5/24/2013 2013 CURRENT ISSUES IN SURGICAL PATHOLOGY Serrated colorectal polyps • Terminology and the emergence of sessile Serrated colorectal polyps serrated adenoma superhighway to colon cancer • Implications for the surgical pathologist • Diagnostic challenges (case examples) Sanjay Kakar, MD UCSF Before 1990 Two main categories of colorectal polyps • Serrated (hyperplastic polyp) • Adenomatous (TA, TVA, VA) • Mixed (collision) 1
5/24/2013 HP : no longer innocent Colorectal polyps • Serrated • Morphologic evidence • Molecular evidence Hyperplastic polyp Serrated adenoma • Adenomatous (TA, TVA, VA) • Mixed HP and cancer WHO criteria for serrated polyposis syndrome morphologic evidence (1) > 5 Serrated polyps proximal to the sigmoid colon with ≥ 2 of these being > 10 mm; or • Adenocarcinoma associated with (2) Any number of serrated polyps proximal to the sigmoid colon in an individual who has a first-degree relative with serrated polyposis; or large (giant) HP >1.0cm (3) >20 serrated polyps of any size, but distributed throughout the • Serrated polyps resembling HP colon. adjacent to colon cancers Serrated polyposis syndrome • High prevalence (30%) of colorectal cancer • Hyperplastic polyposis • Proximal location (>50%) • Young age (average 48 years) 2
5/24/2013 * Serrated polyposis syndrome Leggett, Jass: AJSP, Feb 2001 Study Findings Crowder, Am J Surg 929 patients with at least Path, 2012 one serrated polyp. 17 (1.8%) had SPS. Vemulapilli, Gastrointest 20/529 (4%) with serrated Endosc, 2012 polyp >2 cm had SPS. Failure to apply WHO criteria. Serrations: prominent, extend deep Morphologic heterogeneity in “HP” Sporadic HP: left side, small Serrated polyposis: variant features • Large, right colon • Hypermucinous appearance • Serrations were extensive, complex • Cystic dilatation of crypts at base • Crypt branching, transverse crypts • Mitoses in mid and upper crypts 3
5/24/2013 Crypt branching, lateral orientation Crypt branching, lateral orientation Basal crypts: ‘boot-shaped’, ‘Viking ship’ Dysmaturational crypt displaced crypt proliferative zone 4
5/24/2013 Dystrophic goblet cells - Floating in epithelium -No communication with the lumen -Inverted goblet cells Cytologic atypia 5
5/24/2013 Mitosis in upper portion of crypt Birth of sessile serrated adenoma “Hyperplastic polyps” Normal proliferation • Proliferative zone at base of crypt • Symmetric and continuous Abnormal proliferation • Either criterion absent • Mature mucin containing cells in crypt base 6
5/24/2013 Normal proliferation Abnormal proliferation * Normal Abnormal proliferation proliferation Serrations Mild Marked Horizontal crypts Absent Present Basal crypt dilatation Absent Present Luminal mucin Normal Often increased Asymmetric Absent Present proliferative zone Dystrophic goblet Absent or rare Often prominent cells Cytologic atypia None to absent Mild to moderate Mitoses in upper crypt Absent Can be present Microvesicular HP Normal Proliferation Abnormal Proliferation Hyperplastic polyps Serrated polyps with abnormal proliferation Sessile serrated adenoma Hyperplastic polyps Microvesicular Goblet cell Mucin poor 7
5/24/2013 Goblet cell HP Microvesicular HP Mucin poor HP 8
5/24/2013 Morphology of SSA Colorectal polyps Architectural Cytologic features • Serrated features Hyperplastic Prominent serrations Dystrophic goblet cells Sessile serrated adenoma Crypt branching Cytologic atypia Serrated adenoma Basilar crypt dilatation Mitoses in upper crypt • Adenomatous (TA, TVA, VA) Horizontal crypts No TA-like dysplasia Asymmetric • Mixed proliferative zone Morphologic Sessile serrated Traditional TSA: villous architecture feature adenoma serrated adenoma Exaggerated Often present Often present serrations Transverse Often present Usually absent crypts Basilar crypt Often present Usually absent dilatation Villous Absent Often present architecture Eosinophilic Absent or focal Prominent change Ectopic crypts Absent Often present 9
5/24/2013 Ectopic crypts Eosinophilic cells on the surface TA-like dysplasia Ki-67 activity in ectopic crypts Torlakovic, AJSP, 2008 10
5/24/2013 Colorectal polyps • Serrated Hyperplastic Sessile serrated adenoma Traditional serrated adenoma • Adenomatous (TA, TVA, VA) • Mixed TA-like cytological dysplasia 11
5/24/2013 * Colorectal polyps SSA with perineurial-like proliferation • Serrated Hyperplastic Sessile serrated adenoma SSA with cytological dysplasia Traditional serrated adenoma • Adenomatous (TA, TVA, VA) • Mixed Mixed (collision) polyps Pai, AJSP 2011 * Colorectal polyps Serrated colorectal polyps • Serrated Hyperplastic • Terminology and the emergence of sessile Sessile serrated adenoma serrated adenoma SSA with cytological dysplasia • Implications for the surgical pathologist SSA with perineurial-like proliferation • Case examples Traditional serrated adenoma • Adenomatous (TA, TVA, VA) • Mixed Mixed (collision) polyps 12
5/24/2013 SSA: implications for surgical pathologist • Risk of cancer • Management • Problems in diagnosis Colon cancer: genetic pathways SSA with cytological dysplasia Microsatellite instability: abnormal • SSA caught in the act of progression DNA mismatch repair • Dysplastic portion resembles TA • Lynch syndrome: mutations in MLH1 and • Loss of MLH1 in dysplastic portion MSH2 • Sporadic (15%): hypermethylation of MLH1 gene promoter 13
5/24/2013 SSA with cytological dysplasia SSA with cytological dysplasia: MLH1 SSA: risk of colon cancer Study Results Goldstein, AJCP, 106 right-sided “HP-like polyps” preceding colorectal 2003 cancers All ‘HPs’ had features of sessile serrated adenoma All cancers showed MSI Genta, JCP, 2010 2416 SSA, mean age 61 (1.7% of all polyps) 12% SSA with dysplasia: mean age 66 2% SSA with high-grade dysplasia: mean age 72 1% SSA with adenocarcinoma: mean age 76 14
5/24/2013 SSA: follow-up studies Study CRC risk in CRC risk in SSA TA Lu, AJSP, 2010 5/40 (12.5%) 1/55 (1.8%) Salaria, USCAP 2/40 (5%) 0/40 2010 US Multi-Society Task Force SSA: implications for surgical Surveillance guidelines: Gastroenterology 2012 pathologist • Risk of cancer • Management • Problems in diagnosis Terminology Reproducibility Morphological challenges 15
5/24/2013 Terminology Terminology • Giant hyperplastic polyp • Sessile serrated adenoma or sessile • Hyperplastic polyp with abnormal proliferation serrated polyp • Hyperplastic polyp with atypical features • WHO 2010 • Serrated polyps with abnormal Sessile serrated adenoma/polyp proliferation • Sessile serrated lesion • Sessile serrated polyp • Sessile serrated adenoma SSA: implications for surgical pathologist • Risk of cancer • Management • Problems in diagnosis Terminology Reproducibility Morphologic challenges 16
5/24/2013 SSA: reproducibility • Lack of uniform criteria for diagnosis • Reproducibility low in smaller and left-sided polyps • Role of MUC6 MUC6 positive in TA * SSA: endoscopic features • Indistinct borders • Irregular shape • Cloud-like surface 17
5/24/2013 Morphological challenges Case examples Borderline SSA-like changes • Orientation: basal crypt zone not clearly seen • Prolapse-like changes • Small and left-sided polyps Overlapping changes with TSA 0.8 cm polyp in the cecum 0.3 cm rectal polyp 18
5/24/2013 0.5 cm polyp in transverse colon Morphology of SSA Architectural Cytologic features features Prominent serrations Dystrophic goblet cells Crypt branching Cytologic atypia Basilar crypt dilatation Mitoses in upper crypt Horizontal crypts No TA-like dysplasia Asymmetric proliferative zone 0.5 cm polyp in transverse colon: SSA Rex, et al. Am J Gastroenterol 2012; 107: 1315-29. 19
5/24/2013 0.3 cm polyp in transverse colon SSA and its borderline variant. Mohammadi et al, Pathol Res Pract, 2011 * SSA Borderline Borderline SSA Feature SSA Borderline SSA Synchronous CRC 12% 8% Size >5 mm 89% 88% Proximal 52% 29% BRAF mutation 73% 80% Mohammadi et al, J Clin Pathol, 2012 20
5/24/2013 0.4 cm sigmoid polyp 1 cm sigmoid polyp 21
5/24/2013 SSA-like area TSA-like area SSA diagnosis: recommendations • Be wary of making a diagnosis of right- sided HP, especially >0.5 cm • Basilar crypt changes with dilatation: -serrations -branching and/or -horizontal crypts 22
5/24/2013 US Multi-Society Task Force Gastroenterology 2012 SSA diagnosis: recommendations SSA diagnosis: recommendations • Be wary of making a diagnosis of right- • Serrated polyp with borderline features sided HP, especially >0.5 cm -Typical changes are not seen -MUC6 unlikely to be helpful • Basilar crypt changes with dilatation: -Likely to be followed as SSA -serrations -branching and/or • Raise possibility of serrated polyposis -horizontal crypts syndrome • Left-sided polyps with basilar dilatation -multiple SSAs proximal to sigmoid and without distorted crypts: unlikely to -SSA with multiple HP/TSA/TA be SSA 23
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