大肠癌及其癌前病变 colorectal carcinoma and its precursor lesions...

大肠癌及其癌前病变大肠癌及其癌前病变Colorectal Carcinoma and Its Colorectal Carcinoma and Its

Precursor LesionsPrecursor Lesions

北大医学部病理系北大医学部病理系2004.72004.7

CRC and its precursor lesionsCRC and its precursor lesions

Precursor Lesions of Precursor Lesions of the large intestinethe large intestine

Adenoma: the main precursor lesionsAdenoma: the main precursor lesions

Non-neoplastic polyps occur in polyposiNon-neoplastic polyps occur in polyposis syndromes syndrome

Inflammatory bowel diseases Inflammatory bowel diseases


polyps polyps PolypPolyp is a clinical term or gross description of any cir is a clinical term or gross description of any circumscribed tumor or growth that projects above the scumscribed tumor or growth that projects above the surrounding mucosaurrounding mucosa

PolypsPolyps may be inflammatory, hamartomatous or ne may be inflammatory, hamartomatous or neoplastic in natureoplastic in natureOnly by histologic examination can one be certain Only by histologic examination can one be certain of their nature and clinical significanceof their nature and clinical significance


AdenomaAdenomaDefinitionDefinition An intraepithelial neoplasia, histologically An intraepithelial neoplasia, histologically characterized by hypercellularity with enlargcharacterized by hypercellularity with enlarged, hyperchromatic nuclei, varying degrees ed, hyperchromatic nuclei, varying degrees of nuclear stratification and loss of polarity of nuclear stratification and loss of polarity


IncidenceIncidence Age related: <40y 20%-30%Age related: <40y 20%-30% >40y 40%-50%>40y 40%-50% Familial predisposition: a Familial predisposition: a four-foldfour-fold greater greater

risk among first degree relativesrisk among first degree relatives

Location: Location: 66%-77% in rectosigmoid66%-77% in rectosigmoid

Correlations with CRCCorrelations with CRC 80% sporadic CRC arise from adenomas80% sporadic CRC arise from adenomas Four-foldFour-fold greater risk for CRC greater risk for CRC

AdenomaAdenoma


AdenomaAdenomaMacroscopyMacroscopy ElevatedElevated FlatFlat DepressedDepressed


HistopathologyHistopathologyTubularTubularVillousVillousTubulovillous Tubulovillous Serrated Serrated OthersOthers

AdenomaAdenoma

others

tubul aradenomas

vi l l ousadenomastubul ovi l l ous

adenomasTubulovillous Tubulovillous adenomasadenomas

Villous Villous adenomasadenomas

Tubular adenomas

The others


Tubular adenomaTubular adenomaUsually protrudinUsually protruding, spherical and pg, spherical and pedunculated or nedunculated or non-pedunculatedon-pedunculated


Tubular adenomaTubular adenomaadenomatous epithelium showing gland or tubule formation


Villous adenoma Villous adenoma typicallly sessiletypicallly sessile ffine fingerlets or v

illi that project perpendicularly from the muscularis mucosae to the outer tip of the adenoma


Tubulovillous Tubulovillous adenoma adenoma Mixture of tubMixture of tub

ular and villouular and villous structures structure

Ratio between Ratio between 1:4~4:11:4~4:1


0

10

20

30

40

50

60%

with

car

cino

ma

<1cm 1-2cm >2cm frequency of adenocarcinoma in adenomas relative

to size and architecture

tubular adenomas

tubulovillous adenomas

villous adenomas


Serrated adenoma most commonly

in the rectosigmoid colon

Saw-tooth configuration

dysplasia


GradeGrade Depending on the degree of glandular or Depending on the degree of glandular or

villous complexity, extent of nuclear straitvillous complexity, extent of nuclear straitification, severity of abnormal nuclear moification, severity of abnormal nuclear morphologyrphology

AdenomaAdenoma

Low grade

High grade


Familial adenomatous poFamilial adenomatous polyposis (FAP)lyposis (FAP)

A A autosomal dominantautosomal dominant disorder disorder

Relatively Relatively rarerare ( 1 in 8000 individuals ) ( 1 in 8000 individuals )

Numerous adenomatousNumerous adenomatous colorectal polyps colorectal polyps

Have an Have an intrinsic tendencyintrinsic tendency to progress to to progress to adenocarcinomaadenocarcinoma

Account for Account for 1%1% of CRC of CRC


Diagnostic critDiagnostic criteriaeria ≥≥100100 adenoma adenoma Germline mutGermline mut

ation of ation of APCAPC g geneene

Family history Family history of FAP and of FAP and epepidermoid cystidermoid cystss or or osteomasosteomas or or desmoid tudesmoid tumormor


Caused by a germline mutation in AdenCaused by a germline mutation in Adenomatous Polyposis Coli omatous Polyposis Coli (APC) gene(APC) gene on 5 on 5q21-22q21-22

Serve as the model for the Serve as the model for the APC/β-cateniAPC/β-cateninn pathway pathway of carcinogenesis in the large of carcinogenesis in the large bowelbowel


Inactivation of the other APC gene.β-catenin translocates to the nucleus

Activation or mutation of oncogenes

BCl-2, C-myc, Ki-ras

LOH at 18q21

SMAD4, SMAD2, DCC

Mutation of TP53

P15,P16,cyclinD1,nm23,E-cadherin

7q,17q,14q,22q…….

adenoma-carcinoma sequence

APC/β-cateninAPC/β-catenin pathway pathway

Germ-line (inherited) or somatic (acquired) mutation of APC gene


Non-neoplastic Non-neoplastic polypspolyps

Represent about 90% of all epithelial polRepresent about 90% of all epithelial polyps in the large intestineyps in the large intestineFound in more than half of all persons Found in more than half of all persons >>60y60yTypes Types Most are hyperplastic (metaplastic) polypsMost are hyperplastic (metaplastic) polyps Juvenile polypsJuvenile polyps Peutz-jeghers polypsPeutz-jeghers polyps OthersOthers

inflammatory polyps, schistosomial polyps……inflammatory polyps, schistosomial polyps……


Non-neoplastic polyps are Non-neoplastic polyps are nonott considered precancerous u considered precancerous unless they occur in polyposis nless they occur in polyposis syndromesyndrome


Hyperplastic (metaplastic) polypsHyperplastic (metaplastic) polyps

Nipple like, less tNipple like, less than 5 mm in diamhan 5 mm in diametereter

>50% in the recto>50% in the rectosigmoid regionsigmoid region

Single or multipleSingle or multiple

generally asymptgenerally asymptomaticomatic


HyperplastiHyperplastic polypsc polypsEnlarged serrated Enlarged serrated crypts crypts

Lined by well-Lined by well-differentiated differentiated goblet or goblet or absorptive absorptive epithelial cells epithelial cells

Vast majority have Vast majority have no malignant no malignant potentialpotential


Diagnostic criteriaDiagnostic criteria At least At least 55 hyperplastic polyps hyperplastic polyps proximal proximal

to the sigmoid colonto the sigmoid colon of which of which two are two are greater than 1cmgreater than 1cm in diameter in diameter

Any numberAny number of hyperplastic polyps of hyperplastic polyps occurring occurring proximal to the sigmoid colonproximal to the sigmoid colon in an individual who has a in an individual who has a first degree first degree relativerelative with hyperplastic polyposis with hyperplastic polyposis

More than More than 3030 hyperplastic polyps of hyperplastic polyps of any any sizesize distributing distributing throughout the colonthroughout the colon

Hyperplastic (metaplastic) polyposisHyperplastic (metaplastic) polyposis


A small proportion contains foci of intraepithelial A small proportion contains foci of intraepithelial neoplasia neoplasia

Genetic abnormalityGenetic abnormality Microsatellite instabilityMicrosatellite instability in areas of intraepithe in areas of intraepithe

lial neoplasialial neoplasia Chromosomal rearrangement at Chromosomal rearrangement at 1p1p Ki-rasKi-ras mutationmutation Absence of activation of APC/beta-catenin patAbsence of activation of APC/beta-catenin pat

hwayhwayhyperplastic polyps serrated polyps Cahyperplastic polyps serrated polyps Ca

Hyperplastic (metaplastic) polyposisHyperplastic (metaplastic) polyposis

?


Juvenile Juvenile polypspolyps

A A hamartomatoushamartomatous polyp polyp

Commonly occur in children (2/3)Commonly occur in children (2/3)

Clinical featuresClinical features MelaenaMelaena Prolapsed rectal polypsProlapsed rectal polyps Abdominal painAbdominal pain AnaemiaAnaemia


Typically peduncuTypically pedunculatedlatedThe cut surface shThe cut surface shows mucin-contaiows mucin-containing cystsning cystsInflamed granulatiInflamed granulation tissue surrounon tissue surrounds dilated glandsds dilated glands

Juvenile Juvenile polypspolyps


A familial cancer syndrome witA familial cancer syndrome with h autosomal dominant traitautosomal dominant traitTen-fold less common than FATen-fold less common than FAPPApproximately half of cases ariApproximately half of cases arise in patients with no family hise in patients with no family historystoryGermline mutations involve in Germline mutations involve in the TGF-βsignal transduction the TGF-βsignal transduction pathway pathway SMAD-4SMAD-4 gene on 18q21.1 (50%) gene on 18q21.1 (50%) BMPR1ABMPR1A on 10q22.3 (10%-20%) on 10q22.3 (10%-20%)

Juvenile Juvenile polyposispolyposis


Involving predominantly the Involving predominantly the colorectumcolorectum, b, but also the stomach and the small intestineut also the stomach and the small intestineRisk for GI adenocarcinoma ranges from Risk for GI adenocarcinoma ranges from 220%-70%0%-70%Carcinoma may develop through dysplastiCarcinoma may develop through dysplastic change within a juvenile polypsc change within a juvenile polypsCarcinomas are more likely to be Carcinomas are more likely to be poorly difpoorly differentiated and/or mucinousferentiated and/or mucinousClose colonoscopic surveillance is recomClose colonoscopic surveillance is recommendedmended

Juvenile Juvenile polyposispolyposis


Peutz-Jeghers syndrome (PJS)Peutz-Jeghers syndrome (PJS)An inherited cancer syndrome with An inherited cancer syndrome with autoautosomal dominant traitsomal dominant trait

About ten-fold less common than FAPAbout ten-fold less common than FAP

50% of cases are familial and 50% have 50% of cases are familial and 50% have new mutationsnew mutations

Malignant potential: at least Malignant potential: at least 10%-20%10%-20%

Germline mutation of Germline mutation of LKB (STKⅠ ⅡLKB (STKⅠ Ⅱ ) ) on on 19p13 (70%)19p13 (70%)


CharacterizationCharacterization Mucocutaneous melanin pigmentation Mucocutaneous melanin pigmentation Hamartomatous intestinal polyps, preferentiHamartomatous intestinal polyps, preferenti

ally affecting the ally affecting the small intestinesmall intestine Extra-intestinal neoplasms are less commoExtra-intestinal neoplasms are less commo

nn

Symptoms: Symptoms: abdominal pain, intestinal bleediabdominal pain, intestinal bleeding, aneamia, intussusceptionng, aneamia, intussusception

Peutz-Jeghers syndrome (P-JS)Peutz-Jeghers syndrome (P-JS)


The polyps are lThe polyps are lobulated with daobulated with darkened headrkened head

Size: 5-50mmSize: 5-50mm

Central core of Central core of muscle that shomuscle that shows ws tree-like brantree-like branchingching

Peutz-Jeghers PPeutz-Jeghers Polypsolyps


Dysplasia In Ulcerative colitis Dysplasia In Ulcerative colitis (UC) and Crohn’s disease (CD)(UC) and Crohn’s disease (CD)Patients with inflammatory bowel Patients with inflammatory bowel disease (IBD) have an increased ridisease (IBD) have an increased risk for the development of CRCsk for the development of CRCThe strongest risk factors are the The strongest risk factors are the extent and durationextent and duration of disease of diseaseThe incidence of dysplasia The incidence of dysplasia UC : 5% after 10y , 25% after 20yUC : 5% after 10y , 25% after 20y CD: uncertain, less than UCCD: uncertain, less than UC


ClassificationClassification FlatFlat

• Low gradeLow grade• High gradeHigh grade

Dysplasia associated lesions or mass (DALM) Dysplasia associated lesions or mass (DALM)


Treatment of dysplasia in IBDTreatment of dysplasia in IBD

Dysplasia in IBD

Flat DALM (low and high grade)

Low grade

High grade

Surveillance

Colectomy? Colectomy

polyp

adenoma

IBD-associated polypoid dysplasia

polypectomyPolypectomy

Surveillance

Mass

Colectomy


Difference pattern of genotypic Difference pattern of genotypic abnormalities compared to the aabnormalities compared to the adenoma-carcinoma sequencedenoma-carcinoma sequence Early developmentEarly development TPTP53, 53, Ki-rasKi-ras m m

utations and alterations of utations and alterations of p16p16 Low degree of nuclear Low degree of nuclear β- cateninβ- catenin

expressionexpression


DefinitionDefinitionA malignant new growth that arises from epitheA malignant new growth that arises from epithe

lium in the lining of the large bowel. lium in the lining of the large bowel. Only when tumoOnly when tumors that rs that have penetrated through muscularis mucosa have penetrated through muscularis mucosa into submucosainto submucosa are considered are considered malignentmalignent at this sit at this site.e.

Colorectal carcinomas Colorectal carcinomas (CRC) (CRC)


Incidence Incidence 2.7-44.7/100,0002.7-44.7/100,000 AetiologyAetiology Diet and lifestyleDiet and lifestyle

• MeatMeat• Alcohol consumptionAlcohol consumption• SmokingSmoking

““among the rewards of the westernized lifestyle”among the rewards of the westernized lifestyle”

Chronic inflammation: UC, CD Chronic inflammation: UC, CD Irradiation: rareIrradiation: rare


Localization Localization Most CRC are located in the Most CRC are located in the sigmoid colosigmoid colo

n and rectumn and rectum

Clinical featuresClinical features Haematochezia, anaemia, constipation, fHaematochezia, anaemia, constipation, f

ever, malaise, weight loss, abdominal painever, malaise, weight loss, abdominal pain


MacroscopyMacroscopy


AdenocarcinomaAdenocarcinoma Mucinous (colloid) adenocarcinomaMucinous (colloid) adenocarcinoma >50% of the lesions is composed of mucin >50% of the lesions is composed of mucin

Signet ring carcinomaSignet ring carcinoma>50% of tumor cells have prominent intracytoplasmic >50% of tumor cells have prominent intracytoplasmic

mucinmucin The first three groups make up 95% of colorThe first three groups make up 95% of color

ectal cancer casesectal cancer cases adenosquamous carcinoma adenosquamous carcinoma Squamous carcinomaSquamous carcinomaSmall cell carcinomaSmall cell carcinomaMedullary carcinomaMedullary carcinomaUndifferentiated carcinomaUndifferentiated carcinoma


Tumor gradeTumor grade Grade 1: Well differentiated (glandular structure Grade 1: Well differentiated (glandular structure >95%>95%)) Grade 2: Moderately differentiated (glandular structure Grade 2: Moderately differentiated (glandular structure 50-95%50-95%)) Grade 3: Poorly differentiated (glandular structure Grade 3: Poorly differentiated (glandular structure 5-50%5-50%)) Grade 4: Undifferentiated (glandular structure Grade 4: Undifferentiated (glandular structure <5%<5%))


Grade 3Grade 3


T = Primary TumorT = Primary Tumor• Tis Carcinoma Tis Carcinoma in situin situ (intraepithelial or intramucosal) (intraepithelial or intramucosal)• T1 Invades submucosaT1 Invades submucosa• T2 Invades muscularis propriaT2 Invades muscularis propria• T3 Invades through muscularis propria into T3 Invades through muscularis propria into subserosa or nonperitonealized extramural tissuessubserosa or nonperitonealized extramural tissues• T4 Directly invades other organs or structures (T4a)T4 Directly invades other organs or structures (T4a) or perforates visceral peritoneum (T4b)or perforates visceral peritoneum (T4b)

N = Regional Lymph NodesN = Regional Lymph Nodes• N0 No regional lymph node metastasisN0 No regional lymph node metastasis• N1 Metastasis in 1-3 lymph nodesN1 Metastasis in 1-3 lymph nodes• N2 Metastasis in 4 or more lymph nodesN2 Metastasis in 4 or more lymph nodes

M = Distant MetastasisM = Distant Metastasis• M0 No distant metastasisM0 No distant metastasis• M1 Distant metastasis TNM StagingM1 Distant metastasis TNM Staging

TNM StagingTNM Staging


TNM stage and 5-yr survival ratesTNM stage and 5-yr survival rates

StageStage TNMTNM 5-yr survival rate5-yr survival rate

00 Tis N0 M0Tis N0 M0 100%100%

ⅠⅠaa T1 N0 M0T1 N0 M0 97%97%

ⅠⅠbb T2 N0 M0T2 N0 M0 90%90%

ⅡⅡaa T3 N0 MoT3 N0 Mo 78%78%

ⅡⅡbb T4 N0 M0T4 N0 M0 63%63%

ⅢⅢaa Any T N1 M0Any T N1 M0 66%66%

ⅢⅢbb Any T N2 M0Any T N2 M0 37%37%

ⅣⅣ Any T Any N M1Any T Any N M1 4%4%


Hereditary nonpolyposis colorectal Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome)cancer (HNPCC, Lynch syndrome)An An autosomal dominantautosomal dominant disorder disorderCharacterized by the development of Characterized by the development of colcolorectalorectal carcinoma, carcinoma, endometrialendometrial carcino carcinoma, and cancer of the ma, and cancer of the small intestinesmall intestine, , ururetereter, or , or renal pelvisrenal pelvis

A strong family history of developing coA strong family history of developing colorectal cancer at an early age (average lorectal cancer at an early age (average 46 years46 years) ) Account for Account for 1%-2%1%-2% of colorectal carcinoma of colorectal carcinoma


Diagnostic criteriaDiagnostic criteria There should be at least three relatives with an HNPThere should be at least three relatives with an HNP

CC-associated cancer: CRC, or cancer of the endomCC-associated cancer: CRC, or cancer of the endometrium, small bowel, ureter or renal pelvis.etrium, small bowel, ureter or renal pelvis.

One patient should be a first degree relative of the oOne patient should be a first degree relative of the other twother two

At least two successive generations should be affecAt least two successive generations should be affectedted

At least one tumor should be diagnosis before 50yAt least one tumor should be diagnosis before 50y Familial adenomatous polyposis should be excludeFamilial adenomatous polyposis should be exclude

d in the CRC case(s) if anyd in the CRC case(s) if any Tumors should be verified by histopathological exaTumors should be verified by histopathological exa

minationmination


Rapid progression frRapid progression from adenoma to carcom adenoma to carcinoma inoma Predominantly Predominantly right-right-sidedsidedIncreased proportion Increased proportion of of mucinousmucinous or or poorlpoorly differentiatedy differentiated tumo tumorsrsWith marked With marked host-lyhost-lymphocyticmphocytic infiltratio infiltrationnBetter prognosisBetter prognosis

HNPCHNPCCC


Germline mutations in DNA mismatch reGermline mutations in DNA mismatch repair genespair genes lead to high frequency (90%) lead to high frequency (90%) of microsatellites instability (MSI)of microsatellites instability (MSI)


The MSI pathway of carcinogenesis in the large The MSI pathway of carcinogenesis in the large bowel bowel No clearly identifiable morphologic correlatesNo clearly identifiable morphologic correlates

Mutations in one of the DNA mismatch repair genes

MSH2, MSH6, MSH3 MLH1, PMS1, PMS2,

Microsatellite instability

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

TGFBR2, IGFⅡR, BAX,E2F4

RER+ CRC


P-J polyp

Juvenile polyp

normal

Dysplasia in hamartoma

Early adenoma

Intermediate adenoma

Late adenoma CRC

RER+ CRC

Flat dysplasia

IBD-associated CRC

Serrated adenoma

Cancer in serrated adenoma

?

Hyperplastic polyp ?

APC

Bcl-2 c-myc ki-ras

SMAD4SMAD2DC

C

TP53

MSH2, MSH6, MSH3 MLH1, PMS1, PMS2, TGFBR2, IGFⅡR, BAX,E2F4

LKB1

SMAD4

TP53 ?

?

大肠癌及其癌前病变 colorectal carcinoma and its precursor lesions...

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