The Association Between Clinicopathological Characteristics, Prognosis And Molecular Phenotype In Pulmonary Mucin Producing Adenocarcinoma

Objective:This study aimed to investigate associations between clinicopathologic characteristics, prognosis and mutations in such mucin-producing adenocarcinoma.Methods:1.75 cases diagnosed lung adenocarcinoma with mucin producing were enrolled from October,2002 to September,2014 in Beijing Chest Hospital. All the patients underwent radical resection. The cases were reclassified, according to International Association for the study of lung cancer, the American Thoracic Society and the European Respiratory Society (IASLC/ATS/ERS) adenocarcinoma of lung cancer international multidisciplinary classification method (referred to as the new classification) published in 2011. We analysed the relationship of the clinical and pathological parameters and prognosis to ALK rearrangements and KRAS and EGFR mutations.2. EnVision immunohistochemistry was used to detect the expression of TTF-1 and NapsinA. Benchmark XT automatic immunohistochemical staining apparatus was used to detect the expression of ALK protein. Amplification refractory mutation system(ARMS)was used to detect KRAS and EGFR mutations.3. The patients were followed up through Telephone.4. The data were analysed by SPSS (17.0) statistical software.Result:1.75 patients with mucinous adenocarcinoma was enrolled in this study. Of the 75 cases,36 (48%) were men and 39 (52%) were women. According to the new criteria of classification in 2011,24 (32%) cases were invasive mucious adenocarcinoma(IMA), 21(28%) were acinar or papillary predominant adenocarcinoma with mucin production(A/P).20(26.7%) were solid predominant subtype with mucin production(SA),6(8.0%) were mucinous minimally invasive adenocarcinoma (m-MIA), and 4(5.3%) were colloid carcinoma.2. The total positive rate of ALK protein was 33.3%(25/75). Positive ALK expression was more common in never-smoking, tumor located in upper/middle lobe, late stage (Ⅲ and IV). lymph node metastasis positive patients, and mainly existed in SA and in particular histological structure such as signet ring cells, cribriform and micropapillary structure. The incidence rate of KRAS mutation was 22.7%(17/75). KRAS mutation was mainly existed in IMA, tumor located in the lower lobe of lung and in the cases without signet ring cells. EGFR mutation was rare and freruency was only 6.7%(5/75). Only two patients of ALK rearrangements had KRAS mutation, there was no coexistent of ALK rearrangements and EGFR mutation.3. The positive rates of TTF-1 and NapsinA in SA were significantly higher than those in other subtypes, and the expression in IMA was significantly lower than that in other subtypes. However, these two antibody expression were not significantly associated with the prognosis of mucinous adenocarcinoma in the lung.4. Progression-free survival rates of mucinous adenocarcinoma in the lung in 1 year,3 years, and 5 years were 85%,64%, and 38%. The overall survival rates were 90%,67%, and 50%, respectively. Larger tumors, late stage, lymph node metastasis and KRAS mutation were related to poor prognosis. m-MIA had the best prognosis, followed by IMA, SA, and A/P.Conclusions:1. The molecular phenotype has significantly different in different subtypes of mucinous adenocarcinoma. ALK positive rate in SA and the subtype with signet ring cells, cribriform and micropapillary structure is significantly higher than it in other subtypes. KRAS mutations in IMA and the cases without signet ring cells are significantly higher than it in other subtypes. These results provide a morphological and molecular basis for the screening of targeted therapies in patients with mucinous adenocarcinoma.2. The clinicopathologic features and biomarkers has significantly different in different subtypes of mucinous adenocarcinoma. These results provide evidence for differential diagnosis of mucinous adenocarcinoma in the lung.3. Tumor size, stage and lymph node metastasis are related to the prognosis of mucinous adenocarcinoma. Larger tumors, late stage, and lymph node metastasis were related to poor prognosis. m-MIA had the best prognosis, followed by IMA, SA, and A/P.4. The A/P was not listed as a dependent subtype in the new classification, but this study suggest A/P has important clinical implications.