1	Hyperplastische Polyps Innocent bystanders? K. Geboes Pathologische Ontleedkunde, KULeuven
2	Content Historical Classification Relation Hyperplastic polyps – carcinoma The concept “sessile serrated adenoma” Classification of hyperplastic polyps Sessile serrated adenoma e.a. and carcinoma Conclusions
3	Classification of colorectal polyps until 1996 Epithelial Non-epithelial Hyperplastic = benign Juvenile Adenoma = neoplastic Hamartomas Tubular Inflammatory Tubulovillous ….. Villous
4	Adenomas and classical Hyperplastic polyps
5	Hyperplastic polyp
6	Hyperplastic polyp - microvesicular
7	Adenoma – Normal
8	Hyperplastic polyps and colorectal cancer Hyperplastic polyps are present at the margin of a significant percentage of adenomas (Goldman et al 1970) Sentinel lesions? Hyperplastic polyps can become very large, especially in the ascending colon Occasionally large hyperplastic polyps may contain adenocarcinoma (Urbanski et al 1984) Hyperplastic polyps are more frequent in populations at risk for colorectal cancer (Eide 1986)
9	Hyperplastic polyps and colorectal cancer Histologic serrated? polyps are present adjacent to adenocarcinoma, particularly of the ascending colon (Makinen et al 2001)
10	Hyperplastic polyps and colorectal cancer 1990 : Longacre & Fenoglio Preiser describe a group of patients with mixed features of hyperplastic polyps and adenomas Am J Surg Pathol
11	Mixed Hyperplastic - adenomatous
12	B-1352989 Mixed adenomatous – hyperplastic with squamous metaplasia
13	Hyperplastic polyps and colorectal cancer 1996 : Torlakovic and Snover : Review of cases with hyperplastic polyposis : risk of colorectal cancer is increased Gastroenterology Polyps in hyperplastic polyposis show significant morphologic differences when compared with small sporadic hyperplastic polyps
14	Hyperplastic polyposis (sessile serrated adenomatous polyposis) Rare syndrome Two phenotypes Multiple small, mainly distal polyps Small numbers of large and proximal polyps Polyps : hyperplastic, serrated adenomas, adenomas, admixed hyperplastic / adenomatous Definite but poorly defined cancer risk Diagnostic criteria
15	Hyperplastic polyposis Diagnostic criteria at least five histologically confirmed hyperplastic polyps proximal to the sigmoid colon, of which at least two are greater than 10 mm in diameter any number of hyperplastic polyps proximal to the sigmoid in a patient with a first-degree relative with hyperplastic polyposis more than 30 hyperplastic polyps of any size distributed evenly throughout the colon Pathogenesis Family history (rare, 2/38 cases) Hypermethylation of multiple gene promoters
16	Hyperplastic polyposis Polyps in hyperplastic polyposis show significant morphologic differences when compared with small sporadic hyperplastic polyps The features are similar to mixed lesions but most lesions have a sessile configuration > Sessile serrated adenoma (SSA) (to be distinguished from the traditional serrated adenoma (TSA) which is often pedunculated)
17	Sessile Serrated adenoma A “polypoid” or “discretely elevated” lesion with morphologic features of “architectural dysplasia” rather than “cytologic dysplasia” Diagnosis requires well-oriented sections because the most diagnostic features are present at the base of the crypts Presents as “solitary lesion” or in a setting of a polyposis (Torlakovic & Snover 2006)
18	SSA & HP Hyperplastic polyp Crypts serrated at the surface Base of crypts narrow, lined predominantly with undifferentiated cells Sessile serrated adenoma Serrated feature along the crypt axis Rarity of undifferentiated cells in the lower third of the crypts
19	(Raised sessile) serrated adenoma
20	Hyperplastic polyps (closed arrows) and a sessile serrated adenoma (open arrows)
21	Sessile serrated adenoma 1458015 Abnormal maturation – epithelial hyperchromasia - dilated mucin-filled crypts
22	Sessile Serrated adenoma Areas of mucin production in deep crypts - deep crypt branching (B-1467357)
23	Sessile serrated adenoma p12229 Crypt dilatation and (lateral spread)
24	Hyperplastic polyps Heterogeneous lesion
25	Summary comparison of features of left-sided and right-sided serrated polyps* p <0.001 for these variables; see text for details.† Observation, not recorded for all cases. From: Torlakovic: Am J Surg Pathol, Volume 27(1).January 2003.65-81
26	Hyperplastic polyps Heterogeneous group Serrated polyps with normal proliferation (Torlakovic et al 2003) Serrated polyps with normal maturation (Batts et al) Serrated polyps without dysplasia (Jass et al) Serrated polyps with abnormal proliferation Serrated polyps with abnormal maturation (Torlakovic 2003); dysmaturation (Goldstein 2003) Serrated polyps with dysplasia
27	Grouping of cases based on the site of the polyp and the type of proliferation. Right-sided serrated polyps with normal proliferation separate from left-sided polyps with normal proliferation. Polyps with abnormal proliferation group more with right than left side. From: Torlakovic: Am J Surg Pathol, Volume 27(1).January 2003.65-81
28	Classical – Traditional Hyperplastic polyps
29	Hyperplastic polyps – Serrated polyps Frequency distribution Hyperplastic polyps or serrated polyps with normal proliferation 80-95% Serrated polyps with abnormal proliferation (?) 5-20% Traditional serrated adenoma < 1% Mixed polyps (mixed sessile serrate adenoma-tubular adenoma) < 1% Sessile serrated adenoma 4-19%
30	Classification Serrated polyps with dysplasia (abnormal proliferation Mixed hyperplastic adenomatous (cytologic dysplasia) !!! Serrated adenomas (TSA) (cytologic dysplasia) !!! Serrated polyps with no dysplasia Classic hyperplastic polyps Sessile serrated adenoma (SSA) (no or little cytologic dysplasia) !!!
31	Sessile serrated adenoma
32	Sessile Serrated adenomas as Cancer precursors Case reports of giant HPP associated with adenocarcinoma Hawkins et al J Natl Cancer Inst 2001 Microsatellite unstable colorectal cancers often arise from a background colon with increased hyperplastic polyps but not adenomas Goldstein et al AJCP 2003 91 cases of microsatellite unstable AdCa’s had hyperplastic polyps previously sampled at / near cancer site
33	Sessile Serrated adenomas as Cancer precursors Lazarus et al Am J Clin Pathol Serrated adenomas grow faster than tubular adenomas (retrospective study, 239 colon polyps, mean of 94 months follow up) Goldstein et al Small adenocarcinomas arising in SSA : 6 small right sided AdCa’s, all MSI, all arising in SSA
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35	Sessile serrated adenoma & carcinoma 1460862
36	Sessile serrated adenoma + carcinoma (657634/9) H&E p53
37	Sessile Serrated adenomas as Cancer precursors Molecular data Large survey of a variety of serrated polyps : hypermethylation status of a large number of different genes in SSA (65%) and mixed polyps (82%) compared with HPP (25%) Wynter et al Gut 2004 Large number of MSI
38	Focal loss of nuclear expression of hMLH1 in SSA
39	Sessile Serrated adenomas as Cancer precursors Molecular data Data linking Serrated Polyps to MSI (Iino et al J Clin Pathol) % MSI Traditional Adenoma +/- 14% Hyperplastic polyp +/- 30% Serrated adenoma > 50% Mixed polyps > 80%
40	Sessile Serrated adenomas as Cancer precursors Molecular data SSA frequently show mutation of BRAF, which is a step within the mitogen-activated protein kinase signaling pathway Traditional hyperplastic polyps show K-ras mutation Both are linked to inhibition of apoptosis
41	Sessile Serrated adenomas as Cancer precursors Morphologic similarity between “Mucosal Hyperplasia” of the appendix, an established preneoplastic lesion and sessile serrated adenoma
42	Sessile Serrated adenomas as Cancer precursors Serrated neoplasia pathway Stepwise? Transition from no cytologic dysplasia through cytologic dysplasia (mixed type) Time of progression to cancer : unclear; probably slow (> 3 to 5 yrs) Recurrence rate : unclear (Snover et al Am J Clin Pathol 2005)
43	Recommendations for treatment For right-sided sessile serrated adenomas without cytologic dysplasia (adenomatous change) Endoscopic removal Repeat colonoscopy (begin at 1 yr interval) Evidence of cytologic dysplasia : surgery Left-sided lesions (?) Endoscopic removal Resection : left-sided MSI related cancer is rare
44	Proposal for classification Non-dysplastic serrated polyp Normal architecture Abnormal architecture/abnormal proliferation (= sessile serrated polyp or sessile serrated adenoma) Dysplastic serrated polyp Unclassifiable
45	Conclusions Hyperplastic polyps = Heterogeneous Larger lesions + aberrant histology = evidence points towards preneoplastic potential through serrated pathway There is a terminology problem Sessile serrated adenoma, serrated adenoma and mixed hyperplastic/adenoma polyp were the first names Optimal treatment is complete endoscopic removal and probably adenoma-like follow up
46	Conclusions The majority of small, whitish sporadic polyps are still traditional “hyperplastic polyps” ! (Basal proliferative compartment with immature cells)
47	Sessile serrated adenoma + carcinoma (657634/9) H&E p53
48	Sessile serrated adenoma + carcinoma (657634/9) H&E
49	Inflammatory Cap Polyp Solitary lesion Polyposis
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51	Cap polyposis Rare, but distinct disorder No sex predilection Age range : 17-82 yrs Clinical presentation : mucoid or bloody diarrhea, abdominal pain Endoscopy : multiple sessile polyps; in rectum and sigmoid; rarely entire colon few mm to 2 cm
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56	Cap polyposis Histology Elongated tortuous crypts A cap of granulation tissue Mixed inflammation Splayed smooth muscle fibers may be present
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61	1312779 Inflammatory cap polyp
62	1312779 Inflamm cap polyp (Perls)
63	Inflammatory cap polyp 1317149
64	Cap Polyposis Pathogenesis Unknown Spectrum of mucosal prolapse syndrome Specific inflammation Successfull treatment with anti TNFa
65	Other non-neoplastic colorectal polyps Mucosal prolapse Cap polyp solitary rectal ulcer syndrome Inflammatory cloacogenic polyp Diverticular disease-associated polyps Hamartomatous polyps Juvenile Peutz-Jeghers ….
66	Other non-neoplastic colorectal polyps Benign fibroblastic polyps Inflammatory fibroid polyp Vascular lesions Lymphoid polyps Endometriosis Amyloidosis Neurogenic polyps