请选择 进入手机版 | 继续访问电脑版

医之本

医之本 首页 医资讯 查看内容

外科病理医生在胃肠道息肉病综合征诊断中的作用(全剧终)

2019-12-3 10:42| 发布者: admin| 查看: 35| 评论: 0

摘要: 【摘要】胃肠道息肉是很常见的疾病,大多数是散发性病例。部分类型的息肉与罕见的遗传性息肉病综合征有关,包括幼年性息肉病综合征(Juvenile polyposis syndrome,JPS)、Peutz-Jeghers综合征和Cowden综合征。然而 ...


                           


【摘要】胃肠道息肉是很常见的疾病,大多数是散发性病例。部分类型的息肉与罕见的遗传性息肉病综合征有关,包括幼年性息肉病综合征(Juvenile polyposis syndrome,JPS)、Peutz-Jeghers综合征和Cowden综合征。然而,胃肠道的许多散发性良性病变可以类似于这些综合征性错构瘤性息肉。外科病理学医生应该对这些遗传性息肉有着更高的警觉性,并寻找临床信息,以支持可疑的诊断。2018年,Rosty在《Adv Anat Pathol》杂志发表了题为《The Role of the Surgical Pathologist in the Diagnosis of Gastrointestinal Polyposis Syndromes》的文章,让我们一起来看看外科病理医生应该知道胃肠道息肉病综合征的哪些信息。


【前言】胃肠道息肉是外科病理医生最常见的病变之一。这些息肉绝大多数是散发性良性病变,其中一些可能发展为恶性肿瘤。流行病学参数,如年龄、生活方式和环境因素,与胃肠道息肉,特别是与大肠息肉的发病风险增加有关。遗传易感性是另一个公认的危险因素,是有息肉或胃肠道癌病史的家族亲属患息肉风险增加的原因。遗传性胃肠道息肉病综合征包括一组具有临床、病理和遗传特征均不同的病变。林奇综合征(Lynch综合征)和家族性腺瘤性息肉病是最常见的两种综合征,占所有结直肠癌的5%。错构瘤性息肉病综合征以遗传性为主,比较少见,诊断也较困难。然而,正确识别这些患者很重要,因为他们会增加得胃肠道和胃肠外癌症的风险。这些患者往往是缺乏家族史,这些综合征的诊断基本上是通过基因检测得到证实。外科病理医生可在适当的临床背景下,在鉴别具有遗传性胃肠综合征特征的胃肠道息肉方面发挥重要作用。文中就错构瘤性胃肠综合征中息肉的病理特点进行综述,目的是为病理医生根据组织学表现和临床背景提出1种错构瘤性胃肠综合征。文中描述了腺瘤性息肉病综合征的遗传性原因,总结了锯齿状息肉综合征的诊断及意义。林奇综合征(Lynch综合征)很少表现为息肉病综合征,因2016年《Am J Surg Pathol》杂志发表了一篇关于这个疾病的文章《A practical approach to the evaluation of gastrointestinal tract carcinomas for Lynch syndrome.》,所以本综述不包括这个疾病。


(二)腺瘤性息肉病综合征

并非所有的腺瘤样息肉病综合征都是家族性腺瘤样息肉病。最近描述的聚合酶校对相关息肉病(polymerase proofreading–associated polyposis),由POLE或POLD1胚系系突变引起,是另一种具有常染色体显性遗传的息肉病综合征。目前至少有2种遗传方式为隐性的综合征:MUTYH相关性息肉病和NTHL1相关性息肉病(表2)。

2 总结目前已知的易患结直肠癌的遗传性腺瘤性息肉病综合征

综合征

基因

遗传特征

分子标记

胃肠道息肉病

其他肿瘤风险

典型家族性腺瘤息肉病

APC

常染色体显性遗传

多发(>100)结肠腺瘤;胃底腺息肉和幽门腺腺瘤;小肠腺瘤

胃癌;硬纤维瘤;肝母细胞瘤;甲状腺肿瘤

MUTYH相关息肉病

MUTYH

常染色体隐性遗传

频繁的C:G>A:T置换

多发性结肠腺瘤伴锯齿状息肉;胃底腺息肉;十二指肠息肉

膀胱癌

卵巢癌

十二指肠癌

聚合酶校对-相关息肉病

POLE

POLD1

常染色体显性遗传

具有微卫星

稳定性的高/超突变表型

多发性结肠腺瘤,

十二指肠腺瘤

子宫内膜癌

脑肿瘤

NTHL1相关息肉病

NTHL1

常染色体隐性遗传

频繁的

C:G>T:A置换

多发性结肠腺瘤

子宫内膜增生与子宫内膜癌

(1)家族性腺瘤样息肉病

 APC相关息肉病包括典型家族性腺瘤样息肉病(classic form of familial adenomatous polyposis)、attenuated家族性腺瘤样息肉病(attenuated familial adenomatous polyposis)、胃腺癌和胃近端息肉病(gastric adenocarcinoma and proximal polyposis of the stomach,GAPES)。


家族性腺瘤样息肉病是一种常染色体显性遗传综合征,其特征是在大肠内可见≥100个普通腺瘤(conventional adenomas)。家族性腺瘤样息肉病的患病率估计在1:6850~1:31250之间。息肉诊断的平均年龄为16岁(7~36岁)。大约50%的受影响个体在15岁时已经发展成腺瘤。家族性腺瘤样息肉病腺瘤的组织学与散发性腺瘤相似。在家族性腺瘤样息肉病患者中,可以看到局限于单个结肠隐窝的不典型增生(单个隐窝腺瘤),常提示该综合征。大肠癌的发展是不可避免的,平均年龄为39岁(范围为34~43岁)。


典型家族性腺瘤样息肉病的其他胃肠道表现包括十二指肠和壶腹腺瘤,占50%~90%,腺癌和胃息肉的风险为4%~12%,占60%,腺癌风险低(<1%),亚洲国家除外。胃息肉最常见的是胃底腺息肉(80%),胃小凹型腺瘤和幽门腺腺瘤。家族性腺瘤样息肉病患者也有罹患筛状桑椹样乳头状甲状腺癌、肝母细胞瘤、肾上腺病变、髓母细胞瘤、硬纤维瘤、良性皮肤病变(表皮囊肿、纤维瘤)、骨瘤、牙齿发育异常和先天性视网膜色素上皮肥大(congenital hypertrophy of the retinal pigment epithelium)的风险。


attenuated家族性腺瘤样息肉病以大肠腺瘤较少为特征(10~99个,平均30个),以右侧分布为主。结直肠癌的累积风险在80岁时为70%,平均诊断年龄为50~55岁。上消化道表现与典型家族性腺瘤性息肉病相似。其他情况不常见,如硬纤维瘤。


家族性腺瘤样息肉病是由位于5q染色体的抑癌基因APC的胚系突变引起的,当APC的第二等位基因发生体细胞突变时,Wnt信号通路被激活,导致肿瘤的发生。致病突变在APC基因中的位置与表型相关。Attenuated家族性腺瘤性息肉病与基因5'端的变异有关。肠外表现的风险根据基因位置和致病性亚型的类型而异。大约25%的家族性腺瘤样息肉病患者没有结直肠癌或腺瘤的家族史,而有新的基因突变。


所有典型家族性腺瘤样息肉病患者和一些Attenuated家族性腺瘤样息肉病患者均行结肠切除术。手术方式根据息肉在体内的分布情况而异。建议从20~25岁开始进行上消化道内镜检查,并根据息肉病的严重程度进行间隔监测。


(2)MUTYH相关息肉病

MUTYH相关性息肉病是MUTYH双等位基因突变引起的常染色体隐性遗传综合征。MUTYH相关息肉病的表型与attenuated家族性腺瘤样息肉病和锯齿状息肉病综合征(serrated polyposis syndrome)的表型有重叠。高达14%的受累个体有超过100个息肉。与家族性腺瘤样息肉病相比,MUTYH相关息肉病患者没有影响父母,但可能影响兄弟姐妹(siblings)。通过8项研究资料的累积,MUTYH双等位基因突变携带者在50岁前发生结直肠癌的比例为1.4%,50岁后为0.3%。MUTYH位于染色体1P,编码一个碱基切除修复糖基化酶参与氧化损伤的修复。在受影响的患者中,MUTYH双等位基因丢失可防止清除与8-氧代胍相反的错误结合的腺嘌呤残基(the biallelic MUTYH loss prevents the removal of incorrectly incorporated adenine residues opposite 8-oxoguanine),从而导致C:G>A:T转换。在MUTYH息肉病相关的结直肠癌中,经常观察到c.34G>T-KRAS突变。


MUTYH相关息肉病患者在60岁时患结直肠癌的风险为43%,但实际发病率可能更高。约60%的MUTYH相关息肉病患者在首次就诊时患有结直肠癌,平均诊断年龄为48岁(21~70岁)。据报道,17%的MUTYH相关息肉病患者有4%的十二指肠腺癌风险。胃息肉见于10%~33%的患者,与家族性腺瘤样息肉病患者的类型相似。其他癌症风险包括卵巢癌、膀胱癌、乳腺癌和子宫内膜癌。偶尔,这种表型可以类似林奇综合征(Lynch syndrome)。


息肉病患者根据根据息肉在体内分布情况的不同,每1~2年行结肠镜下息肉切除术或结肠切除术。建议30~35岁时进行上消化道内镜检查。


(3)聚合酶校对相关息肉病(polymerase proofreading–associated polyposis)

聚合酶校对相关息肉病是2012年发现的一种新的常染色体显性遗传性息肉病综合征,由POLE或POLD1突变引起。这两个基因编码DNA聚合酶的亚单位。在受影响的患者中,肿瘤的发展是由于复制相关聚合酶校对的保真度降低,导致突变率增加。POLE突变携带者表现为少息肉病(oligopolyposis)、十二指肠腺瘤和癌。POLD1突变携带者也出现少息肉病(oligopolyposis)和结直肠癌,但也增加了子宫内膜癌和脑瘤的风险,类似于林奇综合征(Lynch syndrome)。然而,这些患者中的结直肠癌具有错配修复能力,并且以高突变或超突变表型为特征。


(4)NTHL1相关息肉病

NTHL1-associated polyposis, first described in 2015, is inherited in an autosomal recessive manner and caused by a homozygous truncating germline mutation in NTHL1. The NTHL1 gene is located in chromosome 16 and encodes a base excision repair glycosylase. The expected frequency of homozygosity is 1 in every 75,076 individuals. In the initial study, 7 affected individuals from 3 unrelated families have been reported with adenomatous polyposis (range, 8 to 50 adenomas). Four of these individuals were diagnosed with colorectal carcinoma at the age of 40 to 67 years. Although MUTYH-associated polyposis –associated colorectal carcinomas frequently harbor C:G > A:T transversions in particular in KRAS, NTHL1-associated polyposis colorectal carcinomas are associated with frequent C:G > T:A transitions. Affected individuals have also been diagnosed with endometrial carcinoma, endometrial hyperplasia, duodenal adenomas, and duodenal carcinoma. More studies are needed to better define the phenotype and tumor spectrum of this recently described syndrome.

2015年首次报道的NTHL1相关息肉病是以常染色体隐性遗传方式遗传的,由NTHL1的纯合截断系突变引起。NTHL1基因位于16号染色体,编码一种碱基切除修复糖基化酶。在75076个个体中,纯合子的预期频率为1。在最初的研究中,来自3个不相关家庭的7名受影响个体被报告患有腺瘤息肉病(850个腺瘤)。其中4人在4067岁时被诊断为结直肠癌。尽管MUTYH息肉病相关结直肠癌常伴有C:G>A:T转换,特别是在KRAS中,NTHL1相关结直肠癌常伴有C:G>T:A转换。患者还被诊断为子宫内膜癌、子宫内膜增生、十二指肠腺瘤和十二指肠癌。需要更多的研究来更好地定义这种最近描述的综合征的表型和肿瘤谱。

(三)胃腺癌与胃近端息肉病

Gastric adenocarcinoma and proximal polyposis of the stomach is an autosomal dominant cancer predisposition syndrome characterized by >100 fundic gland polyps in the oxyntic gastric mucosa and an increased risk of high-grade dysplasia and gastric carcinoma. The gastric carcinomas are typically intestinal-type adenocarcinoma and can occur at a young age (median age, 50 y; range, 33 to 75 y). The genetic cause is a point mutation in the promotor 1B of the APC gene. Compared with familial adenomatous polyposis, patients with gastric adenocarcinoma and proximal polyposis of the stomach do not have an increased risk of colorectal carcinoma, and gastric polyps spare the antrum.

胃腺癌和胃近端息肉病是一种常染色体显性癌易感性综合征,其特征是泌酸腺胃粘膜中的胃底腺息肉>100,高级别不典型增生和胃癌的风险增加。胃癌通常是肠型腺癌,可发生年轻(中位年龄,50岁;年龄范围,3375岁)。遗传原因是APC基因启动子1B的点突变。与家族性腺瘤息肉病相比,胃腺癌和胃近端息肉病患者不会增加结直肠癌的风险,胃息肉不累及胃窦。

(四)锯齿状息肉病综合征

One of the first reports of what is currently known as serrated polyposis syndrome came from the description of the unusual cooccurrence of multiple hyperplastic polyps of the large intestine and colorectal carcinoma, with the youngest reported patient being 23 years old. Formerly known as hyperplastic polyposis syndrome, serrated polyposis syndrome is a condition of unknown genetic cause, characterized by the development of multiple serrated polyps in the large bowel and an increased risk of colorectal carcinoma for affected individuals and their first degree relatives. The a patient fulfils one of the World Health Organization clinical criteria: (1) ≥5 serrated polyps proximal to the sigmoid colon with at least 2 polyps >10mm in size; (2) any number of serrated polyps proximal to the sigmoid colon in an individual who had a first-degree relative with serrated polyposis syndrome; and (3) >20 serrated polyps of any size but distributed throughout the colon. In practice, criterion 2 is usually not used, and the number of polyps is cumulative over time. Any histologic subtype of serrated polyps (hyperplastic polyp, sessile-serrated adenoma/polyp, traditional- serrated adenoma, sessile-serrated adenoma/polyp with dysplasia) is included in the final polyp count.

目前被称为锯齿状息肉病综合征的最早报告之一来自对大肠和大肠癌中多发增生性息肉异常共存的描述,最年轻的患者为23岁。以前被称为增生性息肉病综合征,锯齿状息肉病综合征是一种遗传原因不明的疾病,其特征是在大肠内形成多个锯齿状息肉,患者及其一级亲属患结直肠癌的风险增加。诊断时需符合世界卫生组织临床标准之一:(1)乙状结肠近端≥5个锯齿状息肉,至少2个息肉>10mm;(2)患者一级亲属锯齿状息肉综合征时,乙状结肠近端锯齿状息肉数目无论多少个;(3)>20锯齿状息肉。无论多大,但分布在整个结肠。实际上,通常不使用标准(2),息肉的数量是随着时间的推移而增加的。任何组织学类型的锯齿状息肉(增生性息肉、无柄锯齿状腺瘤/息肉、传统锯齿状腺瘤、伴不典型增生无柄锯齿状腺瘤/息肉)都包含在最终的息肉计数中。

The prevalence of serrated polyposis syndrome in the general population is unknown. From screening programs, the diagnosis of serrated polyposis syndrome is made in about 0.5% of screened individuals. Often, the diagnosis is missed by endoscopists and pathologists.Reassessment colonoscopy may be useful to diagnose more serrated polyposis syndrome patients, with a reported increase in prevalence from 0.32% in initial colonoscopy to 0.90% after reassessment colonoscopy.

锯齿状息肉病综合征在普通人群中的患病率尚不清楚。在筛查项目中,约0.5%的被筛查者诊断出锯齿状息肉病综合征。内窥镜和病理医生常常会漏诊,重新评估结肠镜可能有助于诊断更多的锯齿状息肉病综合征患者,报告的患病率从最初的结肠镜检查的0.32%增加到重新评估结肠镜检查后的0.90%。

The actual risk of colorectal carcinoma in serrated polyposis syndrome patients is not well known. From early studies, most patients were diagnosed with serrated polyposis syndrome at the time of colorectal carcinoma diagnosis. In a recent multicenter study of 296 serrated polyposis syndrome patients, 16% developed colorectal carcinoma at a mean age of 54 years with 8.5% of tumors being detected during surveillance. The cumulative colorectal carcinoma risk was 1.9% in 5 years, much lower than the 7% previously reported from a smaller cohort. For first-degree relatives, the risk of colorectal carcinoma is 5 times that of the general population. A clinicopathologic study of 45 serrated polyposis syndrome–associated colorectal carcinomas showed that nearly half (46%) harbored the somatic BRAFV600E mutation and 38% were mismatch repair deficient. Multiple tumors were frequent, with 26% of patients diagnosed with synchronous or metachronous colorectal carcinomas.

锯齿状息肉病综合征患者结直肠癌的实际风险尚不清楚。从早期研究来看,大多数患者在诊断结直肠癌时被诊断为锯齿状息肉综合征。在最近对296例锯齿状息肉病综合征患者进行的多中心研究中,16%的患者在平均54岁时患上了结直肠癌,其中8.5%的肿瘤是在监测期间发现的。在5年内,结直肠癌的累积风险为1.9%,远低于先前一个较小队列的7%。一级亲属患结直肠癌的风险是普通人群的5倍。45例锯齿状息肉病综合征相关结直肠癌的临床病理研究表明,近一半(46%)存在体细胞BRAFV600E突变,38%存在错配修复缺陷。多发性肿瘤是常见的,26%的患者被诊断为同时性或异时性结直肠癌。

Germline variants in RNF43 and in genes regulating senescence have been reported in some SPS patients. However, these findings have not been replicated in a large cohort of 295 patients. Other genes, such as BMPR1A, SMAD4, PTEN, MUTYH, and GREM1 have been excluded as major causes for serrated polyposis syndrome.

在一些SPS锯齿状息肉病综合征患者中,RNF43和调节衰老的基因中存在胚系变异。然而,这些发现并没有在295名患者中被复制。其他基因,如BMPR1A、SMAD4、PTEN、MUTYH和GREM1不是锯齿状息肉综合征的主要病因。

Pathologists need to be aware of the clinical criteria for serrated polyposis syndrome to make or suggest the diagnosis in their report when the number and size of serrated polyps meet the World Health Organization criterion 1 or 3. The current guidelines recommend yearly colonoscopy surveillance with the intent to clear the proximal colon of all serrated lesions, or all serrated lesions ≥ 5mm in size if there are numerous diminutive lesions. The surveillance interval can be altered depending on subsequent findings during follow-up colonoscopy procedures. Surgery may be required if colonoscopy control of polyps is not feasible. Surgical referral may be as low as 5% when SPS patients are closely monitored with effective reduction of polyp burden by colonoscopy. In first degree relatives, screening colonoscopy should be performed at the age of 40 years, or beginning at an age 10 years younger than the age at diagnosis of the youngest affected relative. Colonoscopy is recommended at 5-year intervals, or more frequently if polyps are found.

病理医生需要了解锯齿状息肉病综合征的临床标准,以便在其报告中提出当锯齿状息肉的数量和大小满足世界卫生组织标准1或3时的诊断建议。目前的指南建议每年结肠镜检查的目的是清除近端结肠所有的锯齿状病变,或所有锯齿状病变的大小超过5mm,如果有许多微小病变。在后续结肠镜检查过程中,可根据后续发现改变监测间隔。如果结肠镜无法控制息肉,可能需要手术。在结肠镜下密切监视SPS患者,有效减少息肉负担时,手术转诊率可低至5%。在一级亲属中,结肠镜检查应在40岁时进行,或在比最小受影响亲属的诊断年龄小10岁时开始。建议每隔5年进行一次结肠镜检查,如果发现息肉则需缩短做结肠镜的时间间隔

(五)小结


The diagnosis of hereditary gastrointestinal polyposis syndromes requires a multidisciplinary approach with good communication between pathologists, gastroenterologists, and geneticists. Surgical pathologists need to be aware of the broad phenotype of these syndromes, in particular extragastrointestinal manifestations (skin), and the types of tumors that affected individuals are at an increased risk of developing. In the appropriate clinical setting, pathologists should raise the possibility of a rare syndrome and comment on their suspicion in the pathology report while being aware of the nonspecific histology of many of these polyps. Searching for clinical clues and combining findings from different pathology reports may lead to the right call and get the proband and family relatives the chance to benefit from appropriate surveillance and clinical management.

遗传性胃肠道息肉病综合征的诊断需要病理、胃肠和遗传学医生之间有良好沟通的多学科合作。外科病理医生需要了解这些综合征的广泛表现,特别是胃肠外表现(皮肤),以及影响个体的增加肿瘤类型发展的风险。在适当的临床背景下,病理医生应提高罕见综合征的警惕性,并在病理报告中对其怀疑作出评论,同时了解许多息肉的非特异性组织学表现。寻找临床线索,结合不同病理报告的发现,有助于正确的诊断,使先证者及其家属有机会受益于适当的监测和临床管理。

~~~全文结束~~~

作者简介

慧海拾穗,主治医师。

从事儿童病理诊断,对淋巴造血、软组织和泌尿生殖系统肿瘤有着浓厚的兴趣

座右铭:《为病寻理》就要爱病理 !



医之本编辑部

www.ezhiben.com


鲜花

握手

雷人

路过

鸡蛋

最新评论