Associations between mutations and histologic patterns of mucin in lung adenocarcinoma: invasive mucinous pattern and extracellular mucin are associated with KRAS mutation

Abstract

Multiple reports indicate that epidermal growth factor receptor (EGFR) mutations are associated with lepidic-pattern lung adenocarcinoma and that KRAS mutations are associated with invasive mucinous adenocarcinoma. We sought to investigate the association between EGFR and KRAS mutations and specific morphologic characteristics, such as predominant histologic subtype and mucinous features. Clinical data for 864 patients with resected lung adenocarcinoma that underwent molecular testing for EGFR and KRAS mutations were collected. Histologic subtyping was performed according to the IASLC/ATS/ERS lung adenocarcinoma classification, with attention given to signet-ring cell feature and extracellular mucin. EGFR mutations were detected using a polymerase chain reaction-based sizing assay, KRAS mutations were detected using Sanger sequencing, and ALK expression was detected using immunohistochemistry. Invasive mucinous adenocarcinoma was associated with KRAS mutation (P<0.001). Among invasive mucinous adenocarcinomas with KRAS mutation, a pure mucinous pattern was more common than a mixed mucinous/nonmucinous pattern (P=0.002). Invasive mucinous adenocarcinoma was associated with KRAS transition mutations (G→A) but not transversion mutations (G→T or G→C) compared with nonmucinous tumors (P=0.009). The lepidic-predominant group was associated with EGFR mutation compared with nonlepidic-predominant tumors (P=0.011). Extracellular mucin was associated with KRAS mutation (P<0.001), whereas signet-ring cell feature was not associated with EGFR or KRAS mutation (P=0.517). ALK expression was associated with signet-ring cell feature (P=0.001) but not with extracellular mucin (P=0.089). Our study shows that histologic patterns of mucin in lung adenocarcinoma-including invasive mucinous adenocarcinoma and extracellular mucin-are associated with KRAS mutation.

FIGURE 1

Mucinous subtypes and features. (A) Invasive mucinous adenocarcinoma. Goblet or columnar tumor cells with abundant intracellular mucin. (B) Colloid-predominant adenocarcinoma. A tumor has a mucin pool within tumoral stroma, with destruction of the alveolar wall. (C) Signet-ring cell feature. Tumor cells have abundant intracellular mucin and a crescentic nucleus displaced toward one end of the cells.

FIGURE 2

Extracellular mucin in each histologic pattern. Extracellular mucin in (A) lepidic, (B) acinar, (C) papillary, and (D) micropapillary pattern.

FIGURE 3

Mucinous features and their predominant subtypes. (A) Signet-ring cell features were identified in 69 tumors (5%): 2 lepidic-predominant, 31 acinar-predominant, 9 papillary-predominant, 4 micropapillary-predominant, 16 solid-predominant, 5 invasive mucinous, and 2 colloid-predominant. (B) Extracellular mucin was identified in 116 tumors (13%): 2 nonmucinous MIA, 11 lepidic-predominant, 56 acinar-predominant, 26 papillary-predominant, 6 micropapillary-predominant, and 15 solid-predominant.

FIGURE 4

Associations between KRAS mutation and invasive mucinous adenocarcinoma (pure mucinous vs. mixed mucinous/nonmucinous). Among invasive mucinous adenocarcinomas (n=36), pure mucinous tumors were significantly more likely to have KRAS mutations, compared with mixed mucinous/nonmucinous tumors (85% vs. 31%).

FIGURE 5

Associations between KRAS mutation and percentage of extracellular mucin. KRAS mutations were most frequent in tumors with ≥50% extracellular mucin (n=21), followed by tumors with 10% to 49% extracellular mucin and those with <10% extracellular mucin (62% vs. 40% vs. 22%).