Fluorescence in-situ hybridization assessment of spindle cell-rich testicular sex cord stromal tumors demonstrates multiple chromosomal gains across histologic subtypes.

Spindle cell-rich testicular sex cord-stromal tumors (TSCSTs) comprise a group that includes mostly (but not exclusively): myoid gonadal stromal tumor (MGST), adult granulosa cell tumor (AGCT), and unclassified TSCST. These entities demonstrate histopathologic overlap, and prior genomic studies have failed to identify specific oncogenic drivers. Results of DNA sequencing suggest that different types of spindle cell-rich TSCSTs harbor a recurrent pattern of chromosomal gains. However, these results have not been validated by alternative methods and the extent of these changes within individual tumors remains unknown. We used a combination of commercially available fluorescence in-situ hybridization (FISH) probes (3q11.2, 6p24.3, 6q11.1, 6q23, 7q11.21-q11.22, 9p21.3, 11q13.3, 17p11.2) to enumerate a subset of chromosomes identified as altered (gained) in prior studies. We analyzed 10 cases (3 MGST, 4 unclassified TSCST, 3 AGCT), including 7 that had been previously sequenced. FISH demonstrated gains of chromosomes 3, 6, 7, 9, and 11 above the pre-established threshold (25%) in 50%, 80%, 70%, 20%, and 40% of cases, respectively, with gains of chromosome 17 being present in only 1 unclassified TSCST. The proportion of cells with chromosomal gains ranged from 26% to 60%. Tumors with available copy number data from prior genomic analyses showed a partial discordance between FISH and sequencing results. This study demonstrates that spindle-cell rich TSCSTs harbor a recurrent pattern of chromosomal gains, which are present in variable subsets of neoplastic cells. Further studies are needed to determine if these chromosomal changes represent a mechanism relevant for oncogenesis or a secondary event.

Acosta AM ，Fletcher CDM ，Sholl LM ，van Leenders GJ ，Oliva E ，Cornejo KM ，Repetto F ，Collins K ，Idrees MT ，Hirsch MS ，Trpkov K ，Ulbright TM ，Bridge JA ... -  《-》

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.

Michalova K ，McKenney JK ，Kristiansen G ，Steiner P ，Grossmann P ，Putzova M ，Martinek P ，Chottova-Dvorakova M ，Michal M ，Hes O ，Michal M ... -  《-》

Testicular Neoplasms With Sex Cord and Stromal Components Harbor a Recurrent Pattern of Chromosomal Gains.

Acosta AM ，Sholl LM ，Maclean F ，Kao CS ，Ulbright TM ... -  《-》

Myoid gonadal stromal tumours are characterised by recurrent chromosome-level copy number gains: molecular assessment of a multi-institutional series.

Myoid gonadal stromal tumours (MGST) represent a rare type of testicular sex cord-stromal tumour that has recently been recognised as a distinct entity by the World Health Organization (WHO) classification of genitourinary tumours. MGSTs affect adult men and have been reported to behave in an indolent fashion. Histologically, MGSTs are pure spindle cell neoplasms that coexpress SMA and S100 protein. Given that the molecular features of these neoplasms remain largely undescribed, we evaluated a multi-institutional series of MGSTs using DNA and RNA sequencing. This study included 12 tumours from 12 patients aged 28 to 57 years. Tumour sizes ranged from 0.6 to 4.3 cm. Aggressive histologic features, such as vascular invasion, necrosis, invasive growth, and atypical mitoses were invariably absent. Mitotic activity was low, with a median of less than 1 mitosis per 10 high power fields (HPF; maximum: 3 mitoses per 10 HPF). Molecular analyses did not identify recurrent mutations or gene fusions. All cases with interpretable copy number variant data (9/10 cases sequenced successfully) demonstrated a consistent pattern of chromosome arm-level and whole-chromosome-level copy number gains indicative of ploidy shifts, with recurrent gains involving chromosomes 3, 6, 7, 8, 9, 11, 12, 14q, 15q, 17, 18q, 20, and 21q. Similar findings have also been recognised in pure spindle cell and spindle-cell predominant sex cord-stromal tumours without S100 protein expression. MGSTs are characterised by ploidy shifts and may be part of a larger spectrum of spindle cell-predominant sex cord-stromal tumours, including cases without S100 protein expression.

Collins K ，Sholl LM ，Siegmund S ，Dickson BC ，Colecchia M ，Michalová K ，Hwang M ，Ulbright TM ，Kao CS ，van Leenders GJLH ，Mehta V ，Trpkov K ，Yilmaz A ，Cimadamore A ，Matoso A ，Epstein JI ，Maclean F ，Comperat E ，Anderson WJ ，Fletcher CDM ，Acosta AM ... -  《-》

Testicular Juvenile Granulosa Cell Tumors Demonstrate Recurrent Loss of Chromosome 10 and Absence of Molecular Alterations Described in Ovarian Counterparts.

Testicular juvenile granulosa cell tumors (JGCTs) are a rare type of sex cord-stromal tumor, accounting for <5% of all neoplasms of the prepubertal testis. Previous reports have demonstrated sex chromosome anomalies in a small subset of cases, but the molecular alterations associated with JGCTs remain largely undescribed. We evaluated 18 JGCTs using massive parallel DNA and RNA sequencing panels. The median patient age was <1 month (range, newborn to 5 months). The patients presented with scrotal or intra-abdominal masses/enlargement, and all underwent radical orchiectomy (17 unilateral and 1 bilateral). The median tumor size was 1.8 cm (range, 1.3-10.5 cm). Histologically, the tumors were purely cystic/follicular or mixed (ie, solid and cystic/follicular). All cases were predominantly epithelioid, with 2 exhibiting prominent spindle cell components. Nuclear atypia was mild or absent, and the median number of mitoses was 0.4/mm2 (range, 0-10/mm2). Tumors frequently expressed SF-1 (11/12 cases, 92%), inhibin (6/7 cases, 86%), calretinin (3/4 cases, 75%), and keratins (2/4 cases, 50%). Single-nucleotide variant analysis demonstrated the absence of recurrent mutations. RNA sequencing did not detect gene fusions in 3 cases that were sequenced successfully. Recurrent monosomy 10 was identified in 8 of 14 cases (57%) with interpretable copy number variant data, and multiple whole-chromosome gains were present in the 2 cases with significant spindle cell components. This study demonstrated that testicular JGCTs harbor recurrent loss of chromosome 10 and lack the GNAS and AKT1 variants described in their ovarian counterparts.

Collins K ，Sholl LM ，Vargas SO ，Cornejo KM ，Kravtsov O ，Dickson BC ，Idrees MT ，Ulbright TM ，Acosta AM ... -  《-》