3/23/2017. Disclosure of Relevant Financial Relationships. Pathologic Staging Updates in Lung Cancer T STAGE OUTLINE SURVIVAL ACCORDING TO SIZE ONLY

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1 Pathologic Staging Updates in Lung Cancer Disclosure of Relevant Financial Relationships USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. Sanja Dacic has no conflict(s) of interest to disclose. Sanja Dacic, MD, PhD March 5, T o Size o Multiple tumor nodules OUTLINE It is all about size T STAGE N o Number of lymph nodes or stations 3 4 SURVIVAL ACCORDING TO SIZE ONLY T STAGE Tumor size (cm) AJCC 7 th edition AJCC 8 th edition 1 cm Every centimeter counts ( ) 5 Rami-Porta R. et al. JTO 2015; 10: T1a T1a >1-2 T1a T1b >2-3 T1b T1c >3-4 T2a T2a >4-5 T2a T2b >5-7 T2b T3 >7 T3 T4 6 Rami-Porta R. et al. JTO 2015; 10:

2 HOW TO ACCURATELY MEASURE TUMOR SIZE? PATHOLOGIC ASSESSMENT OF GROSS SIZE CT size Gross vs. microscopic size 7 Three dimensional size includes not only tumor but also fibrosis, organizing pneumonia and inflammatory process 8 GROSS vs. MICROSCOPIC SIZE HOW TO STAGE LEPIDIC ADENOCARCINOMA? Tis Mean gross size 2.5 cm (range 1-5 cm) Adjusted microscopic size 1.5 cm (range cm) Adenocarcinoma in situ (AIS) T1a-mi T any Tumor & Scar = mm2 Scar = mm2 37.6% of the gross size Minimally Invasive Adenocarcinoma (MIA) 9 10 Invasive adenocarcinoma, lepidic subtype HOW TO MEASURE LEPIDIC SUBTYPE OF INVASIVE ADENOCARCINOMA? WHAT IS THE REPRODUCIBILITY OF INVASION CRITERIA? Total tumor size should be recorded, but only the invasive component used as a descriptor of the T-categories

3 EASY CASES (κ=0.55±0.06) DIFFICULT CASES (κ=0.08±0.02) Thunissen E. et al. Mod Pathol 2012; 25: Thunissen E. et al. Mod Pathol 2012; 25: GEOGRAPHY SEEMS TO BE IMPORTANT MULTIPLE TUMOR NODULES Group A invasion Group B no-invasion 15 % reported incidence Increased detection o HRCT o screening of smokers o closer follow up of patients after initial surgical resection P= Thunissen E. et al. Mod Pathol 2012; 25: MARTINI AND MELAMED CRITERIA MULTIPLE PRIMARY LUNG CANCERS Different histology Same histology Anatomically separated Temporally separated (2-4 years, no systemic metastases) SATELLITE NODULES Same histology Same lobe No systemic metastases SYNCHRONOUS LUNG NODULES Tumor nodule 1 Tumor nodule 2 Martini N. et al. J Thorac Cardiovasc Surg Oct;70(4):

4 SYNCHRONOUS CARCINOMA STAGING AJCC 7 TH EDITION When multiple tumors are of the same cell type, they should only be considered to be synchronous primary tumors if in the opinion of the pathologist, based on features such as associated carcinoma in situ or differences in morphology, immunohistochemistry, and or molecular studies, they represent differing subtypes of the same histopathological cell type, and 8 th edition AJCC PATTERNS OF DISEASE Detterbeck FC et al. JTO 2016:11(5): DIAGNOSTIC APPROACH TO MULTIPLE LUNG NODULES COMPREHENSIVE HISTOLOGIC ASSESSMENT Histologic type/subtype Molecular characterization o Specific mutations, gene rearrangements o Comparative genomic hybridization o Next-generation sequencing Shimizu S. et al. CCR 2000:6:3994; Van Rens MT. et al. Cancer 2002;94:188 Wang X et al..jnci 2009; 101:560; Warth A. et al. Eur Respir J 2012; Arai J.et al. Lung Cancer 2012; Wu et al. JTO 2015 ; Schneider F. et al.mod Pathol Detterbeck FC et al. JTO 2016; 11 (5): REPRODUCIBILITY OF HISTOLOGIC ASSESSMENT IN P STAGING OF MULTIPLE LUNG NODULES GENOMIC PROFILING OF MULTIPLE NSCLC Overall assessment: kappa score 0.60 Most useful features in distinction between multiple primary tumors vs. metastases: main tumor type predominant patterns acinus formation nuclear pleomorphism cell and nucleolar size mitotic rate WCLC 2016 P ; JTO 2016 S593 Independent primaries Metastases Girard N. et al. Clin Cancer Res 2009; 15 (16):

5 INTEGRATION OF CLINICAL, MOLECULAR AND HISTOLOGIC DATA Routine molecular testing for targeted mutations/gene rearrangements and staging of lung carcinomas Martini- Melamed Molecular assessment Histology Girard N. et al. AJSP 2009;33(12): GENETIC ALTERATIONS IN LUNG ADENOCARCINOMA WT ALK KRAS EGFR KRAS EGFR ALK NF1 METexon14 HER2-mut BRAF PI3KCA MET amp AKT MAP2KI ROS1 KIF5B-RET HRAS NRAS CAP/IASLC/AMP 2017 BIOMARKER SELECTION PROPOSAL STRONG RECOMMENDATION o EGFR mutations, ALK rearrangement RECOMMENDATION o ROS1 rearrangement EXPERT CONSENSUS OPINION o BRAF, RET, ERBB2, KRAS, MET WT HIGH CONCORDANCE OF GENOMIC CHANGES BETWEEN MATCHED PRIMARY NSCLC METASTASIS CHROMOSOMAL REARRANGEMENTS BY NGS 3 to 276 breakpoints per tumor identified independent primary tumors based on histology did not share any genomic rearrangements lung primary tumors and paired distant metastases shared rearrangements in all tumor pairs Concordance between histology and genomic data occurred in the majority of samples. Vignot S. et al. JCO 2013; 31 (17): Murphy SJ et al. JCO 2014;32:

6 PATHOLOGIC CRITERIA FOR MULTIPLE LUNG NODULES (8 TH AJCC) SECOND PRIMARY Different histologic type (adeno vs squamous) Different based on comprehensive histologic assessment RELATED TUMORS Exactly matching breakpoints identified by CGH Separate tumors with a similar histologic appearance to a primary lung cancer AND NOT judged to be synchronous primary lung cancers NOT multiple foci of LPA, MIA or AIS N STAGE Squamous carcinoma arisen from CIS RELATIVE ARGUMENTS Different biomarker pattern Absence of nodal or systemic metastases The same biomarker pattern Significant nodal or systemic metastases Matching appearance on comprehensive histologic assessment N STAGE AND SURVIVAL pn1/n2 SINGLE AND MULTIPLE POSITIVE LYMPH NODES 33 Asamura H. et al. JTO 2015 Asamura H. et al. JTO 2015 N STAGE N STAGE Lymph node descriptors Single station N1 Multiple stations N1 Single station N2 without N1 (skip metastasis) Single station N2 with N1 Multiple station N2 Contralateral nodal stations AJCC 8 th edition N1a N1b N2a1 N2a2 N2b N3 we recommend that physicians record the number of metastatic lymph nodes (or stations) and to further classify the N category using new descriptors Asamura H. et al. JTO

7 HOW DO PATHOLOGISTS COUNT LYMPH NODES? One (1) LN Three (3) fragments Four (4) fragments Few fragments Several fragments Multiple fragments No tumor seen 37 If we didn t figure it out... For consistency, nonspecific terms used in pathology reports were standardized: multiple was translated into four lymph nodes, aggregate into three, several into three, few fragments into three, and numerous into five. Concordance between the two reviews was within one lymph node 90% of the time. Chest 2011;139: SUMMARY More emphasis on tumor size- every cm counts Staging of multiple lung tumors include clinical, pathological and molecular data Acknowledgement of lymph node counts Better prognostication groups, but no change in therapy 39 7