幽門桿菌陰性胃癌其流行病學、臨床病理與存活分析

Abstract

胃幽門桿菌的感染是一普遍的全球性疾病其盛行率在 20%-90%，在亞洲如日本、韓國、大陸與台灣均屬幽門桿菌感染的高盛行地區，研究顯示幽門桿菌的慢性感染是胃癌發生的危險因子，隨著高盛行區進行幽門桿菌感染的篩檢與早期幽門桿菌的根除性治療，各國胃癌的發生率已逐年下降。胃癌依勞倫氏分類法分為腸道型與瀰漫型，腸道型胃癌經由長期幽門桿菌慢性發炎導致萎縮性胃炎進一步造成胃黏膜的腸化生的癌前病變，經由adenoma-carcinoma sequence 途徑發展為進行性胃癌。瀰漫型胃癌的發生則是透過denovo pathway 發展成進行癌。病理分子層次而言，胃癌發生是一異質性多重因素的複雜過程，除了幽門桿菌的感染之外，先天性或後天環境的基因缺陷如遺傳性瀰漫型胃癌、遺傳性非瘜肉症大腸直腸癌、不同地區種族的基因的多形性、生活型態如高鹽飲食、含亞硝酸鹽食物的食用、糖尿病與代謝症候群、EB 病毒感染均與胃癌發生有關。近十年來日本、韓國、大陸的流行病學研究顯示幽門桿菌陰性的胃癌與幽門桿菌相關的胃癌在流行病學與臨床病理特徵的表現不同；幽門桿菌陰性的胃癌在發病年齡較為年輕、性別比例相當、多瀰漫型胃癌、多賁門部癌且預後不佳。隨著幽門桿菌的大規模篩檢與根除治療，幽門桿菌陰性胃癌族群的重要性日益增加。在高盛行區以血清蛋白酶偵測幽門桿菌高度相關的萎縮性胃炎與幽門桿菌抗體或以C13 吹氣測試、組織學、細菌培養檢查以確診幽門桿菌的感染狀態，區分幽門桿菌陰性胃癌族群有其臨床意義與重要性至今較多的證據說明幽門桿菌陰性胃癌其臨床預後較差但仍未有定論。我們自 1998 Nov.- 2011 Dec.收集533 名個案的胃癌族群進行回朔性世代研究，以血清的幽門桿菌抗體濃度陰性與任一檢查的組織學、碳13 尿素氮呼氣試驗、細菌培養的檢查陰性定義為Negative H.P status，而血清pepsinogen I < 70 ng/ml 且pepsinogen I/II < 3.0 定義為血清學的萎縮性胃炎因萎縮性胃炎與幽門桿菌感染高度相關陰性個案符合定義則歸於幽門桿菌陽性個案。研究結果顯示幽門桿菌陰性胃癌發病年齡較年輕(58.1 歲v.s 63.3 歲)、腫瘤位置多近端胃癌(19.7% v.s 11.8%)、多瀰漫性胃癌(58.2% v.s 48.1%)、病理特徵與臨床分期表現出較高的遠端轉移性(AJCC 7th 第四期40% v.s 26%)、血型表現以非A 血型為主(76% v.s65%)。台灣幽門桿菌陰性胃癌臨床預後的存活分析顯示幽門桿菌陽性胃癌存活率為39.3 %而幽門桿菌陰性胃癌存活率為26.6% (log-rank test,p= 0.04)而多變數分析顯示陰性幽門桿菌感染狀態為一獨立的不良預後因子(hazard ratio 1.40,95% confidence interval 1.02–1.96,p =0.04 )在AJCC 7th II 與IIIa 的次族群中顯示陰性幽門桿菌感染狀態為唯一獨立的不良預後因子(HR 2.84,C.I 1.24-6.51, P=0.01 )我們的研究顯示幽門桿菌陰性胃癌其臨床預後較差尤其在AJCC 7th II 與IIIa 的次族群在根除性手術後應該小心密切追蹤.

There are sufficient evidence that Helicobacter pylori is a definite carcinogen of gastric cancer. Early H.P eradication truly declines the gastric cancer incidence. The mortality of gastric cancer has continued to decrease in decades. In the era of mass screening of H.P infection and developing regimen for H.P eradication, H.P associated gastric cancer(HPPGC) incidence has declined in Taiwan. Recent studies show helicobacter pylori negative gastric cancer (HPNGC) is truly another disease entity. From 1998 Nov. to 2011 Dec. We retrospectively enrolled 533 cases for study.Accurate diagnosis of HPNGC is crucial and clinical challenge in high prevalence area of H.P such as Taiwan. The H. pylori IgG antibodies detected by the enzyme-linked immunosorbent assay (ELISA) indicate current or past H. pylori infection. Invasive examination such as histology, culture or urea breathe test for H. pylori infection is done. Atrophic gastritis is a precancerous lesion which is highly associated with chronic H.P infection. We define sera pepsinogen I level < 70 ng/dl and pepsinogen I/II ratio < 3 as severe serologic atrophic gastritis which represent pass infection of H.P. We surely yield high diagnostic accuracy of H. pylori infection status according to serologic test, invasive examination and sera pepsinogen level. Survival analysis will be performed according to H.pylori infection status.We used the Pearson chi-squared test to investigate association between H. pylori status and categorical variable. For comparison of continuous variable such as age, pepsinogen level,we used the two tail student t test to detect the difference. The log-rank test in Kaplan-Meier survival analyses was used to assess the effect of variables on survival. Cox proportional-hazards regression model is performed. We chose Stata 12 (64-bit) software for all the analyses.Our result showed that the HPNGC group has the characteristic of younger disease onset age, diffuse type dominant, more proximal gastric cancer, non A blood group dominant and poor clinical outcome. By AJCC 7th gastric cancer stage, it showed more proportion of the stage IV patients (40% versus 26%, p=0.02) in HPNGC The tumor behavior in HPNGC showed more potential of distal metastasis. In Kaplan Meier survival analysis, the long term overall survival rate was 39.3 % in HPPGC patients and 26.6% in HPNGC patients.(log-rank test, p = 0.04) Cox proportional-hazards regression model showed negativity of H. pylori status is an independent poor prognostic factor. (hazard ratio 1.40, 95% confidence interval 1.02–1.96, p= 0.04 ) The prognostic significance is strongest in patients with AJCC 7th stage II or stage IIIa. (HR 2.84,C.I 1.24-6.51, P=0.01 ) In the subgroup, patients may need more careful follow up or adjuvant chemotherapy after curative surgery.