Serrated Colorectal Polyps New Challenges to Old Dogma. Kenneth Batts, M.D. Abbott Northwestern Hospital Minneapolis, MN

Transcription

1 Serrated Colorectal Polyps New Challenges to Old Dogma Kenneth Batts, M.D. Abbott Northwestern Hospital Minneapolis, MN

2 A Sneak Preview.... This was in the good old days: Adenomas HPPs Mixed Polyps

3 A Sneak Preview.... This is today: TSA Adenomas HPPs SSAs CIMP + AdCA Mixed Polyps

4 The emergence of a subgroup of hyperplastic polyps.....

5 A Computer-Based Look at 289 Serrated Polyps Hyperplastic Polyps* 24 Histologic Features Discriminant Analysis Microvesicular Goblet cell rich Sessile Serrated Adenoma 18% Torlakovic and Snover, Am J Surg Pathol, 2003 Jan;27(1):65-81 Mucin Depleted (Rare)

6 SSA Architecture Dilated Mucin-Filled Crypts

7 SSA Architecture Deep Crypt Branching

8 SSA Architecture Lateral Spread of Deep Crypts

9 SSA Architecture Sessile Growth

10 SSA Architecture Sessile Growth

11 SSA Architecture Inverted Growth

12 SSA Architecture Excessive Serrations

13 SSA Maturation Abnormalities* Histopathology: Hyperchromasia into mid or upper crypt Mitoses in mid to upper crypt Dysplastic goblet cells Surface w/ mild hyperchromasia with nucleoli Sometimes prominent mucin in basal epith. Termed: Abnormal maturation (Torlakovic( 03) Dysmaturation (Goldstein 03) *Torlakovic, Snover, et al; Gastroenterology, 1996 Mar;110(3): *Torlakovic, Snover, et al; Am J Surg Pathol., 2003 Jan;27(1):65-81 *Goldstein NS, et al. Am J Clin Pathol Jun;119(6):778-96

14 SSA Crypt Base Mucin

15 SSA Mid-crypt Mitoses = Mitotic Figures

16 SSA Mid-crypt Hyperchromasia

17 SSA Hyperchromasia in Mid to Upper Crypt and Surface

18 SSA Surface Nucleoli

19 O SSA Dysplastic Goblets Dysplastic goblet cells Normal

20 Serrated Polyps and Proliferation KI-67 (%) SSA s have more proliferative activity in mid-crypts than HPPs HPP SSA 0 Lower Third Middle Third Upper Third Higuchi T, et al; Histopathology 2005;47:32-40

21 Hamatani S, et al. J Jpn Soc Coloproctol 51: , 1998 Similar Japanese Observations 60 Colorectal Polyps with Epithelial Serrated Proliferation (CP-ESPs ESPs), with no CA Divided them into 5 types based on basal zone formation and lateral branching:

22 Sessile vs traditional serrated adenomas.....

23 Longacre et al 1990 Serrated Adenoma * Original Definition: Architectural features of hyperplastic polyp (serrated) Cytologic features of adenoma (dysplasia( dysplasia) Rare (<1% of all colorectal polyps) (Note: vs 15-20% incidence of sessile serrated adenomas ) Through 90 s s lumped with adenomatous polyps Now termed traditional serrated adenomas by Torlakovic and Snover** When pure, they look different than what Torlakovic and Snover call sessile serrated adenomas * Longacre TA, Fenoglio-Preiser C. AJSP, 1990 Jun;14(6): **Torlakovic, Snover, et al; Am J Surg Pathol., 2003 Jan;27(1):65-81

24 The Traditional Serrated Adenoma Usually villiform. Pencillate nuclei on surface Endoscopically usually semi-sessile, protuberant. Eosinophilic cytoplasm w/ mucin depletion

25 Serrated Adenomas and Proliferation Sessile vs Traditional Types KI-67 (%) SSA s have bottom heavy proliferation; TSA more uniform from top to bottom SSA TSA 0 Lower Third Middle Third Upper Third Higuchi T, et al; Histopathology 2005;47:32-40

26 Traditional vs. Sessile Serrated Adenoma

27 Evidence linking sessile serrated adenomas with cancer.....

28 SSA s as Cancer Precursors The Hyperplastic Polyposis Angle Hyperplastic Polyposis Multiple hyperplastic polyps WHO Definition: 5 or more HPPs prox to sigmoid; 2 > 10 mm Any # of HPPs prox to sigmoid in first degree relative of HPPosis pt > 30 HPPs (any size, throughout colon) Clearly have a risk of dysplasia and adenoca Torlakovic and Snover noted that most polyps in HPPosis look like sessile serrated adenomas Sessile serrated adenoma = cancer risk *Torlakovic, Snover, et al; Gastroenterology, 1996 Mar;110(3):748-55

29 SSA s as Cancer Precursors The Giant Hyperplastic Polyp Angle Numerous case reports series exist of giant or large HPPs associated with adenocarcinomas Histology traditionally not well-described or illustrated in publications, but in daily practice most polyps look like the SSA of Torlakovic and Snover Giant HPP = Sessile serrated adenoma = cancer risk

30 SSA s as Cancer Precursors The Polyps Antedating Cancers Angle Goldstein et al, AJCP 2003* 91 cases of microsatellite unstable AdCA s had HPP s previously sampled at/near the CA site In retrospect the HPPs looked like Torlakovic and Snover s SSA s FYI - They also noted that about 20% of control HPPs had the histologic features of SSA (about the same percent as Torlakovic found in 2003) Sessile serrated adenoma = cancer risk *Goldstein NS, et al. Am J Clin Pathol 2003;119:

31 SSA s as Cancer Precursors The Serrated Milieu Angle Microsatellite unstable colorectal cancers often arise from a background colon which has increased numbers of HPPs and SAs but not adenomas: 29 MSI Cancers: 114 HPPs* * 12 SAs 29 Control Cancers: 4 HPPs 3 SAs *This article presumes HPPs are a homogeneous group, but I ll bet a lot looked like SSAs. Sessile serrated adenomas = cancer risk Hawkins NJ, Ward RL. J Natl Cancer Inst 2001;93:

32 SSA s as Cancer Precursors The Natural History Angle Retrospective study, 239 colon polyps with mean of 94 months follow-up: Did not use Torlakovic histologic criteria, but likely lumped sessile and traditional SA s Serrated adenomas grow faster than tubular adenomas Serrated adenomas have similar cancer risk to usual tubular adenomas (5 % vs 2.2%) Sessile serrated adenoma = cancer risk Lazarus R et al., Am J Clin Pathol; 2005 Mar;123(3):

33 SSA s as Cancer Precursors The Seeing is Believing Angle Goldstein et al Small adenocarcinomas arising in SSAs Goldstein et al, in press 6 small right sided AdCAs All MSI All arising in SSAs Sessile serrated adenoma = cancer risk *Goldstein NS, et al. in press

34 SSA s as Cancer Precursors The Seeing is Believing Angle Makinen et al Found serrated adenomas adjacent to 5.8% of colorectal cancers Their illustrated SAs look more like SSA s to me Sessile serrated adenoma = cancer risk Suggests that if we look carefully at the cancers in our practices we should see the same thing Makinen MJ, et al. J Pathol 2001;193:

35 Case 1. Right hemicolectomy in 71 O y/o female; 2.2 cm sessile mass SSA Component

36 Case 1. Transition to a Usual-type O Adenoma ( Mixed polyp ) Interface with SSA Low Grade Dysplasia High Grade Dysplasia Block 2

37 O Case1. AdenoCA with High Likelihood of MSI

38 S Case 2. Endoscopic polypectomy of 2.5 cm right colon polyp, 81 y/o female SSA Adenoma A Mixed Polyp

39 High Grade Dysplasia S Case 2. Transition to Adenoma Low Grade Dysplasia Traditional Adenoma/ SSA Interface

40 S Case 2. AdenoCA with High Likelihood of MSI Ordinary CA Medullary CA (focal)

41 A brief look at molecular data supporting these concepts.....

42 Molecular Support for Subdividing the Serrated Polyp Family * * * * * * * * * * GCSP MVSP SPAP SA (SSA) (TSA) CIMP-H BRAF KRAS O Brien MJ, et al. Am J Surg Pathol 2004: 28: Yang S, et al. Am J Surg Pathol 2004;28(11):

43 Data Linking Serrated Polyps to CIMP (and Mixed Polyps into Serrated Family) Wynter, Jass et al: Large survey of a variety of serrated polyps and methylation status of a large number of different genes 90 Avg. % of Genes Methylated Wynter et al, Gut 2004;53(4): HPP (25%) SSA (65%) Mixed (82%)

44 Data Linking Serrated Polyps to MSI (and Mixed Polyps into Serrated Family) Adenoma % MSI SA Mixed HPP Serrated adenoma TA HPP MSI Mixed Iino H, Jass JR, et al; J Clin Pathol 1999;52:5-9

45 BRAF, MSI, and CIMP Data Linking Serrated Polyps and Cancer % Adenoma SSA Mixed Sporadic MSI AdCA MSI AdCA HNPCC MSS AdCA 10 0 HPP BRAF Mutation (%) BRAF also correlated w/ methylation, p=0.002 and p<0.001 Kambara, Jass, et al, 2004 Aug;53(8):

46 Colorectal Cancer The Big Picture Hypermethylation and MSI Percent of CA's Pure MSS CIMP+/MSS CIMP+/MSI-H Pure MSI-H Theoretically, the CIMP + pathway could account for up to 30% of colon cancers. vanrijnsoever M, et al. Clin Cancer Res, 2003;9(8):

47 A summary of current understanding of the serrated pathway.....

48 Serrated Neoplasia My Best Guess in 2006 TSA (<1%) Mixed Polyps (?<1%) HPPs (80-95%) SSAs 5-20% CIMP + AdCA BRAF, Methylation

49 If you see one of these.... Complete endoscopic removal advisable If endoscopic removal impossible,?? annual debulking or potential open removal?? Follow-up similar to an adenoma protocol Remember this patient will often make more serrated polyps in the future I call them sessile serrated adenoma and add canned comment

50 Key Elements of The Canned Comment Remember your audience: Gut docs gastroenterologists, colorectal surgeons General docs internists, family docs, etc Nurses Patients Key points to make: Used to be called HPPs,, but evidence exists that these have preneoplastic potential through serrated pathway Optimal Rx is complete endoscopic removal and probably adenoma-like follow up Call you if they have questions about mgmt (? Add your phone # for their convenience)

51 Remember we do have a terminology problem for these things.... Sessile serrated adenoma (SSA) Serrated polyp with abnormal proliferation (SPAP) Sessile serrated polyp Type CP-ESP ESP None of the names are perfect, but Torlakovic and Snover were first, so I go with sessile serrated adenoma in my practice. And it works fine in Minneapolis. Whatever you call it, a canned comment will be key.

52 Hamatani S, et al. J Jpn Soc Coloproctol 51: , 1998 We also have a reproducibility problem.. Torlakovic and Snover Goblet cell HPP Microvesicular HPP Sessile Serrated Adenoma

53 If you see one of these.... Treat like a usual adenoma: Complete endoscopic removal advisable If endoscopic removal impossible, open removal (like a regular adenoma)?? Follow-up similar to an adenoma protocol Remember they are in the serrated family but are rare (<1%) I call them traditional serrated adenoma

54 If you see one of these.... Treat like a usual adenoma, but perhaps act quickly: Complete endoscopic removal advisable If endoscopic removal impossible, open removal (like a regular adenoma)?? Follow-up similar to an adenoma protocol Remember they are probably a serrated polyp going bad Might progress to cancer quickly???? I call them mixed SSA/tubular adenoma (etc)

55 Yes, hyperplastic polyps do still exist I call them HPPs and don t further subdivide at present.