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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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
AdenomaAdenomaMacroscopyMacroscopy ElevatedElevated FlatFlat DepressedDepressed
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
Tubular adenomaTubular adenomaUsually protrudinUsually protruding, spherical and pg, spherical and pedunculated or nedunculated or non-pedunculatedon-pedunculated
CRC and its precursor lesionsCRC and its precursor lesions
Tubular adenomaTubular adenomaadenomatous epithelium showing gland or tubule formation
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
Serrated adenoma most commonly
in the rectosigmoid colon
Saw-tooth configuration
dysplasia
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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……
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
?
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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%)
CRC and its precursor lesionsCRC and its precursor lesions
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)
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
ClassificationClassification FlatFlat
• Low gradeLow grade• High gradeHigh grade
Dysplasia associated lesions or mass (DALM) Dysplasia associated lesions or mass (DALM)
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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)
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
MacroscopyMacroscopy
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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%))
CRC and its precursor lesionsCRC and its precursor lesions
Grade 3Grade 3
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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%
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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)
CRC and its precursor lesionsCRC and its precursor lesions
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
CRC and its precursor lesionsCRC and its precursor lesions
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 ?
?