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

Precursor Lesions of the large intestine 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 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 lesions Adenoma Definition An intraepithelial neoplasia, histologically characterized by hypercellularity with enlarged, hyperchromatic nuclei, varying degrees of nuclear stratification and loss of polarity

Adenoma Incidence Location: 66%-77% in rectosigmoid CRC and its precursor lesions Adenoma Incidence Age related: <40y 20%-30% >40y 40%-50% Familial predisposition: a four-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 Macroscopy Elevated Flat Depressed CRC and its precursor lesions Adenoma Macroscopy Elevated Flat Depressed

Tubulovillous adenomas CRC and its precursor lesions Adenoma Histopathology Tubular Villous Tubulovillous Serrated Others Villous adenomas Tubulovillous adenomas The others Tubular adenomas

CRC and its precursor lesions Tubular adenoma Usually protruding, spherical and pedunculated or non-pedunculated

CRC and its precursor lesions Tubular adenoma adenomatous epithelium showing gland or tubule formation

Villous adenoma typicallly sessile 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

Tubulovillous adenoma CRC and its precursor lesions Tubulovillous adenoma Mixture of tubular and villous structure Ratio between 1:4~4:1

CRC and its precursor lesions

Serrated adenoma most commonly in the rectosigmoid colon CRC and its precursor lesions Serrated adenoma most commonly in the rectosigmoid colon Saw-tooth configuration dysplasia

CRC and its precursor lesions Adenoma Grade Depending on the degree of glandular or villous complexity, extent of nuclear straitification, severity of abnormal nuclear morphology Low grade High grade

Familial adenomatous polyposis (FAP) 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 to adenocarcinoma Account for 1% of CRC

Diagnostic criteria ≥100 adenoma Germline mutation of APC gene 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) gene on 5q21-22 Serve as the model for the APC/β-catenin pathway of carcinogenesis in the large bowel

CRC and its precursor lesions

adenoma-carcinoma sequence CRC and its precursor lesions adenoma-carcinoma sequence Activation or mutation of oncogenes BCl-2, C-myc, Ki-ras Inactivation of the other APC gene.β-catenin translocates to the nucleus Germ-line (inherited) or somatic (acquired) mutation of APC gene P15,P16,cyclinD1,nm23,E-cadherin 7q,17q,14q,22q……. LOH at 18q21 SMAD4, SMAD2, DCC Mutation of TP53 APC/β-catenin pathway

Non-neoplastic polyps CRC and its precursor lesions Non-neoplastic polyps Represent about 90% of all epithelial polyps in 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 in polyposis syndrome

Hyperplastic (metaplastic) polyps 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

Hyperplastic polyps Enlarged serrated crypts CRC and its precursor lesions Hyperplastic polyps Enlarged serrated crypts Lined by well-differentiated goblet or absorptive epithelial cells Vast majority have no malignant potential

Hyperplastic (metaplastic) polyposis CRC and its precursor lesions Hyperplastic (metaplastic) polyposis 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 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 Hyperplastic (metaplastic) polyposis A small proportion contains foci of intraepithelial neoplasia Genetic 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 ?

Juvenile polyps A hamartomatous polyp Commonly occur in children (2/3) CRC and its precursor lesions Juvenile polyps A hamartomatous polyp Commonly occur in children (2/3) Clinical features Melaena Prolapsed rectal polyps Abdominal pain Anaemia

Juvenile polyps Typically pedunculated CRC and its precursor lesions Juvenile polyps Typically pedunculated The cut surface shows mucin-containing cysts Inflamed granulation tissue surrounds dilated glands

CRC and its precursor lesions Juvenile polyposis 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-βsignal transduction pathway SMAD-4 gene on 18q21.1 (50%) BMPR1A on 10q22.3 (10%-20%)

CRC and its precursor lesions Juvenile polyposis 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 poorly differentiated and/or mucinous Close colonoscopic surveillance is recommended

Peutz-Jeghers syndrome (PJS) 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 mutations Malignant potential: at least 10%-20% Germline mutation of LKB Ⅰ(STKⅡ ) on 19p13 (70%)

Peutz-Jeghers syndrome (P-JS) CRC and its precursor lesions Peutz-Jeghers syndrome (P-JS) Characterization Mucocutaneous melanin pigmentation Hamartomatous intestinal polyps, preferentially affecting the small intestine Extra-intestinal neoplasms are less common Symptoms: abdominal pain, intestinal bleeding, aneamia, intussusception

Peutz-Jeghers Polyps The polyps are lobulated with darkened head CRC and its precursor lesions Peutz-Jeghers Polyps The polyps are lobulated with darkened head Size: 5-50mm Central core of muscle that shows tree-like branching

Dysplasia In Ulcerative colitis (UC) and Crohn’s disease (CD) CRC and its precursor lesions Dysplasia In Ulcerative colitis (UC) and Crohn’s 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 UC

Dysplasia associated lesions or mass (DALM) CRC and its precursor lesions Classification Flat Low grade High grade Dysplasia associated lesions or mass (DALM)

Treatment of dysplasia in IBD CRC and its precursor lesions Treatment of dysplasia in IBD Dysplasia in IBD DALM (low and high grade) Flat Low grade High grade polyp Mass adenoma IBD-associated polypoid dysplasia Surveillance  Colectomy? Colectomy Colectomy Polypectomy Surveillance  polypectomy

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 β- catenin expression

Colorectal carcinomas (CRC) CRC and its precursor lesions Colorectal carcinomas (CRC) 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.

Incidence 2.7-44.7/100,000 Aetiology Diet and lifestyle CRC and its precursor 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

Localization Clinical features CRC and its precursor lesions Localization Most CRC are located in the sigmoid colon and rectum Clinical features Haematochezia, anaemia, constipation, fever, malaise, weight loss, abdominal pain

CRC and its precursor lesions Macroscopy

Adenocarcinoma Mucinous (colloid) adenocarcinoma Signet ring carcinoma 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 prominent intracytoplasmic mucin The first three groups make up 95% of colorectal cancer cases adenosquamous carcinoma Squamous carcinoma Small cell carcinoma Medullary carcinoma Undifferentiated carcinoma

Tumor grade Grade 1: Well differentiated (glandular structure >95%) CRC and its precursor lesions Tumor grade Grade 1: Well differentiated (glandular structure >95%) 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

TNM Staging T = Primary Tumor N = Regional Lymph Nodes CRC and its precursor lesions TNM Staging T = Primary Tumor Tis Carcinoma in situ (intraepithelial or 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 node 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 stage and 5-yr survival rates CRC and its precursor lesions TNM stage and 5-yr survival rates Stage TNM 5-yr survival rate Tis N0 M0 100% Ⅰa T1 N0 M0 97% Ⅰb T2 N0 M0 90% Ⅱa T3 N0 Mo 78% Ⅱb T4 N0 M0 63% Ⅲa Any T N1 M0 66% Ⅲb Any T N2 M0 37% Ⅳ Any T Any N M1 4%

Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) CRC and its precursor lesions Hereditary nonpolyposis colorectal 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 years) 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

HNPCC Rapid progression from adenoma to carcinoma CRC and its precursor lesions HNPCC Rapid progression from adenoma to carcinoma Predominantly right-sided Increased proportion of mucinous or poorly differentiated tumors With marked host-lymphocytic infiltration Better prognosis

CRC and its precursor lesions Germline mutations in DNA mismatch repair genes lead to high frequency (90%) of microsatellites instability (MSI)

The MSI pathway of carcinogenesis in the large bowel CRC and its precursor lesions The MSI pathway of carcinogenesis in the large bowel No clearly identifiable morphologic correlates Microsatellite instability TGFBR2, IGFⅡR, BAX,E2F4 Mutations in one of the DNA mismatch repair genes If microsatellite sequences are located in the coding or promoter region of genes involved in regulation of cell growth Accumulation of abnormalities in growth-regulating genes MSH2, MSH6, MSH3 MLH1, PMS1, PMS2, RER+ CRC

Cancer in serrated adenoma CRC and its precursor lesions P-J polyp Dysplasia in hamartoma LKB1 SMAD4 Early adenoma Intermediate adenoma Late adenoma CRC Juvenile polyp Bcl-2 c-myc ki-ras SMAD4SMAD2DCC TP53 normal APC MSH2, MSH6, MSH3 MLH1, PMS1, PMS2, ? TGFBR2, IGFⅡR, BAX,E2F4 ? TP53 Flat dysplasia IBD-associated CRC RER+ CRC Hyperplastic polyp ? ? Cancer in serrated adenoma Serrated adenoma