectives on testicular sex cord-stromal tumors and those composed of both germ cells and sex cord-stromal derivatives with a comparison to corresponding ovarian neoplasms. Hum Pathol 65:1–14
Matoska J, Talerman A (1989) Mixed germ cell-sex cord stroma tumor of the testis. A report with ultrastructural findings. Cancer. 64:2146–2153
Sperga M, Martinek P, Vanecek T, Grossmann P, Bauleth K, Perez-Montiel D, Alvarado-Cabrero I, Nevidovska K, Lietuvietis V, Hora M, Michal M, Petersson F, Kuroda N, Suster S, Branzovsky J, Hes O (2013) Chromophobe renal cell carcinoma--chromosomal aberration variability and its relation to Paner grading system: an array CGH and FISH analysis of 37 cases. Virchows Archiv 463:563–573
Munchel S, Hoang Y, Zhao Y, Cottrell J, Klotzle B, Godwin AK, Koestler D, Beyerlein P, Fan JB, Bibikova M, Chien J (2015) Targeted or whole genome sequencing of formalin fixed tissue samples: potential applications in cancer genomics. Oncotarget. 6:25943–25961
Donati M, Kastnerova L, Martinek P, Grossmann P, Sticová E, Hadravský L, Torday T, Kyclova J, Michal M, Kazakov DV (2020) Spitz tumors with ROS1 fusions: a clinicopathological study of 6 cases, including FISH for chromosomal copy number alterations and mutation analysis using next-generation sequencing. Am J Dermatopathol 42:92–102
Bolen JW (1981) Mixed germ cell-sex cord stromal tumor. A gonadal tumor distinct from gonadoblastoma. Am J Clin Pathol 75:565–573
Talerman A (1980) The pathology of gonadal neoplasms composed of germ cells and sex cord stroma derivatives. Pathol Res Pract 170:24–38
Rames RA, Richardson M, Swiger F, Kaczmarek A (1995) Mixed germ cell-sex cord stromal tumor of the testis: the incidental finding of a rare testicular neoplasm. J Urol 154:1479
Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM (2016) The 2016 WHO classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. Eur Urol 70:93–105
Ulbright TM, Young RH (2007) Reply: mixed germ cell sex cord-stromal tumors of the testis and ovary. Virchows Archiv 450:131–132
Michal M, Hes O, Mukensnabl P, Kazakov DV (2007) Mixed germ cell sex cord-stromal tumours of the testis. Virchows Archiv 451:1095–1096
Roth LM, Michal M, Michal M Jr, Cheng L (2018) Protein expression of the transcription factors DMRT1, TCLF5, and OCT4 in selected germ cell neoplasms of the testis. Hum Pathol 82:68–75
Rosai J, Khodadoust K, Silber I (1969) Spermatocytic seminoma. II Ultrastructural study. Cancer 24:103–116
Jorgensen A, Nielsen JE, Blomberg Jensen M, Graem N, Rajpert-de Meyts E (2012) Analysis of meiosis regulators in human gonads: a sexually dimorphic spatio-temporal expression pattern suggests involvement of DMRT1 in meiotic entry. Mol Hum Reprod 18:523–534
Giannoulatou E, Maher GJ, Ding Z, Gillis AJM, Dorssers LCJ, Hoischen A, Rajpert-de Meyts E, WGS500 Consortium, McVean G, Wilkie AOM, Looijenga LHJ, Goriely A (2017) Whole-genome sequencing of spermatocytic tumors provides insights into the mutational processes operating in the male germline. PLoS One 12:e0178169
Looijenga LH, Hersmus R, Gillis AJ et al (2006) Genomic and expression profiling of human spermatocytic seminomas: primary spermatocyte as tumorigenic precursor and DMRT1 as candidate chromosome 9 gene. Cancer Res 66:290–302
Verdorfer I, Rogatsch H, Tzankov A, Steiner H, Mikuz G (2004) Molecular cytogenetic analysis of human spermatocytic seminomas. J Pathol 204:277–281
Goriely A, Hansen RM, Taylor IB et al (2009) Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat Genet 41:1247–1252
Knapp M, Stiller M, Meyer M (2012) Generating barcoded libraries for multiplex high-throughput sequencing. Methods Mol Biol (Clifton) 840:155–170
Zheng H, Jin H, Liu L, Liu J, Wang WH (2015) Application of next-generation sequencing for 24-chromosome aneuploidy screening of human preimplantation embryos. Mol Cytogenet 8:38
Sheikine Y, Genega E, Melamed J, Lee P, Reuter VE, Ye H (2012) Molecular genetics of testicular germ cell tumors. Am J Cancer Res 2:153–167
Perrone F, Bertolotti A, Montemurro G, Paolini B, Pierotti MA, Colecchia M (2014) Frequent mutation and nuclear localization of beta-catenin in sertoli cell tumors of the testis. Am J Surg Pathol 38:66–71
Colecchia M (2014) Observations on the paper "sclerosing Sertoli cell tumor of the testis: a clinicopathologic study of 20 cases" by Kao et al. Am J Surg Pathol 38:1160
Roth LM, Cheng L (2018) Classical gonadoblastoma: its relationship to the 'dissecting' variant and undifferentiated gonadal tissue. Histopathology. 72:545–555
Scully RE (1970) Gonadoblastoma. A review of 74 cases. Cancer. 25:1340–1356
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Supported by the National Sustainability Program I (NPU I) Nr. LO1503 provided by the Ministry of Education Youth and Sports of the Czech Republic and by Charles University Fund SVV 2019-260391.
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Kvetoslava Michalova:, case selection, results evaluation, manuscript, and figures. Jesse K. McKenney: case contribution, and discussion. Glen Kristiansen: case contribution. Petr Steiner: genetic analyses. Petr Grossmann: genetic analyses. Martina Putzova: genetic analyses. Petr Martinek: genetic analyses. Magdalena Chottova-Dvorakova: microdissection analysis. Michael Michal: results’ evaluation and discussion. Ondrej Hes: discussion. Michal Michal: study design, discussion, and figures.
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This study has been approved by the ethics committee of both Faculty of Medicine and Faculty Hospital in Pilsen, Czech Republic. Informed consent was not required for the study.
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Michalova, K., McKenney, J.K., Kristiansen, G. et al. Novel insights into the mixed germ cell-sex cord stromal tumor of the testis: detection of chromosomal aneuploidy and further morphological evidence supporting the neoplastic nature of the germ cell component. Virchows Arch 477, 615–623 (2020). https://doi.org/10.1007/s00428-020-02843-3
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DOI: https://doi.org/10.1007/s00428-020-02843-3