篩檢性大腸鏡檢出之結腸增生性息肉—以組織病理學及基因變異再複檢

Abstract

研究背景與研究目的:大腸癌之盛行率日漸攀升，目前已知篩檢並切除贅生性息肉是有效且安全的預防結腸癌的方法。自1960年代以來，結腸息肉被分為兩大類，一類是贅生性息肉，包含了管狀、絨毛狀腺瘤;另一類是非贅生性息肉，主要以增生性息肉為主。由於大部分之結腸癌是經由腺瘤-腺癌程序的途徑，因此增生性息肉被認為是不具威脅性的。但是在1990年起學者發現了一群和增生性息肉有相似的鋸齒狀腺隱窩之息肉，但是其細胞卻和腺瘤一樣有不良分化的現象，而將之稱為鋸齒狀腺瘤。在2003年又發現扁平以及短莖形的鋸齒狀腺瘤，其腺隱窩又呈水平分枝以及好發於女性和近端結腸。這群息肉由於都具有鋸齒狀腺隱窩，統稱為鋸齒狀息肉。然而病理科醫師在診斷這類息肉常常相當困擾，彼此間的共識度也偏低。約有10-15%的偶發性大腸癌來自鋸齒狀腺瘤，因此其臨床重要性日益被肯定，而其致癌途徑並非一般APC基因對偶突變的腺瘤-腺癌途徑，可能是經由KRAS或BRAF基因突變導致CpG Island 甲基化，此途徑稱為鋸齒腺瘤途徑(serrated pathway)。由於此類鋸齒狀腺瘤在結構上與增生性息肉相似，但在細胞行為上卻和腺瘤相似，診斷上面臨許多瓶頸，因此我們設計此一回溯性研究來探討。 研究方法：由健檢中心資料庫回溯性收集253例病理診斷為增生性息肉之個案，將其交由兩位專精腸胃道病理之醫師再次判讀，以相符之判斷為最終診斷，並將發現之可能贅生性息肉以基因直接定序法做BRAF V600E以及KRAS G12D的基因檢測。 結果：在253例增生性息肉中，平均直徑為4.5mm，經由兩位病理科醫師複檢後確認其中175例為鋸齒狀息肉，58例為發炎性息肉，17例為管狀腺瘤，3例為黏膜突疣。在175例鋸齒狀息肉中包含有163例的增生性息肉、5例的傳統鋸齒狀腺瘤與7例的短莖型鋸齒狀腺瘤。兩位病理科醫師在診斷這群鋸齒狀息肉的共識信度上屬於高度信度(Substantial, Kappa值=0.66721, 95% C.I.=0.445 to 0.889)。大於10mm的大型息肉有較高的比例被發現具贅生性(21.4% vs. 7.5%)，針對贅生性與非贅生性息肉和性別、年齡、分布位置作檢定，顯示10mm以上息肉好發於近端結腸(p=0.0004)。針對複檢出的7例短莖型鋸齒狀腺瘤、5例傳統型鋸齒狀腺瘤、17例管狀腺瘤以及27例增生性息肉做基因直接定序，其中兩例短莖型鋸齒狀腺瘤(0.6cm與1.0cm)與一例傳統鋸齒狀腺瘤(1.8cm)在BRAF V600E有突變(GTG/GAG)，另外在一例傳統鋸齒狀腺瘤(0.2cm)發現有KRAS突變(G12D, GGT/GAT)。 結論：經由病理科醫師複檢後的結腸鋸齒狀息肉中，有6.9%是鋸齒狀腺瘤，不同醫師的診斷一致性屬高度信度。針對BRAF V600E 和KRAS G12D基因檢測部分，3例呈現BRAF變異及1例呈現KRAS變異者均分屬傳統及短莖型鋸齒狀腺瘤，目前認為這些腺瘤可能經由另一途徑發展成腸癌。內視鏡醫師在施行大腸鏡檢查時若發現鋸齒狀息肉，尤其是大於10mm或位於近端結腸時，應特別仔細的觀察，尤其是近端大腸清腸不易，扁平息肉容易被忽略，而病理科醫師也應該對鋸齒狀腺瘤的觀念謹記在心。

Backgrounds and Aim: Screening colonoscopy is one of the most effective methods to detect and prevent colorectal cancer by removing neoplastic polyps. Hyperplastic polyps are traditionally considered nonneoplastic and innocent ones. However, the recent discovery of serrated polyps with neoplastic potential has reclassified these polyps into hyperplastic polyps, sessile serrated adenoma and traditional serrated adenoma according to macroscopic morphology and microscopic histology. BRAF or K-RAS mutations play crucial role in these so-called serrated adenoma pathways. We aimed to revisit hyperplastic polyps identified during screening endoscopy by histologic reevaluation and genetic alterations. Methods: A total of 253 hyperplastic polyps found by screening endoscopy were rechecked by two pathologists, and mutual agreement on diagnosis of polyps was subjected for further statistical analysis. Direct sequencing for gene mutation at BRAF V600E and KRAS G12D was performed. Results: Among 253 hyperplastic polyps, 175 were reclassified as serrated polyps. Concordance among pathologists in diagnosing these serrated polyps was substantial (kappa=0.6672). 11.5% of the hyperplastic polyps turned out to be with neoplastic potential, including 7 sessile, 5 traditional serrated adenomas, as well as 17 conventional adenomas. Subgroup analyses revealed polyps larger than 10mm were more likely to locate in proximal colon (p=0.0004) and tended to harbor neoplastic components. Two sessile serrated adenomas and one traditional sessile adenoma had BRAF mutation, while one traditional serrated adenoma had KRAS mutation. The mean size of these mutated adenomas (9.0mm) was larger than those with wild-type genes (4.9mm). Conclusions: Serrated polyps with neoplastic potential were prone to be overlooked as hyperplastic and innocent ones in screening colonoscopy. Both endoscopists and pathologists should pay attention to recognize the importance of serrated adenoma, especially for those polyps larger than 10mm, or locate in the proximal colon.