Distinct clinicopathologic characteristics of lung mucinous adenocarcinoma with KRAS mutation

Summary

Primary mucinous adenocarcinomas are uncommon, and their pathogenesis remains unclear. We recently reported the clinicopathologic characteristics of surgically resected mucinous adenocarcinoma, including the frequent involvement of the left and lower lung and absence of central fibrosis. The present study attempted to clarify the pathogenesis of mucinous adenocarcinoma based on KRAS mutation status. We selected 45 mucinous adenocarcinoma cases from among 2474 surgically resected primary lung adenocarcinomas. Of these, 22 had a KRAS mutation (48.9%), whereas only 7 (15.6%) had an epidermal growth factor receptor mutation, and 2 cases had both mutations. The mucinous adenocarcinomas with KRAS mutations were located in the lower lung lobe significantly more often (P < .05) than were tumors without KRAS mutation. The mucinous adenocarcinoma cases with KRAS mutations also had a significantly lower frequency of nuclear atypia (P < .05). We compared the degree of immunostaining for matrix metalloproteinase-7 (MMP-7), laminin-5, and geminin in the mucinous adenocarcinoma with and without KRAS mutation. The proportion of geminin-positive cells was lower among the cases with a mutation than among those without (0.7% versus 2.1%; P < .05). No significant differences in the extent of staining of the other markers were observed between the groups. The current study clearly demonstrated that mucinous adenocarcinomas with KRAS mutations have clinicopathologic characteristics different from those of mucinous adenocarcinoma without such mutations.

Introduction

Lung adenocarcinomas are characterized by a high degree of morphologic heterogeneity. With reference to the cytologic features of the cells, Shimosato et al [1] and Kimula [2] subclassified primary tumor cells into 5 subgroups: goblet, bronchial cell surface type, bronchial gland, Clara, and type II pneumocyte. In recent years, lung adenocarcinoma composed predominantly of goblet cells has been classified as mucinous adenocarcinoma (MA) [3]. Previous authors have reported that MA is less frequently associated with lymph node metastasis than other adenocarcinomas but is associated with lobar pneumonic clinical features [4]. Wislez et al [5] reported that MA appears to be resistant to epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs). On the other hand, they may be more sensitive to taxane [6], [7].

Malignant neoplasms are considered to develop through the accumulation of genetic abnormalities. In lung cancer, KRAS and EGFR mutations frequently are detected. KRAS mutation is the most common driver mutation in human cancers, although the prevalence of mutations and the affected codons differ according to the type of cancer. In lung adenocarcinoma, the frequency of KRAS mutation–positive cases is 5% to 40%, and mutations are more common in male patients and in smokers [8], [9], [10], [11], [12]. On the other hand, EGFR mutation has been an area of particular interest because of the finding that the administration of EGFR-TKIs in clinical trials resulted in a high response rate among patients with lung adenocarcinoma carrying an EGFR mutation. These mutations were correlated with the observed clinical characteristics of responders to TKIs, including female sex, Asian ethnicity, an absent or infrequent smoking history, and a diagnosis of lung adenocarcinoma [13], [14], [15]. Furthermore, mutations in KRAS and EGFR usually are mutually exclusive.

We recently reported that the clinicopathologic characteristics of MA include the frequent involvement of the left and lower lung and absence of central fibrosis [4]; these adenocarcinomas form a distinct subset and should be considered different from other lung adenocarcinomas. The present study attempted to clarify the pathogenesis of MA with special reference to KRAS and EGFR mutation status. We analyzed the correlations between the mutations and clinicopathologic characteristics.