Clinicopathological features of patients with RET fusion-positive non-small cell lung cancer / 中华病理学杂志

Objective: To investigate the clinicopathological features, treatment and prognosis of patients with RET fusion positive non-small cell lung cancer (NSCLC). Methods: A total of 1 089 NSCLCs were retrieved at Affiliated Hospital of Jiangnan University from August 2018 to April 2020. In all cases, multiple gene fusion detection kits (fluorescent PCR method) were used to detect the gene status of RET, EGFR, ALK, ROS1, KRAS, BRAF and HER2; and immunohistochemical method was used to detect the expression of PD-L1 and mismatch repair related proteins. The correlation between RET-fusion and patients' age, gender, smoking history, tumor stage, grade, pathologic type, and PD-L1, mismatch repair related protein expression was analyzed. Results: There were 22 cases (2.02%) detected with RET fusion-positive in 1 089 NSCLC patients, in which 11 males and 11 females; and the median age was 63.5 years. There were 20 adenocarcinomas, including 11 acinar predominant adenocarcinoma (APA), five solid predominant adenocarcinoma (SPA) and four lepidic predominant adenocarcinoma (LPA); There were one case each of squamous cell carcinoma (non-keratinizing type) and sarcomatoid carcinoma (pleomorphic carcinoma). There were 6 and 16 patients with RET fusion-positive who were in stage Ⅰ-Ⅱ and Ⅲ-Ⅳ respectively, and 16 cases with lymph node metastasis, 11 cases with distant metastasis. Among RET fusion-positive cases, one was detected with HER2 co-mutation. The tumor proportion score of PD-L1≥1% in patients with RET fusion positive lung cancer was 54.5% (12/22). Defects in mismatch repair protein expression were not found in patients with RET fusion positive NSCLC. Four patients with RET fusions positive (two cases of APA and two cases of SPA) received pratinib-targeted therapy, and two showed benefits from this targeted therapy. Conclusions: The histological subtypes of RET fusions positive NSCLC are more likely to be APA or SPA. RET fusion-positive NSCLC patients are associated with advanced clinical stage, lymph node metastases, and they may benefit from targeted therapy with RET-specific inhibitors.

Clinical prognosis in BRAF-mutated PTC

BRAF mutation has recently emerged as a potential prognostic marker for papillary thyroid carcinoma (PTC) due to several studies suggesting that it may condition the development of tumors with aggressive behavior. A study of the phenotypes of thyroid follicular cell lines and transgenic mice characterized by targeted expression of BRAF mutation indicates that, at variance with RET/PTC rearrangement, it induces or facilitates genomic instability and higher invasiveness and eventually deeper tumor de-differentiation and more significant suppression of apoptosis. An analysis of differential gene expression of PTCs harboring BRAF mutation versus PTCs characterized by other genetic alterations shows an important impairment of the expression of genes related to intra-thyroidal iodine metabolism machinery, up-regulation of Glut-1 mRNA, methylation-induced gene silencing of tumor suppressor genes and up-regulation of pro-angiogenetic proteins such as VEGF. Correlation of BRAF mutation with PTC clinico-pathological features yields controversial results, with several studies showing the association with unfavourable clinico-pathological qualities, while others do not confirm the findings. This review will summarize the studies in favor of or in contrast with a role of BRAF mutation as a prognostic marker in PTC. We will also indicate what information we still need in order to routinely introduce this indicator in clinical practice.

Mutações no BRAF surgiram recentemente como potenciais marcadores prognósticos do carcinoma papílifero de tiróide (CPT) graças a vários estudos que sugerem que ele possa condicionar o desenvolvimento de tumores com comportamento agressivo. Um estudo do fenótipo das células de linhagem folicular de tiróide em camundongos transgênicos caracterizados pela expressão direcionada de mutações BRAF, indicam, à semelhança dos rearranjos RET/PTC, que ele induz ou facilita a instabilidade genômica, a alta invasividade e, por fim, uma profunda desdiferenciação tumoral com supressão mais significativa da apoptose. Uma análise da expressão gênica diferencial do CPT associado com mutações BRAF versus o CPT caracterizado por outras alterações gênicas mostra uma redução importante da expressão dos genes relacionados com a maquinaria do metabolismo do iodo intratiroideano, aumento da regulação do mRNA do Glut-1, silenciamento gênico induzido por metilação dos genes supressores tumorais e aumento da regulação das proteínas pró-angiogênicas, como a VEGF. A correlação da mutação BRAF com os achados clínico-patológicos do CPT mostra resultados controversos, com vários estudos indicando associação com parâmetros clínico-patológicos desfavoráveis e outros não confirmando esses achados. Esta revisão sumariza os estudos a favor ou não do papel da mutação BRAF como um marcador prognóstico no CPT. Indicaremos, também, quais informações são ainda necessárias para a introdução rotineira deste indicador na prática clínica.

RET proto-oncogene expression of papillary thyroid carcinomas in Thai patients.

BACKGROUND: Ret proto-oncogene activation has been found in papillary thyroid carcinoma with different frequencies according to geographic location. The rate of expression ranges from 0-100 percent in the literature. This gene expression has also been studied in many Asian countries but it has never been studied in Thailand. OBJECTIVE: To study the frequency of the RET expression and their roles in predicting prognosis of papillary thyroid carcinoma among Thai patients treated at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. MATERIAL AND METHOD: One hundred and one cases of papillary carcinomas were studied with immunohistochemistry for RET antibodies. All slides with routine staining were reviewed to classify cell variants and record other prognostic parameters such as size, multicentricity, extrathyroid invasion. The clinical data such as age and sex were also included for analyses. RESULTS: Forty-seven of the total 101 cases (46.5%) showed positive RET protein staining. The mean age among patients with RET negative neoplasms was 43.9 years compared with 39.8 years in RET positive group (p = 0.16). The average size of the tumors without RET expression was 2.5 cm, slightly larger than the RET positive tumors (2.1 cm)(p = 0.26). Extrathyroid invasion of the RET-positive tumors was found to be 33.2 percent while the RET negative neoplasms had 38.8 percent of this feature (p = 1). According to AMES score, the RET positive cases had only 11 percent of high-risk tumors, whereas the RET negative group comprised 23.1 percent of high-risk malignancies (p = 0.20). There was no significant difference in RET expression among cell variants (p = 1). CONCLUSION: The study of 101 papillary thyroid carcinomas at the King Chulalongkorn Memorial Hospital disclosed high frequency of RET expression (46.5%) and this is the only data among Thai patients that has ever been documented in the literature. Although, the gene expression in the tumor tends to be associated with good prognostic features but it was not distinct enough to be statistically significant.