04/09/2018. Follicular Thyroid Tumors Updates in Classification & Practical Tips. Dissecting Indeterminants. In pursuit of the low grade malignancy

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1 Follicular Thyroid Tumors Updates in Classification & Practical Tips Jennifer L. Hunt, MD, MEd Aubrey J. Hough Jr, MD, Endowed Professor of Pathology Chair of Pathology and Laboratory Medicine University of Arkansas for Medical Sciences 1 Dissecting Indeterminants Indeterminates : Benign vs. Malignant Follicular variant of PTC Follicular carcinoma Molecular testing In pursuit of the low grade malignancy 2 1

2 Benign Indeterminant Malignant Case 1 37 year old male with a thyroid mass Fine needle aspiration Follicular lesion Molecular testing done on FNA RAS mutation 5 2

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4 Case 1 Diagnosis: Follicular variant of papillary carcinoma 10 Follicular Variant of Papillary Chen KTK, Rosai J. Follicular variant of thyroid papillary carcinoma: A clinicopathologic study of six cases. American Journal of Surgical Pathology, 1(2):123, Juan Rosai 11 Follicular Variant Histology: Definition Pure follicular architecture Papillary carcinoma nuclei Growth Pattern Invasive and infiltrative Encapsulated 12 4

5 Invasive follicular variant PTC Conventional papillary carcinoma Old Challenge Is this follicular variant or is this follicular adenoma? 15 5

6 Immunohistochemistry Stains might be useful, when. Nuclear features are incomplete Nuclear features are only patchy Stains are not diagnostic, they are only supportive 16 Immunohistochemistry FA FVPTC HBME-1 Galectin CK19 Nakamura et al, Endo Path, 17:213, Incomplete and patchy nuclear features 6

7 CK19 HBME 19 New Challenge Is this follicular variant or is this noninvasive follicular tumor with papillary like nuclear features (NIFT-P)? Second new challenge: Can you remember what NIFT-P stands for? 20 NIFT-P: Inclusion Criteria A complete capsule or clear demarcation of tumor from adjacent thyroid A pure follicular growth pattern Nuclear features of papillary carcinoma Not defined Tumors < 1 cm Multifocal tumors 21 7

8 NIFT-P: Exclusion Criteria No papillary architecture (change) No psammoma bodies No capsular or vascular invasion Mitotic activity >3 per 10 HPF No tumor necrosis No vascular or capsular invasion No more than 30% solid, trabecular, insular growth BRAF gene: negative for mutation (change) 22 Implications of NIFT-P A very low risk of adverse outcome when the tumor is non-invasive Based on original study of 109 cases But, not everyone agrees In a study of 102 NIFT-P (very strict criteria), 6% had adverse outcome Parente, World J Surg, 2018, 42: Using NIFT-P in Practice Adhere to absolutely strict criteria Entire capsule must be embedded There can be no hint of invasion There can be no true papillary growth Mitoses and atypia should be minimal There can be no high grade features 24 8

9 Implications of NIFT-P How does this diagnosis affect the Bethesda system for FNA diagnosis? Malignancy rate will change Category Pre-NIFT-P malignancy rate Benign 5.5% 2.5% AUS/FLUS 42.3% 22.3% Follicular neoplasm 48.7% 17.9% Suspicious 93.6% 61.7% Malignant 100% 97% Based on 750 thyroid FNAs with surgical follow-up Post-NIFT-P malignancy rate Lau, Am J clin Pathol, (1): Issues with NIFT-P What will happen with retrospective review? Reclassification? New treatment recommendations? Legal implications? 26 NIFT-P in my Practice Occasionally for lesions I used to call adenomas After struggling with mild nuclear atypia) Rarely for something I would have called follicular variant of papillary carcinoma After applying strict criteria Change in terminology is not a substitute for meaningful patient education and multidisciplinary discussion to highlight the low-risk nature of these cancers. Parente, World J Surg. 27 9

10 Case 2 54 year old male with 5 cm thyroid mass Fine needle aspiration Follicular lesion 28 10

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12 Dissecting Indeterminate Thyroid nodule management Indeterminate : Benign vs. Malignant Follicular variant of PTC Follicular carcinoma Molecular testing In pursuit of the low grade malignancy 35 Thin capsule Intermediate capsule 36 Thick capsule 12

13 Follicular carcinoma, NOS Minimally Invasive Widely Invasive Minimally Invasive Encapsulated Angio-invasive Mortality in Follicular Tumors Capsular invasion Vascular invasion Widely invasive Measured Van Heerden (1992) D Avanzo (2004) 0% 28% N/A Disease specific mortality 2% 20% 62% 5-year mortality Van Heerden, Surgery 112:1130, 1992 D Avanzo, Cancer 100:1123, WHO Classification Traditional AFIP 2014 WHO 2017 Minimally invasive Minimally invasive With capsular invasion Minimally invasive With limited vascular invasion (<4 foci) Encapsulated With extensive angio-invasive vascular invasion (>4 foci) Widely invasive Widely invasive Widely invasive 39 13

14 Follicular carcinoma Minimally Invasive, encapsulated By definition: Capsular invasion alone What is capsular invasion? Invasion through the capsule (into the surrounding thyroid parenchyma) Often has a mushroom type appearance Not associated with an FNA track 40 Not Capsular Invasion 42 14

15 Capsular Invasion Capsular Invasion Capsular Invasion 15

16 Diagnostic Clues: FNA track Diagnostic Clues: FNA track Follicular carcinoma Angio-invasive, encapsulated By definition: Vascular invasion What is vascular invasion Tumor in medium to large sized vessels Reaction around tumor thrombus Endothelialization or fibrin deposition Fibrin deposition At or beyond level of tumor capsule 48 16

17 Not Vascular Invasion Vascular Invasion Vascular Invasion Vascular Invasion 51 17

18 Vascular Invasion Vascular Invasion Diagnostic Clues: Capsular Vessel Right angle turns 18

19 Diagnostic Clues: Vascular Invasion Tumor with right angle turns Diagnostic Clues: Vascular Invasion Tumor with right angle turns Diagnostic Clues: Vascular Invasion 57 19

20 Follicular carcinoma Widely invasive Extensive invasion throughout the thyroid Invasion into perithyroidal soft tissues Often with extensive vascular invasion Important: Differentiate from poorly differentiated thyroid carcinoma 58 Widely invasive carcinoma 60 20

21 Widely invasive carcinoma 61 Dissecting Indeterminates Thyroid nodule management Indeterminates : Benign vs. Malignant Follicular variant of PTC Follicular carcinoma Molecular testing In pursuit of the low grade malignancy 62 Using Molecular in Practice Identifying malignancy pre-operatively (on FNA) Diagnosing difficult tumors FA vs. FVPTC FVPTC vs. NIFT-P Variants or challenging cases Prognostic setting 63 21

22 Molecular Mutations in Thyroid Cancer Papillary carcinoma BRAF gene mutations RET/PTC translocations RAS mutations Follicular carcinomas RAS mutations PPARγ/PAX8 translocations 64 BRAF Gene Mutations Oncogene Activating mutation in exon 15 Thyroid cancer T1799A (Nucleotide: T > A) V600E (Codon: Valine > glutamate) Also seen in other tumors Colon cancer (nonhereditary MSI cancers) Melanomas 65 BRAF Mutations in Thyroid Lesions 66 22

23 Translocations RET/PTC Translocations Up to 15 different partner genes ELE1 and H4 most common More common in radiation papillary carcinoma Difficult to detect (intra-chromosomal rearrangement) PAX8-PPARγ Translocation Relatively specific to follicular carcinoma 67 Using Molecular Diagnostically 70% 60% 50% 40% 30% 20% 10% 0% Conventional Invasive FV Encapsulated FV FA/FCC Metastases BRAF RET/PTC RAS PPAR/PAX8 68 Rivera M, Mod Path; 23:1191, 2012 Reported Molecular Profiles Category Name RAS BRAF RET/ PTC PAX8/ PPAR Conventional Papillary Ca 10-20% 50-75% ~30% 0 Follicular carcinoma ~30-50% 0 0 ~30-35% Follicular Adenoma ~30% 0 0 ~5-10% Follicular Variant PTC ~25% ~5% ~5% ~35% 69 23

24 Molecular Mutations in PTC 70 BRAF Mutation and Sensitivity % 80.00% 60.00% 40.00% FNA (s) FNA+BRAF (s) 20.00% 0.00% Marchetti Zatelli Kim SW Pellizzo 71 Commercial Assays Gene expression array testing Mutation panel approach 72 24

25 Expression Array Assay Proprietary assay: 142 gene expression markers are not published Most published studies are industry sponsored Performance characteristics are difficult to assess 73 Panel Based Testing Commercial assay Laboratory Developed Tests can also be obtained 74 The Real Question Will the results of the molecular test change the treatment algorithm? Will some patients be spared unnecessary surgery? Will some patients be given more extensive (appropriate) surgery? Will there be overall cost savings? 75 25

26 <1% risk 5-10% risk 20-30% risk 50-75% risk <1% risk 5-10% risk 20-30% risk 50-75% risk Thyroid Fine Needle Aspiration Benign Molecular Result Suspicious Molecular Result 7% risk 47% risk Summary Indeterminate : Benign vs. Malignant Follicular variant of PTC Follicular carcinoma Molecular testing In pursuit of the low grade malignancy 78 26