TGF-β1 SECRETED FROM MACROPHAGES ACCUMULATING IN METASTATIC LYMPH NODES INDUCES FIBROSIS AFTER NEOADJUVANT CHEMOTHERAPY FOR ESOPHAGEAL SQUAMOUS CELL CARCINOMA
Shinichiro Shiomi*, Sachiyo Nomura, shoh yajima, yasuhiro okumura, koichi Yagi, Yasuyuki Seto
Tokyo Daigaku Igakubu Fuzoku Byoin, Bunkyo-ku, Tokyo, Japan
Introduction Mapping the lymphatic flow from a tumor, including lymph nodes (LNs) and lymphatic vessels, using near-infrared imaging with indocyanine green, has been used for the intraoperative prediction of lymph node metastasis in esophageal cancer. However, we found a decline in the diagnostic accuracy of this technique in patients undergoing neoadjuvant chemotherapy (NAC). Fibrosis in metastatic LNs after NAC has been considered a reason for the alteration of the lymphatic flow. Nonetheless, the mechanism for chemotherapy-induced fibrosis in metastatic LNs has not been elucidated. We focused on the accumulation of macrophages in the necrotic tumor cells. This study explores the role of macrophages contributing to fibrosis in metastatic LNs in esophageal cancer patients who received NAC.
Methods We enrolled 21 patients who underwent curative esophagectomy for esophageal squamous cell carcinoma (ESCC) at our institution between 2017 and 2022. One or two LNs diagnosed with pathologically N-positive by permanent histological diagnosis or with clinically N-positive by CT scans performed before NAC were selected arbitrarily from each patient's specimen. We conducted the immunohistochemistry for obtained LNs, targeting human macrophage marker (CD68) and TGF-β1. The ratio of the number of CD68-positive cells in the tumor or fibrosis area to those in the surrounding subcapsular sinus area was used as a degree of macrophage accumulation (AM score). Moreover, we defined the intensity/population (IP) score (0-15), which was the product of scored staining intensity (0-3) and scored stained cell frequency (1-5), as an expression index for TGF-β1. We classified LNs into four groups according to their response to NAC as follows: LNs obtained from patients who had not received NAC (nLN), LNs with poor response (pLN), with good response (gLN), and with complete response (cLN), obtained from patients who had received NAC. Good response was defined as a decrease of ≥ 50 % in areas of viable tumor cells.
Results A total of 30 LNs obtained from enrolled patients, including seven categorized as nLN, five as pLN, eight as gLN, and ten as cLN were analyzed. AM scores of gLN and cLN were higher than those of nLN and pLN (nLN 0.75, pLN 0.46, gLN 1.79, and cLN 2.56). Furthermore, gLN had a higher IP score than other groups (nLN 1.0, pLN 1.0, gLN 7.5, and cLN 1.0) (Fig.1). The double immunofluorescence staining for LNs categorized as gLN showed the co-expression of CD68 and TGF-β1 (Fig.2).
Conclusions Macrophages accumulating in LNs with necrotic tumor cells and their TGF-β1 secretion may induce fibrosis in metastatic LNs in ESCC patients who received NAC. Blocking TGF-β1 activity may prevent fibrosis and lymphatic flow alteration and allow the intraoperative prediction of nodal involvement using near-infrared imaging, even for ESCC patients who received NAC.
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