Abstract 1617: Utility of a solid-tumor NGS panel in the differential diagnosis of composite neoplasms with divergent phenotypes

Abstract

Abstract Introduction: Composite neoplasms (CN) are rare, diagnostically challenging lesions that require differentiating between three possibilities: clonal tumors with divergent phenotypes (mixed tumors, MT), collision of two synchronous adjacent tumors (CT) and tumor-to-tumor metastasis (TTM). To make this distinction, pathologists have relied on morphology, immunohistochemistry and limited molecular techniques such as single-gene sequencing. In this study, we performed next-generation sequencing (NGS) on 4 CN to illustrate the diagnostic utility of NGS-based approach in these rare tumors. Materials and Methods: Of the 4 CN included in the study, 2 had been diagnosed as MT containing phenotypically different cell populations (mixed adenoneuroendocrine carcinoma of the gallbladder and metastatic papillary thyroid carcinoma with squamous dedifferentiation), while the remaining 2 had been interpreted as TTM (esophageal adenocarcinoma to lung adenocarcinoma and small cell carcinoma of the lung to meningeal melanoma). Pathology diagnoses were made using clinical, histologic and immunophenotypic information. Manual dissection of the tumor components was performed on formalin-fixed, paraffin-embedded tissue sections for extraction of DNA and RNA. NGS was performed using the Oncomine Comprehensive Panel on Ion S5XL sequencer. Ion Reporter variant caller pipeline was used for data analysis. Results: Sequencing results confirmed the histopathologic diagnosis in all cases (Table 1). Importantly, comparison of our results with data from TCGA studies allowed a meaningful interpretation of the genetic aberrations found, and shed light on the biology of these lesions. Table 1 – Integration of immunophenotypic and massively parallel sequencing data from 4 composite neoplasmsNDiagnosisComponentsIHCGeneType of aberrationVariant effect (AA change)InterpretationCN1Mixed adenoneuroendocrine carcinomaAdenocarcinomaCK20 -/p53 -/p63 -/CK7 +/ CDX2 +ERBB2CNV–Amplification8.57CCNE1CNV–Amplification16.7Large cell neuroendocrine carcinomaCK20 -/p53 -/p63 -/CK7 +/ CDX2 +/Chromo +/Synapto +CCND1CNV–Amplification4.63ATMCNV–Deletion0.39TP53CNV–Deletion0.56CCNE1CNV–Amplification402Metastatic papillary thyroid carcinoma with squamous dedifferentiationPapillary thyroid carcinomaCK 5/6 -/p40 -/PAX8 +/TTF1 +/TG +BRAFMutation (c.1799T>A)Missense (p.Val600Glu)Deleterious (GOF)–Squamous cell carcinomaCK5/6 +/p40 +/PAX8 +/TTF1 -/TG -BRAFMutation (c.1799T>A)Missense (p.Val600Glu)Deleterious (GOF)–PIK3CAMutation (c.1633G>A)Missense (p.Glu545Lys)Deleterious (GOF)–3Esophageal adenocarcinoma metastatic to lung adenocarcinomaLow grade adenocarcinoma (lung)TTF1 +/HER2 -CDKN2ACNV–Deletion0.76CDKN2AMutation (c.170C>T)Missense (p.Ala57Val)Deleterious (LOF)–KRASMutation (c.35G>T)Missense (p.Gly12Val)Deleterious (GOF)–STK11Mutation (c.580G>T)Missense (p.Asp194Tyr)Deleterious (LOF)–High grade adenocarcinoma (lung)TTF1 -/HER2 +CDKN2AMutation (c.170C>T)Missense (p.Ala57Val)Deleterious (LOF)–KRASMutation (c.35G>T)Missense (p.Gly12Val)Deleterious (GOF)–STK11Mutation (c.580G>T)Missense (p.Asp194Tyr)Deleterious (LOF)–High grade adenocarcinoma (esophagus)–CDKN2AMutation (c.170C>T)Missense (p.Ala57Val)Deleterious (LOF)–KRASCNV–Amplification22.01TP53Mutation (c.614A>G)Missense (p.Tyr205Cys)Deleterious (LOF)–4Small cell carcinoma of the lung combined metastatic to meningeal melanomaSmall cell carcinomaTTF1 +/Synapto +/Chromo +/AE1+3 +/CAM 5.2 +/MelanA -/HMB 45 -RB1Mutation (c.1183C>T)NonsenseDeleterious (LOF)GAS6CNV–Amplification6.14TP53Mutation (c.473G>T)Missense (p.Arg158Leu)Deleterious (LOF)MelanomaTTF1 -/Synapto -/Chromo -/AE1+3 -/CAM 5.2 -/Melan-A +/Pan-M +/MITF +NRASMutation (c.35G>A)Missense (p.Gly12Asp)Deleterious (GOF)TERTCNV–Amplification21.34 Conclusion: This study illustrates the diagnostic utility of NGS in tumors with more than a single histologic component. Additionally, it demonstrates a potential role for NGS in the detection of clinically actionable targets in a group of neoplasms that lack standardized treatment. Citation Format: Andres M. Acosta, Mohamed Rizwan H. Al Rasheed, Dipti Panchal, Magdalena Rogozinska, Frederick G. Behm, Gayatry Mohapatra. Utility of a solid-tumor NGS panel in the differential diagnosis of composite neoplasms with divergent phenotypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1617.