Locoregional recurrence via mucus-mediated extension following lung resection for mucinous tumors

The institutional review board of the Kusatsu General Hospital approved our study (Chairman: Sueyoshi Moritani; Number: 2019–015). The requirement for informed patient consent was waived because of the retrospective nature of the study. All methods were performed in accordance with the journal’s guidelines.

The present study was a retrospective analysis of the medical records of 152 patients who underwent pulmonary resection for metastases at our hospitals between September 2007 and December 2019. The inclusion criteria for patients who underwent surgery were as follows: 1) the primary tumor was controlled and 2) there was no effective therapy other than surgery. We defined the primary tumor as “controlled” when the tumor had been surgically resected and there were no recurrences at the time of pulmonary resection. Furthermore, we enrolled patients whose pulmonary metastases could have been macroscopically resected. The medical record of each patient was reviewed for age, sex, primary tumor, tumor size, number of pulmonary lesions, regions of pulmonary nodules, the surgical procedure for the metastasectomy, and postoperative chemotherapy. We performed wedge resection for metastatic lesions, using an automated suturing device (Endo GIA tri-stapler, Covidien or Endopath stapler Echeron flex, Ethicon, Cincinnati, OH). During the resection, we decided to cut the lung at approximately 1 cm from the tumor edge. We selected segmentectomy, lobectomy, or pneumonectomy when the tumors were located in the hilum or when multiple nodules were present in the same lobe. Lymph node dissection was not routinely performed. Following metastasectomy, the patients were followed-up for a maximum of 5 years. All recurrences were confirmed by radiological assessment. Locoregional recurrence was defined as a nodule occurring on the resection stump of the lung or bronchus and the nodule expanding during follow-up computed tomography examinations.

We classified patients into the mucinous and non-mucinous tumor groups. If mucus was partially or wholly present in the tumor based on macro- or microscopic identification, we assigned the tumor as mucinous. We analyzed the recurrence-free survival and the cumulative incidence of locoregional recurrence in the mucinous tumor group, and compared these values with those of the control (non-mucinous tumor group). If there were multiple lesions in a single patient, we judged that recurrence had occurred in cases where at least one lesion recurred. Furthermore, in the mucinous tumor group, the primary tumor, tumor size, regions of pulmonary nodules, surgical procedure, postoperative chemotherapy, and presence of mucus extension were recorded.

The surgically resected specimens were fixed by injecting 10% formalin slowly into lung parenchyma by 23-gauge needle. The fixed specimens were cut into 5–10 mm slices with only one stroke using a new knife. All sections that contained a tumor tissue and a surrounding normal lung tissue were embedded in paraffin. Additional 5-μm sections were cut from a selected tissue block and stained with hematoxylin and eosin.

We microscopically examined the edge of the tumor or mucus. Specimen sections were divided into two groups: those where the border between the tumor and normal lung tissue was clear (Fig. 2a, b) and those where the border was not clear (Fig. 2c, d). In the former group, the tumor edge was identified as a smooth surface easily recognizable at gross or low-power field examination, as indicated by the dotted line in Fig. 2a and b. In the latter group, we found mucus in the normal alveoli. To distinguish the mucus in the normal alveoli from the mucus in the tumor, we performed the following procedure: First, we observed the size of normal alveoli apart from the tumor cells or mucus. When the mucus existed in the normal size alveoli, we judged the mucus spreading to normal alveoli. When alveoli sizes were expanded or alveolar structure was destroyed by the mucus, we judged it as the mucus within the tumor (indicated by arrows in Fig. 2c, d). We named this phenomenon “mucus extension.” The above pathological diagnoses were performed by YK, and one expert pathologist (MI) checked the diagnoses.

To examine the association between mucinous tumors and locoregional recurrence, we compared recurrence-free survival between patients with and without mucinous tumors who underwent pulmonary resection for metastases. The characteristics of both groups are presented in Table 1. In total, 38 patients were diagnosed with a mucinous tumor, where the primary tumors were originated from gastrointestinal cancer (26 patients), pseudomyxoma peritonei (10 patients), lung cancer (one patient), and urinary tract cancer (one patient). Moreover, 114 patients were diagnosed with a non-mucinous tumor, where the primary tumors were originated from gastrointestinal cancer (73 patients), kidney/urinary tract cancer (16 patients), head and neck cancer (12 patients), uterine cancer (six patients), lung cancer (one patient), and cancer in other sites (six patients). In gastrointestinal cancers, which were most mucinous tumors, intestinal (Hazard Ratio [HR], 0.98) and pancreatic cancer (HR, 12.0) have a risk of presenting a mucinous tumor (Table 2). The pathological types of tumors, including the number of patients and the number of metastatic lesions, are presented in Table 3. The mucinous tumors comprised adenocarcinoma in 37 patients (97%) and urothelial carcinoma in one patient (3%). The non-mucinous tumors comprised adenocarcinoma, squamous cell carcinoma, clear cell carcinoma, urothelial carcinoma, and other types in 84 (74%), seven (6%), 12 (11%), four (4%), and seven patients (6%), respectively. The recurrence-free survival rate after pulmonary resection in the patients with mucinous tumors was 11.3%, which was significantly lower than that observed in patients with non-mucinous tumors (31.2%; Fig. 3). We suspected that this low recurrence-free survival rate in patients with mucinous tumors was mainly the result of locoregional recurrences. Therefore, we examined the CIR rate and found that the 5-year CIR rate in patients with mucinous tumors was 48.1%, which was significantly higher than that observed in patients with non-mucinous tumors (14.9%; Fig. 4).

We suspected that locoregional recurrence would easily occur in mucinous tumors via mucus-mediated extension. We identified 70 metastatic lesions in 38 patients with mucinous tumors, and 13 lesions developed locoregional recurrences. In contrast, we identified 179 metastatic lesions in 114 patients with non-mucinous tumors, while in 14 lesions, locoregional recurrences were developed. Of the 70 lesions in mucinous tumors, we identified 35 (50%) with mucus extension present. We extracted the potential risk factors of locoregional recurrence as follows: histological type, maximum tumor size, central region of the tumor (tumor existing partially or wholly inside one-third of the area of a pulmonary pleura), postoperative chemotherapy absent, and limited resection (enucleation, wedge resection, or segmentectomy). Associations between these risk factors and mucus extension are analyzed and summarized in Table 4. The risk of developing locoregional recurrence was higher in patients with a maximum tumor size ≥20 mm, tumors in the central region, postoperative chemotherapy absent, and mucus extension. In multivariate analysis, the presence of mucus extension was the independent risk factor for locoregional recurrence (HR, 5.52; P = 0.019) (Table 5).

In gastrointestinal mucinous tumors, mucus extension was more frequently observed in pancreatic (HR, 2.54) and intestinal cancers (HR, 0.92) (Table 6).

We considered that limited resection may increase the risk of locoregional recurrence. Of 70 lesions, seven and 63 were resected using lobectomy and limited resection (enucleation, wedge resection, and segmentectomy; Table 4), respectively. There was no locoregional recurrence in lesions resected using lobectomy. However, in 13 lesions (20.6%) where limited resection was applied, locoregional recurrence was developed (Fig. 5).