The New Diagnostic Paradigms in Thyroid Surgical Pathology and Affects on Reporting of Thyroid Fine Needle Aspiration Specimens Deliberations, Criticisms & Discussions Zubair W. Baloch, MD, PhD. Professor of Pathology & Laboratory Medicine University of Pennsylvania Medical Center Perelman School of Medicine Philadelphia, PA, USA Let s Make Sense of Present & Predict Future In Light of Past 1
A Quick Look Back at 2007 The Birth of Bethesda System of Reporting Thyroid FNA 2
Proposals, Recommendations & Accomplishments Proposed Tiered Classification Scheme Spanning the spectrum of benign to malignant diagnoses Inclusive of Gray Zone in both cytologic and surgical pathology diagnoses Implied risk of malignancy based on available literature review A thoughtful process to recommendations inclusive of everyday practice of cytopathology and thyroid nodule management (courtesy of clinical colleagues) Thyroid FNA Bethesda Classification Scheme The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC): Implied Risk of Malignancy and Recommended Clinical Management Diagnostic Category Risk of Malignancy (%) Usual Management Non-diagnostic or Unsatisfactory Repeat FNA with ultrasound guidance Benign 0-3% Clinical follow-up Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance (AUS/FLUS) ~ 5-15% Repeat FNA Follicular Neoplasm or Suspicious for a Follicular Neoplasm (Specify if Hurthle type or Oncocytic) 15-30% Surgical lobectomy Suspicious for Malignancy 60-75% Near-total thyroidectomy or surgical lobectomy Malignant 97-99% Near-total thyroidectomy 3
The Timing of TBSRTC Growing Body of Literature Showing Inconsistencies in Surgical Pathology Diagnosis of Thyroid Cancer Among Experts Encapsulated Follicular Variant of PTC The Cytology Gold Standard is not so Gold TBSRTC 4
Case 1 Thyroid Experts Diagnoses The Cytopathologists Gold Standard LiVolsi Rosai Asa Lloyd Diagnoses: Hyperplastic nodule Benign or Follicular Adenoma Benign or Follicular Variant of Papillary Thyroid Carcinoma Malignant Follicular patterned lesions Controversial Thyroid Lesions Am I Satisfied with this Statement of Controversy? Regarding one of the Most Common Thyroid Lesion Seen in My Practice 5
Follow up Clinicopathologic Studies Showing Over diagnosis and Over treatment of Thyroid Carcinoma PTC. Concept of Low and High Risk Disease TBSRTC TBSRTC Clinical and Radiology Guidelines American & European Thyroid Association American College of Radiology American Society of Radiologist in Ultrasound 6
TBSRTC Molecular Profiling of Thyroid Tumors + Molecular Diagnosis of Thyroid Nodules Diagnostic Tests with High Negative and Positive Predictive Value Mutational Analysis Gene Expression Classifier Next Gene Sequencing Growing Body of Literature Showing Inconsistencies in Surgical Pathology Diagnosis of Thyroid Cancer Among Experts Encapsulated Follicular Variant The Cytology Gold Standard is not so Gold Follow up Clinicopathologic Studies Showing Over diagnosis and Overtreatment of Thyroid Carcinoma PTC. Concept of Low and High Risk Disease TBSRTC Clinical and Radiology Guidelines American & European Thyroid Association American College of Radiology American Society of Radiologist in Ultrasound Molecular Profiling of Thyroid Tumors Molecular Diagnosis of Thyroid Nodules Diagnostic Tests with high Negative and Positive Predictive Value 7
TBSRTC The Aftermath Literature Influx since 12/2007 PUBMED 1635 publications mentioning TBSRTC in title and abstract content English Literature >20% focused on AUS/FLUS Category 8
The Malignancy rate of AUS/FLUS is Not Different from Suspicious/Consistent with Follicular Neoplasm Get rid of AUS/FLUS Lets Pace ourselves Most reported studies from tertiary referral centers with different malignancy rates What is being classified as AUS/FLUS? High rate of downgraded or upgraded diagnosis Malignancy rate differ between cases with first time diagnosis to surgery vs. repeat FNA with AUS/FLUS to surgery Are we overestimating the risk of malignancy 9
Brandon S. Sheffield et.al. Expert Rev. Endocrinol. Metab. 9(2), 97 110 (2014) Preoperative diagnosis of thyroid nodules using the Bethesda System for Reporting Thyroid Cytopathology: a comprehensive review and meta analysis. Total Cases Surgical Excision Malignant ROM AUS/FLUS 1906 805 194 24.10% FON/SFON/SHCN 3182 2183 660 30.23% Are We Overestimating the # of Malignant Cases by Calculating the Risk of Malignancy Based on Selected Group of Cases Undergoing Surgery? Brandon S. Sheffield et.al. Expert Rev. Endocrinol. Metab. 9(2), 97 110 (2014) Preoperative diagnosis of thyroid nodules using the Bethesda System for Reporting Thyroid Cytopathology: a comprehensive review and meta analysis. Can we Calculate Overall Risk of Malignancy (OROM)? Total Cases Surgical Excision Malignant ROM OROM AUS/FLUS 1906 805 194 24.10% 10% FON/SFON/SHCN 3182 2183 660 30.23% 21% 10
Reality Check There is More to How Thyroid Nodules are Managed Then Just Cytologic Diagnosis Thyroid Nodule Management Paradigms Aka Personalized Approach Clinical Presentation + Ultrasound + FNA Diagnosis + Molecular Testing 11
Molecular Tests vs. Clinical Application & Practice Increase rate of Suspicious GEC Afirma Results in Oncocytic Nodules Suspicious nodules w surgery Benign Malignant Harell et al. Endo Pract 2014 30 13 (43%) 9 (69%) oncocytic lesions McIver et al. JCEM 2014 32 27 (84%) 12 (44%) oncocytic lesions 17 (57%) 5 (16%) Brauner et al. Thyroid 2015 43* 37 (84%) 6(14%) Lastra et al. Cancer Cytopath 2014 48 26 (54%) 15 (58%) oncocytic lesions 22(46%) Total 153 103 (67%) 73 (71%) oncocytic lesions 50 (33%) 12
Next Generation Sequencing Assay Nikiforov et al. Cancer 2014,120:3627 34 Changes in Surgical Pathology Diagnosis / Classification of Low Risk Tumor(s) 13
The Endocrine Society Working Group for Re evaluation of the Encapsulated Follicular Variant of Papillary Thyroid Carcinoma Project Goals Review a cohort of cases by experts in the field of endocrine pathology Establish a consensus on diagnostic histologic criteria Define the risk of adverse events based on long follow up Recommend new terminology that reflects tumor biology and patient outcome Naming Non Invasive Follicular Variant of PTC as anything but Not Carcinoma New Terminology Recommendation Non invasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP) *Adequate sampling of entire tumor capsule is required to establish this diagnosis Molecular profile RAS and RAS like mutations Non invasive FVPTC Negligible risk of recurrence Invasive EFVPTC Increased risk of distant metastases 14
TCGA. Integrated genomic characterization of papillary thyroid carcinoma Cell : 2014 Integrated Genomic Characterization of Papillary Thyroid Carcinoma. Cell (2014) Classic PTC Encapsulated FVPTC Foll Thyr CA Poorly Diff Thy CA Anapl Thyr CA Foll Adenoma MUTATIONS BRAF V600E +++ + + BRAF K601E +++ + + NRAS +++ ++ + + ++ HRAS ++ + + KRAS + ++ + ++ PTEN + ++ TSHR + ++ GNAS ++ GENE FUSIONS RET/PTC +++ PAX8/PPARG ++ +++ ALK fusions + ++ ++ BRAF fusions + ETV6/NTRK3 ++ NTRK1 fusion ++ 15
New Terminology Recommendation Non invasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP) *Adequate sampling of entire tumor capsule is required to establish this diagnosis Changes in the Implied Risk of Malignancy for TBSRTC Categories AUS/FLUS Suspicious for Follicular Neoplasm Suspicious for Malignancy 50% decrease (Strickland et al. Thyroid 2015 & Faquin et al. Cancer Cytopathology 2015) Institutional Data Showing TBSRTC Diagnostic Categories, Surgical Follow-Up, Risk Of Malignancy With and Without Cases of Non-Invasive Follicular Variant of Papillary Thyroid Carcinoma (NI-FVPTC) Faquin et al. Cancer Cytopathology 2015 Institution A Institution B* Institution C Institution D Institution E TBSRTC Diagnoses ND 37 79 51 225 14 Benign 190 1015 1112 1773 131 AUS/FLUS 115 190 480 235 8 FN/SFN 80 154 125 98 6 SM 34 38 108 31 27 Malignant 26 91 300 158 12 Surgical FU Benign Surgical FU 103 183 393 238 32 Malignant Surgical FU 69 176 428 189 15 No Surgery 310 1207 1355 2093 151 Total NI FVPTC 33 66 38 34 2 Risk of Malignancy for all TBSRTC Categories ROM 40.12% 48.89% 52.13% 44.26% 31.91% OROM 14.32% 11.23% 19.67% 7.50% 7.58% ROM excluding NI FVPTC Cases 20.93% 30.56% 47.50% 36.30% 27.66% OROM excluding NI FVPTC Cases 7.47% 7.02% 17.92% 6.15% 6.57% % Decrease in Risk of Malignancyfor all TBSRTC Categories ROM excluding NI FVPTC Cases 19.19% 18.33% 4.63% 7.96% 4.26% OROM excluding NI FVPTC Cases 6.85% 4.21% 1.75% 1.35% 1.01% 16
Combined Institutional Data Showing TBSRTC Diagnostic Categories, Surgical Follow-Up, Risk Of Malignancy With and Without Cases of Non-Invasive Follicular Variant of Papillary Thyroid Carcinoma (NI-FVPTC) TBSRTC Diagnostic Categories ND Benign AUS/FLUS FN/SFN SM Malignant Total number of FNABs, n=6943 406 (5.8%) 4221 (60.8%) 1028 (14.8%) 463 (6.6%) 238 (3.4%) 587 (8.4%) Surgical FU Benign Surgical FU, n=949 52 386 273 203 31 4 Malignant Surgical FU, n=877 18 40 124 101 148 446 Total PTC, n=756 Total NI FVPTC, n=173 1 15 54 46 42 15 Risk of Malignancy ROM 25.3% 9.3% 31.2% 33.2% 82.6% 99.1% OROM 4.4% 0.9% 12.0% 21.8% 62.1% 75.9% ROM excluding NI FVPTC Cases 23.9% 5.8% 17.6% 18.0% 59.2% 95.7% **p value 0.19 0.04 0.03 0.03 0.01 0.1 OROM excluding NI FVPTC Cases 4.1% 0.5% 6.8% 11.8% 44.5% 73.4% **p Value 0.18 0.05 0.02 0.04 0.02 0.1 % Decrease in Risk of Malignancy ROM excluding NI FVPTC Cases 1.4% 3.5% 13.6% 15.1% 23.4% 3.3% OROM excluding NI FVPTC Cases 0.2% 0.3% 5.2% 9.9% 17.6% 2.5% Cytologic Features and Molecular Alterations in a Cohort of 39 NFVPTCs and cptcs. Brooke E. Howitt et al. Am J Clin Pathol 2015;144:850-857 Copyright by the American Society for Clinical Pathology 17
Thyroid nodules are Common 2012 450,000 FNAs estimated in USA Palpation Autopsy & US Ann Intern Med 1968 69:537; N Engl J Med 1993 328:553 18
The Data from future thyroid FNA studies based on changes in surgical pathology diagnoses will be important for recommending potential changes in TBSRTC The Adjunct Molecular tests are here to stay Never going to replace thyroid FNA cytology Play a role in the current management paradigm of thyroid nodules What I Struggle with? How to avoid loosing thyroid FNA specimens? Good relationship with the clinicians History Results discussion All matters Good relationship with radiologist and knowledge of ultrasound Empowering the workforce of cytopathology 19