9/6/2016 DISCLOSURES. None to disclose. The Present WHERE WE ARE NOW?

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1 9/6/2016 SESSION #3000 CHANGING PARADIGMS IN THE DIAGNOSIS OF ENCAPSULATED FOLLICULAR VARIANT OF PAPILLARY THYROID CARCINOMA DELIBERATIONS, DISCUSSIONS AND CONTROVERSIES. Virginia A. LiVolsi, Raja R. Seethala & Zubair W. Baloch. DISCLOSURES None to disclose WHERE WE ARE NOW? The Present 1

2 9/6/2016 Fig. 1 Thyroid Nodule Management Paradigm Otolaryngologic Clinics of North America , DOI: ( /j.otc ) - Selection of Thyroid Nodules for Sampling US Features Maximal Diameter, cm FNA Requested % Respondents Meets 2015 ATA Criteria for FNA Hypoechoic with microcalcifications No Solid, isoechoic No Complex cystic No Solid, hypoechoic Yes Spongiform No Pure cyst No Thyroid FNA Bethesda Classification Scheme The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC): Implied Risk of Malignancy and Recommended Clinical Management Diagnostic Category Non-diagnostic or Unsatisfactory Risk of Malignancy (%) Usual Management 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 2

3 9/6/2016 Monotonous cells, Microfollicles, Nuclear overlapping & Crowding Colloid Watery Susp Malig Malignant Nuclear Atypia Benign AUS/FLUS Foll Neop Susp Malig Malignant Follicular Cells Colloid Watery Nuclear Atypia Benign AUS/FLUS Foll Neop Susp Malig Malignant Follicular Cells Management of patients found to have an indeterminate or malignant result on initial FNA Published in: Henry B. Burch; Kenneth D. Burman; David S. Cooper; James V. Hennessey; Nicole O. Vietor; The Journal of Clinical Endocrinology & Metabolism 2016, 101,

4 9/6/2016 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 Encapsulated / Well Demarcated Follicular Patterned Lesions Follicular Adenoma Non Invasive NIFTP Well Demarcated Solid and cystic Usually mixed follicular growth pattern Isolated papillae comprising <1% of tumor mass Nuclear Features of PTC Absent Nuclear Features of PTC Present Follicular Carcinoma Invasive (Tumor Capsule & Vascular Invasion) FVPTC Invasive (Tumor Capsule & Vascular Invasion) POTENTIAL Ethical issues ISSUES & WITH Legal NIFTP implications DIAGNOSIS Should we reclassify cases diagnosed in the past as Encapsulated FVPTC to NIFTP? NO Standard of care Past vs. Present 4

5 9/6/2016 Potential Issues with NIFTP Diagnosis Cytopathology Diagnosis Based on Nuclear Morphology Increase in the number of False Positive diagnosis? 1. NIFTP is a Surgical Disease 2. Diagnosis based upon application of strict diagnostic criteria **Noninvasive nature has to be documented based on adequate sampling of tumor periphery and capsule Potential Issues with NIFTP Diagnosis Cytopathology Diagnosis Increase in the number of False Positive diagnosis? Too early to tell Most Encapsulated FVPTC are Classified as: Follicular Neoplasm / Suspicious for Follicular Neoplasm Or Suspicious for Papillary Carcinoma Cytology Dx: Suspicious for PTC, Surg Path NIFTP 5

6 9/6/2016 Cytology Dx: Follicular Neoplasm, Gene Expression Classifier Suspicious, Surg Path NIFTP 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 Benign AUS/FLUS FN/SFN SM Malignant Surgical FU Benign Surgical FU Malignant Surgical FU No Surgery Total NI FVPTC Risk of Malignancy for all TBSRTC Categories ROM OROM 40.12% 48.89% 52.13% 44.26% 31.91% 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 18.33% 4.63% 7.96% ROM excluding NI FVPTC Cases 19.19% 4.26% OROM excluding NI FVPTC Cases 6.85% 4.21% 1.75% 1.35% 1.01% 6

7 9/6/2016 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= (5.8%) 4221 (60.8%) 1028 (14.8%) 463 (6.6%) 238 (3.4%) 587 (8.4%) Surgical FU Benign Surgical FU, n= Malignant Surgical FU, n= Total PTC, n=756 Total NI FVPTC, n= 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 OROM excluding NI FVPTC Cases 4.1% 0.5% 6.8% 11.8% 44.5% 73.4% **p Value % 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: Copyright by the American Society for Clinical Pathology Maletta, F. et.al. Cytological features of non invasive follicular thyroid neoplasm withpapillary like nuclear features and their correlation with tumor histology. Hum Pathol

8 9/6/2016 Thyroid Nodule Management Paradigms Aka Personalized Approach Clinical Presentation + Ultrasound + FNA Diagnosis + Molecular Testing MOLECULAR TESTS vs. Clinical Application & Practice Sensitivity and specificity are characteristics of the test. The population does not affect the results. The relevant questions for the clinician and patient What is the chance that a person with a positive test truly has the disease? What is the chance that a person with a negative test result is disease free? Positive and negative predictive values are influenced by the prevalence of disease in the population being tested. 8

9 9/6/2016 Test: 90% sensitivity and 90% specificity Example 1: 20% of population has cancer PPV TP/all positive results= 18/26 = 69% NPV TN/all negative results=72/74 = 97% Example 2: 70% of population has cancer PPV TP/all positive results= 63/66 = 95% NPV TN/all negative results= 27/34 = 79% NPV Decreases as Cancer Prevalence Rises TEST A Sens 90% Spec 50% 100 TEST B Sens 60% Spec 95% NPV (%) Prevalence of Cancer (%) NPV & PPV for Afirma GEC for FLUS, FN based upon N Engl J Med :206 NPV NPV 94% 38% PPV Prevalence of malignancy NEJM paper PPV 9

10 9/6/2016 Afirma and NIFTP Follow up Study Suspicious by Afirma Nodules wsurgery Benign Malignant (NIFTP) Wong et al (Thyroid 2016) 63 41(65%) 22(35%) (14 cases 88%) Samulski et al (Diag Cytopath 2016) (65%) 45(35%) (11 cases 24%) Integrated Genomic Characterization of Papillary Thyroid Carcinoma. Cell (2014) Classic PTC Encapsulated FVPTC Foll Thyr CA Poorly Diff Thy Anapl Thyr CA Foll CA 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 ++ NexGen additions Using NexGen sequencing UPMC developed custom panel ThyroSeq ver2 TM Point mutations in 14 genes (BRAF, NRAS, KRAS, HRAS, AKT1, PTEN, TP53, TSHR, GNAS, CTNNB1, RET, PIK3CA, TERT, EIF1AX) 38 gene fusions (RET, PPAR, NTRK1, NTRK3k, ALK, THADA,BRAF) Therefore >60 genetic markers Nikiforov Cancer 2014;120:3627; Nikiforov Thyroid epub Sept

11 9/6/2016 THE FUTURE Conclusions Still Need More Data to Provide Opinions CONCLUSIONS? NIFTP Beneficial to patients Stricter set of exclusion criteria Grossing of encapsulated or well demarcated nodule Initial pathologic approach to diagnose and manage low-risk thyroid neoplasms. WHAT TO EXPECT TOO EARLY TO TELL NIFTP IS A SURGICAL DISEASE Change in the malignancy risk for Bethesda Classification categories especially suspicious for PTC 50-60%. Should the suspicious category be divided? Suspicious for malignancy & PTC? Change in the malignancy risk for AUS/FLUS & Follicular Neoplasm / Suspicious for Follicular Neoplasm 11

12 9/6/2016 WHAT CRITERIA I SHOULD USE TO DIAGNOSE CONSISTENT WITH PTC? Before Opinions? Consider sampling issues, ultrasound features and disease presentation True papillae presence of fibrovascular core(s)? Diffuse rather than focal presence of major diagnostic nuclear features of PTC IF RENDERING A DIAGNOSIS OF SUSPICIOUS FOR PTC Suspicious for papillary thyroid carcinoma, see note. Note: The specimen shows a distinct population of atypical follicular cells with nuclear features suspicious but not diagnostic of papillary thyroid carcinoma. According to the published data 50-75% of thyroid FNA cases diagnosed as such are found to be malignant on surgical excision The histologic follow-up of thyroid FNA cases diagnosed as such can include one of the following entities: papillary thyroid carcinoma and non-invasive follicular tumor with papillary like nuclei (NIFTP). Molecular Analysis Which test Mutation and Translocation Panel 12

13 Virginia A. LiVolsi, MD Perelmann School of Medicine of the University of Pennsylvania I have consulted with Veracyte, Inc.

14 FOLLICULAR VARIANT OF PTC: HISTORICAL PERSPECTIVE Prior to 1970s, the definition of Papillary vs Follicular Thyroid Carcinoma Rested on the predominant (>50%) pattern of the tumor at low power. Hence if tumor was mostly follicular in pattern, it was diagnosed as follicular carcinoma (AFIP FASCICLE 1969)

15 FOLLICULAR VARIANT OF PTC: HISTORICAL PERSPECTIVE In 1960s, Dr. Stuart Lindsay defined the follicular variant of papillary carcinoma looking to the nuclei. The seminal paper in 1977 by Chen and Rosai described 7 cases of follicular variant of PTC based on nuclear features.

16 FOLLICULAR VARIANT OF PTC: HISTORICAL PERSPECTIVE Cytopathologists liked this idea and the diagnosis of PTC could be made on FNA material The WHO (2004) defined PTC as a malignant tumor of the thyroid with a distinctive set of nuclear features. The WHO defined FTC as not having those nuclear features.

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19 FOLLICULAR VARIANT OF PTC: HISTORICAL PERSPECTIVE So in a span of two decades, pathologists changed their diagnostic emphasis from pattern to nuclear cytology. Papillary carcinoma whether it had papillae or how many it had was recognized by its nuclei and even if the entire tumor was follicular in pattern, if the nuclei were present it was a papillary carcinoma.

20 FOLLICULAR VARIANT OF PTC: HISTORICAL PERSPECTIVE This had important clinical relevance Papillary carcinoma tended to show lymphatic spread (both in the gland and into lymph nodes) and was often multifocal; Whereas follicular carcinoma was unifocal and hardly ever spread to nodes; if it spread it went hematogenously to distant sites.

21 FOLLICULAR VARIANT OF PTC: HISTORICAL PERSPECTIVE The follicular variant was therefore expected to behave as a papillary carcinoma. And some of them did!

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23 FOLLICULAR VARIANT OF PTC: HISTORICAL PERSPECTIVE BUT, The fly in the ointment landed when pathologists noted some tumors which grew like follicular carcinoma (encapsulated, pushing invasion, vascular invasion) YET had nuclei of papillary carcinoma.

24 INVASION CAPSULE VASCULAR INVASION

25 CD 31 stain

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27 FOLLICULAR VARIANT OF PTC: HISTORICAL PERSPECTIVE In the first decade of the 21 st century, two major forms of follicular variant of papillary carcinoma were recognized: Infiltrative --behave like ordinary papillary carcinoma; Encapsulated less (??any) nodal mets, unifocality, more vascular invasion and probably distant mets.

28 FOLLICULAR VARIANT OF PTC: HISTORICAL PERSPECTIVE Then things got interesting Subvariants of FVPTC Infiltrative Encapsulated with invasion Encapsulated without invasion Encapsulated with multifocal nuclear features Encapsulated with incomplete nuclear featues Microcarcinoma in an adenoma Diffuse follicular variant Macrofollicular variant

29 FOLLICULAR VARIANT OF PTC: HISTORICAL PERSPECTIVE Could we make sense out of this? MAYBE molecular analysis could help. And it clarified some of the confusion The infiltrative FVPTC shared much with classic PTC The encapsulated FVPTC seemed to be more closely related to FTC/FA.

30 FOLLICULAR VARIANT OF PTC: HISTORICAL PERSPECTIVE What could most pathologists do? Agree that if a tumor with a follicular pattern showed invasive growth infiltrative into the gland without capsule IT IS A CANCER. The subtype is often in dispute.

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33 FOLLICULAR VARIANT OF PTC: HISTORICAL PERSPECTIVE NONINVASIVE tumors. How common are they? This is difficult to determine since diagnostic criteria differ. It is estimated that about 45,000 or 50,000 cases are seen per year in North America.

34 FOLLICULAR VARIANT OF PTC: HISTORICAL PERSPECTIVE The main problem is the NONINVASIVE tumors. WHAT TO NAME THEM? HOW TO DEFINE THEM?

35 FOLLICULAR VARIANT OF PAPILLARY CARCINOMA ENCAPSULATED NONINVASIVE HISTORICAL CLUES Williams et al UMP Liu et al behave benign Kakudo et al not malignant OTHERS----suggested benign behavior.

36 SO THE IDEA TO EVALUATE THESE LESIONS IN AN ORDERLY SCIENTIFIC WAY

37 Changing Paradigms in the Diagnosis of Non-Invasive Follicular Variant of Papillary Thyroid Carcinoma: Deliberations, Discussions and Controversies ENTER NIFTP:DIAGNOSTIC AND MOLECULAR FEATURES Raja R. Seethala, M.D. University of Pittsburgh Medical Center I have no financial disclosures

38 NON-INVASIVE FOLLICULAR THYROID NEOPLASM WITH PAPILLARY LIKE NUCLEAR FEATURES (NIFTP) Inception Pathologic features of NIFTP Limitations and Challenges

39 The problem - Non invasive FVPTC Malignancy based on only nuclear features - subtle and subjective Treated like other well differentiated cancers Discordance between subtlety and perceived penalty for being incorrect

40 Indolent behavior to match the appearance Reference Follow-up Type and number of FVPTC cases Baloch Z, et al. Encapsulated Mod Pathol 2000 N=5 Liu J, et al. Cancer 2006 Widder S, et al. Surgery 2008 Piana S, et al. AJSP 2010 Liu Z, et al. Cancer science 2011 Median, 11.1 y Mean 8.75 y Mean 11.9 y Average 6.75 y Encapsulated N=61 Infiltrative N=17 Encapsulated N=26 Encapsulated N=66 Encapsulated\ N=30 Invasion Lymph node metastasis Recurrence/distant metastasis Tumor-related death 1 without invasion All 5-bone metastases 1- capsular invasion 3- vascular invasion Without invasion N=43 With invasion 3 (17%) 1/18 (6%) 0 N=18 11 (65%) 11 (65%) Without invasion N=26 Without invasion N=45 Without invasion N= Vivero M, et al. Thyroid 2013 Rosario PW, et al. Clinical endocrinology 2014 Median, 9.25 y Median 6 y Encapsulated N=27 Partially encapsulated/well circumscribed N=35 Without invasion N=14 With invasion N=13 Without invasion N= /30 Infiltrative N=9 7 (78%) Encapsulated Without invasion N=57 N=57 Howitt BE, et al. Histopathology 2015 Median 3 y Encapsulated N=79 Without invasion N = Ganly I, et al. Human Pathology 2015 Median 9.5 y Encapsulated N= 83 Without invasion N= 57 With invasion N= ~0.5% non invasive FVPTC have recurrence or metastasis (range of median f/u 3 to 11.9 years). Recurrent metastatic cases w/o invasion with extenuating circumstances (incomplete lesional capsule submission, incomplete excision)?overtreatment or overdiagnosis

41 Consensus group to address the problem 24 surgical pathologists, 2 endocrinologists, 1 surgeon, 1 molecular pathologist, 1 biostatistician, 1 psychiatrist, 1 patient Led by Dr. Yuri Nikiforov Review of 268 cases with f/u Numerous teleconferences and a face to face meeting in Boston 3/20-3/21/2015 Heated discussion regarding nomenclature shift

42 Summary of the Consensus Group Proceedings Inclusion and exclusion criteria were established for non-invasive FVPTC Nuclear scoring scheme was devised and validated 109 cases accepted as non-invasive FVPTC no adverse outcomes (median f/u 13 years) 101 cases designated as encapsulated/well demarcated FVPTC with invasion 12% with adverse outcome, 2% death Final consensus terminology Non Invasive Follicular Thyroid Neoplasm with Papillary Like Nuclear Features (NIFTP) Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors. Nikiforov YE et al., JAMA Oncol Apr 14. doi: /jamaoncol [Epub ahead of print]

43 Aftermath Accepted as an entity by upcoming WHO Will have its own provisional ICD-O3 histology code: 8349/1 CAP protocol modifications to accommodate NIFTP underway Endorsed by several organizations (though not yet ATA)

44 Diagnosis of NIFTP Abridged Anything that you would have called encapsulated/well demarcated/noninvasive FVPTC, now consider NIFTP BUT. You must be stricter in excluding invasion, other growth patterns, and morphologies Complete submission of tumor normal interface is no longer optional (get over it) NIFTP nuclear features are usually subtle, if it s too easy to find these, then you should worry about a more aggressive carcinoma.

45 Inclusion Criteria Border Non infiltrative Encapsulated Partly Encapsulated Well Demarcated Follicular Patterned Micro to macrofollicular/cystic Intercalation of microfollicles between macrofollicles Accentuation of cellularity at periphery Nuclear features of PTC Diffuse to heterogeneous (recommend a minimum of 30% of tumor) Typically not as obvious as classic/conventional PTC

46 Exclusion Criteria Invasion Encapsulated tumors tumoral capsular invasion Unencapsulated/well demarcated tumors infiltration of adjacent parenchyma Vascular, lymphatic invasion Perineural invasion, extrathyroidal extension Growth pattern Solid/trabecular/insular growth >30% True or well formed papillae >1% Aggressive morphologies (i.e. tall cell, columnar cell, hobnail) Distinctive morphologies (i.e. cribriform morular variant) Psammoma bodies High grade features Mitoses >3 per 10 hpf Tumor necrosis

47 ALGORITHM FOR DIAGNOSIS OF NIFTP Encapsulated or Well-demarcated Yes No N Infiltrative FVPTC Capsular and/or Lymphovascular invasion No >30% solid/insular/trabecular and/or >1% true papillary pattern and/or Psammoma bodies identified and/or Tall cell or columnar cell variants No Predominantly follicular pattern Yes Tumor necrosis and/or >3 mitoses/10 HPFs No Yes Yes No Yes O T N I F T EFVPTC or FC with invasion Solid PTC and/or Classical PTC and/or Tall cell or columnar cell variants Classical PTC encapsulated and/or Follicular adenoma Poorly differentiated tumor Nuclear features of papillary thyroid carcinoma (score 2 or 3) No P Follicular adenoma and/or adenomatoid nodule Yes NIFTP

48 Nuclear Features Still defining in NIFTP Main point of contention Poor to mediocre reproducibility and geographic variation

49 A scoring system capturing what you would do anyway Nuclear features Enlargement Elongation Overlap Grooves, Irregular nuclear contours Pseudoinclusions Glassy nuclei Margination of chromatin (and nucleoli) Clearing Restructuring Size and Shape (0-1 pt) Enlargement Elongation Overlap Membrane Irregularities (0-1 pt) Irregular nuclear contours Grooves Pseudoinclusions Chromatin Characteristics (0-1 pt) Glassy nuclei Margination of chromatin (and nucleoli) Clearing If combined score of 2 or 3: Nuclear features are adequate for NIFTP

50 Score 0 (insufficient) Score 1 (adequate) Size and Shape Enlargement Elongation Overlap Normalize to normal Careful here Membrane Irregularities Irregular nuclear contours Grooves Pseudoinclusions Chromatin Characteristics Glassy nuclei Margination of chromatin (and nucleoli) Clearing

51 Performance Characteristics with a Molecular Endpoint Test Set Sensitivity = 86.5% (82.7% %) Specificity = 80.8% (73.8% %) PPV = 92.2% (89.1% %) NPV = 69.8% (62.2% %) Classification Accuracy = 85.0% (82.8% %) Validation Set Sensitivity % (96.3% %) Specificity % (86.0% %) PPV % (87.1% %) NPV % (96.0% %) Classification Accuracy 94.3% (92.1% %)

52 Molecular alterations in NIFTP ~60% overall with clonal alterations (n=44 tested) ~80% cases classified as NIFTP (by mean score 2 or more) show clonal alterations 12/26 RAS +/- EIF1AX 7/26 PAX8/PPARG 5/26 THADA 1/26 ALK 1/26 BRAF K601E No BRAF V600E, RET/PTC in NIFTP Cases not considered NIFTP because of insufficient nuclear score were negative for mutation Integrated genomic characterization of papillary thyroid carcinoma. Cancer Genome Atlas Research Network. Cell Oct 23;159(3):676-90

53 FAQ about molecular phenotype Do you use molecular findings to diagnosis NIFTP? NO Does NIFTP have characteristic findings? YES RAS PAX8-PPARG THADA BRAF K601E What molecular alterations should make you doubt a NIFTP diagnosis? BRAF V600E Conventional Tall Cell spectrum RET/PTC CTNNB1 Cribriform Morular variant Multiple mutations TP53 Progression to poorly differentiated TERT

54 Gross Examination and Reporting Some things are the same, some are different

55 Grossing Entire tumor normal interface (no arguments) Mean NIFTP size ~3 cm = Usually <20 cassettes Stepwise submission acceptable if very large or grossly evident invasion Grossing need to map discrete lesions sampled more methodically

56 Sample Templated Gross The specimen is received fresh, labeled with the patient s name, initials [] and []. SPECIMEN TYPE: [total thyroidectomy] or [R/L subtotal thyroidectomy/lobectomy/lobectomy with isthmusectomy/other(specify] SPECIMEN INTEGRITY: [intact/disrupted/fragmented],[suture demarcating ] WEIGHT: [] grams OVERALL DIMENSIONS: [] x [] x [] cm right lobe: [] x [] x [] cm left lobe: [] x [] x [] cm isthmus: [] x [] x [] cm other(specify):[lymph nodes, parathyroid, skeletal muscle, skin] [] x [] x [] cm NUMBER OF DISCRETE LESIONS [] LESION #[]:* Location: [left/right/isthmus], [upper/middle/lower] Size: [] x [] x [] cm Border: [well demarcated +/- encapsulated, poorly defined] Capsular thickness: [](if >0.1 cm) Characteristics: [shape and color], [homogeneous/heterogeneous], [hemorrhagic/cystic/calcified] Distance to inked margin: [] cm SURROUNDING UNINVOLVED PARENCHYMA: []. OTHER FINDINGS: [] ADDITIONAL STUDIES/PROCEDURES: [] INK CODE: Black Thyroid capsule Green Isthmic/resection margin Red Area banked CASSETTE SUMMARY: *add up to 6 as needed.

57 Reporting: A work in progress AJCC stage no longer relevant Relevant parameters Size Laterality Margin status CAP Synoptic??? Likely an OPTIONAL limited dataset still important for possible population level data accumulation in registries

58 Limitations and Challenges A starting point not a final solution

59 This does not solve a more fundamental problem NIFTP does not solve the underlying problem of dumbing down neoplasia into binary categories in cancer care ATA 2015 Guidelines A spectrum not discrete groupings

60 Does not solve all diagnostic challenges of follicular patterned lesions Pros Cushion category between benign and overtly malignant Systematic approach to assess nuclear features Cons Nuclear features were scrutinized but other features (infiltration, vascular invasion, papillae, etc) were not Still lots of room for subjectivety Shift in the challenge and controversy Then Nuclear features Now Other features that were not well vetted

61 Specific issue: Mitoses Most problematic feature in UPMC experience Many follicular patterned neoplasms, benign and malignant may have increased mitotic counts Intent of NIFTP Not to scrutinize to find the absolute worst area Use this as a marker of high grade nuclear features not in isolation Recommendations 10 consecutive 40x fields Away from hemorrhage, cystic change (i.e. FNA tract) Only in cellular microfollicular patterned areas.

62 Other limitations Awkward name (?untranslatable in some languages) Retrospective nature, selection bias Absence of neck dissection to confirm pn0 Limited data on extreme long term follow-up (i.e. 30 years) Scale of hundreds of cases is not population level data

63 NIFTP has not been validated for.. Multiple tumors Small tumors (<1.0 cm) Heavily oncocytic tumors Scoring would fail since it is automatically 2 Molecular endpoints may not work as well Pediatric population

64 In Summary NIFTP has gained traction and has a position in the spectrum of follicular derived thyroid neoplasia Perhaps the first systematic response to the NIH directive from 2013 Histologic criteria are not novel, simply reframed to a new context Diagnosis, reporting, and clinical management are all evolving Start point not endpoint