胃粘膜不典型增生性肠化及异型增生：形态学和分子生物学研究
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摘要
背景胃粘膜上皮异型增生是胃癌的癌前病变,具有重要的临床意义,但仅靠H&E诊断有时难以与反应性或化生性病变相鉴别,并且相当一部分病例在随访中病变可退缩,仅少部分病例最终进展为癌。因此,人们希望找到相关的分子生物学标记物辅助异型增生的诊断,甚至帮助筛选出具有高危风险发生癌变的病例。此外,由于我国幽门螺旋杆菌的感染率高,慢性萎缩性胃炎伴肠化的病例常见,当肠化伴增生,尤其伴不典型增生时,常带来诊断困难。到目前为止,对于伴细胞和／或结构不典型性的不典型增生性肠化(intestinal metaplasia with atypical hyperproliferation, IMAH)的发病率、形态学和生物学特征的研究还很有限,该部分病例暂被归入“不确定性异型增生”。本课题试图通过横断面和回顾性研究对上述问题进行初步探讨。
材料与方法检索北京协和医院病理科2009年全年胃粘膜活检标本4167例,以及2003-2007年间首次诊断为异型增生并有随访资料的胃粘膜活检标本151例。横断面研究最终入组2009年554例伴有慢性萎缩性胃炎,和／或异型增生的胃粘膜活检,根据形态学分为1)简单肠化(SIM)；2)增生性肠化(IMH)；3)不典型增生性肠化(IMAH)和4)异型增生(GED),并对各亚型的临床病理特征(包括性别、年龄、部位、幽门螺旋杆菌感染情况)、组织化学分型(Ⅰ型、Ⅱ/ⅡA型和Ⅲ/ⅡB型)、粘液免疫表型(胃型、胃肠混合型、肠型及小肠型)和分子生物学特点(p53、Ki-67指数、AMACR)进行了研究,以对不典型增生性肠化的生物学性质进行初步探讨。此外,回顾性研究的151例胃粘膜异型增生病例中,随访>6个月的病例44例,复习切片最终入组20名患者的83例胃粘膜活检/切除标本,进行临床病理特征、粘液免疫表型、分子生物学以及预后研究。
结果横断面研究入组的554例包括SIM424例(76.5%),IMH93例(16.8%),IMAH16例(2.9%),GED21例(3.8%)。IMAH的发病率为2.8%,与GED相似(3.8%)。四组形态学亚型间,患者的年龄、性别不具有统计学差异。SIM和IMH主要见于胃窦(SIM,94.8%; IMH,95.7%),而IMAH和GED在胃底/体的比例高于前两组(IMAH,12.5%; GED,42.9%)(p<0.001)。本组病例中幽门螺旋杆菌的总感染率为78.3%,GED的感染率(10/17,57.1%)显著高于前三组(SIM,113/330,34.2%; IMH,19/74,25.8%;IMAH,5/13,38.5%),差异具有边际意义(p=0.049)。与SIM(2/25,8%)和IMH(10/25,40%)相比,IMAH(11/16,68.8%)和GED(19/21,90.5%)腺体的杯状细胞数量明显减少(杯状细胞<10%)(p<0.001)。此外,中性粒细胞浸润多见于IMAH(10/16,62.5%)和GED(18/21,85.7%),而SIM(9/25,36%)和IMH (7/25,28%)中性粒细胞浸润的比例较低(p<0.001)。其它组织学特征,如胃粘膜萎缩程度、中-重度慢性炎细胞浸润,在四组间无明显差异。粘蛋白免疫表型中,小肠型(I-S)和胃肠混合型(GI)可见于所有四组形态学亚型,且小肠型在SIM(17/25,68%)和IMH(19/25,76%)显著高于IMAH(7/16,43.7%)和GED(4/21,19%).肠型(Ⅰ)和胃型(G)仅见于异型增生,所占比例分别为19%(4/21)和23.8%(5/21)(p<0.001).AMACR主要表达于异型增生(13/21,61.9%),以及25%(4/16)IMAH(p<0.001).p53过表达除1例IMAH(1/16,6.3%)外,仅见于异型增生(10/21,47.6%)(p<0.05)。异型增生病例中,表面上皮和小凹的ki-67表达显著高于其它三组(p<0.001).MUC6异位表达(累及胃小凹及表面上皮)仅见于异型增生(15/21,71.4%)(p<0.001),且与高ki-67增值指数密切相关。82例病例有组织化学染色结果,分为Ⅰ型(35例),Ⅱ/ⅡA型(20例)和Ⅲ/ⅡB型(27例)。Ⅰ型多见于SIM(12/25,48%),IMH(13/25,52%)和IMAH(7/15,46.7%)。与之相反,Ⅲ/ⅡB型在GED(11/17,64.7%)的比例显著高于其它三组：SIM(5/25,20%),IMH(6/25,24%),IMAH(5/15,33%)(p=0.018).Ⅲ/ⅡB型p53的过表达率(6/27,22.2%)高于Ⅰ型(1/35,2.9%)和Ⅱ/ⅡA型(1/20,5%),差异具有统计学意义(p<0.05).MUC6异位表达在Ⅲ/ⅡB型(8/27,29.6%)中显著高于Ⅰ型(2/35,5.7%)和Ⅱ/ⅡA型(1/20,5%)(p<0.05)
对2003-2007年有首次诊断胃粘膜异型增生并有后续随访活检或切除标本的病例151人。首次诊断异型增生时的平均年龄为60.3(33-85岁),男女比为2.02：1。异型增生位于胃窦部者115人(76.2%),胃底/体者36人(23.8%)。45%(68/151)患者首次异型增生诊断为低级别；随访>6个月的病例中,78.8%(26/33)退缩(随访6-54月,平均31.0月),12.1%(4/33)持续(随访6-63月,平均35.3月),9.1%(3/33)进展(2例,分别随访15,43个月)。83人(55%)首次异型增生诊断为高级别病变,其中59人行粘膜切除或手术切除,24人活检随访。61.4%(51/83)的病例在随后的切除标本或活检中诊断为癌,其中98%(50/51)的病例为诊断后3个月内手术,1例随访39个月后进展为癌；16.9%(14/83)病变持续(随访1-47月,平均15.7月),21.7%(18/83)病变退缩为低级别异型增生(随访1-37月,平均11.3月)。对20名患者的83例标本进行进一步的免疫组化研究。粘液免疫表型在10例退缩病人中为胃肠混合型(5例),小肠型(2例)或胃型(1例)。2人首次异型增生诊断为高级别者,在随访过程中退缩为低级别异型增生,其粘蛋白免疫表型分别为小肠型(1例)和肠型(1例)。6例病变持续的病人中,3例低级别异型增生为小肠型(2例)和胃肠混合型(1例),其中1例小肠型在随访46个月后转变为胃型；3例高级别异型增生分别为胃型(1例)、胃肠混合型(1例)和小肠型(1例)。4例进展的病例中,3例表型从首次活检的小肠型(2例)或胃肠混合型(1例)转变为胃型。p53过表达在退缩、持续和进展的三组病例中表达率分别为20%(2/10),16.7%(1/6)和50%(2/4)；AMACR阳性率在三组中分别为分别为20%(2/10),33.3%(2/6)和75%(3/4);MUC6异位表达率分别为30%(3/10)、33.3%(2/6)和50%(2/4)。
结论(1)胃粘膜肠化可分为两大类：1)不伴不典型增生的肠化,包括简单肠化和增生性肠化,是最常见的肠化形式；2)伴不典型增生的肠化,即不典型增生性肠化。(2)本研究首次报道了不典型增生性肠化在慢性萎缩性胃炎病人中的患病率为2.9%,与异型增生相似(3.8%)。不典型增生性肠化在胃底/体分布比例增加,杯状细胞数量明显减少,具有与异型增生相似的分子生物学改变,如p53和AMACR,但表达率低于异型增生。因此,不典型增生性肠化可能是肠化恶变过程中先于传统异型增生的癌变早期阶段,对于这部分病例应采取与低级别异型增生一样的随访策略,但该结论还需随访资料进一步证实。(3)中国人群胃粘膜上皮异型增生的患病率比西方国家略高(3.8%vs.0.5-3.75%),但远低于之前人们的预期。低级别异型增生近一半病例可退缩,约10-15%在随访中进展为高级别病变,应对其进行定期随访；高级别异型增生伴发浸润癌或短期内进展为浸润癌的比例显著增加(61.4%),应给予积极的治疗或密切随访。(4)联合检测p53过表达、表面上皮和小凹Ki-67增殖指数的增高、MUC6的异位表达和AAMCR有助于胃粘膜上皮异型增生的诊断。(5)根据MUC5AC,MUC6, MUC2和CD10免疫组化结果得出的四种粘蛋白免疫表型中,胃肠混合型是一种不稳定的过渡状态,可进一步分化成熟为小肠型,或发展为不成熟的胃型或肠型,后两者,尤其是胃型癌变的风险增加。
Background Gastric epithelial dysplasia (GED) is a precancerous lesion of gastric cancer and has crucial clinical meanings. It is notoriously difficult sometimes to distinguish dysplasia from regenerative or metaplastic lesions. In addition, only small portion of cases will develop gastric cancer and the majority may regress or persist during long-term follow up. Therefore, it would be useful if we could find some adjuvent markers for helping identify dysplasia and even cases with high risk for cancer. Since the prevalence of H. pylori is relatively high in Chinese population, chronic atrophic gastritis with intestinal metaplasia (IM) is frequently seen. IM can be hyperprolifered and display cytoarchitectural atypia which often cause diagnostic difficulty. Yet, few studies have evaluated the prevalence, the morphologic and biologic characteristics of intestinal metaplasia with atypical hyperproliferation (IMAH), which classified into "indefinite for dysplasia" presently because of lack of knowing of its biologic nature. These are the questions we are going to answer in this research.
Material and methods Searching data base from PUMCH for gastric biopies performed during2009and from2003through2007. In the first cohort, during whole year of2009,554biopsies with chronic atrophic gastritis and/or dysplasia were identified, we categorized the cases as either1) simple IM (SIM);2) IM with hyperplasia (IMH);3) IM with atypical hyperproliferation (IMAH) and4) gastric dysplasia (GED). The relationship between histologic subtypes and various clinicopathological features (i. e. sex, age, site, H. pylori status), histochemstry, mucin immunophenotypes (i.e. gastric, gastrointestinal, intestinal and small intestinal)and biologic characteristics (i. e. p53, ki-67index and AMACR) was evaluated. In the second cohort,151patients diagnosed as dysplasia and with follow-up biopsies or resection specimen were identified.44out of151patients had interval of follow-up longer than six months.83biopsies or resection specimen from20patients were finally enrolled to evaluate clinicopathological featuers, mucin phenotypes, biologic features and prognosis.
Results The first cohort from2009biopsies comprised of424cases of SIM,93IMH,16IMAH, and21GED. IMAH had a prevalence of2.8%and similar to GED3.7%. There were no significant difference regarding to age and sex. Both of IMAH and GED were similar in body/fundus distribution (12.5%) and paucity of goblet cells (68.8%). IMAH and GED seem to share some biologic similarities but with a lower frequency of AMACR expression (25%vs.62%), p53expression (6.3%vs.47.6%) and increased Ki-67index on surface/pit and isthmus in IMAH. Alternatively, SIM and IMH did not differ statistically with regard to the various characteristics evaluated. The second cohort initially selected151patients with follow-up data. The mean age was60.3ranging from33-85years old. Male and female ratio was2.02:1.76.2%of cases were found in antrum, the rest were in body/fundus (23.8%).45%(68/151) patients were first diagnosed as low-grade dyplasia. Among patients with follow-up period longer than6months,78.8%(26/33) were regressed,12.1%(4/33) persisted, and9.1%(3/33) progressed.55%(83/151) patients were first diagnosed as high-grade dysplasia,59of whom performed EMR or surgical resection, and24of whom were follow-up closely. Among patients with follow-up period longer than6months,54.4%(6/11) were regressed,36.4%(4/11) persisted, and9.1%(1/11) progressed to adenocarcinoma.20patients were evaluated for further immunostains. Mucin phenotypes among patients whose lesions were regressed were gastrointestinal (5patients), small intestinal (2patients) or gastric subtype (1patient).2patients with first diagnosed as high-grade dysplasia and regressed to low-grade displayed small intestinal (1patient) and intestial subtyps (1patient). Among6patients with persistent dysplasia,3low-grade dysplasia cases showed small intestinal (2patients) and gastrointestinal (1patient) phenotype. One of the patients converted to gastric phenotype from small intestianl phenotype after46months follow-up. The phenotypes of3persistent high-grade dysplasia were gastric, gastrointestinal and small intestinal, respectively.3out of4progressed cases were converted to gastric phenotype from small intestinal (2patients) and gastrointestinal phenotype (1patient). p53overexpression were found in20%(2/10) regressed,16.7%(1/6) persistent and50%(2/4) progressed patients. AMACR positivity were20%(2/10),33.3%(2/6) and75%(3/4), respectively among three groups. MUC6ectopic exression were30%(3/10),33.3%(2/6) and50%(2/4)
Conclusion (1)Gastric IM can be divided into2broad categories, that is IM without atypia, including SIM and IMH, and IM with atypia, i.e. IMAH.
(2) We first reported the prevalence of IMAH among patients with chronic atrophic gastritis was2.9%, similar with the rate for dysplasia (3.8%). In addtion, the prevalence of dysplasia in Chinses population was slightly higher than western but much lower than what was expected previously.
(3) Based on the characteristics of IMAH and in keeping with others, we confirm that this subtype could represent a preneoplastic lesion that should initiate endoscopic surveillance.
(4) AMACR was positive in25%IMAH and the positivity rate increased with the progression of lesions. We assume that AMACR could be an early biomarker for gastric intraepithelial tumor.
(5)Conbimed detection of p53,, ki-67index and MUC6ectopia may adjuvent for GED diagnosis.
(6) Regarding to four mucin phenotypes, gastrointestinal phenotype may represent a transitional condition which is unstable and could further differentiate into small intestinal phenotype which represent a more mature stage, or become gastric or intestinal types which contain higher risk for cancer.
材料与方法检索北京协和医院病理科2009年全年胃粘膜活检标本4167例,以及2003-2007年间首次诊断为异型增生并有随访资料的胃粘膜活检标本151例。横断面研究最终入组2009年554例伴有慢性萎缩性胃炎,和／或异型增生的胃粘膜活检,根据形态学分为1)简单肠化(SIM)；2)增生性肠化(IMH)；3)不典型增生性肠化(IMAH)和4)异型增生(GED),并对各亚型的临床病理特征(包括性别、年龄、部位、幽门螺旋杆菌感染情况)、组织化学分型(Ⅰ型、Ⅱ/ⅡA型和Ⅲ/ⅡB型)、粘液免疫表型(胃型、胃肠混合型、肠型及小肠型)和分子生物学特点(p53、Ki-67指数、AMACR)进行了研究,以对不典型增生性肠化的生物学性质进行初步探讨。此外,回顾性研究的151例胃粘膜异型增生病例中,随访>6个月的病例44例,复习切片最终入组20名患者的83例胃粘膜活检/切除标本,进行临床病理特征、粘液免疫表型、分子生物学以及预后研究。
结果横断面研究入组的554例包括SIM424例(76.5%),IMH93例(16.8%),IMAH16例(2.9%),GED21例(3.8%)。IMAH的发病率为2.8%,与GED相似(3.8%)。四组形态学亚型间,患者的年龄、性别不具有统计学差异。SIM和IMH主要见于胃窦(SIM,94.8%; IMH,95.7%),而IMAH和GED在胃底/体的比例高于前两组(IMAH,12.5%; GED,42.9%)(p<0.001)。本组病例中幽门螺旋杆菌的总感染率为78.3%,GED的感染率(10/17,57.1%)显著高于前三组(SIM,113/330,34.2%; IMH,19/74,25.8%;IMAH,5/13,38.5%),差异具有边际意义(p=0.049)。与SIM(2/25,8%)和IMH(10/25,40%)相比,IMAH(11/16,68.8%)和GED(19/21,90.5%)腺体的杯状细胞数量明显减少(杯状细胞<10%)(p<0.001)。此外,中性粒细胞浸润多见于IMAH(10/16,62.5%)和GED(18/21,85.7%),而SIM(9/25,36%)和IMH (7/25,28%)中性粒细胞浸润的比例较低(p<0.001)。其它组织学特征,如胃粘膜萎缩程度、中-重度慢性炎细胞浸润,在四组间无明显差异。粘蛋白免疫表型中,小肠型(I-S)和胃肠混合型(GI)可见于所有四组形态学亚型,且小肠型在SIM(17/25,68%)和IMH(19/25,76%)显著高于IMAH(7/16,43.7%)和GED(4/21,19%).肠型(Ⅰ)和胃型(G)仅见于异型增生,所占比例分别为19%(4/21)和23.8%(5/21)(p<0.001).AMACR主要表达于异型增生(13/21,61.9%),以及25%(4/16)IMAH(p<0.001).p53过表达除1例IMAH(1/16,6.3%)外,仅见于异型增生(10/21,47.6%)(p<0.05)。异型增生病例中,表面上皮和小凹的ki-67表达显著高于其它三组(p<0.001).MUC6异位表达(累及胃小凹及表面上皮)仅见于异型增生(15/21,71.4%)(p<0.001),且与高ki-67增值指数密切相关。82例病例有组织化学染色结果,分为Ⅰ型(35例),Ⅱ/ⅡA型(20例)和Ⅲ/ⅡB型(27例)。Ⅰ型多见于SIM(12/25,48%),IMH(13/25,52%)和IMAH(7/15,46.7%)。与之相反,Ⅲ/ⅡB型在GED(11/17,64.7%)的比例显著高于其它三组：SIM(5/25,20%),IMH(6/25,24%),IMAH(5/15,33%)(p=0.018).Ⅲ/ⅡB型p53的过表达率(6/27,22.2%)高于Ⅰ型(1/35,2.9%)和Ⅱ/ⅡA型(1/20,5%),差异具有统计学意义(p<0.05).MUC6异位表达在Ⅲ/ⅡB型(8/27,29.6%)中显著高于Ⅰ型(2/35,5.7%)和Ⅱ/ⅡA型(1/20,5%)(p<0.05)
对2003-2007年有首次诊断胃粘膜异型增生并有后续随访活检或切除标本的病例151人。首次诊断异型增生时的平均年龄为60.3(33-85岁),男女比为2.02：1。异型增生位于胃窦部者115人(76.2%),胃底/体者36人(23.8%)。45%(68/151)患者首次异型增生诊断为低级别；随访>6个月的病例中,78.8%(26/33)退缩(随访6-54月,平均31.0月),12.1%(4/33)持续(随访6-63月,平均35.3月),9.1%(3/33)进展(2例,分别随访15,43个月)。83人(55%)首次异型增生诊断为高级别病变,其中59人行粘膜切除或手术切除,24人活检随访。61.4%(51/83)的病例在随后的切除标本或活检中诊断为癌,其中98%(50/51)的病例为诊断后3个月内手术,1例随访39个月后进展为癌；16.9%(14/83)病变持续(随访1-47月,平均15.7月),21.7%(18/83)病变退缩为低级别异型增生(随访1-37月,平均11.3月)。对20名患者的83例标本进行进一步的免疫组化研究。粘液免疫表型在10例退缩病人中为胃肠混合型(5例),小肠型(2例)或胃型(1例)。2人首次异型增生诊断为高级别者,在随访过程中退缩为低级别异型增生,其粘蛋白免疫表型分别为小肠型(1例)和肠型(1例)。6例病变持续的病人中,3例低级别异型增生为小肠型(2例)和胃肠混合型(1例),其中1例小肠型在随访46个月后转变为胃型；3例高级别异型增生分别为胃型(1例)、胃肠混合型(1例)和小肠型(1例)。4例进展的病例中,3例表型从首次活检的小肠型(2例)或胃肠混合型(1例)转变为胃型。p53过表达在退缩、持续和进展的三组病例中表达率分别为20%(2/10),16.7%(1/6)和50%(2/4)；AMACR阳性率在三组中分别为分别为20%(2/10),33.3%(2/6)和75%(3/4);MUC6异位表达率分别为30%(3/10)、33.3%(2/6)和50%(2/4)。
结论(1)胃粘膜肠化可分为两大类：1)不伴不典型增生的肠化,包括简单肠化和增生性肠化,是最常见的肠化形式；2)伴不典型增生的肠化,即不典型增生性肠化。(2)本研究首次报道了不典型增生性肠化在慢性萎缩性胃炎病人中的患病率为2.9%,与异型增生相似(3.8%)。不典型增生性肠化在胃底/体分布比例增加,杯状细胞数量明显减少,具有与异型增生相似的分子生物学改变,如p53和AMACR,但表达率低于异型增生。因此,不典型增生性肠化可能是肠化恶变过程中先于传统异型增生的癌变早期阶段,对于这部分病例应采取与低级别异型增生一样的随访策略,但该结论还需随访资料进一步证实。(3)中国人群胃粘膜上皮异型增生的患病率比西方国家略高(3.8%vs.0.5-3.75%),但远低于之前人们的预期。低级别异型增生近一半病例可退缩,约10-15%在随访中进展为高级别病变,应对其进行定期随访；高级别异型增生伴发浸润癌或短期内进展为浸润癌的比例显著增加(61.4%),应给予积极的治疗或密切随访。(4)联合检测p53过表达、表面上皮和小凹Ki-67增殖指数的增高、MUC6的异位表达和AAMCR有助于胃粘膜上皮异型增生的诊断。(5)根据MUC5AC,MUC6, MUC2和CD10免疫组化结果得出的四种粘蛋白免疫表型中,胃肠混合型是一种不稳定的过渡状态,可进一步分化成熟为小肠型,或发展为不成熟的胃型或肠型,后两者,尤其是胃型癌变的风险增加。
Background Gastric epithelial dysplasia (GED) is a precancerous lesion of gastric cancer and has crucial clinical meanings. It is notoriously difficult sometimes to distinguish dysplasia from regenerative or metaplastic lesions. In addition, only small portion of cases will develop gastric cancer and the majority may regress or persist during long-term follow up. Therefore, it would be useful if we could find some adjuvent markers for helping identify dysplasia and even cases with high risk for cancer. Since the prevalence of H. pylori is relatively high in Chinese population, chronic atrophic gastritis with intestinal metaplasia (IM) is frequently seen. IM can be hyperprolifered and display cytoarchitectural atypia which often cause diagnostic difficulty. Yet, few studies have evaluated the prevalence, the morphologic and biologic characteristics of intestinal metaplasia with atypical hyperproliferation (IMAH), which classified into "indefinite for dysplasia" presently because of lack of knowing of its biologic nature. These are the questions we are going to answer in this research.
Material and methods Searching data base from PUMCH for gastric biopies performed during2009and from2003through2007. In the first cohort, during whole year of2009,554biopsies with chronic atrophic gastritis and/or dysplasia were identified, we categorized the cases as either1) simple IM (SIM);2) IM with hyperplasia (IMH);3) IM with atypical hyperproliferation (IMAH) and4) gastric dysplasia (GED). The relationship between histologic subtypes and various clinicopathological features (i. e. sex, age, site, H. pylori status), histochemstry, mucin immunophenotypes (i.e. gastric, gastrointestinal, intestinal and small intestinal)and biologic characteristics (i. e. p53, ki-67index and AMACR) was evaluated. In the second cohort,151patients diagnosed as dysplasia and with follow-up biopsies or resection specimen were identified.44out of151patients had interval of follow-up longer than six months.83biopsies or resection specimen from20patients were finally enrolled to evaluate clinicopathological featuers, mucin phenotypes, biologic features and prognosis.
Results The first cohort from2009biopsies comprised of424cases of SIM,93IMH,16IMAH, and21GED. IMAH had a prevalence of2.8%and similar to GED3.7%. There were no significant difference regarding to age and sex. Both of IMAH and GED were similar in body/fundus distribution (12.5%) and paucity of goblet cells (68.8%). IMAH and GED seem to share some biologic similarities but with a lower frequency of AMACR expression (25%vs.62%), p53expression (6.3%vs.47.6%) and increased Ki-67index on surface/pit and isthmus in IMAH. Alternatively, SIM and IMH did not differ statistically with regard to the various characteristics evaluated. The second cohort initially selected151patients with follow-up data. The mean age was60.3ranging from33-85years old. Male and female ratio was2.02:1.76.2%of cases were found in antrum, the rest were in body/fundus (23.8%).45%(68/151) patients were first diagnosed as low-grade dyplasia. Among patients with follow-up period longer than6months,78.8%(26/33) were regressed,12.1%(4/33) persisted, and9.1%(3/33) progressed.55%(83/151) patients were first diagnosed as high-grade dysplasia,59of whom performed EMR or surgical resection, and24of whom were follow-up closely. Among patients with follow-up period longer than6months,54.4%(6/11) were regressed,36.4%(4/11) persisted, and9.1%(1/11) progressed to adenocarcinoma.20patients were evaluated for further immunostains. Mucin phenotypes among patients whose lesions were regressed were gastrointestinal (5patients), small intestinal (2patients) or gastric subtype (1patient).2patients with first diagnosed as high-grade dysplasia and regressed to low-grade displayed small intestinal (1patient) and intestial subtyps (1patient). Among6patients with persistent dysplasia,3low-grade dysplasia cases showed small intestinal (2patients) and gastrointestinal (1patient) phenotype. One of the patients converted to gastric phenotype from small intestianl phenotype after46months follow-up. The phenotypes of3persistent high-grade dysplasia were gastric, gastrointestinal and small intestinal, respectively.3out of4progressed cases were converted to gastric phenotype from small intestinal (2patients) and gastrointestinal phenotype (1patient). p53overexpression were found in20%(2/10) regressed,16.7%(1/6) persistent and50%(2/4) progressed patients. AMACR positivity were20%(2/10),33.3%(2/6) and75%(3/4), respectively among three groups. MUC6ectopic exression were30%(3/10),33.3%(2/6) and50%(2/4)
Conclusion (1)Gastric IM can be divided into2broad categories, that is IM without atypia, including SIM and IMH, and IM with atypia, i.e. IMAH.
(2) We first reported the prevalence of IMAH among patients with chronic atrophic gastritis was2.9%, similar with the rate for dysplasia (3.8%). In addtion, the prevalence of dysplasia in Chinses population was slightly higher than western but much lower than what was expected previously.
(3) Based on the characteristics of IMAH and in keeping with others, we confirm that this subtype could represent a preneoplastic lesion that should initiate endoscopic surveillance.
(4) AMACR was positive in25%IMAH and the positivity rate increased with the progression of lesions. We assume that AMACR could be an early biomarker for gastric intraepithelial tumor.
(5)Conbimed detection of p53,, ki-67index and MUC6ectopia may adjuvent for GED diagnosis.
(6) Regarding to four mucin phenotypes, gastrointestinal phenotype may represent a transitional condition which is unstable and could further differentiate into small intestinal phenotype which represent a more mature stage, or become gastric or intestinal types which contain higher risk for cancer.
引文
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