Papillary Thyroid Carcinoma TCGA and beyond: Impact on thyroid cancer pre-operative diagnosis, prognostication, and reclassification of encapsulated follicular variant of papillary carcinoma Yuri E. Nikiforov, MD, PhD Has Nothing To Disclose Yuri E. Nikiforov, MD, PhD Division of Molecular & Genomic Pathology University of Pittsburgh Medical Center Precision Medicine Precision Medicine refers to the tailoring of medical treatment to the individual characteristics of each patient and ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease, in the biology and/or prognosis of those diseases, or in their response to a specific treatment. (National Research Council) Endocrine Pathology Society Companion Meeting Impact of Large-Scale Genomic Data on Practicing Endocrine Pathology 1
Thyroid Cancer Precision Medicine for Thyroid Cancer Use of large scale genomic data: Better diagnose cancer in thyroid nodules Better prognosticate thyroid cancer Better recognize and treat aggressive types of thyroid cancer Nikiforov Y & Nikiforova M Nat Rev Endocrinol (2011) Precision Medicine for Thyroid Cancer Better diagnose cancer in thyroid nodules Precision Medicine for Thyroid Cancer Better prognosticate thyroid cancer Nodules by Ultrasound or Autopsy 526,700 thyroid FNA in U.S. in 2011 16% annual growth rate 19.8% of thyroidectomies result in cancer diagnosis?? Sosa, JA et al. Surgery, 2013; 154:L1420-7. Nodules by Palpation Cancer 2
Genetic Basis of Thyroid Cancer Major pathways involved: MAPK, PI3K Main mutation mechanisms: Point mutations and chr. rearrangements 496 PTC 69.4% classical type 21.2% follicular variant 7.5% tall cell var. 2% rare variants Density of Somatic Mutations in Thyroid PTC Density of Somatic Mutation in PTC and Other Cancer Types Average frequency: 0.41 nonsynonymous mutations /Mb Correlates with risk of recurrence and MACIS score Increases with age Lawrence MS et al. Nature. 2013 Jul 11; 499(7457): 214 218 3
Genomic Landscape of PTC Genomic Landscape of PTC Point mutations Point mutations 74% Gene fusions 15% BRAF RAS EIF1AX Copy number variations 9% Genomic Landscape of PTC TERT mutations Genomic Landscape of PTC Gene fusions TERT mutations: 9.4% of PTC Strong association with: older age MACIS score high risk of recurrence BRAF fusions RET fusions 4
Driver mutations define carcinogenic mechanisms BRAFV600E-like and RAS-like scores Thyroid Differentiation Status in PTC Unsupervised mirna Clusters in PTC Summary of TCGA Data Mutation frequency of PTC is very low Distinct driver mutations are found in most tumors (90 98%) Tumor morphology/variants overall correlates with genotype BRAF V600E like and RAS like PTC, additional clusters, broad variation in differentiation and other molecular characteristics and outcomes Prognostic indicators (high mutation rate, TERT) 5
The Bethesda System for Reporting Thyroid Cytopathology Diagnostic impact of TCGA and other genomic data Diagnostic Category Risk Usual of cancer management I. Nondiagnostic or Unsatisfactory 1 4% Repat FNA with US II. Benign 0 3% Clinical follow up III. Atypia of Undetermined Significance 5 15% Repeat FNA or Follicular Lesion of Undetermined Significance (AUS/FLUS) IV. Follicular Neoplasm or Suspicious 15 30% Surgical lobectomy for a Follicular Neoplasm (FN/SFN) V. Suspicious for malignancy 60 75% Total or lobectomy VI.Malignant 97 99% Total thyroidectomy Baloch ZW et al. Diagn Cytopathol 2008;36:425 Cibas ES & Ali SZ. Am J Clin Pathol 2009;132:658 Expansion of Diagnostic Mutational Panels for Thyroid FNA Samples Single gene tests Conventional sequencing Small gene panels Conventional sequencing BRAF V600E ~35% 50-65% Large gene panels NGS ~90% 143 consecutive patients with Bethesda IV cytology and known surgical outcome at UPMC Retrospective and prospective groups Test performance: Sensitivity 90% (CI: 80-99%) Specificity 93% (CI: 88-98%) NPV 96% (CI: 92-95%) PPV 83% (CI: 72-95%) Accuracy 92% (CI: 88-97%) Cancer prevalence after surgery 39/143 (27.3%) Cancer 2014, 120:3627-34 6
Clinical Utility of ThyroSeq FNA Cytology FLUS (BC III) FN/SFN (BC IV) SUSP (BC V) Cancer Risk 10 15% 20 30% 50 70% ThyroSeq v2 + + + Sensitivity 91% (CI: 78-100%) Specificity 92% (CI: 86-98%) NPV 97% (CI: 93-100%) PPV 77% (CI: 61-93%) Accuracy 92% (CI: 86-97%) Modified Cancer Risk 3% 75 99%* Recommended Management Observation Therapeutic Surgery 4% 75 99%* Observation Therapeutic Surgery 20% 90 99%* Lobectomy Therapeutic Surgery Thyroid 2015;25:1217-23 *Depending on the type of mutation Nikiforov et al. Cancer 2014, 120:3627-34 Nikiforov et al. Thyroid 2015 Sep 10. [Epub ahead of print] Data on file; UPMC MGP lab Prognostic impact of TCGA and other genomic data Yip et al. Ann Surg 262:519 25 (2015) USA, SEER data Mean follow up 33 ± 21.2 months 7
Tumor Prognostication Aggressive Tumors Have Multiple Mutations Thyroid Cancer Prognostication Aggressive Tumors Have TERT Mutations 469 patients with FCDTC Mean follow up 7.8±5.8 years Ricarte-Filho JC et al. Cancer Res (2009) n=57 BRAF NRAS HRAS KRAS PIK3CA TSHR TP53 Papillary Carcinomas 0 20 40 Nikiforova M et al. JCEM (2013) Cum Survival Univariate analysis FCDTC Papillary Carcinoma Follicular Carcinoma TERT wt TERT wt TERT wt TERT mut Multivariate analysis TERT mut Univariate analysis TERT mut Multivariate analysis Presence (%) OR (95%CI) P value OR (95%CI) P value Presence (%) OR (95% CI) P value OR (95%CI) P value TERT wt 34 (12.5) 1 <0.001 1 0.002 48 (24.6) 1 0.001 1 0.007 TERT mut 10 (43.5) 5.36 (2.18 13.18) 4.60 (1.73 12.21) 10 (62.5) 5.10 (1.76 14.78) 4.68 (1.54 14.27) Follow up (years) Melo M et al. JCEM (2014) Thyroid Cancer Prognostication Aggressive Tumors Have TERT Mutations Potential cancer risk stratification based on molecular profiling Risk of Recurrence Molecular Signature PTC (all types) PTC (conventional type) High Risk BRAF + TERT Multiple driver mutations (eg. BRAF and PIK3CA) TP53 TERT BRAF+TERT BRAF+TERT Intermediate Risk BRAF V600E ALK fusions NTRK1 fusions NTRK3 fusions RET/PTC Xing M. et al. JCO (2014) Low Risk RAS PAX8/PPARG BRAF K601E 8
Follicular Variant of PTC Infiltrative vs. Encapsulated Change in nomenclature of highly indolent forms of thyroid cancer Follicular variant PTC: Follicular growth pattern <1% papillae Nuclear features of PTC 2 main histologic types: Infiltrative Encapsulated With no invasion With capsular or vascular invasion Infiltrative FV PTC Encapsulated FV PTC Diagnosis of EFVPTC: High inter-observer variability Hirokawa M. et al. AJSP, 2002, 26; 1508 8 pathologists (4 Japanese; 4 American) 21 encapsulated lesions with follicular growth pattern 10% cases had full agreement; 62% agreement on benign or malignant Lloyd RV et al. AJSP, 2004, 28, 1336 10 pathologists 87 tumors with 8.4% years mean follow up; 24% metastatic 39% cases had full diagnostic agreement; 67% for metastatic cases No significant morphologic difference between invasive and non invasive ca Elsheikh TM et al. AJCP, 2008, 130, 736 6 pathologists 15 tumors suspected FVPTC 27% full agreement; 40% majority agreed EFVPTC: Follow-up data Ref. Baloch & LiVolsi Mod Pathol 2000 Liu J. et al. Cancer 2006 Vivero M. et al. Thyroid 2013 Followup Widder S et al. Surgery 2008 Mean, 8.75 y Piana S. et al. AJSP Mean, 2010 11.9 y Type and number of FV PTC cases Encapsulated n=5 Invasion L/n Recurrence/ distant mts 1 capsular invasion 3 vascular invasion All 5 bone metastases Median, no invasion (n=43) 0 0 11.1 y Encapsulated n=61 Invasion (n=18) 3 (17%) 1/18 (6%) Infiltrative (n=17) 11 (65%) Median, 9.25 y Encapsulated n=27 PE/WC n=35 Infiltrative n=9 Encapsulated n=26 Encapsulated n=66 No invasion (n=14) 0 0 Invasion (n=13) 0 0 No invasion 0 1*/30 (*pos. res. margin) 7 (78%) No invasion (n=26) 0 0 Invasion n=45 Many patients with EFV of PTC receive completion of thyroidectomy, RAI 9
Mutational Profiles of Various Types of Thyroid Cancer The Endocrine Pathology Society Conference for Re-examination of the Encapsulated Follicular Variant of Papillary Thyroid Cancer cptc EFVPTC FTC PDTC ATC FA POINT MUTATIONS BRAF V600E +++ + + BRAF K601E +++ + + NRAS +++ ++ + + ++ HRAS ++ + + KRAS + ++ + ++ PTEN + ++ TSHR + ++ GNAS ++ GENE FUSIONS RET/PTC +++ PAX8/PPARG ++ +++ ALK fusions + ++ ++ NTRK1/3 fusions ++ TCGA study: most FVPTC in RAS like group Boston, MA, March 20-21, 2015 (from left to right) R. Ghossein, A. El Naggar, R. Lloyd, E. Khanafshar, M. Papotti, M. Nikiforova, L. Thompson, G. Randolph, A. Al Ghuzlan, F. Basolo, A. Tischler Y. Nikiforov, S. Asa, S. Hodak, T. Giordano, K. Kakudo, K. Wall, V. Nosé, V. LiVolsi, G. Maytal, B. Wenig, V. Alves, G. Tallini, O. Mete, J. Barletta, Z. Baloch, P. Sadow, R. Seethala, D. Poller Not Pictured: W. Gooding, M. Tuttle Diagnostic criteria for EFVPTC Encapsulation or clear demarcation Follicular growth pattern with: <1% papillae No psammoma bodies <30% solid/trabecular/insular Nuclear features of PTC 1. Enlargement, crowding/overlapping 2. Elongation 3. Irregular contours 4. Grooves 5. Pseudoinclusions 6. Chromatin clearing 1 4 5 2 6 3 Summary of Follow up Information on Patients with EFVPTC Group 1 (non invasive EFVPTC) Group 2 (invasive EFVPTC) N of cases with consensus (initiallysubm) 109 (138) 101 (130) Age 45.9 years 42.8 years Gender (Female:Male) 5:1 2.4:1 Tumor size, mean (range) 3.1 cm (1.1 9.0 cm) 2.5 cm (0.6 5.5 cm) Extent of surgery Lobectomy 67 Total thyroidectomy 42 Follow up: range 10 26 years 1 18 years mean 14.4 years 5.6 years median 13.0 years 3.5 years Adverse events during follow up 0 12 (12%) Lobectomy 15 Total thyroidectomy 86 10
Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors JAMA Oncology (In press) A distinct class of thyroid tumors: Clonal process driven by distinct oncogenic mutations RAS and RAS like gene mutations Non invasive, follicular patterned, moderately to well developed nuclear features of PTC (nuclear score 2 3) Highly favorable outcome (<1% risk of recurrence in 15 y) Recommended new terminology: Non Invasive Follicular Thyroid neoplasm with Papillary like nuclear features (NIFTP) Recommended patient management: No immediate completion thyroidectomy and RAI therapy Summary Papillary Thyroid Carcinoma TCGA and beyond Impact of large scale genomic data: More accurate cancer diagnosis in thyroid nodules avoid unneeded surgeries Better prognostication of thyroid cancer and prediction of therapeutic response to RAI prevent overtreatment Support reclassification of indolent forms of PTC NIFTP Thanks for your attention! Pittsburgh, PA, USA 11