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The New Diagnostic Paradigms in Thyroid Surgical Pathology and 

Affects on Reporting of Thyroid Fine‐Needle Aspiration SpecimensDeliberations, Criticisms & Discussions

Zubair W. Baloch, MD, PhD.Professor of Pathology & Laboratory MedicineUniversity of Pennsylvania Medical Center

Perelman School of MedicinePhiladelphia, PA, USA

Let’s Make Sense of Present & 

Predict Future

In Light of Past

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A Quick Look Back at 2007

The Birth 

of 

“Bethesda System of Reporting Thyroid FNA”

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Proposals, Recommendations& Accomplishments

• Proposed Tiered Classification Scheme

– Spanning the spectrum of benign to malignantdiagnoses

• Inclusive of “Gray Zone” in both cytologic and surgicalpathology diagnoses

– Implied risk of malignancy based on availableliterature review

– A thoughtful process to recommendations inclusiveof everyday practice of cytopathology and thyroidnodule 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

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The Timing of TBSRTC

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

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Case 1Thyroid Experts DiagnosesThe Cytopathologists Gold Standard

Diagnoses: Hyperplastic nodule – BenignorFollicular Adenoma – Benignor Follicular Variant of Papillary Thyroid Carcinoma ‐Malignant

LiVolsi Rosai Asa Lloyd

Controversial Thyroid Lesions

Follicular patterned lesions 

Am I Satisfied with this Statement of Controversy? Regarding one of the 

Most Common Thyroid Lesion Seen in My Practice

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TBSRTC

Follow‐up Clinicopathologic Studies Showing Over‐diagnosis and Over‐treatment of Thyroid Carcinoma – PTC.

Concept of  Low and High Risk Disease

TBSRTC

Clinical and Radiology GuidelinesAmerican & European Thyroid Association

American College of RadiologyAmerican Society of Radiologist in Ultrasound

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TBSRTCMolecular 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

TBSRTC

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 Over‐treatment of Thyroid Carcinoma – PTC.Concept of  Low and High Risk Disease

Clinical and Radiology GuidelinesAmerican & European Thyroid Association

American College of RadiologyAmerican Society of Radiologist in Ultrasound

Molecular Profiling of Thyroid TumorsMolecular Diagnosis of Thyroid Nodules

Diagnostic Tests with high Negative and Positive Predictive Value

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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

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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

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Brandon S. Sheffield et.al. Expert Rev. Endocrinol. Metab. 9(2), 97–110 (2014)

Preoperative diagnosis of thyroid nodules using the Bethesda System for ReportingThyroid 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 ReportingThyroid Cytopathology: a comprehensive review and meta‐analysis.

Total Cases

Surgical Excision Malignant ROM OROM

AUS/FLUS 1906 805 194 24.10% 10%

FON/SFON/SHCN 3182 2183 660 30.23% 21%

Can we Calculate Overall Risk of Malignancy (OROM)?

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There is More to How Thyroid Nodules are Managed Then Just Cytologic Diagnosis

Reality Check

Thyroid Nodule Management ParadigmsAka 

Personalized Approach

Clinical Presentation

+

Ultrasound

+

FNA Diagnosis

+ 

Molecular Testing

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Molecular Tests

vs.

Clinical Application & Practice

Increase rate of Suspicious GEC ‐Afirma Results in Oncocytic Nodules

Suspicious  nodules  wsurgery

Benign Malignant

Harell et al. Endo Pract 2014 30 13 (43%)‐ 9 (69%) oncocytic lesions

17 (57%)

McIver et al. JCEM 2014 32 27 (84%)‐ 12 (44%) oncocytic lesions

5 (16%)

Brauner et al. Thyroid 2015 43*  37 (84%) 6(14%)

Lastra et al. Cancer Cytopath2014

48 26 (54%)‐ 15 (58%) oncocytic lesions

22(46%)

Total 153 103 (67%)‐73 (71%) oncocytic lesions

50 (33%)

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Next‐Generation Sequencing AssayNikiforov et al. Cancer 2014,120:3627‐34

Changes in Surgical Pathology Diagnosis / Classification of 

“Low Risk Tumor(s)”

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The Endocrine Society Working Group for Re‐evaluationof 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

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TCGA. Integrated genomic characterization of papillary thyroid carcinoma Cell : 2014

Classic PTC Encapsulated‐FVPTC Foll Thyr CA Poorly Diff Thy CA

Anapl Thyr CA FollAdenoma

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 ++

Integrated Genomic Characterization of Papillary Thyroid Carcinoma.  Cell (2014)

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Changes in the Implied Risk of Malignancy for TBSRTC Categories

AUS/FLUSSuspicious for Follicular Neoplasm

Suspicious for Malignancy – 50% decrease(Strickland et al. Thyroid 2015 & Faquin et al. Cancer Cytopathology 2015)

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

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%

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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%

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)

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

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Thyroid nodules are Common

Palpation

Ann Intern Med 1968 69:537; N Engl J Med 1993 328:553

Autopsy & US

2012450,000 FNAs estimated in USA

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• 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?

• Good relationship with the clinicians

– History

– Results discussion

– All matters

• Good relationship with radiologist and knowledge of ultrasound

• Empowering the workforce of cytopathology

How to avoid loosing thyroid FNA specimens?