Advanced lung adenocarcinomas with ROS1-rearrangement frequently show hepatoid cell

Abstract

Defining distinctive histologic characteristics of ROS1-rearranged non-small-cell lung carcinomas (NSCLCs) may help identify cases that merit molecular testing. However, the majority of previous reports have focused on surgical specimens but only limited studies assessed histomorphology of advanced NSCLCs. In order to identify the clinical and histological characteristics of ROS1-rearranged advanced NSCLCs, we examined five hundred sixteen Chinese patients with advanced NSCLCs using ROS1 fluorescence in situ hybridization and real-time polymerase chain reaction and then analyzed for clinical and pathological features. We performed univariate and multivariate analyses to identify predictive factors associated with ROS1 rearrangement. 19 tumors were identified with ROS1 rearrangement (3.7% of adenocarcinomas). 16 ROS1+ and 122 ROS1- samples with available medical records and enough tumor cells were included for histological analysis. Compared with ROS1-negative advanced NSCLCs, ROS1-rearranged advanced NSCLCs were associated with a younger age at presentation. ROS1 rearrangements were not significantly associated with sex, smoking history, drinking history and metastatic sites. The most common histological pattern was solid growth (12/16), followed by acinar (4/16) growth. 66.7% cases with solid growth pattern showed hepatoid cytology (8/12) and 75% cases with acinar growth pattern showed a cribriform structure (3/4). 18.8% cases were found to have abundant extracellular mucus or signet-ring cells (3/16). Only one case with solid growth pattern showed psammomatous calcifications. In conclusion, age, hepatoid cytology and cribriform structure are the independent predictors for ROS1-rearranged advanced NSCLCs, recognizing these may be helpful in finding candidates for genomic alterations, especially when available tissue samples are limited.

Targeted Therapy for Non-Small Cell Lung Cancer

“…238,239,249 While ROS1-rearranged NSCLC is similar to ALK-rearranged NSCLC in that it is associated with a younger age at presentation (median: 49.8 years) and adenocarcinoma histology, significant associations do not hold for smoking, especially in Asian cohorts, and indoor radon gas exposure has been identified as a primary risk factor in nonsmokers. 238,[249][250][251] In terms of histology, ROS1 signet-ring cells are also prevalent in Western populations while in an evaluation of over 500 Chinese patients with advanced NSCLC, 11 of 16 (68.8%) ROS1 fusion-positive tumors had hepatoid cytology or cribriform structure. 249,250 Overall, prognosis with ROS1 is favorable with 40% alive at 4 years without targeted therapy and 60% alive with targeted therapy.…”

“…238,[249][250][251] In terms of histology, ROS1 signet-ring cells are also prevalent in Western populations while in an evaluation of over 500 Chinese patients with advanced NSCLC, 11 of 16 (68.8%) ROS1 fusion-positive tumors had hepatoid cytology or cribriform structure. 249,250 Overall, prognosis with ROS1 is favorable with 40% alive at 4 years without targeted therapy and 60% alive with targeted therapy. 249…”

ALK and ROS1 testing on lung cancer cytologic samples: Perspectives

“…These patients are predominantly young women and never‐smokers . In addition to the morphologic features of fusion‐positive ALK lung adenocarcinomas (extracellular mucin, cribriform pattern, and signet ring cells), ROS1 ‐positive tumors exhibit hepatoid cytology (abundant eosinophilic cytoplasm, round and relatively monomorphic nuclei, and prominent nucleoli) . Crizotinib, which induced an impressive dramatic objective clinical response in 72% of ROS1 ‐positive patients with advanced‐stage NSCLC, recently was approved by the FDA also for ROS1 ‐rearranged adenocarcinomas.…”

“…73 In addition to the morphologic features of fusion-positive ALK lung adenocarcinomas (extracellular mucin, cribriform pattern, and signet ring cells), 14 ROS1-positive tumors exhibit hepatoid cytology (abundant eosinophilic cytoplasm, round and relatively monomorphic nuclei, and prominent nucleoli). 74 Crizotinib, which induced an impressive dramatic objective clinical response in 72% of ROS1-positive patients with advanced-stage NSCLC, 9 recently was approved by the FDA also for ROS1-rearranged adenocarcinomas. In the clinical trials with crizotinib, ROS1-positive patients were identified by break-apart FISH; consequently, the FDA considers this method to be the "gold standard" procedure with which to determine ROS1 positivity.…”

Cytomorphological features of anaplastic lymphoma kinase‐positive lung cancer

“…A retrospective analysis of 48 lung adenocarcinoma cases reported that presence of flat mono‐layered sheets and acini, mild nuclear atypia, fine chromatin and smooth nuclear margins are important predictors of EGFR mutated status . Similarly, another study showed that the presence of a solid pattern on histology with hepatoid cytology or acinar pattern with cribriform structure along with abundant extracellular mucus or signet‐ring cells are independent predictors of ROS1‐rearranged advanced lung cancer . Due to lack of uniformity in parameters evaluated and possible overlapping features, there is a need to define a standardised set of cytomorphological parameters that could clearly differentiate among the three types of mutated adenocarcinoma.…”