晚期下咽癌臨床病理表現及其對手術治療預後的影響

The clinicopathological expressions in resected advanced hypopharyngeal squamous cell carcinoma and the prognostic impact thereof

羅武嘉(Wu-Chia Lo)

指導教授 ： 張逸良

國立臺灣大學/醫學院/病理學研究所/博士(2017年)

https://doi.org/10.6342/NTU201701427

摘要

下咽癌其組織學表現如同其他頭頸部癌症一樣都是以鱗狀上皮細胞癌居多，然而其臨床的表現卻和其他部位的頭頸癌不一樣。常常在診斷之時已經是晚期、病人營養狀況差、時常有淋巴結甚至是遠端的轉移，以及經常伴隨有第二癌的發生等這些因素使的下咽癌的患者其預後較其他頭頸癌來的差。在現實中，大多數的病人不管其原發部位的大小或淋巴轉移的程度是如何，往往在診斷之時都是第三期或第四期，在這樣不同的排列組合(原發與頸部)之下，有時候不易預估治療的效果與預後，因此，本研究目的在於調查腫瘤大小達到分類3-4(T3-4)或第四期(stage IV)的下咽鱗狀上皮細胞癌患者其臨床病理之預後因子以及希望能擴展傳統的腫瘤、淋巴和轉移(TNM)分期系統使其更具有預測預後的能力。

本回朔性分析，共收納了台大醫院2001年至2008年間接受完整手術治療腫瘤大小達到分類3-4(T3-4)或第四期(stage IV)的下咽癌病人。所有患者在病理診斷下皆為T3-4或stage IV，並且在手術後接受了完整的合併性放化療或放射線治療。第一部分的研究共有105位T3-4的患者被納入，這群病人五年disease-free，disease-specific及overall 存活率分別為47.2%，50.6%及44.8%，治療前的噬中性球比淋巴球比值(neutrophil-to-lymphocyte ratio, NLR)和病人的復發以及存活相關。高NLR(≥ 3.22)的病人和低NLR(< 3.22)的病人相比，其五年的疾病復發率分別為60.4% 和36.5%，達到統計上有意義的差異。多變項分析也顯示高NLR的病人其disease-free，disease-specific及overall 存活率都出現顯著的下降，因此，我們發現在T3-4的患者中治療前若出現有高NLR(≥ 3.22)則和疾病的復發以及較差的存活有關。

第二部分的研究共有120位stage IV的患者被納入，這群病人五年disease-free，disease-specific及overall 存活率分別為48.0%，51.6%及44.6%，我們發現惡性淋巴結比率(LN ratio)和病人的復發以及存活有關。多變項分析也顯示在同樣是第四期的患者當中高LN ratio (≥ 0.113)的病人其disease-free，disease -specific及overall存活率和低LN ratio (< 0.113)的病人相比都出現顯著的下降，另外，高LN ratio (≥ 0.113)的患者其原發部位復發率、頸部復發率或遠端轉移率都較低LN ratio (< 0.113)來的高，就整個疾病有無復發來看，高LN ratio和低LN ratio的病人相比，其疾病復發率分別為68.2%及39.5%，達到統計上顯著的差異。

總結而言，我們發現手術治療前的NLR ≥ 3.22或著是手術後的LN ratio ≥ 0.113分別在T3-4或著是stage IV的下咽癌患者中和疾病復發與存活顯著相關。我們提出可用NLR及LN ratio來擴充現有的TNM分期系統的預後能力；另外，我們需要發展一套更有效的治療策略用在治療高NLR和高LN ratio的病人族群上，這群高風險的下咽癌病人，不論是在臨床或基礎試驗上，均是我們未來的努力方向。

關鍵字

下咽癌 ； 鱗狀上皮細胞癌 ； 惡性淋巴結比率(LN ratio) ； 噬中性球比淋巴球比值(NLR) ； 預後 ； 放射線化學治療 ； 存活

並列摘要

The behavior of hypopharyngeal cancer is different from those cancers arising from other head and neck subsites, despite their similar histological presentation. Frequent advanced stage at presentation, poor nutrition, common lymphatic and systemic spread, and predisposition to development of second malignancies are the main causes of its poor prognosis. Owing to the reality that most patients are diagnosed to have stage III or IV disease in spite of different size of primary lesions or even nodal classification, it is sometimes difficult to estimate treatment outcome in this heterogeneous combination. Therefore, this study aimed to investigate the clinicopathological prognostic predictors of resected T3-4 or stage IV hypopharyngeal squamous cell carcinomas (SCCs) and extend the traditional TNM classification system to advance its predictive ability.

We performed a case note review of T3-4 or stage IV hypopharyngeal SCC patients treated with pharyngolaryngectomy and neck dissection between January 2001 and December 2008 in one tertiary center. All patients had pathological T3-4 or stage IV disease and received planned adjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) treatment. In the first part of our study, a total of 105 patients with pathologically T3-4 hypopharyngeal cancer were enrolled. The 5-year disease-free, disease-specific and overall survivals of all the patients were 47.2%, 50.6% and 44.8%, respectively. The pretreatment neutrophil-to-lymphocyte ratio (NLR; median, 3.22; range, 0.62-46.50) was associated with disease recurrence and patient survival. A difference in the 5-year cumulative disease recurrence rate between patients with high NLRs (≥ 3.22) and low NLRs (< 3.22) was significant (60.4% and 36.5%, respectively; p = 0.004). A multivariate analysis confirmed that an NLR ≥ 3.22 was an independent indicator of a poor prognosis for advanced hypopharyngeal SCC per the following parameters: overall survival [hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.48-4.30, p = 0.001], disease-specific survival (HR 2.45, 95% CI 1.38-4.34, p = 0.002), and disease-free survival (HR 2.18, 95% CI 1.24-3.83, p = 0.007). An NLR ≥ 3.22 is associated with a higher risk of disease recurrence and poor survival in patients with resected T3-4 hypopharyngeal SCCs.

In the second part of our study, a total of 120 patients with pathologically stage IV hypopharyngeal cancer were enrolled. The 5-year disease-free, disease-specific and overall survivals of all the patients were 48.0%, 51.6% and 44.6%, respectively. The lymph node ratio (mean, 0.113; range, 0-1) was associated with disease recurrence and patient survival. In multivariate analysis, lymph node (LN) ratio ≥ 0.113 was a significant poor prognostic factor for OS [hazard ratio (HR) 1.89, 95 % confidence interval (CI) 1.17-3.05, p = 0.009], DSS (HR 2.17, 95 % CI 1.29-3.64, p = 0.003), and DFS (HR 2.24, 95 % CI 1.12-4.52, p = 0.024) in stage IV hypopharyngeal cancer. Patients with LN ratio ≥ 0.113 had significantly ( all ps < 0.05) higher rates of local failure (25.0 % vs. 6.4 %), regional recurrence (25.0 % vs. 9.2 %) and distant metastases (50.0 % vs. 31.6 %) than those with LN ratio < 0.113. Furthermore, we found that patients with LN ratio ≥ 0.113 or < 0.113 had significantly difference in disease recurrence (68.2 % vs. 39.5 %, respectively; p = 0.002).

In conclusion, we found that pretreatment NLR ≥ 3.22, and LN ratio ≥ 0.113 had significant relation with disease control and treatment outcomes in patients with T3-4, and stage IV hypopharyngeal SCCs, respectively. We propose the use of an NLR and LN ratio to broaden the current TNM staging system to advance its predictive ability; the development of a more effective treatment protocol for patients with either high NLRs or high LN ratio will be essential and merits basic or clinical studies in the future.

並列關鍵字

hypopharyngeal cancer ； squamous cell carcinoma ； lymph node ratio ； neutrophil-to-lymphocyte ratio ； prognosis ； chemoradiation ； survival

參考文獻

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