The purpose of this study was to clarify whether mucinous tumors are associated with locoregional recurrence after pulmonary resection and establish whether mucus extension is a risk factor for locoregional recurrence according to the type of surgical procedure.
Previously, STAS was not accepted as a form of invasion because it is unique to the lungs. Anatomically, the lungs have air pathways, which permit tumor cells to spread. Kadota et al identified STAS in 40% of lung adenocarcinoma cases and found that locoregional recurrence after pulmonary resection significantly increased in STAS-positive tumors. Shiono et al. also demonstrated that aerogenous spread with floating cancer cell clusters was an independent prognostic factor; moreover, floating cancer cell clusters and a malignant positive surgical margin in the resected specimens carry significantly higher risk for local recurrence in cases of colorectal pulmonary metastasis. Based on these reports, STAS is coming to be recognized as a pattern of invasion. Previously, we showed that mucinous tumors can spread through mucus-mediated extension in a manner resembling dissemination. We, therefore, hypothesized that mucus could easily spread through air spaces and that it might be possible for cancer cells to extend via the mucus, resulting in local recurrence. Here, we demonstrated that recurrence-free survival after pulmonary resection in patients with mucinous tumors was significantly lower than in patients with non-mucinous tumors. This result is similar to those of reports on mucinous tumors found elsewhere in the body, which were also associated with high recurrence rates[6, 7, 9, 12].
We consider that mucus extension could be a sensitive marker of locoregional recurrence similar to STAS. We found mucus extension, identified microscopically based on the lack of a distinct border between the tumor and normal lung tissue, to be present in 48% of mucinous tumors. We considered that mucus extension might cause tumor spread in these cases and therefore hypothesized that mucus extension might be a risk for locoregional recurrence. Indeed, we found that the 3-year CIR was higher in patients showing mucus extension and that mucus extension was the key independent risk factor for locoregional recurrence following pulmonary resection.
Surgeons need to select the optimal surgical procedure for complete resection of lung tumor. Tumor STAS can be difficult to recognize on the frozen section because STAS tumor cells and alveolar macrophages have similar morphologies. If distinction is difficult, immunohistochemistry for keratin and a macrophage marker such as CD68 may be needed. Conversely, mucus extension could be identified using a frozen section during the operation. In this study, we showed that locoregional recurrence occurred in patients who underwent enucleation, wedge resection, and segmentectomy but did not in those who underwent lobectomy, suggesting that limited resection may increase the risk of locoregional recurrence. Therefore, in the future, if mucus extension can be identified during the operation, this may help surgeons decide on the need for additional resection or anatomical lung resection. In this study, locoregional recurrence occurred in cases of mucinous tumors with 1-cm resection margins; therefore, margins larger than 1 cm from the tumor edge should be selected to avoid recurrence.
The main limitation of this study was the heterogeneity of the primary tumor histology. We resected the metastatic tumors irrespective of their primary histology because a recent report showed the effectiveness of pulmonary metastasectomy. However, tumor characteristics such as growth speed, invasive capacity, and metastatic potential differ both according to mucus existence and according to the histology of the primary lesion. In particular, there was histological variability between patients with mucinous and non-mucinous tumors, which might have affected the recurrence-free survival. A second limitation was the small number of cases, which did not provide sufficient power to detect significant differences; as a result, the statistical may be questionable. Third, we may have underestimated the mucus extension. We observed only the maximum surface of the tumor, and the other surfaces may have potentially contained mucus extension. Finally, the diagnosis of local recurrence was equivocal. We confirmed locoregional recurrence through radiological assessment, not by biopsy, which may sometimes misinterpret inflammatory consolidation as locoregional recurrence.
Based on this original study, we intend to spread awareness of the potential risk of postoperative locoregional recurrence in patients with mucinous tumor and mucus extension. Furthermore, a large trial targeting mucinous tumor resection is required to achieve more precise results in the future.