The present study revealed the incidence of SMPC(+) lung adenocarcinoma in consecutive surgical cases to be 3.4%, which is lower than that of AMPC(+) lung adenocarcinoma (17.7%). In non-pulmonary organs, the incidence of invasive micropapillary carcinoma was reported to be 7% in breast carcinoma , 0.9% in urinary bladder cancer , and 9.4% in colon cancer . Generally, invasive micropapillary carcinomas occur infrequently in any organ.
Prognosis of lung adenocarcinoma with MPC has been reported to be worse and have the potential for high malignancy [17, 18], but no studies have separately evaluated SMPC and AMPC. We showed that SMPC(+) tumors as well as AMPC(+) tumors are associated with several biological factors including tumor size, lymph node metastasis, advanced stage disease, and pleural and lymphovascular invasion. Univariate analysis also revealed the presence of SMPC and AMPC as a significant predictor of unfavorable outcome. However, the most remarkable finding was observed in multivariate analysis: among the patients in p-stage I, patients with not AMPC but SMPC showed a significantly poorer DFS than those without MPC. We used immunohistochemistry with monoclonal antibody D2-40 against lymphatic endothelium in TMA specimens and found that lymphatic vessels are involved within SMPC areas in 4 (21%) of 19 SMPC(+) tumors (data not shown). When compared with AMPC(+) tumors, SMPC(+) tumors significantly more often showed pleural, lymphatic, and vascular invasion than AMPC(+) tumors (68% vs. 33%, P = 0.004; 74% vs. 30%, P < 0.001; 74% vs. 41%, P = 0.010, respectively). Therefore, these data suggest that a strong association between SMPC(+) tumors and pleural and lymphovascular invasion may in part explain their aggressive behavior.
Moreover, we investigated the immunohistochemical differences between SMPC and AMPC. In the study, we observed high E-cadherin expression and low CD44 expression in SMPC. Phospho-c-Met expression generally decreases in SMPC to a greater extent than in AMPC. Recently, it has been suggested that E-cadherin repression and CD44 expression are associated with the epithelial-mesenchymal transition (EMT), which was thought to lead to tumor invasion [19, 20]. Additionally, Elliot et al. reported that hepatocyte growth factor (HGF) and c-Met signaling promotes EMT in breast cancer , and Orian-Rousseau et al. reported that CD44 is strictly required for c-Met activation by HGF in human carcinoma . Consistent with these data, EMT may not occur in SMPC despite its existence in the stroma, or invasion of SMPC may occur through a different invasion mechanism from EMT. Our immunohistochemical findings of SMPC showed lower expression of SP-A than that of nMPC. Many studies have reported that SP-A deletion is correlated with patient survival, and reduced SP-A in MPC may be an excellent indicator for poor prognosis in small-size lung adenocarcinoma [23, 24]. Reduced SP-A may contribute to an unfavorable outcome of SMPC(+) tumors.
Some studies have reported a significant association between the presence of MPC and EGFR mutations and effectiveness of EGFR tyrosine kinase inhibitor (EGFR-TKI) for MPC(+) tumors [25–28]. Since SMPC of lung adenocarcinoma may be associated with a high incidence of EGFR mutations, EGFR-TKI may be effective against SMPC(+) tumors. Patients with these pathological features of lung adenocarcinoma may benefit from EGFR-TKI as postoperative chemotherapy or first-line chemotherapy of relapsed lung adenocarcinoma.
In conclusion, we observed SMPC(+) adenocarcinoma. The incidence of SMPC(+) tumors is low, and SMPC(+) tumors have a different prognostic impact compared to AMPC(+) tumors. Particularly for the early stage tumors, SMPC(+) tumors have different pathobiological characteristics from AMPC(+) tumors, and SMPC(+) tumors frequently contain the EGFR mutation. Therefore, it is important to determine the presence of SMPC in lung adenocarcinoma, particularly p-stage I tumors, and the presence of SMPC should be noted in a pathology report to alert the clinician to the possibility of poor prognosis.