serrated lesion of colon and rectum-1.pptx

Serrated lesion of colon and rectum

1. Serrated lesion of colon and rectum Presenter- Dr.Madhuri verma Moderator- Dr. Seema gupta

2. AN A T OMY T he l a rge bo w e l com p r ises the termi n al 1–1 . 5 m o f the gastrointestinal tract and is divided into the following regions: Cecum, Ascending (right) colon, Transverse colon, Descending (left) colon, Sigmoid colon, and Rectum The rectum forms the distal 8–15 cm Extraperitoneal Lies within the pelvis Ends at the anal canal

3. Histology The large bowel wall is composed of four layers : Mucosa, Submucosa , Muscularis propria , and Serosa The mucosa has three components : Epithelium, Lamina propria , and Muscularis mucosae . . The mucosal surface is covered by a single layer of cuboidal to low columnar epithelium

4. HISTOLOGY OF COLONIC MUCOSA The mucosa consists of cells of two types: absorptive cells and mucus secreting goblet cells arranged in closely packed straight tubular glands or crypts , which extend down to sit on to the muscularis mucosae.

5. Serrated Polyps - Why so importa n t? High frequency in proximal colon : Missed in colonoscopy Flat/Sessile Morphology: Easily Overlooked Ill-defined Borders : Inc o mpl e te Resection Putative rapid growth of MSI cancers Aggressive biological behavior and poorer outcomes of BRAF, MSS cancer

6. Criteria For Serrated Lesions Serrated appearance at the base of the crypts Horizo n t a lisa t i o n of crypts with branching Dilatation of the crypts Increase in epithelium- stroma ratio > 50% Mitoses on the surface of the crypts Cellular atypia : Enlarged nucleus, overproduction of mucin 2 of 6 criteria must be present for diagnosing sessile serrated lesions

7. Serrated Polyps Serrated polyp is a general term for any polyp that shows a serrated (sawtooth or stellate) architecture of the epithelial compartment.

8. The diagnosis is largely dependent on morphological assessment with limited utility of immunohistochemical and molecular tests in refining the diagnosis. The diagnostic accuracy of serrated lesions is important as the different types carry different levels of risk and require different endoscopic surveillance intervals. The diagnosis of serrated/HPS is important for other family members and should always be considered when there is history or endoscopic evidence of multiple serrated lesions

9. Benign serrated polyps HYPERPLASTIC POLYPS Left side >Right side of the large bowel, males >female Endoscopy -small (often <10 mm) sessile polyps on the mucosal surface of the large bowel Grossly, small, dome-shaped (convex) structures that are paler than, the surrounding mucosa. They often sit on the crest of the mucosal folds or may be pedunculated

10. Hyperplastic polyp with elongated crypts, serrated architecture in the upper one third, small, basally placed nuclei without atypia in cytology and architecture (×100) Smooth nodular protrusion of mucosa

11. Microscopically, Three types: MVHP (m/c) Goblet cell hyperplastic polyps (GCHPS)-limited serration but more resembles mucosal changes adjacent to mass lesion Mucin -poor hyperplastic polyps(MPHPS)- Showing uniform and prominent serrations with almost no evidence of mucin and “ cytologic atypia ,” There are molecular differences between the subtypes of HPS. K- ras mutations, more common in GCHPS Braf (v600e) mutations in MPHPS

12. Microvesicular Hyperplastic Polyp Columnar cells with apical vesicular mucin that alternate with eosinophilic - like absorptive and goblet cells The goblet cells Serration- upper one-third to one-half of the crypt Thickening of the subepithelial basement membrane. MVHP has a large proliferative zone that occupies much of the basal half of the mucosa. The cells at the base of the crypt show depletion of mucin and often have scattered paneth cells. In well-oriented material, the cells at the basal portion of the crypt tend to show nuclear elongation, crowding, and increased mitotic rate compared with the normal surrounding mucosa. The muscularis mucosae -splaying, with muscle fibers extending into the mucosa and surrounding individual crypts.

13. ) Microvesicular hyperplastic polyp (MVHP). The crypts and surface epithelium show a luminal serrated or saw-toothed contour more prominent in the upper levels of the crypts than at the base. The epithelial layer is composed of cells with goblet cell differentiation and others with microvesicular cytoplasmic mucin .

14. Goblet Cell Hyperplastic Polyp Seen predominantly in the distal colon and rectum associated with mucosal changes adjacent to “mass lesions.” Serrations are not prominent and, when present, are usually limited to the surface/luminal aspects of the mucosa. The mucosa is thickened, as is the subepithelial basement membrane, and goblet cells are quite prominent

15. Goblet cell hyperplastic polyp . less pronounced serrated or saw-toothed luminal epithelial and shows a preponderance of goblet cells and an absence of cells with microvesicular mucin . The crypts are straight, linear, and without architectural distortion.

16. Mucin -Poor Hyperplastic Polyp Very uncommon prominent serration that often runs the entire length of the crypt. Goblet cells are uncommon, and the columnar cells are mucin depleted. The changes mimic those of epithelial regeneration or are similar to those seen in prolapse .

17. Sessile Serrated Adenoma/Polyp A/k/a/ sessile serrated lesions Flat sessile lesions. Are more frequent in the right colon Females > males. Endoscopically large, sessile, yellow in colour or poorly defined Microscopically - Branching and dilation of the base of the crypt The crypts seem to grow parallel to the muscularis mucosae,in inverted T shape or L shape. At the base of the crypt- mature cells with a goblet cell or gastric phenotype and prominent serrations are seen Crypts shows asymmetry of cell maturation or proliferation/ pseudostratification with bland nuclei,

18. The WHO criteria requires at least two to three abnormal contiguous crypts to make the diagnosis of SSA/P SSA/Ps have a characteristic Ki-67 pattern that shows irregular, asymmetric, and highly variable expression of Ki-67. They show abnormal proliferation on MIB-1/Ki-67 immunostaining , but have a normal subepithelial collagen plate. I loss of MLH1 expression or expression of MUC5AC or MUC6

19. Sessile serrated adenoma. a Branched crypts (bold arrow), T and L-shaped bases of the crypts (thin arrows) and columnar dilatation of the crypts (×2.5); b serration reaching to the lower third of the crypts (thin arrows), inverted crypts below the muscularis mucosae (bold arrow) (×2.5)

20. Traditional serrated adenomas occur in older adults (F>M) least common comprising <6% of serrated polyps and <1% of all colorectal polyps [ Macroscopically,-pedunculated , exclusively limited to the left side of the colon and in the rectum. Microscopically, show prominent serration and diffuse low-grade dysplasia to high-grade dysplasia. The dysplastic epithelium shows luminal infoldings aligned perpendicular to the main axis of the crypt, termed ectopic crypt formation or short ectopic budding crypts Cellular features include prominent eosinophilic cytoplasm with no maturation towards the surface, stratification and nuclear hyperchromasia with elongated nuclei (pencil-like nuclei)

21. These nuclei, although “atypical,” do not have the dysplastic features of nuclei seen in traditional adenomas, TSAs uniformly have ectopic crypt foci (ECF)-not seen in SSA/P or HPs ectopic crypt foci (ECF )are defined as abnormal development of crypts with loss of orientation to the muscularis mucosae with the luminal end of the crypt oriented in a normal relationship to the lumen but not abutting on the muscularis mucosae . In TSA, the Ki-67 pattern is limited to the ECF in contrast to SSA/P and HP Uncommon form - filiform TSA that shows multiple and prominent thin, elongated projections of TSA-like dysplastic epithelium with serrated contours

22. Traditional serrated adenoma (TSA). This shows the typical appearances of dysplastic epithelium with luminal infoldings aligned perpendicular to the main axis of the crypt, in ectopic crypt formations or short ectopic budding crypts. There is prominent eosinophilic cytoplasm, elongated (pencil-like) nuclei with hyperchromasia and low-grade dysplasia (magnification x100).

23. Mixed polyps A/K/A Sessile Serrated Adenoma/Polyp with Dysplasia Contain a mixture of foci of hyperplastic polyp and foci of dysplastic adenoma, either conventional or serrated adenoma. Represent links between HPs and either serrated adenomas, of usual type or TSA in the serrated neoplasia pathways. Frequency: 2% of all colonic polyps and 4% of all serrated neoplasia of the colon.

24. Mixed hyperplastic- adenomatous polyp. A, Typical features of tubular adenoma (TA) on the left and hyperplastic polyp (HPP) on the right , with a sharp transition of two elements. Note the high-grade dysplasia within the TA ( hematoxylin-eosin,x 40). B, A higher-power view of high-grade dysplasia showing cribriform glands and full thickness nuclear stratification. Note the serration of the surface epithelium, with minimal nuclear stratification and lack of cytologic dysplasia within the HPP on the right ( hematoxylin -eosin, x100).

25. Hyperplastic polyposis syndrome A/K/A serrated polyposis syndrome familial clustering of multiple and large,hyperplastic polyps Sex: M=F Age= 40-60years Site: proximal colon Gross: sessile polyps or flat lesions, <1cm, multiple Usually asymptomatic Increased risk of CRC formation with MSI

26. criteria includes the findings of either: (1) >5 hyperplastic polyps proximal to the sigmoid colon, of which two are >10 mm in diameter; or (2) >30 hyperplastic polyps of any size, proximal to the sigmoid colon (3) any number of hyperplastic polyps with a first-degree relative with known HPS Exclude other syndromic forms of polyposis – (FAP) and its attenuated variant (AFAP), MUTYH-associated polyposis , Peutz – Jeghers syndrome, juvenile polyposis syndrome Cowden’s syndrome.

27. SERRATED ADENOCARCINOMA Account for approximately 7.5% of all crcs , but 17.5% of right-sided colonic adenocarcinomas Represent the end-points of the serrated pathways: The majority of left-sided serrated colorectal carcinomas arise from tsas and are microsatellite stable (MSS) or show only low-frequency MSI (MSI-L) Right-sided serrated adenocarcinomas appear to arise from ssls /serrated adenomas and show a high-frequency MSI (MSI-H) with 30% microsatellite markers displaying changes in length

28. Serrated Adenocarcinoma Serrated architecture often in irregularly elongated crypt-like structures, but little tubular or papillary growth pattern, Cells are cuboidal to short columnar Moderate e o sin o philic cytoplasm Commonly a/w mucinous component Very large nuclei Open chromatin Prominent nucleoli. Preserved nuclear polarity

29. Low power view of serrated high grade dysplasia-accentuated serrated pattern and obvious eosinophillia . High power view -High grade vesicular nuclei with prominent nucleoli

30. Low power view of invasive cancer with obvious serrated pattern High power view -serrated cancer with distinct nuclei and prominent nucleoli

31. Mucinous component High power view showing balls and papillary rods floating in mucin

32. Pathogenesis of colorectal cancer Adenoma carcinoma sequence-CLASSIC PATHWAY SERRATED NEOPLASTIC PATHWAY MICROSATELLITE INSTABILITY

33. Adenoma Carcinoma Sequence - Classic The classic adenoma-carcinoma sequence, Accounts for as much as 80% of sporadic colon tumors Involves mutation of the APC tumor suppressor on chromosome 5q early in the neoplastic process. For adenoma to develop, Both copies of the APC gene must be functionally inactivated.

34. Adenoma Carcinoma Sequence - Classic APC is a key negative regulator of β-catenin, a component of the WNT signaling pathway. β- catenin accumulates and translocates to the nucleus, where it activates the transcription of genes which promote proliferation. This is followed by additional mutations, including activating mutations in KRAS, SMAD2, and SMAD4, and the tumor suppressor gene TP53 which also promote growth and prevent apoptosis.

35. chromosome instability pathway

36. Serrated Neoplasia Pathways

37. The pathways for left sided and right sided colon differ and are now cumulatively called ‘THE SERRATED NEOPLASTIC PATHWAY’

38. Microsatellite Instability Pathway Oc c u r s i n patie n ts with DN A mismatch re p air deficiency. M uta t ions in microsatellite seq u ences in coding/promoter regions Type II TGF-β receptor- uncontrolled cell proliferation (inhibits epithelial proliferation) Pro-apoptotic protein BAX- inhibits survival. Mutations in the oncogene BRAF along with hypermethylation of CpG islands within gene promoters- CpG island methylator phenotype (CIMP) also occur.

39. Microsatellite Instability Pathway Thus,signat u re o f this pa t hw a y of carcinogenesis is the combination of Microsatellite instability, BRAF mutation, and Methylation of specific targets (MLH1)

40. MOLECULAR ABNORMALITIES APC - mutation/ deletion in around 80% conventional (non-serrated) adenomas and carcinomas Very early event in association with normal epithelium changing to monocryptal or oligocryptal adenomas,( seen in FAP coli, an inherited syndrome of bowel adenoma and carcinoma susceptibility due to germline APC mutation) KRAS mutations -they occur mostly during the early stages of adenoma growth and can synergise either with APC mutations or defective mismatch repair (MMR) to accelerate colorectal tumour formation TP53 - late event around the time of transition from conventional adenoma to carcinoma Many other genetic and epigenetic changes, including MMR abnormalities,loss of a large part of chromosome 18, containing the SMAD4 and SMAD2 genes, loss of expression and promoter methylation of SLIT2

41. Lynch syndrome and DNA mismatch repair ,A/K/A HNPCC syndrome syndrome of inherited susceptibility to cancers of the large bowel endometrium , ovary, stomach, small intestine, ureter , renal pelvis, skin (sebaceous tumours ) and brain ( gliomas ) Carcinogenesis involves the acquisition of defective DNA MMR in tumour cells. The syndrome is due to dominant inheritance of a mutant MMR gene. During tumour formation there is inactivation of the second MMR allele, such that the tumour cell has both MMR alleles inactivated immunohistochemical demonstration of abnormal expression or loss of expression of MMR proteins only in the tumour cells, but not in adjacent stromal or lymphoid cells: loss of MLH1 protein expression is usually accompanied by loss of its heterodimeric binding partner PMS2, whereas loss of MSH2 protein expression is usually accompanied by loss of its heterodimeric binding partner MSH6 .

42. CpG island methylator phenotype and serrated neoplasia CpG island methylator phenotype’ positivity (CIMP+)- within a distinct subset of CRC and adenomas sporadic DNA hypermethylation leading to MLH1 silencing occurs ‘in which there increased methylation of the promoters of a range of susceptible genes (e.g. MLH1 , p16 , MGMT , IGF2 , RUNX3 , SOCS1, and NEUROG1 ) Occur on right-sided with an older average age CIMP+ defined using MethyLight quantitative DNA methylation technology as >10% methylation of >2 out of a panel of 5 gene promoters ( CACNA1G , IGF2 , NEUROG1 , RUNX3 and SOCS1 ) CRCs two types-CIMP-H or low-moderate levels of promoter methylation phenotype - low (CIMP-L)

43. The role of immunohistochemistry in the diagnosis of serrated lesions Ki-67 immunostaining patterns can be helpful in distinguishing HPs, SSLs and TSAs In HPs- Ki-67 staining is predominantly limited to the lower third or so of the crypts. SSLs showed a similar pattern to HPs but with only slightly increased Ki-67 staining within the middle third of the crypts. TSAs have more uniform Ki-67 staining throughout the length of the crypts. adenomas have more uniform Ki-67 staining, but with an even more widespread labelling towards the upper third of the crypts Other immunohistochemical markers such as cytokeratin 20, MGMT, MLH1, CDX2, b- catenin and P53 were found not to be helpful in subtyping serrated lesions

44. CLINICAL IMPLICATIONS AND PREDICTIVE FACTORS It is suggested that serrated lesions are biomarkers of future risk of malignancy, as well as having the potential to be part of serrated lesion-serrated adenoma–carcinoma pathways of progression, with the exception of diminutive distal hyperplastic polyps (unless part of hyperplastic /serrated polyposis syndrome)

45. THANKS