Practical Issues in Serrated (MSI) colorectal carcinoma Colorectal - - PowerPoint PPT Presentation

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Practical Issues in Serrated Colorectal Polyps

Wendy L Frankel, MD

Chair of Pathology Director of GI/Liver Pathology Fellowship

Serrated polyps- definitions Differential and mimics Serrated pathway to microsatellite unstable (MSI) colorectal carcinoma

Outline

• A. Traditional serrated

adenoma (TSA)

• B. Hyperplastic polyp (HP)
• C. Sessile serrated

adenoma/polyp (SSA/P)

• D. SSA/P with dysplasia
• E. Tubulovillous adenoma

(TVA)

A. B. C. D. E.

53% 2% 20% 4% 22%

What is Your Diagnosis? Colorectal Polyps

Adenomas and hyperplastic polyps used to be easy Adenomas precursors to cancer; genetic alterations in tumor suppressor genes (APC, p53) and oncogenes (KRAS) Hyperplastic polyps not Or are they??

5/28/2016 2 Evolution of a Shift

1984; Urbanski described CRC arising in HP/TA 1990; Longacre and Fenoglio-Prieser described polyps architectural features of HP but with dysplasia- serrated adenoma 1996; Torlakovic & Snover characterized lesions in patients with hyperplastic polyposis; serrated adenomatous polyposis 2003; Torlakovic studied sporadic serrated lesions and identified some with abnormal proliferation, SSA

Urbanski, Am J Surg Pathol , 1984; Longacre, Am J Surg Pathol , 1990; Torlakovic and Snover, Gastroenterol, 1996; Torlakovic, Am J Surg Pathol , 2003

CURRENT ISSUES IN GI POLYP PATHOLOGY Moderator: Wendy Frankel Agenda: 1:30 Diagnosis and management of polyps in IBD Robert D. Odze 2:05 Adenocarcinoma in adenomas: Diagnosis and management Mary P. Bronner 2:40 Annoying polyps without names: Pimples and zits of the gut Henry D. Appelman 3:15BREAK 3:45 Serrated colorectal polyps: New challenges to old dogma Kenneth P. Batts RODGER C. HAGGITT MEMORIAL LECTURE 4:20 Gastric lumps and bumps Robert M. Genta

USCAP 2004 Rodger Haggitt GIPS Companion Meeting

Hyperplastic Polyp (HP)

75-90% of serrated polyps Throughout colon, distal predominance Lower crypts narrow without dilatation and serration Serration may be in upper half Lower crypts with proliferative cells

Hyperplastic Polyp

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Hyperplastic Polyp Subtype

Microvesicular Mucin-poor Goblet cell rich

Sessile Serrated Adenoma (SSA/P)

Approximately 10-20% of serrated polyps Right colon predominance Architectural rather than cytologic dysplasia

Crypt branching and basal dilatation Transverse, L or T shaped crypts Serration at base, goblet or gastric foveolar cells rather than proliferative cells

No surface cytologic dysplasia This is the serrated lesion (we previously called them HP) that CRC appears to arise in

Dilatation and Serration to the Base

5/28/2016 4 Small SSA/P

2012: 1 convincing crypt 2010: 2-3 contiguous crypts

Rex, Am J Gastroenterol, 2012

TA HP SSA/P SSA/P

Traditional Serrated Adenoma (TSA)

Rare, 1-2% of CR polyps Distal predominance Usually villous or tubulovillous May be focally flat like SSA/P Surface dysplasia Usually not as high grade as TVA

Traditional Serrated Adenoma

Uniform cytologic dysplasia Eosinophilic cytoplasm, centrally located nuclei Luminal serration Ectopic crypts-not sine qua non 50% coexist SSA/P, HP or TA/TVA

Bettington, Hum Path, 2015; Hafezi-Bakhtiari S, Histopath, 2015; Chetty, J Clin Path, 2015 and 2016

5/28/2016 5 Tubulovillous Adenoma (TVA)

• A. TSA
• B. SSA/P
• C. SSA/P with dysplasia
• D. TVA

What is This Polyp?

A. B. C. D.

73% 23% 1% 2%

• A. TSA
• B. SSA/P
• C. HP
• D. Prolapse polyp

What is This Polyp?

A. B. C. D.

1% 0% 12% 86%

• A. TSA
• B. SSA/P
• C. HP
• D. Prolapse polyp

What is This Polyp?

A. B. C. D.

1% 1% 73% 24%

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• A. TSA
• B. SSA/P
• C. SSA/P with

dysplasia

• D. Prolapse polyp

What is This Polyp?

A. B. C. D.

15% 21% 4% 60%

• Other serrated polyps (HP, TSA, mixed polyps)
• Prolapse, SRUS
• Inflammatory polyp
• Serrated crypts and stromal polyp

SSA/P Differential and Mimics

Differential Diagnostic Features - HP

• vs. SSA/P

Surface may be similar Base of crypts with serration, dilatation and transverse architecture (SSA/P) Mitotic figures upper crypts (SSA/P)

Differential Diagnostic Features

Problems with SSA/P and TSA and clues

Surface cytologic dysplasia (TSA) Villiform architecture (TSA) Ectopic crypts (TSA)

Problems with TSA and TVA and clues

Degree of dysplasia (lower in TSA) Uniform eosinophilic cytoplasm (TSA) Ectopic crypts (TSA)

5/28/2016 7 Practical Immunohistochemistry for Differential Diagnosis

Ki67 MUC6 Annexin A10 Maspin Hes1 MLH1 Many others I do not use IHC H&E levels, colleagues

• A. TSA
• B. SSA/P
• C. SSA/P with dysplasia
• D. HP with prolapse

change

What is This Polyp?

A. B. C. D.

0% 86% 2% 12%

Rectal polyps- Hyperplastic Polyp and/or Prolapse Change

Huang, Hum Pathol, 2013

Many rectal polyps misdiagnosed as SSA/P; BRAF does not help in differential

Rectal Prolapse

5/28/2016 8 Rectal Prolapse TA with Prolapse Inflammatory Polyp

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Serrated Polyp?

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5/28/2016 9 Ulcerative Colitis with Adenocarcinoma

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Stromal Polyp

S-100

Neuromatous polyp (Schwann cell hamartoma)

Mucosal Perineurioma Associated with SSA/P

Benign nerve sheath tumor Associated with serrated polyp 70-80% EMA weak, Claudin-1 S100, SMA negative

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Hornick, Am J Surg Pathol, 2005; Pai, Am J Surg Pathol, 2011; Doyle, Surg Pathol Clin, 2013

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• A. TSA
• B. SSA/P
• C. SSA/P with

dysplasia

• D. TA

What is This Polyp?

A. B. C. D.

3% 31% 62% 5%

Mixed Serrated Polyps- Cytologic Dysplasia Arising in SSA/P

Progression in SSA/P TA or TSA-like Loss of MLH1 protein by IHC (MMR gene) likely due to methylation of MLH1 promoter

Sheridan, Am J Clin Pathol, 2006

SSA/P with Dysplasia SSA/P with Dysplasia

TA-like TSA-like

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• A. TSA
• B. SSA/P
• C. SSA/P with

dysplasia

• D. TA

What is This Polyp?

A. B. C. D.

0% 54% 46% 0%

• A. TA
• B. SSA/P
• C. SSA/P with

dysplasia

• D. TA and SSA/P

What is This Polyp?

A. B. C. D.

10% 74% 16% 0%

Clinical and Endoscopic Features of Colorectal Serrated Polyps

WHO Prevalence Endoscopy Distribution Malignant Potential HP Very common Sessile/flat smooth Mostly distal Very low SSA Common Sessile/flat mucous cap Mostly proximal Without D Low With D Significant TSA Rare Sessile/ pedunculated Mostly distal Low/Significant Lieberman, Gastroenterol, 2012

Risk of Colorectal Cancer

Modified from Rex, Am J Gastroenterol, 2012

Number of polyps Size of polyps Type of polyps Site of polyps

Cancer risk

None/few Small HP Left Lower Many Large SSA Right Higher Type of polyps Type of polyps SSAd

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Histology Size Number Location Interval (yrs)

HP <10mm Any number Rectosigmoid 10 HP ≤5mm ≤3 Proximal Sigmoid 10 HP Any ≥4 Proximal Sigmoid 5 HP >5mm ≥1 Proximal Sigmoid 5 SSA/P or TSA <10mm <3 Any 5 SSA/P or TSA ≥10mm 1 Any 3 SSA/P or TSA <10mm ≥3 Any 3 SSA/P ≥10mm ≥2 Any 1-3 SSA/P w/dysplasia Any Any 1-3

Proposed Endoscopic Surveillance

Rex, Am J Gastroenterol, 2012

Proximal HP >10mm considered SSA by clinicians

SSA/P- Pitfalls and Misconceptions

Not associated with Lynch

Do not do mismatch repair stains Lynch usually has TA not SSA

SSA/P may not have > risk than TA

SSA/P with dysplasia may progress fast and need increased surveillance

Sporadic SSA/P not same risk as SSA/P in Serrated Polyposis Syndrome

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• A. No, it is an H&E diagnosis
• B. Yes, to distinguish polyp type
• C. Yes, to confirm dysplasia
• D. Yes, to confirm LS

A. B. C. D.

97% 1% 1% 0%

Would IHC for MMRP be Useful to Classify this Polyp?

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Link Between SSA and Microsatellite Unstable (MSI) Cancers

Serrated pathway to CRC

Many series/case reports Epidemiology and H&E CRC arises in SSA/P

Molecular link to CpG island methylation (CIMP), BRAF mutation and MSI cancers

Iino, J Clin Pathol 52,1999; Wynter, Gut 53, 2004; Goldstein, Am J Clin Pathol 119, 2003; Jass, Am J Clin Pathol 119, 2003; Goldstein, Am J Clin Pathol 125, 2006; Sheridan, Am J Clin Pathol 126, 2006

MLH1 Lost with Progression

SSA Dysplasia Adenocarcinoma

13% 1% 80+%

FAP Sporadic MSI (Microsatellite Instability) CIN (Chromosome Instability) Lynch Sx Sporadic

Germline mutation MMR genes, 40-50y. MLH1 MSH2 MSH6 PMS2

15% 2-3%

Epigenetic silencing of MLH1 by hypermethylation of its promoter region, >80y.

85%

Colorectal Cancer (Simplified)

Acquired APC, p53, DCC, K-ras, LOH…, 60-70y. Germline Mutation APC, 20y.

SPS?

5/28/2016 14 Serrated Polyposis (SPS)

First described 1977 by Spjut and Estrada Frequently presents with features consistent with genetic predisposition to CRC Individuals develop CRC on a background of multiple polyps, most serrated polyps Wide age range, 50-70 y/o (11 y/o reported)

Genetic predisposition to hypermethylation of gene promoters (CIMP), BRAF

Spjut and Estrada, Pathol Annu, 1977

Diagnostic Criteria (WHO)

Classification unclear and non-uniform

At least 5 SP proximal to the sigmoid, 2 must be > 10 mm in diameter Any # SP proximal to sigmoid in anyone who has a 1st degree relative with SPS > 20 SP distributed throughout the colon

Possibly 2 different types with different risk and molecular (BRAF vs. KRAS)

Higuchi and Jass, J Clin Pathol, 2004; Snover, WHO, 2010

SPS- Can We Help Identify?

Methods: Review pathology reports 6 months, for #, size, type colon polyps Results: 929 patients with ≥ 1 SP

17 (1.8%) met WHO No statistical cut-off in number/size to suggest SPS

Conclusions:

SPS underdiagnosed (1.8% with SP in 6 months) If ≥ 3 SP at index endoscopy, only 58.8% would have been identified (no clear cut-off)

Crowder, Am J Surg Pathol, 2012

Summary and Take Home Message

SSA/P can be diagnosed when at least 1 convincing abnormal crypt is present

Gastroenterologists will likely treat as SSA/P if >1 cm proximal to sigmoid Be careful in rectum with features of prolapse SSA/P is not part of Lynch- do not do IHC

SSA/P with dysplasia is progression

More frequent surveillance This is in the pathway to some MSI cancer (serrated pathway)

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Thanks, Questions?