Aims: Pulmonary enteric adenocarcinoma (PEA) is composed mainly of tall columnar cells arranged in an irregular acinar or cribriform pattern with extensive central necrosis, closely resembling the appearance of intestinal epithelial and colorectal carcinomas under the microscope. PEA is usually positive for CK7. However, some cases lack CK7 expression and are positive for intestinal differentiation markers, such as CDX2, villin, and CK20. It is difficult to distinguish between PEA and pulmonary metastases of colorectal carcinoma (MCRC), so new identification methods need to be explored. Methods and Results:We found that SATB2 was highly tissue-specific by bioinformatics analysis. It is highly expressed in intestinal tissues, and its expression level in lung tissues is very low. Then, according to the WHO diagnostic criteria, the cases of lung tumor were preliminary screened to obtain PEA and MCRC cases. In the preliminary screening process, immunohistochemical staining of common lung adenocarcinoma immunomarkers (CK7, TTF-1, and NapsinA) and common intestinal cancer immunomarkers (CK20, CDX2, and villin) were performed to aid identification. Then, after combined with clinical history, imaging examination and colonoscopy, 28 primary PEA specimens and 42 MCRC specimens were final included. The above process was independently reviewed by two pathologists. PEA and MCRC had differences in the number of tumor nodules. The positive rates of SATB2 in PEA and MCRC were 0.00% and 92.86%, respectively. The sensitivity, specificity and diagnostic accuracy of SATB2 for distinguishing MCRC from PEA were 92.86%, 100% and 95.71%, respectively. The diagnostic accuracy of CK7 was 88.57%, which was slightly inferior to SATB2, and the results of CK7 could be used as a reference for SATB2 differential diagnosis. Conclusions:Our study showed that SATB2 can be viewed as the best immunomarkers for distinguishing PEA from MCRC. At the same time, CK7 could be used as references for SATB2 differential diagnosis.