RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis

Abstract

Background: To elucidate clinicopathological characteristics of non-small-cell lung carcinoma (NSCLC) cases carrying RET rearrangements causing oncogenic fusions to identify responders to therapy with RET tyrosine kinase inhibitors.

Methods: We investigated 1874 patients with carcinomas, including 1620 adenocarcinomas (ADCs), 203 squamous cell carcinomas (SCCs), 8 large cell carcinomas, and 43 sarcomatoid carcinomas (SACs). Fluorescence in situ hybridisation (FISH) and/or reverse transcription-PCR (RT-PCR) were performed to detect RET gene rearrangement.

Results: In all, 22 cases (1.2%) showed RET rearrangements; all cases were of ADC histology. Of the 22 patients, 19 possessed KIF5B-RET fusion genes, whereas 3 possessed CCDC6-RET fusion genes. The RET-rearranged tumours were significantly more common in younger patients (P=0.038) and tended to occur in patients with no history of smoking (P=0.051). In addition, RET rearrangements were not associated with gender, occupational history (particularly radioactive exposure), tumour size, lymph node status, tumour stage, or patient survival. The predominant growth pattern in RET-rearranged ADCs was lepidic in 6 cases, papillary in 9 cases, acinar in 2 cases, micropapillary in 1 case, and solid in 4 cases. Cells with cytoplasmic mucin production were at least focally present in 12 of the 22 (54.5%) RET-rearranged ADC cases. Among the 21 analysed RET-rearranged tumours, RET immunopositivity was observed in 15 cases (71.4%), and was significantly associated with RET rearrangement (P<0.001).

Conclusions: The RET rearrangements were observed in 1.2% of NSCLCs. All cases of RET rearrangement were ADCs. The RET rearrangements were more likely to be observed in younger patients. Although cytoplasmic mucin production was at least focally present in 54.5% of RET-rearranged ADCs, specific histological features were not detected.

Figure 1

Representative image of fluorescence in situ hybridisation using a break-apart probe for RET-rearranged carcinoma. White arrows indicate split red–green signals. A full colour version of this figure is available at the British Journal of Cancer journal online.

Figure 2

Representative images of RET-rearranged adenocarcinoma of the lung. (A and B) Many RET-rearranged adenocarcinomas displayed a papillary growth pattern (A: low magnification, and B: high magnification). (C) Solid signet-ring cell pattern was observed in a minority of RET-rearranged adenocarcinoma (original magnification × 200). (D) Some tumour cells displayed homogeneously eosinophilic-to-pale inclusions in the nuclei (original magnification × 200).

Figure 3

Representative images of RET-immunostaining positivity in a RET-rearranged adenocarcinoma. Diffuse, fine granular cytoplasmic staining was observed in the adenocarcinoma component, as shown in the left part of the figure, whereas negative signals were observed in nontumourous areas, as shown in the right part of the figure (original magnification × 400).

Figure 4

Overall survival analysis in RET-rearranged lung carcinoma. (A) The overall survival curves for patients with RET-rearranged (green line) and RET-wild-type (blue line) non-small-cell lung carcinomas (P=0.9613). (B) The overall survival curves for patients with RET-rearranged (green line) and RET-wild-type (blue line) adenocarcinoma (P=0.9665). (C) The overall survival curves for patients with RET-rearranged (green line) and RET-wild-type (blue line) consecutively resected adenocarcinoma (P=0.547). A full colour version of this figure is available at the British Journal of Cancer journal online.