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

2. 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

3. 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

4. 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

5. Adenoma Incidence Location: 66%-77% in rectosigmoid
CRC and its precursor lesions
Adenoma
Incidence
Age related: <40y %-30%
>40y %-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

6. Adenoma Macroscopy Elevated Flat Depressed
CRC and its precursor lesions
Adenoma
Macroscopy
Elevated
Flat
Depressed

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

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

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

10. 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

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

12. CRC and its precursor lesions

13. 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

14. 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

15. 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

16. 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

17. 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

18. CRC and its precursor lesions

19. 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

20. 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……

21. CRC and its precursor lesions
Non-neoplastic polyps are not considered precancerous unless they occur in polyposis syndrome

22. 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

23. 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

24. 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

25. 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 ?

26. 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

27. 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

28. 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%)

29. 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

30. 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%)

31. 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

32. 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

33. 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

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

35. 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

36. 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

37. 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.

38. Incidence 2.7-44.7/100,000 Aetiology Diet and lifestyle
CRC and its precursor lesions
Incidence /100,000
Aetiology
Diet and lifestyle
Meat
Alcohol consumption
Smoking
“among the rewards of the westernized lifestyle”
Chronic inflammation: UC, CD
Irradiation: rare

39. 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

40. CRC and its precursor lesions
Macroscopy

41. 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

42. 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%)

43. CRC and its precursor lesions
Grade 3

44. 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)
T Invades submucosa
T Invades muscularis propria
T Invades through muscularis propria into
subserosa or nonperitonealized extramural tissues
T Directly invades other organs or structures (T4a)
or perforates visceral peritoneum (T4b)
N = Regional Lymph Nodes
N No regional lymph node metastasis
N Metastasis in 1-3 lymph nodes
N Metastasis in 4 or more lymph nodes
M = Distant Metastasis
M No distant metastasis
M Distant metastasis TNM Staging

45. 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 N M0
100% Ⅰa
T N M0
97% Ⅰb
T N M0
90% Ⅱa
T N Mo
78% Ⅱb
T N M0
63% Ⅲa
Any T N M0
66% Ⅲb
Any T N M0
37% Ⅳ
Any T Any N M1 4%

46. 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

47. 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

48. 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

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

50. 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

51. 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