Serrated Colorectal Polyps New Challenges to Old Dogma Kenneth Batts, M.D. Abbott Northwestern Hospital Minneapolis, MN
A Sneak Preview.... This was in the good old days: Adenomas HPPs Mixed Polyps
A Sneak Preview.... This is today: TSA Adenomas HPPs SSAs CIMP + AdCA Mixed Polyps
The emergence of a subgroup of hyperplastic polyps.....
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)
SSA Architecture Dilated Mucin-Filled Crypts
SSA Architecture Deep Crypt Branching
SSA Architecture Lateral Spread of Deep Crypts
SSA Architecture Sessile Growth
SSA Architecture Sessile Growth
SSA Architecture Inverted Growth
SSA Architecture Excessive Serrations
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):748-55 *Torlakovic, Snover, et al; Am J Surg Pathol., 2003 Jan;27(1):65-81 *Goldstein NS, et al. Am J Clin Pathol. 2003 Jun;119(6):778-96
SSA Crypt Base Mucin
SSA Mid-crypt Mitoses = Mitotic Figures
SSA Mid-crypt Hyperchromasia
SSA Hyperchromasia in Mid to Upper Crypt and Surface
SSA Surface Nucleoli
O-02-4162 SSA Dysplastic Goblets Dysplastic goblet cells Normal
Serrated Polyps and Proliferation KI-67 (%) 70 60 50 40 30 20 10 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
Hamatani S, et al. J Jpn Soc Coloproctol 51:555-566, 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:
Sessile vs traditional serrated adenomas.....
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):524-37 **Torlakovic, Snover, et al; Am J Surg Pathol., 2003 Jan;27(1):65-81
The Traditional Serrated Adenoma Usually villiform. Pencillate nuclei on surface Endoscopically usually semi-sessile, protuberant. Eosinophilic cytoplasm w/ mucin depletion
Serrated Adenomas and Proliferation Sessile vs Traditional Types KI-67 (%) 70 60 50 40 30 20 10 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
Traditional vs. Sessile Serrated Adenoma
Evidence linking sessile serrated adenomas with cancer.....
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
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
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;119:778-796
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;93:1307-1313
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):349-59.
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
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;193:286-294
Case 1. Right hemicolectomy in 71 O-01-7103 y/o female; 2.2 cm sessile mass SSA Component
Case 1. Transition to a Usual-type O-01-7103 Adenoma ( Mixed polyp ) Interface with SSA Low Grade Dysplasia High Grade Dysplasia Block 2
O-01-7103 Case1. AdenoCA with High Likelihood of MSI
S-01-10090 Case 2. Endoscopic polypectomy of 2.5 cm right colon polyp, 81 y/o female SSA Adenoma A Mixed Polyp
High Grade Dysplasia S-01-10090 Case 2. Transition to Adenoma Low Grade Dysplasia Traditional Adenoma/ SSA Interface
S-01-10090 Case 2. AdenoCA with High Likelihood of MSI Ordinary CA Medullary CA (focal)
A brief look at molecular data supporting these concepts.....
Molecular Support for Subdividing the 90 80 70 60 50 40 30 20 10 0 Serrated Polyp Family * * * * * * * * * * GCSP MVSP SPAP SA (SSA) (TSA) CIMP-H BRAF KRAS O Brien MJ, et al. Am J Surg Pathol 2004: 28:423 434. Yang S, et al. Am J Surg Pathol 2004;28(11):1452-1459.
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):573 80 70 60 50 40 30 20 10 0 HPP (25%) SSA (65%) Mixed (82%)
Data Linking Serrated Polyps to MSI (and Mixed Polyps into Serrated Family) 90 80 70 Adenoma % MSI 60 50 40 30 SA Mixed HPP Serrated adenoma 20 10 0 TA HPP MSI Mixed Iino H, Jass JR, et al; J Clin Pathol 1999;52:5-9
BRAF, MSI, and CIMP Data Linking Serrated Polyps and Cancer 90 80 70 % 60 50 40 30 20 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):1137-44
Colorectal Cancer The Big Picture 60 50 Hypermethylation and MSI 40 30 20 10 0 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):2898-2903
A summary of current understanding of the serrated pathway.....
Serrated Neoplasia My Best Guess in 2006 TSA (<1%) Mixed Polyps (?<1%) HPPs (80-95%) SSAs 5-20% CIMP + AdCA BRAF, Methylation
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
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)
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.
Hamatani S, et al. J Jpn Soc Coloproctol 51:555-566, 1998 We also have a reproducibility problem.. Torlakovic and Snover Goblet cell HPP Microvesicular HPP Sessile Serrated Adenoma
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
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)
Yes, hyperplastic polyps do still exist I call them HPPs and don t further subdivide at present.