Pallavajjala, Aparna

A subset of desmoplastic melanomas (DMs) can show extensive morphologic and immunohistochemical overlap with cutaneous diffuse-type neurofibroma. Neurofibroma-like desmoplastic melanoma (NFLDM) thus poses a significant diagnostic pitfall because the clinical implications of these 2 entities differ dramatically. A series of 17 DMs, including 5 cases of NFLDM, were compared with a cohort of 53 cutaneous diffuse-type neurofibromas to explore the utility of molecular testing in the differential diagnosis between NFLDM and neurofibroma and to determine potentially useful morphologic features in this differential diagnosis. Unlike NFLDM, cutaneous diffuse-type neurofibromas: (1) rarely feature intratumoral or peritumoral lymphoid aggregates, (2) consistently harbor an intrinsic stromal support vasculature composed of evenly spaced capillary-sized vessels, and (3) infiltrate adjacent adipose tissue in a dermatofibrosarcoma protuberans–like manner with a complete lack of chronic inflammation or fat necrosis at the leading edge of the tumor. Conversely, DMs, including NFLDM: (1) do not contain Wagner-Meissner bodies, (2) often induce fat necrosis and/or chronic inflammation at the interface with adjacent fibroadipose tissue, (3) lack the intrinsic capillary-sized stromal vasculature observed in most neurofibromas, and (4) may harbor foci of perineuriomatous differentiation, mimicking a hybrid nerve sheath tumor. Any deviation from the expected clinical or morphologic features of cutaneous diffuse-type neurofibroma should raise suspicion for NFLDM. Although not entirely sensitive or specific, molecular testing can help to support the diagnosis of NFLDM by demonstrating genetic abnormalities associated with melanoma, including a UV-light–induced mutational signature, high tumor mutational burden, and/or chromosomal copy number alterations typical of melanoma.

Abstract Despite the well-established role of recurrent gene fusions as oncogenic drivers, current practices for characterizing and interpreting gene fusion events in clinical testing and in biomedical literature are inconsistent. From the conceptual definition of gene fusions to the salient elements that characterize these alterations, a lack of community-driven standards for the curation of gene fusions has resulted in a disparate landscape of fusion representations and supporting tools. Consequently, the evidence-based clinical evaluation of gene fusions requires extensive expert review for accurate interpretation of observed gene fusions with respect to putative evidence from biomedical literature. Furthermore, the lack of these standards inhibits the interoperability of tools, resources, and pipelines - impeding data sharing and downstream utility.To address these challenges, a cross-consortia initiative between the Variant Interpretation for Cancer Consortium and ClinGen was formed to develop a standard operating procedure (SOP) for the curation of gene fusions. The SOP is under development by an international and diverse set of experts in the representation, detection, and clinical interpretation of gene fusions. Participating stakeholders across academic, government, and industry sectors showcased challenges and solutions, and participated in community surveys and discussions to define and develop the SOP for this diverse class of alterations.An initial result of this effort was the precise molecular definition of genomic events and features constituting gene fusions. We distinguish these from similar but distinct classes of structural alterations through clinically-relevant examples. Next, we discuss our findings on community practices around the description and evaluation of gene fusions. We provide our recommendations for characterization and representation of gene fusions from these practices, and compare these recommendations to existing variant representation standards and formats (e.g. HGVS variant nomenclature). We also discuss the concurrent application of formats for standardized human- and machine-readable representations of gene fusion events.We conclude with discussion of the salient elements to enable rapid, scalable, and consistent evaluation of fusions curated from the biomedical literature. Recommendations are provided for the standardized capture of these elements to enable both intuitive and precise characterization of this diverse class of alterations in clinical reporting and literature. In summary, we provide a clinical-practice driven framework and nomenclature for gene fusions, including recommendations for human readability, computational precision, and data integrity within the SOP. This work is a substantial advancement towards standardized communication, investigation, and sharing of gene fusion data across clinical and research domains and specialties. Citation Format: Alex H. Wagner, Ioannis S. Vlachos, Dmitriy Sonkin, Panieh Terraf, Chimene Kesserwan, Andrea Sboner, Thomas Coard, Christian Reich, Deborah I. Ritter, Peter Horak, Ying S. Zou, Anna Tanska, Aaron M. Berlin, Anna Lu, Daniel Cameron, Heather E. Williams, Wan-Hsin Lin, Gokce Toruner, Arpad Danos, Jason Saliba, Huiling Xu, Xinjie Xu, Georgina Ryland, Michele Ceccarelli, Liying Zhang, Sarah Rapisardo, Catherine Rehder, Xuelu Liu, Aparna Pallavajjala, Nicole Park, Laveniya Satgunaseelan, Kristy Lee, Jie Liu, Obi Griffith, Robert R. Freimuth, Albrecht Stenzinger, Linda B. Baughn, Michael Baudis, Jennifer Lee, Marilyn Li, Angshumoy Roy, Gordana Raca. A standard operating procedure for the curation of gene fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 449.

Abstract Purpose: Choriocarcinoma is most commonly gestational (androgenetic or biparental) but can be of germ cell origin or can develop as a component of a somatic neoplasm (genetically related to the patient). The latter type are aggressive neoplasms for which the underlying genetic alterations are not well characterized. Experimental Design: To investigate the relationship between the different components of somatic neoplasms with choriocarcinomatous elements, the genetic differences between gestational and nongestational tumors, and identify potential targetable alterations, we analyzed 23 samples from 11 tumors, including five gynecologic-type somatic neoplasms with choriocarcinomatous differentiation (two to three different components each) and six pure choriocarcinomas, for somatic mutations, single-nucleotide polymorphisms, and PD-L1 expression. Results: In mixed tumors, gynecologic-type carcinoma components demonstrated lineage-characteristic and lineage-specific alterations, with choriocarcinomatous components sharing some of these as well as demonstrating novel alterations, supporting a clonal relationship with divergent differentiation of the choriocarcinoma from the somatic carcinoma. TP53 mutation only occurred in nongestational tumors. Diffuse PD-L1 expression was characteristic of choriocarcinoma in both pure and mixed tumors but not seen in the gynecologic-type carcinoma components. Conclusions: Given that the somatic carcinomatous and choriocarcinomatous components of mixed tumors have distinct genetic alterations and biomarker expression, separate analysis of these components is required to guide targeted therapy. High PD-L1 expression suggests a role for checkpoint inhibitor–based immunotherapy in tumors with a choriocarcinoma component. The underlying mechanisms by which cancer stem cells reprogram and initiate trophoblastic retrodifferentiation in some somatic tumors warrant further investigation.

AbstractGranular cell astrocytoma (GCA) is a rare adult infiltrating glioma subtype. We studied a series of 39 GCAs. Median age of presentation was 57.8 years and most cases developed in the frontal or temporal lobes. Tumors included grade II (n = 14), grade III (n = 11), and grade IV (n = 14) by WHO criteria. Granular cell morphology was diffuse in 31 (79%) cases and partial in eight (21%). Immunohistochemistry showed frequent positivity for GFAP (28 of 31), OLIG2 (16 of 16), and CD68 (27 of 30), but HAM56, CD163, and IBA‐1 histiocytic markers were all negative (22 of 22). IDH1(R132H) was negative in all the cases tested (16 of 16), while ATRX expression was retained (12 of 12). Cytogenetics demonstrated monosomy 10 (6 of 6) cases, +7 in 4 (of 6), −13q in 4 of 6, and −14 in 4 of 6. Next‐generation sequencing demonstrated mutations in PTEN/PIK3 genes in 6/13 (46%), NF1 in 3 of 10 (30%), TP53 in 3 of 13 (23%), PALB2 in 3 of 10 (30%), STAG2 in 3 of 10 (30%), EGFR mutation/amplification in 3 of 13 (23%), and AR in 2 of 10 (20%). CDKN2A/B deletion was identified in 5 of 13 (30%) cases (homozygous deletion in 4). The TERT C228T mutation was identified in 9 of 13 (69%). No mutations were encountered in IDH1, IDH2, CIC, FUBP1, H3F3A, BRAF or ATRX genes. The mean overall survival was 11.3 months. Patients >60 years old at diagnosis had a worse survival than patients <60 years (P = 0.001). There were no statistically significant differences in survival by WHO grade, extent of granular cell change, sex or MIB‐1 (P > 0.05). GCA is a variant of IDH‐wildtype diffuse glioma with aggressive behavior irrespective of grade and extent of granular cell morphology, and with molecular genetic features corresponding to primary glioblastoma.

Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare but extremely aggressive tumor. While high-risk human papillomavirus (HPV) is involved at an early stage of oncogenesis in many tumors, additional driving events have been postulated to facilitate the progression of SCNECs. Identification of oncogenic drivers could guide targeted therapy of this neoplasm. Clinicopathologic features of 10 cervical SCNECs are reported. Analyses included immunohistochemical evaluation of p16, p53, synaptophysin, and chromogranin expression; in situ hybridizations and polymerase chain reaction for high-risk HPV and/or HPV 18; and next-generation sequencing based on a 637-gene panel. The patients ranged in age from 28 to 68 years (mean, 45.6 y; median, 40.5 y). All tumors had diffuse p16 and synaptophysin expression. All but 1 tumor was positive for chromogranin (extent of staining ranged from focal to diffuse). HPV 18 was detected in 6 tumors and HPV 35 in 1 tumor. At least 1 driver mutation was detected in 8 tumors. Four cases harbored TP53 somatic mutations, 3 of which correlated with an aberrant p53 staining pattern. Four PIK3CA mutations (p.G106A, p.N345T, p.E545K, and p.E545D) were detected in 3 tumors, 2 of which also harbored TP53 mutations. Oncogenic driver mutations involving KRAS , Erbb2 , c-Myc , NOTCH1 , BCL6 , or NCOA3 were detected in 4 tumors. Mutations in caretaker tumor suppressors PTEN , RB1 , BRCA1 , BRCA2 , and ARID1B were also identified in 4 tumors that commonly coharbored activating oncogenic mutations. Targeted next-generation gene sequencing identified genetic alterations involving the MAPK, PI3K/AKT/mTOR, and TP53/BRCA pathways in SCNECs. The presence of genetic alterations that are amenable to targeted therapy in SCNECs offers the potential for individualized management strategies for treatment of this aggressive tumor.