Clinicopathological features of cytokeratin 5‐positive pulmonary adenocarcinoma

Abstract

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.

Distinction of ALK fusion gene‐ and EGFR mutation‐positive lung cancer with tumor markers

“…These findings suggest that ALK–TKI may be less effective in CYFRA21‐1‐positive patients. Previous reports showed a similar trend, in which TKIs were less effective in squamous cell carcinoma, and CK5‐positive lung adenocarcinomas had a worse prognosis 18,20 . It is not clear why TKI efficacy is worse in CYFRA21‐1‐positive ALK lung cancer, but this will need to be examined in future studies, because many ALK‐positive lung cancers are positive for CYFRA21‐1, as shown in our study.…”

“…Previous reports showed a similar trend, in which TKIs were less effective in squamous cell carcinoma, and CK5-positive lung adenocarcinomas had a worse prognosis. 18,20 It is not clear why TKI efficacy is worse in CYFRA21-1-positive ALK lung cancer, but this will need to be examined in future studies, because many ALK-positive lung cancers are positive for CYFRA21-1, as shown in our study. Furthermore, our study found that patients with high tumor markers were more likely to have poor PS and visceral metastases.…”

“…Terada et al reported that cytokeratin 5 (CK5), a marker of squamous cell carcinoma, was detected in lung adenocarcinomas. 18 The CK5-positivity rate was significantly higher in ALK-positive lung adenocarcinomas compared with the wild-type (WT) and was significantly lower in EGFR-positive lung adenocarcinomas compared with the WT. Because CYFRA21-1 measures fragments of cytokeratin, the different cytokeratin positivity rates may explain the difference in CYFRA21-1 values in ALK-and EGFR-positive lung cancer.…”

“…These histological differences may affect the tumor marker profile. Terada et al reported that cytokeratin 5 (CK5), a marker of squamous cell carcinoma, was detected in lung adenocarcinomas 18 . The CK5‐positivity rate was significantly higher in ALK‐positive lung adenocarcinomas compared with the wild‐type (WT) and was significantly lower in EGFR‐positive lung adenocarcinomas compared with the WT.…”