Staging Updates In AJCC 8th Ed Colorectal And Selected GI .

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2018 Park City AP UpdateStaging updates in AJCC 8th edColorectal and selected GI sites.AJCC 8th edition and CAP protocol updatesSanjay Kakar, MDUniversity of CaliforniaSan Francisco, USAOutline Updates in Colorectal cancerDefinition of T4aTumor depositsIsolated tumor cellsAdenocarcinoma arising in a polyp Selected other updatesLiver, pancreas, gallbladder, ampullaDefinition of pT4AJCC 8th editionT categorypT4apT4bDefinitionTumor invades through thevisceral peritoneumTumor directly invades otherorgans or structures1

Criteria for serosal involvement Tumor directly extends to involveserosal surface Tumor continuous with serosal surfacethrough perforation (inflammatoryreaction)Shepherd, Gastroentrol 1997Peterson, Gut 2002Ludeman, Histopathol 2005Stewart, Histopathol 2006Tumor directly extends to serosal surfaceColonic adenocarcinoma with perforation 2016 College of American Pathologists. All rights reserved.62

Perforation: tumor continuous with serosal surfacethrough inflammatory reaction 2016 College of American Pathologists. All rights reserved.7T4a: challenges Free floating tumor cells Tumor within 1 mm of serosalsurface Acellular mucin on serosal surface Elastic stainFree floating tumor cells in clefts and mesothelial ‘ulceration’3

Disrupted serosal surface with free floating tumor cellsAdditional sections: obvious pT4aTumor 1 mm with reactionStudyPanarelli, , AJCP2003-Douard, AJCP2004ResultsPositive cytology from serosal surface ofspecimens:46% pT3 1 mm from serosal surface55% of pT4aPeritoneal recurrence: 11% in pT3 1 mm18% in pT4aResultsPeritoneal/pelvic recurrence only withDirect invasion of serosal surfaceFree floating tumor cells4

Not T4a (AJCC 8th) Tumor close to serosal surface withserosal reaction Acellular mucinDeeper levels, additional sectionsElastic stain Submesothelial elastic lamina Involvement associated withpoor prognosis in some studiesShinto, Dis Col Rectum 2004Kojima, AJSP 2010Grin, Hum Pathol 2013Elastic stainDifficult to interpret Elastic laminadiscontinuous Retracted bydesmoplasia Variable distancefrom mesothelium5

pT4a: clinical significance Prognosis Peritoneal recurrence Choice of therapyNCCN guidelines: High risk feature in stage IILikely adjuvant chemotherapyPossible local radiation or intraperitoneal chemo in the futureASCO GI meeting 2017 Some but not all studies: advocated HIPEC No clear guidelinesBaratti, Ann Surg Oncol 2016Elias, J Clin Oncol 2009Outline Updates in Colorectal cancerDefinition of T4aTumor depositsIsolated tumor cells6

Tumor deposits: AJCC 7th Edition-Discrete foci of tumor in pericolic fat-No evidence of residual lymph nodetissue-N1c in the absence of nodalinvolvementTumor DepositsReasons for discrepancy Minimum distance from invasive front Minimum size Venous invasion/perineural invasionor tumor deposit Tumor deposit after neoadjuvanttherapyChallenges in InterpretationDistancefromInvasiveFront 2 mm 5 mm 10 mmStudyUeno, Am J Surg 2014Nagoyoshi, Dis ColonRectum 2014Gopal, Mod Pathol 2014StudySize of TumorDepositNagtegaal, J ClinOncol 2011 3 mmNagayoshi, DisOnly if grosslyCol Rectum 2014 identifiedLin, Oncol Targets2015Other studiesCriteria not specifiedAJCC definition No minimum distance No minimum size7

Venous invasion or tumor depositGoldstein (2000)Lin (2015)Nagoyoshi (2014)Ueno (2011)VI withVI confined toextravascularvessel wallspreadTumor depositTumor DepositVascularinvasionTumor deposits: AJCC 8th Edition Tumor focus in the pericolic/perirectal fat or inadjacent mesentery within the lymph drainagearea of the primary tumor, but withoutidentifiable lymph node or vascular structure Vessel wall or its remnant (H&E, elastic, or anyother stain): vascular (venous) invasion Tumor focus in or around a large nerve: PNI'Protruding Tongue' sign 2016 College of American Pathologists. All rights reserved.248

'Orphan Artery' sign 2016 College of American Pathologists. All rights reserved.25Elastic stain: venous invasion 2016 College of American Pathologists. All rights reserved.26T3 tumor, negative lymph nodesT3N1c: stage IIIorT3N0 with VI: Stage II9

CRC: Extramural venous invasion Independent predictor of poor outcome NCCN: High risk feature in stage IIdisease Likely to receive chemotherapyRecommendations: Record separately from small vessel invasion Consider elastic stainMessenger, J Clin Pathol 2011Kirsch, Human Pathol 2012Challenges in Interpretation Minimum distance from invasive front Minimum size Replaced lymph node or tumordeposit Venous invasion/perineural invasionor tumor deposit Tumor deposit after neoadjuvanttherapyTumor deposit after therapy Residual primary tumor can bemistakenly classified as N1c Proximity to areas of fibrosis oracellular mucin favors residualprimary tumor Elastic stain: venous invasionNagtegaal, J Clin Oncol 201110

N1c in practiceLymph nodeVenous invasionPerineural invasionTumor depositThick capsuleSubcapsular sinusRim of lymphocytesAccompanying arteryElastic stainLarge nervesNo remnant lymph node, largenerve or veinDo not add tumor deposits and lymph nodes for N category Assessing adequacy of LN dissectionRock, Arch Path Lab Med, 2014Liu/Kakar, USCAP 2016Isolated tumor cellsSize of nodalmetastasis0.2 to 2 mmLess than 0.2 mmAJCC 7th editionMicrometastasis pN1miIsolated tumor cells (ITC)pN0 (i )pN0 (mol )Isolated tumor cells, micrometastasisStudyDesignConclusionSloothak,Eur J SurgOncol 2014Meta-analysis5 studies-Increased recurrence with micrometastasis-No increased risk with ITCRahbari,JCO 2012Meta-analysis39 studies-Increased recurrence with micrometastasis-Insufficient data for ITCMescoli,JCO 2012Keratin in N0,n 312-Higher relapse with ITC (14% vs. 5%)Protic, J AmColl Surg2015Keratin in N0,n 312Prospective-Higher relapse with ITC (17% vs. 3%)-T3 and T4 (not T1 and T2)Greenson,Keratin in N0,Cancer 1994 n 50-Higher relapse with ITC (43% vs. 3%)11

AJCC 8th editionSize of nodal AJCC 8th editionmetastasis0.2 to 2 mmUse pN1pN1mi not necessaryLess than 0.2 Use N0mmNo definite recommendation for using N0(i )Isolated tumor cellsAdenocarcinoma in polypAJCC 8th edition: definitions clarified Intramucosal adenocarcinoma (Tis)Not beyond muscularis mucosa Invasive adenocarcinoma (T1 orbeyond)Submucosa or beyond12

Tis and T1 in practice Clarify in reportIntramucosal adenocarcinoma is Tis andhas virtually no propensity for LN mets T1 adenocarcinoma in polypInclude prognostic factors to enabledecision about resectionInvasive adenocarcinoma (T1) in polypIndications for colectomyPrognostic featuresGrade: poor differentiationLymphovascular: presentMargin: 1 mmDepth of submucosal invasionTumor buddingPedunculatedpolyp: HaggittlevelsLevel 1: HeadLevel 2: NeckLevel 3: StalkLevel 4: Beyondstalk13

Kikuchi levelsSM1, SM2 and SM3 Difficult to judge depth in absence of muscularispropria Measure depth from base of muscularis mucosa: 1 mm is a high risk feature-Mucosa on allsides-?Depth ofinvasionInvasive adenocarcinoma (T1) in polypIndications for colectomyPrognostic featuresGrade: poor differentiationLymphovascular: presentMargin: 1 mmDepth of submucosal invasionTumor budding14

Tumor budding Individual or small discrete cellclusters ( 5 cells) at the invasive edge Independent adverse prognostic factorAdjuvant therapy in stage IIColectomy for malignant polyps Recommended:UICC, ADASP, CAP, UK Royal CollegeNot included in NCCNConsensus statementsCounting tumor buds Tumor budding is counted on H&EUse of cytokeratin Most of the data is based on H&E stain Can increase tumor bud counts 3x Can use it in challenging cases (obscuring inflammation), butfinal count should be done on H&E15

Go back to H&E stain forbudding countConsensus statementsCounting tumor buds The hot spot method (single fieldat the invasive front, size 0.785mm2) is recommended Choose a 'hotspot' Count in 20x field Apply appropriate correction factor for your microscope16

Conversion tableObjective Magnification: 20xEyepieceFNEyepiece FN Specimen Specimen NormalizationDiameterRadiusFN 613.00.6501.3271.690Consensus statementsCounting tumor buds A three-tier system should be used alongwith the budding count in order to facilitaterisk stratification in CRCTumor budding score (0.785 mm2)Low0-4Intermediate5-9High 10Other changes: CAP protocolMicrosatellite instability Morphologic features omitted Universal testing recommended MMR immunohistochemistry or PCRNCCN guidelinesEGAPP guidelines, Nat Genetics, 200917

Outline Updates in Colorectal cancerDefinition of T4aTumor depositsIsolated tumor cells Selected other updatesPancreas, gallbladder, ampullaAmpulla: staging challengesLocation Intra-ampullary Peri-ampullaryHistologic subtype Pancreaticobiliary IntestinalAmpulla: AJCC 8th editionChange DetailsT1subdivisionT1a: Limited to ampulla of Vater or sphincter ofOddiT1b: Invades beyond the sphincter of Oddi and/orinto the duodenal submucosaT2 redefined Invasion into the muscularis propria of duodenumT3subdivisionT3a: Directly invades the pancreas (up to 0.5 cm)T3b: Extends more than 0.5 cm into the pancreasor extends into peripancreatic or periduodenaltissue or duodenal serosaAdsay, Semin Diagn Pathol 201218

AmpullaChange DetailsT4Tumor involves the celiac axis, superiormesenteric artery, and/or common hepatic artery,irrespective of sizeAdsay, Semin Diagn Pathol 2012Ampullary adenocarcinomaPancreaticobiliary vs intestinalKim, J Surg Oncol 2012AJCC 8th edition: AmpullaRecommendation Histologic subtypes should be characterized forpatient care May help guide the use of adjuvant therapyGemcitabine-based (pancreaticobiliary) vs.5-FU based (gastrointestinal)19

PancreaticobiliaryIntestinal-Rounded, cuboidal to lowcolumnar-No pseudostratification-Marked variation in size shape-Desmoplastic stroma-Resemble colon cancer-Cribriform architecture-Tall, pseudostratified columnar- ‘Dirty necrosis’- Extracellular mucinAmpullary adenocarcinomaImmunohistochemistryStudyDefinition of subtypeAng, AJSP 2014 INT: CK20 or CDX2 or MUC2 andCK20, CDX2,MUC1 negative, orMUC1, MUC2 CK20 CDX2 and MUC2 Irrespective of MUC1 25% stainingconsidered vePB: MUC1 , CDX2- MUC2Irrespective of CK20 92% were classified 75% poorly differentiated, 69% mixedCK20-veCK20 ve20

MUC1CK20MUC2Ampullary adenocarcinomaImmunohistochemistryStudyDefinition of subtypeScheuneman,Br J Cancer 2015 PB: PB histology, MUC1 , CDX2MUC1: anyINT: all othersCDX2: score 35Ampullary adenocarcinomaHistologic typing: Problems 15-20% ambiguous even afterimmunohistochemistry Not independent predictor of outcome insome studies Biopsies may not be representativeReid, Mod Pathol 2016Perysinakis, Int J Surg Pathol 201721

Pancreas: staging updates Changes in T category Changes in N category Definition of positive uncinate marginPancreas: Problems instaging in AJCC 7th editionT stageT1 T2 T3T3 criteriaProblem-Uneven stage groupings-Lack of correlation with outcome-Extrapancreatic involvement22

T1 vs. T2 vs. T3uneven stage groupingsStudyFerrone, Surgery 2012(n 499)Saka/Adsay, USCAP2014 (n 250)Basturk/Allen/Klimstra,MSKCC, unpublished(n 397)T groupingT1: 9% T2: 15%T3: 76%T1: 2% T2: 2%T3: 95%T1: 5% T2: 5%T3: 90%Allen, Ann Surg 2017Pancreas staging: 8th editionChangeDetailsT1 subcategories T1: Up to 2 cmT1a 0.5 cm T1b 0.5 1 cmT1c 1-2 cmT2 and T3 based T2: 2 and 4 cmon sizeT3: 4 cmExtrapancreatic extension is nolonger part of the definitionSaka, Ann Surg Oncol 2016Allen, Ann Surg 201723

Saka, Ann Surg Oncol 2016p-value 0.0011Allen, Ann Surg 2017Pancreas staging: 8th editionChangeDetailsN categoriesN1: Up to 3 lymph nodesN2: 4 or more lymph nodesSaka, Ann Surg Oncol 2016Allen, Ann Surg 201724

Allen, Ann Surg Oncol 20171.00No. of Pos NodesProbability of overall survival01-30.75 40.500.250.00050100150Months since surgeryDefinition of positive uncinate marginReferenceOutcomeCampbell,Histopathol, 2009(n 163)Chang, J Clin Pathol,2009Van Den Broek, Eur JOncol, 2009 (n 145)Survival in tumor at margin same astumor 1 mmSurvival in tumor at margin same astumor 1.5 mmTumor 1 mm adverse prognosticfactorDefinition of positive uncinate marginReferenceOutcome: R0 and R1Royal College UKNegative: Tumor 1 mm from marginPositive: Tumor at or 1 mm from marginAdopted the same definitionCAP protocol25

Modified Ryan scoring scheme (CAP)DescriptionTumor RegressionScoreNo viable cancer cells(complete response)0.Single cells or rare small groups of cancercells (near complete response)1.Residual cancer with evident tumorregression, but more than single cells orrare small groups of cancer cells(partial response)2.Extensive residual cancer with no evidenttumor regression (poor or no response)3Size of tumor after neoadjuvant therapyStudy DesignSubmit the entire tumor bed Measure viable tumor fociand add them, or Measure extent acrossviable tumor foci arepresent includingintervening non-tumorareasChatterjee, Am J Surg Pathol 2017GallbladderChangeDetailsSubdivision T2a: Tumors on the peritoneal sideof T2T2b: Tumors on the hepatic sideAJCC 8th Ed.Shindoh, Ann Surg 201526

Intrahepatic cholangiocarcinomaAJCC 7th editionT categoryT1T2T3T4DefinitionSolitary tumor without vascular invasionT2a: Solitary with vascular invasionT2b: Multiple tumorsInvolving visceral peritoneum or directinvasion into extrahepatic structuresTumor with periductal invasionPeriductal invasion Intrahepatic CC, macroscopic typesMass forming, periductal, intraductal, mixed Periductal: worse prognosisExtensive intraductal growth: T4 ProblemsHow extensive is 'extensive'Recent studies do not confirm worse outcomeHirohashi, Hepatogastroeterol 2002Uno, Surg Today, 2012Intrahepatic cholangiocarcinoma, 3 cm, no VI27

T1 or T4Intrahepatic cholangiocarcinomaAJCC 8th editionT categoryDefinitionT1a: Solitary tumor 5 cm without vascularinvasionT1a: Solitary tumor 5 cm without vascularinvasionSolitary with intrahepatic vascular invasion ormultiple tumorsInvolving visceral peritoneumDirect invasion into extrahepatic structuresT1T2T3T4Distal bile duct adenocarcinomaAJCC 8th editionT categoryT1T2T3T4DefinitionTumor invades the bile duct wall with a depthof less than 5 mmTumor invades the bile duct wall with a depthof 5-12 mmTumor invades the bile duct wall with a depthmore than 12 mmTumor involves celiac axis, superiormesenteric artery, and/or common hepaticarteryDepth is measured from the basement membrane ofadjacent normal or dysplastic epithelium to the point ofdeepest tumor invasion28

Perihilar bile duct adenocarcinomaAJCC 8th editionT categoryT1DefinitionTumor confined to the bile duct, with extensionup to the muscle layer or fibrous tissueT2a: Tumor invades beyond the wall of the bileduct to surrounding adipose tissueT2b: Tumor invades adjacent hepaticparenchymaTumor invades unilateral branches of the portalvein or hepatic arteryTumor invades main portal vein or its branchesbilaterally, or the common hepatic artery; orunilateral second-order biliary radicals withcontralateral portal vein or hepatic arteryT2T3T4AJCC stagingThe FutureConsensus Molecular Subtypes (CMS)6 gene expression cMesenchymal37%13%23%14%MSI-highCIMP-highHigh copyLow copy numberHigh copynumber alterationalterationnumber alterationRightLeftBRAF mutationWnt activationHigh stageKRAS mutationTGFβ ent stromaMyc activationImmuneinfiltrationWorse outcomeafter relapseEMT genesWorse outcomeGuinney, Nat Genetics, 201529

Host immune response better prognosticindicator than TNM ‘Immunoscore’: Quantify the immune infiltrateGalon, J Pathol 2014TNM-I stagingImmunoscore CD3 and CD8 Numbers in center and invasive front 5 categories: I-0 to I-4Galon, J Transl Med 201230

Staging updates in AJCC 8th ed Colorectal and selected GI sites . AJCC 8th edition and CAP protocol updates 2018 Park City AP Update Outline Updates in Colorectal cancer Definition of T4a Tumor deposits Isolated tumor cells Adenocarcinoma arising in a polyp Selected other updates Liver, pancreas, gallbladder, ampulla Definition of pT4

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