大肠癌及其癌前病变.ppt

1、大肠癌及其癌前病变Colorectal Carcinoma and Its Precursor Lesions,北大医学部病理系 2004.7,CRC and its precursor lesions,Precursor Lesions of the large intestine,Adenoma: the main precursor lesions Non-neoplastic polyps occur in polyposis syndrome Inflammatory bowel diseases,CRC and its precursor lesions,polyps,Polyp

2、is a clinical term or gross description of any circumscribed tumor or growth that projects above the surrounding mucosa,Polyps may be inflammatory, hamartomatous or neoplastic in nature,Only by histologic examination can one be certain of their nature and clinical significance,CRC and its precursor

3、lesions,Adenoma,Definition An intraepithelial neoplasia, histologically characterized by hypercellularity with enlarged, hyperchromatic nuclei, varying degrees of nuclear stratification and loss of polarity,CRC and its precursor lesions,Incidence Age related: 40y 40%-50% Familial predisposition: a f

4、our-fold greater risk among first degree relatives Location: 66%-77% in rectosigmoid Correlations with CRC 80% sporadic CRC arise from adenomas Four-fold greater risk for CRC,Adenoma,CRC and its precursor lesions,Adenoma,Macroscopy Elevated Flat Depressed,CRC and its precursor lesions,Histopathology

5、 Tubular Villous Tubulovillous Serrated Others,Adenoma,Tubulovillous adenomas,Villous adenomas,Tubular adenomas,The others,CRC and its precursor lesions,Tubular adenoma Usually protruding, spherical and pedunculated or non-pedunculated,CRC and its precursor lesions,Tubular adenoma adenomatous epithe

6、lium showing gland or tubule formation,CRC and its precursor lesions,Villous adenoma typicallly sessile fine fingerlets or villi that project perpendicularly from the muscularis mucosae to the outer tip of the adenoma,CRC and its precursor lesions,Tubulovillous adenoma Mixture of tubular and villous

7、 structure Ratio between 1:44:1,CRC and its precursor lesions,CRC and its precursor lesions,Serrated adenoma most commonly in the rectosigmoid colon Saw-tooth configuration dysplasia,CRC and its precursor lesions,Grade Depending on the degree of glandular or villous complexity, extent of nuclear str

8、aitification, severity of abnormal nuclear morphology,Adenoma,Low grade,High grade,CRC and its precursor lesions,Familial adenomatous polyposis (FAP),A autosomal dominant disorder Relatively rare ( 1 in 8000 individuals ) Numerous adenomatous colorectal polyps Have an intrinsic tendency to progress

9、to adenocarcinoma Account for 1% of CRC,CRC and its precursor lesions,Diagnostic criteria 100 adenoma Germline mutation of APC gene Family history of FAP and epidermoid cysts or osteomas or desmoid tumor,CRC and its precursor lesions,Caused by a germline mutation in Adenomatous Polyposis Coli (APC)

10、gene on 5q21-22 Serve as the model for the APC/-catenin pathway of carcinogenesis in the large bowel,CRC and its precursor lesions,CRC and its precursor lesions,Inactivation of the other APC gene.-catenin translocates to the nucleus,Activation or mutation of oncogenes BCl-2, C-myc, Ki-ras,LOH at 18q

11、21 SMAD4, SMAD2, DCC,Mutation of TP53,P15,P16,cyclinD1,nm23,E-cadherin 7q,17q,14q,22q.,adenoma-carcinoma sequence,APC/-catenin pathway,Germ-line (inherited) or somatic (acquired) mutation of APC gene,CRC and its precursor lesions,Non-neoplastic polyps,Represent about 90% of all epithelial polyps in

12、the large intestine Found in more than half of all persons 60y Types Most are hyperplastic (metaplastic) polyps Juvenile polyps Peutz-jeghers polyps Others inflammatory polyps, schistosomial polyps,CRC and its precursor lesions,Non-neoplastic polyps are not considered precancerous unless they occur

13、in polyposis syndrome,CRC and its precursor lesions,Hyperplastic (metaplastic) polyps,Nipple like, less than 5 mm in diameter 50% in the rectosigmoid region Single or multiple generally asymptomatic,CRC and its precursor lesions,Hyperplastic polyps,Enlarged serrated crypts Lined by well-differentiat

14、ed goblet or absorptive epithelial cells Vast majority have no malignant potential,CRC and its precursor lesions,Diagnostic criteria At least 5 hyperplastic polyps proximal to the sigmoid colon of which two are greater than 1cm in diameter Any number of hyperplastic polyps occurring proximal to the

15、sigmoid colon in an individual who has a first degree relative with hyperplastic polyposis More than 30 hyperplastic polyps of any size distributing throughout the colon,Hyperplastic (metaplastic) polyposis,CRC and its precursor lesions,A small proportion contains foci of intraepithelial neoplasia G

16、enetic abnormality Microsatellite instability in areas of intraepithelial neoplasia Chromosomal rearrangement at 1p Ki-ras mutation Absence of activation of APC/beta-catenin pathway hyperplastic polyps serrated polyps Ca,Hyperplastic (metaplastic) polyposis,?,CRC and its precursor lesions,Juvenile p

17、olyps,A hamartomatous polyp Commonly occur in children (2/3) Clinical features Melaena Prolapsed rectal polyps Abdominal pain Anaemia,CRC and its precursor lesions,Typically pedunculated The cut surface shows mucin-containing cysts Inflamed granulation tissue surrounds dilated glands,Juvenile polyps

18、,CRC and its precursor lesions,A familial cancer syndrome with autosomal dominant trait Ten-fold less common than FAP Approximately half of cases arise in patients with no family history Germline mutations involve in the TGF-signal transduction pathway SMAD-4 gene on 18q21.1 (50%) BMPR1A on 10q22.3

19、(10%-20%),Juvenile polyposis,CRC and its precursor lesions,Involving predominantly the colorectum, but also the stomach and the small intestine Risk for GI adenocarcinoma ranges from 20%-70% Carcinoma may develop through dysplastic change within a juvenile polyps Carcinomas are more likely to be poo

20、rly differentiated and/or mucinous Close colonoscopic surveillance is recommended,Juvenile polyposis,CRC and its precursor lesions,Peutz-Jeghers syndrome (PJS),An inherited cancer syndrome with autosomal dominant trait About ten-fold less common than FAP 50% of cases are familial and 50% have new mu

21、tations Malignant potential: at least 10%-20% Germline mutation of LKB (STK ) on 19p13 (70%),CRC and its precursor lesions,Characterization Mucocutaneous melanin pigmentation Hamartomatous intestinal polyps, preferentially affecting the small intestine Extra-intestinal neoplasms are less common Symp

22、toms: abdominal pain, intestinal bleeding, aneamia, intussusception,Peutz-Jeghers syndrome (P-JS),CRC and its precursor lesions,The polyps are lobulated with darkened head Size: 5-50mm Central core of muscle that shows tree-like branching,Peutz-Jeghers Polyps,CRC and its precursor lesions,Dysplasia

23、In Ulcerative colitis (UC) and Crohns disease (CD),Patients with inflammatory bowel disease (IBD) have an increased risk for the development of CRC The strongest risk factors are the extent and duration of disease The incidence of dysplasia UC : 5% after 10y , 25% after 20y CD: uncertain, less than

24、UC,CRC and its precursor lesions,Classification Flat Low grade High grade Dysplasia associated lesions or mass (DALM),CRC and its precursor lesions,Treatment of dysplasia in IBD,Dysplasia in IBD,Flat,DALM (low and high grade),Low grade,High grade,Surveillance Colectomy?,Colectomy,polyp,adenoma,IBD-a

25、ssociated polypoid dysplasia,polypectomy,Polypectomy Surveillance ,Mass,Colectomy,CRC and its precursor lesions,Difference pattern of genotypic abnormalities compared to the adenoma-carcinoma sequence Early development TP53, Ki-ras mutations and alterations of p16 Low degree of nuclear - catenin exp

26、ression,CRC and its precursor lesions,Definition A malignant new growth that arises from epithelium in the lining of the large bowel. Only when tumors that have penetrated through muscularis mucosa into submucosa are considered malignent at this site.,Colorectal carcinomas (CRC),CRC and its precurso

27、r lesions,Incidence 2.7-44.7/100,000 Aetiology Diet and lifestyle Meat Alcohol consumption Smoking “among the rewards of the westernized lifestyle” Chronic inflammation: UC, CD Irradiation: rare,CRC and its precursor lesions,Localization Most CRC are located in the sigmoid colon and rectum Clinical

28、features Haematochezia, anaemia, constipation, fever, malaise, weight loss, abdominal pain,CRC and its precursor lesions,Macroscopy,CRC and its precursor lesions,Adenocarcinoma Mucinous (colloid) adenocarcinoma 50% of the lesions is composed of mucin Signet ring carcinoma 50% of tumor cells have pro

29、minent intracytoplasmic mucin The first three groups make up 95% of colorectal cancer cases adenosquamous carcinoma Squamous carcinoma Small cell carcinoma Medullary carcinoma Undifferentiated carcinoma,CRC and its precursor lesions,Tumor grade Grade 1: Well differentiated (glandular structure 95%)

30、Grade 2: Moderately differentiated (glandular structure 50-95%) Grade 3: Poorly differentiated (glandular structure 5-50%) Grade 4: Undifferentiated (glandular structure 5%),CRC and its precursor lesions,Grade 3,CRC and its precursor lesions,T = Primary Tumor Tis Carcinoma in situ (intraepithelial o

31、r intramucosal) T1 Invades submucosa T2 Invades muscularis propria T3 Invades through muscularis propria into subserosa or nonperitonealized extramural tissues T4 Directly invades other organs or structures (T4a) or perforates visceral peritoneum (T4b) N = Regional Lymph Nodes N0 No regional lymph n

32、ode metastasis N1 Metastasis in 1-3 lymph nodes N2 Metastasis in 4 or more lymph nodes M = Distant Metastasis M0 No distant metastasis M1 Distant metastasis TNM Staging,TNM Staging,CRC and its precursor lesions,TNM stage and 5-yr survival rates,CRC and its precursor lesions,Hereditary nonpolyposis c

33、olorectal cancer (HNPCC, Lynch syndrome),An autosomal dominant disorder Characterized by the development of colorectal carcinoma, endometrial carcinoma, and cancer of the small intestine, ureter, or renal pelvis A strong family history of developing colorectal cancer at an early age (average 46 year

34、s) Account for 1%-2% of colorectal carcinoma,CRC and its precursor lesions,Diagnostic criteria There should be at least three relatives with an HNPCC-associated cancer: CRC, or cancer of the endometrium, small bowel, ureter or renal pelvis. One patient should be a first degree relative of the other two At least two successive generations should be affected At least one tumor should be diagnosis before 50y Familial adenomatous polyposis should be excluded in the CRC case(s) if any Tumors should be verified by histopathological examination,CRC and its precursor lesio