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Lung adenocarcinoma with micropapillary pattern (MPP) has an aggressive malignant behavior. Limited resection should be avoided because of its high recurrence rate. If adenocarcinoma with MPP is diagnosed preoperatively, the selection of proper treatment is possible. To explore a preoperative biomarker for diagnosing MPP, we undertook RNA sequencing analysis of 25 clinical samples as the training set, including 6 MPP, 16 other adenocarcinoma subtypes, and 3 normal lung tissues. Unsupervised hierarchical clustering analysis suggested a presence of subgroup with MPP showing different gene expression phenotype. We extracted differentially expressed genes with high expression levels in MPP samples, and chose  VSIG1 ,  CXCL14 , and  BAMBI  as candidate biomarkers for MPP. Reverse transcription‐quantitative PCR analysis confirmed a significantly higher expression of  VSIG1  ( P  = .03) and  CXCL14  ( P  = .02) in MPP than others. In a validation set of 4 MPP and 4 non‐MPP samples,  CXCL14  expression was validated to be significantly higher in MPP than in non‐MPP ( P  = .04). Comparing a total of 10 MPP and 20 non‐MPP samples, the area under the curve of  CXCL14  to distinguish MPP from others was 0.89. The threshold value was 0.0116, corresponding to sensitivity 80% and specificity 90%. In immunostaining of CXCL14, the staining score was significantly higher in MPP cases than others, where not only the MPP component but also other components showed heterogeneous staining in adenocarcinoma tissues with MPP. Moreover, a higher staining score of CXCL14 was significantly associated with poorer prognosis in all patients ( P  = .01) or within cases in stage I‐III ( P  = .01). In summary, we identified  CXCL14  as a possible diagnostic biomarker of MPP.

High expression of CXCL14 is a biomarker of lung adenocarcinoma with micropapillary pattern