晚期口腔癌特殊病理表現及其對治療預後的影響

Abstract

對於晚期口腔癌病人而言，現今建議的治療方式仍然令人力有未逮，存在著許多努力的空間。對臨床醫師而言，現今治療晚期口腔癌仍然存在著許多的挑戰。如何藉由臨床病理的特殊表現中，尋找最具高危險群，最需要關注的病人，嘗試著給予更有效及可行的治療方式，一直是臨床醫師值得努力的方向，更是理想的目標。本研究試圖從過往晚期口腔癌治療預後最差的病人-出現轉移淋巴結外擴散(extranodal extension, ENE)或治療前腫瘤壞死(necrosis)，從病理的特殊變化，尋找可能的蛛絲馬跡。 本回朔性分析，共收納了台大醫院2004年2011年間，218位晚期(第三，四期)口腔癌病人。這群病人五年disease-free，disease-specific及overall 存活率相當低，分別只有33.5%，35.8%及33.8%，整體治療成績不盡理想。首先，針對轉移頸部淋巴結外擴散病理診斷作探討。在原發部位腫瘤及轉移淋巴結中，口腔腫瘤細胞細胞核phosphorylated mammalian target of rapamycin (p-mTOR)的表現和腫瘤細胞分化(differentiation)息息相關。分化不佳(lower grade differentiation)的腫瘤細胞其細胞核p-mTOR往往呈明顯的陽性表現。若深入觀察淋巴結外擴散之口腔腫瘤細胞表現，可以發現腫瘤細胞有無細胞核p-mTOR的表現，對治療預後有極大的影響。對於晚期轉移口腔癌病人無淋巴結外擴散，有或無淋巴結外擴散併擴散細胞細胞核p-mTOR表現的病人而言，五年disease-free存活率為54.3%，23.4%及55.2%，五年overall存活率為55%，18.7%及51.3%。經多變項分析校正後發現，淋巴結外擴散細胞細胞核p-mTOR為顯著的危險因子。有淋巴結外擴散細胞細胞核p-mTOR表現的口腔癌病人，其治療後存在著頸部復發或遠端轉移的高風險。因此，淋巴結外擴散細胞細胞核p-mTOR除了可被視為治療預後的有效預測因子外，更可增加有意義的資訊於傳統ENE分級系統中。 另外，回顧治療前腫瘤necrosis的影響發現，在轉移淋巴結上，治療前核磁共振影像檢查出現壞死與病理出現壞死有高度相關性(kappa value 0.64)。就壞死組織免疫組織染色Hypoxia-inducible factor 1-α(HIF-1α)及Program death ligand 1(PD-L1)後發現，腫瘤缺氧後引起壞死旁殘存腫瘤細胞HIF-1α和PD-L1的表現，在原發部位腫瘤及轉移淋巴結上，分別有中度(kappa 0.54)及極高(kappa 0.86)的相關性。根據有無出現治療前壞死及壞死旁殘存腫瘤細胞PD-L1表現，與存活資料做對比分析，發現出現治療前壞死及殘存腫瘤細胞陽性PD-L1之病人，有相對較差的疾病控制率及存活率。由於陽性PD-L1腫瘤細胞可以有效的避免免疫T細胞的攻擊，因此位於壞死旁的殘存陽性PD-L1腫瘤細胞，似乎是治療失敗的可能原因。 總結而言，治療晚期口腔癌可謂困難重重。我們發現頸部淋巴結外擴散的腫瘤細胞與壞死旁殘存腫瘤細胞之型態，對於治療預後有著重要的影響。這群高風險的口腔癌病人，不論是在臨床或基礎試驗上，均是我們未來的努力方向。

For the patients with advanced oral cancer disease, the treatment outcomes and disease control under current therapy are disappointed. For the clinicians, it is still full of challenges and difficulties need to be overcome when facing the advanced oral cancer disease. In our opinion, how to identify the risk of failure and its underlying mechanism from the pathological findings were of paramount importance. Therefore, the main purpose of our study was to identify the possible and specific pathological expressions from the worst patients with advanced oral cancer disease, the patients with positive extranodal extension (ENE) and/or pretreatment tumor necrosis. We retrospectively reviewed 218 eligible patients with stage III/IV oral squamous cell carcinoma (OSCC) and neck lymph node metastasis and also had received comprehensive treatment at our department between January 2004 and December 2011. The 5-year disease-free, disease-specific and overall survivals of all the patients in our series were 33.5%, 35.8% and 33.8%, respectively. In the first part of our study, we focused on the specific pathological expression in extranodal tumor. First, we noted that the nuclear phosphorylated mammalian target of rapamycin (p-mTOR) expression was highly associated with differentiation of OSCC. The moderately and poorly differentiated OSCC always demonstrated varying degrees of nuclear p-mTOR expression. By the discrimination from pathological expression of extranodal tumors, the 5-year disease-free survival of the patients without ENE, with and without nuclear p-mTOR expression in extranodal tumors was 54.3%, 23.4% and 55.2%, respectively. The 5-year overall survival of the patients without ENE, with and without nuclear p-mTOR expression was 55%, 18.7% and 51.3%, respectively. After the stratification of multivariate analysis, the nuclear p-mTOR expression in extranodal tumors was a significant independent adverse factor for disease control and treatment outcome. Its expression in extranodal tumors could add more significant information in traditional ENE grading system. In the second part of study, we focused on the specific pathological expression of hypoxic OSCC surrounding necrosis. First of all, the necrosis finding in pretreatment magnetic resonance imaging (MRI) image had great association with pathological cystic necrosis. Both of them had substantial positive association (kappa value 0.64) in metastatic lymph nodes. Then, we always noted that hypoxic OSCC surrounding necrosis, either in primary tumor or metastatic lymph nodes, frequently showed colocalized expression of and immunohistochemical associations between Hypoxia-inducible factor-1α (HIF-1α) and programmed death ligand 1 (PD-L1). There were moderate (kappa value 0.54) and almost perfect (kappa value 0.86) positive association between positive HIF-1α and PD-L1 expression in primary tumor and metastatic lymph node, respectively. Finally, the patients with both necrosis and positive PD-L1 expression in OSCC surrounding necrosis had worse treatment outcome and disease control. The dissemination of these hypoxic and immune-privileged positive PD-L1 tumor cells may play an important role for the worse disease control, especially the worse distant disease control. In conclusion, we found that both the positive nuclear p-mTOR expression in extranodal OSCC and positive PD-L1 OSCC surrounding necrosis had significant relation with disease control and treatment outcomes. Among the patients with advanced OSCC disease, the patients with either of two specific pathological expression must be worth of the target for basic or clinical studies in the future.