Browsing by Author "Snuderl, Matija"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Clinicopathologic and molecular spectrum of testicular sex cord-stromal tumors not amenable to specific histopathologic subclassification
    (Elsevier, 2022-12) Siegmund , Stephanie E.; Sholl , Lynette M.; Tsai , Harrison K.; Yang, Yiying; Vasudevaraja, Varshini; Tran, Ivy; Snuderl, Matija; Fletcher, Christopher D. M.; Cornejo, Kristine M.; Idrees, Muhammad T.; Al-Obaidy, Khaleel I.; Collins , Katrina; Gordetsky, Jennifer B.; Wobker, Sara E.; Hirsch, Michelle S.; Trpkov , Kiril; Yilmaz , Asli; Anderson, William J.; Quiroga-Garza, Gabriela; Magi-Galluzzi, Cristina; Canete-Portillo, Sofia; Acosta , Andres M.; Pathology and Laboratory Medicine, School of Medicine
    A subset of testicular sex cord-stromal tumors (SCST), which includes neoplasms with mixed histology, cannot be classified into a specific histologic subtype. This study evaluated the clinicopathologic, immunophenotypic and molecular features of 26 SCST not amenable to specific classification by expert uropathologists. Median age at diagnosis was 43 years and median tumor size was 2.4 cm. Follow-up information was available for 18 (69%) patients, with evidence of an aggressive clinical course in 6 patients (4 alive with disease, 2 dead of disease 3 months and 6 months after orchiectomy). Microscopically, SCST not amenable to specific classification demonstrated monophasic epithelioid (9/26, 35%), monophasic spindle cell (5/26, 19%), and biphasic or mixed histology (12/26, 46%). One or more aggressive histopathologic features were seen in 11 cases. DNA sequencing was successful in 22 tumors. Pathogenic CTNNB1 and APC alterations were seen in 7 (33%) and 2 (10%) cases, respectively, with additional variants (e.g., CDKN2A, RB1, TP53, BRCA2) being identified in individual cases. Combined evaluation of morphology, sequencing data and beta-catenin immunohistochemistry resulted in reclassification of 6 (23%) tumors as Sertoli cell tumor, not otherwise specified. This was supported by comparing the methylation profiles of a subset of these tumors and those of typical Sertoli cell tumors. Additionally, a subset of 5 neoplasms (19%) with spindle cell or biphasic histology and SMA expression was characterized by hyperdiploid genomes with recurrent chromosomal gains and absence of driver mutations, possibly representing a distinct tumor type. The SCST that remained not amenable to specific histologic classification (15/26, 58%) were enriched for aggressive histologic features and malignant clinical behavior. In conclusion, this study demonstrated that a subset of testicular SCST that were originally not amenable to specific classification could be reclassified by combined evaluation of morphology, immunohistochemistry and molecular data.
  • Thumbnail Image
    Item
    MicroRNA‐371–373 cluster and methylome analysis suggests that a subset of ‘somatic‐type’ malignancies arising in germ cell tumors may originate in yolk sac tumor components
    (Wiley, 2025) Lobo, João; Tavares, Nuno Tiago; Fonseca, Diana; Jerónimo, Carmen; Henrique, Rui; Wyvekens, Nicolas; Yang, Yiying; Snuderl, Matija; Maclean, Fiona; Gordetsky, Jennifer; Fletcher, Christopher D. M.; Hirsch, Michelle S.; Hornick, Jason L.; Idrees, Muhammad T.; Collins, Katrina; Warmke, Laura; Ulbright, Thomas M.; Acosta, Andres M.; Pathology and Laboratory Medicine, School of Medicine
    Somatic-type malignancies (SMs) arising in germ cell tumors (GCTs) are aggressive neoplasms resistant to systemic treatment. Most are diagnosed in metastatic sites after chemotherapy; however, they have also been well-documented in primary testicular GCTs. Historically, SMs were thought to originate in components of teratoma that acquire molecular alterations equivalent to those that characterize their true somatic counterparts. However, recent studies have shown that SMs typically lack the hallmark molecular alterations seen in similar somatic tumors. Additionally, clinicopathologic and molecular data suggest that a subset may derive from yolk sac tumor (YST) rather than teratoma. In this study, we evaluated the relationship between conventional histological types of GCTs and SMs by comparing expression of microRNA (miR)-371-373 and genomic methylation profiles. A total of 96 samples (including multiple paired conventional GCT-SM samples from individual tumors) were assessed for miR-371-373 expression by RT-qPCR and genomic DNA methylation using a clinically validated assay. Expression of miR-371-373 was higher in conventional GCTs than in SMs (considered as a single category encompassing all histological subtypes). However, miR-371-373 expression was heterogeneous among SMs, with significantly higher levels in sarcomatoid YST (SYST) and glandular neoplasms than in other SMs. Genomic DNA methylation analysis showed that SMs (considered as a single category) did not form a distinct cluster. Instead, they grouped into multiple clusters that did not show perfect correspondence with histology and often included conventional GCTs. Genome-wide methylation assessment showed a higher abundance of hypermethylated regions in SMs than in conventional GCTs. Analysis of paired conventional GCT and 'somatic-type' components that did not meet size criteria for SMs dissected from individual tumors demonstrated separation according to histology, suggesting that epigenetic processes play a role in the transition from conventional GCT to 'somatic-type' phenotypes. Gene-level and pathway-level analyses identified MAPK/RAS signaling, mitosis/proliferation, differentiation towards neural tissue/neuroectoderm, epithelial-to-mesenchymal transition, and DNA repair as key differentially regulated processes in components with somatic-type histology, suggesting mechanisms of progression from conventional to 'somatic' phenotypes in GCT. These results support the hypothesis that a subset of SMs derive from YST and suggest that some subtypes (such as SYST) may represent 'intermediate' phenotypes. Additionally, analysis of differentially methylated promoter regions in SM identified genes and biologic processess that may underlie 'somatic tranformation' in GCTs.