title: RET-rearranged lung adenocarcinomas with lymphangitic spread, psammoma bodies, and clinical responses to cabozantinib.
abstract: Oncogenic rearrangements of the RET gene have recently been described in 1% to 2% of lung adenocarcinomas. We report five cases of RET-rearranged lung adenocarcinoma with an unusual constellation of clinical and histologic features that has not previously been described in tumors with this genomic alteration. The age at diagnosis of the five patients (4F, 1M) ranged from 44 to 77 years. All were never-smokers. Radiologically, four tumors showed lymphangitic spread within the lungs at presentation; three of these had multiple bilateral lung nodules. Histology showed psammoma bodies within the tumor in four of five cases. Molecular testing for activating EGFR mutations by standard genotyping and ALK expression by immunohistochemistry was negative in all cases. Additional molecular analysis was prompted by the clinical profile in that all five patients were never-smokers with metastatic, relapsed, and/or refractory disease; and also by unusual histologic findings in two cases. Comprehensive genomic profiling performed by means of a clinical grade cancer gene panel next-generation sequencing assay demonstrated a KIF5B-RET fusion in three; and fluorescence in-situ hybridization documented a RET rearrangement in two. Three of the patients were treated with the RET inhibitor cabozantinib. By Response Evaluation Criteria In Solid Tumors (RECIST) criteria, two had a confirmed partial response (at 6 weeks and 4 weeks) and one had stable disease. Our findings suggest that the combination of lymphangitic spread and psammoma bodies may be characteristic of a subset of advanced stage RET-rearranged lung adenocarcinomas. These findings should prompt additional molecular testing for RET translocations, particularly in never-smokers with EGFR- and ALK-negative lung adenocarcinoma.
authors.affiliation: *Departments of Pathology, †Solid Tumor Oncology, and ‖Translational Hematology and Oncology Research, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH; ‡Foundation Medicine, Cambridge, MA; and §Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Pennell
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Ma
authors.forename: Vamsidhar
authors.initials: V
authors.lastname: Velcheti
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000813:Anilides / Q000627:therapeutic use*; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors / Q000235:genetics*; D011725:Pyridines / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000813:Anilides; D011725:Pyridines; C558660:cabozantinib; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human