18F-fluorodeoxyglucose uptake in PET is associated with the tumor microenvironment in metastatic lymph nodes and prognosis in N2 lung adenocarcinoma.

ABSTRACT

Positron emission tomography is a useful technique for diagnosing lymph node (LN) metastasis. This study aimed to elucidate the association between fluorodeoxyglucose accumulation and the microenvironment in metastatic LNs in lung adenocarcinoma. We retrospectively analyzed 62 patients with surgically resected pathological N2 lung adenocarcinoma who underwent preoperative PET. The maximum standardized uptake value (SUVmax ) in the metastatic LNs was measured. Lymph node specimens were immunohistochemically analyzed for CD8+ , FoxP3+ , and CD79a+ lymphocytes, CD204+ tumor-associated macrophages (TAMs), and alpha-smooth muscle actin-positive cancer-associated fibroblasts (αSMA+ CAFs). We compared the clinicopathologic and immunohistochemical characteristics between two groups with high and low LN SUVmax . Using novel 3D hybrid spheroid models, we investigated the change in invasiveness of cancer cells in the presence of CAFs. In the multivariate analyses, LN SUVmax was an independent prognostic factor. The overall survival in the LN SUVmax high group was significantly worse than in the low group (P = .034). In the LN SUVmax high group, metastatic cancer cell invasion of extranodal tissue was more frequent (P = .005) and the number of CD204+ TAMs and αSMA+ CAFs in metastatic LNs was significantly higher than in the low group (P < .001 and P = .002, respectively). Hybrid spheroid models revealed that cancer cells coexisting with CAFs were more invasive than those without CAFs. Our results indicated a strong association between LN SUVmax and poor prognosis in patients with N2 lung adenocarcinoma. Moreover, LN SUVmax was suggested to be associated with the presence of tumor-promoting stromal cells in metastatic LNs.