Clinicopathological features of cytokeratin 5-positive pulmonary adenocarcinoma

Cytokeratin 5 (CK5) is a marker for pulmonary squamous cell carcinoma; however, CK5 is sometimes present in pulmonary adenocarcinoma (ADC), and there is insufficient information regarding the clinicopathological features of CK5-positive ADC. We aimed to explore the clinicopathological characteristics of CK5-positive ADC using immunohistochemistry. We prepared the following two cohorts: a resected cohort containing 220 resected tumours for primarily studying the detailed morphological characteristics, and a tissue microarray (TMA) cohort containing 337 samples for investigating the associations of CK5 expression with other protein expressions, genetic and prognostic findings. CK5-positive ADC was defined to have ≥ 10% tumour cells and presence of CK5-positive tumour cells in the resected and TMA cohorts, respectively. CK5-positive ADCs were identified in 91 (16.3%) patients in the combined cohort. CK5-positive ADCs had male predominance (P = 0.012), smoking history (P = 0.001), higher stage (P < 0.001), histological high-grade components (P < 0.001), vascular invasion (P < 0.001), mucinous differentiation (P < 0.001), spread through airspaces (P < 0.001), EGFR wild-type (P < 0.001), KRAS mutations (P < 0.001), ALK rearrangement (P < 0.001) and ROS1 rearrangement (P = 0.002). In the resected cohort, more than half the CK5-positive ADCs (19 cases, 65.5%) showed mucinous differentiation; the remaining cases harboured high-grade components. In the TMA cohort, CK5-positive ADCs correlated with TTF-1 negativity (P = 0.002) and MUC5B, MUC5AC and HNF4alpha positivity (P < 0.001, 0.048, < 0.001). Further, CK5-positive ADCs had significantly lower disease-free and overall survival rates than CK5-negative ADCs (P < 0.001 for each). Additionally, multivariate analysis revealed that CK5 expression was an independent poor prognostic factor. CK5-positive ADCs showed aggressive clinical behaviour, with high-grade morphology and mucinous differentiation.