Conflict of Interest. Overdiagnosis. Beyond Bethesda: Challenges with Indeterminate Thyroid Aspirates 4/17/2015. Jeffrey F.

Size: px

Start display at page:

Download "Conflict of Interest. Overdiagnosis. Beyond Bethesda: Challenges with Indeterminate Thyroid Aspirates 4/17/2015. Jeffrey F."

Emil Potter
8 years ago
Views:

1 Beyond Bethesda: Challenges with Indeterminate Thyroid Aspirates Jeffrey F. Krane, MD PhD Associate Professor of Pathology Harvard Medical School Chief, Head and Neck Pathology Service Associate Director, Cytology Division Brigham and Women s Hospital Boston, MA Conflict of Interest The speaker has no disclosures to make Overdiagnosis The diagnosis of disease that if left undetected or untreated would not cause the patient harm (symptoms or death) Thyroid cancer Prevalence of incidental disease is high (~33%) Mortality rate is low (>95% long term survival) 1

Division Brigham and Women s Hospital Boston, MA Conflict of Interest The speaker has no disclosures to make Overdiagnosis The diagnosis of

2 Overdiagnosis of thyroid cancer 15X increase Ahn et al N Engl J Med (2014) The risk of overdiagnosis Incidence correlates with screening intensity At one center <1 cm: 14% to 56% in 10 years <0.5 cm: 25% Complications of treatment outweigh harm of disease 11% hypoparathyroidism 2% vocal cord paralysis Over 4000 complications/year deaths/year Ahn et al N Engl J Med (2014) Overview Indeterminate aspirates Diagnostic challenges Clinical management issues Role of molecular testing Rethinking thyroid cancer (over)diagnosis 2

5 cm: 25% Complications of treatment outweigh harm of disease 11% hypoparathyroidism 2% vocal cord paralysis Over 4000

3 The Bethesda System for Reporting Thyroid Cytopathology Diagnostic Category Risk of Malignancy Usual Management I. Nondiagnostic / Unsatisfactory 1 4% Repeat FNA II. Benign 0 3% Clinical follow up III. Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance 5 15% Repeat FNA IV. Follicular neoplasm or Suspicious for a Follicular Neoplasm 15 30% Lobectomy V. Suspicious for Malignancy 60 75% N T Thyroidectomy or Lobectomy VI. Malignant 97 99% N T Thyroidectomy Adapted from Ali and Cibas, TBSRTC, Bethesda benefits Improve communication Facilitate cytologic histologic correlation Facilitate research into the epidemiology, molecular biology, pathology, and diagnosis of thyroid diseases Easy and reliable sharing of data from different laboratories for collaborative studies 3

Follicular neoplasm or Suspicious for a Follicular Neoplasm 15 30% Lobectomy V. Suspicious for Malignancy 60 75% N T Thyroidectomy or Lobectomy VI.

4 Bethesda use in practice Category Average (%) Range (%) AUS/FLUS SFN SUS Overall Indeterminate Adapted from Bongiovanni et al Acta Cytol(2012) AUS/FLUS use often exceeds 7% proposed upper limit Indeterminate use is a mess Uniform terminology Uniform practice Bethesda risk in practice Diagnostic Category Predicted Risk of Malignancy (%) Actual Risk of Malignancy in Nodules Surgically Excised (%) Non Diagnostic/Unsat (9 32) Benign (1 10) AUS/FLUS (6 48) FN/SFN (14 34) Suspicious for Malignancy (53 97) Malignant (94 100) Derived from Kholová and Ludvíková Acta Cytol (2014) and Bongiovanni et al Acta Cytol (2012) 4

in practice Diagnostic Category Predicted Risk of Malignancy (%) Actual Risk of Malignancy in Nodules Surgically Excised (%) Non Diagnostic/Unsat 1 4 20 (9 32) Benign 0 3 2.

5 AUS/FLUS subqualifiers Summary of 7 published studies (resected cases only) Qualifier Malignancy rate (%) Cytologic atypia (r/o PTC) 55 Architectural atypia (r/o FN) 22 Hürthle cell atypia 6 NOS 35 Overall 39 Adapted from Nishino and Wang Cancer Cytopathol (2014) Cytologic atypia is high risk Architectural atypia is low risk Hürthle cell atypia is very low risk AUS/FLUS management TBS recommends repeat FNA in most instances Hürthle cell lesions are the exception In practice, many patients go directly to surgery 2009 ATA guidelines offer no guidance ATA guidelines Revised guidelines under review Recommend that all FNAs be reported using Bethesda System 5

Hürthle cell atypia is very low risk AUS/FLUS management TBS recommends repeat FNA in most instances Hürthle cell lesions are the exception In practice, many

6 Revised ATA guidelines For AUS/FLUS If not clinically or sonographically worrisome Repeat FNA or molecular testing acceptable Surveillance or diagnostic surgery also acceptable For FN/SFN Molecular testing acceptable Or diagnostic surgery Molecular testing Indeterminate thyroid FNAs Molecular Testing Options: Afirma GEC (Veracyte) MiRInform (Asuragen) 6

acceptable For FN/SFN Molecular testing acceptable Or diagnostic surgery Molecular

7 Molecular testing and thyroid FNA PROS: Convenient Objective result Avoids waiting for repeat FNA Defines management and save dollars CONS: Expensive if inappropriately applied Requires dedicated material Reflex testing Takes clinician out of picture Can add to overall expense (unnecessary testing) Loss of cyto histo correlation The Afirma test The Afirma test Benign fingerprint {high NPV} rule out test Microarray data from 167 genes Benign vs Suspicious classification $3350 cost Requires 2 additional FNA passes NPV = 94 95% for AUS/FLUS and FN/SFN ~40% Benign can avoid surgery NPV = 85% for suspicious for malignancy Too low 7

histo correlation The Afirma test 2012 20 The Afirma test Benign fingerprint {high NPV} rule out test Microarray data from 167 genes Benign vs Suspicious

8 MiRInform test Malignant fingerprint {high PPV} rule in test Testing for 7 genes: BRAF V600E RAS mutations (NRAS, KRAS, HRAS) RET/PTC (RET/PTC1, RET/PTC3) PAX8/PPARgamma $ 2250 cost PPV = 95% for SUS Helps determine extent of surgery What s new with molecular testing Afirma Recent post clinical trial studies Mutational testing New tests New mutations What s new with Afirma testing Multiple studies published post clinical trial Hürthle cell lesions Test performance varies in different settings 8

with molecular testing Afirma Recent post clinical trial studies Mutational testing New tests New mutations What s new with

9 Afirma for Hürthle cell lesions Hürthle cell lesions may be problematic Not specifically addressed in NEJM trial Small studies, pooled data Cytology pattern Afirma benign Malignancy rate for suspicious Hürthle cell 11/59 (19%) 6/32 (19%) Non Hürthle cell 83/165 (50%) 42/78 (54%) Pooled data from McIver et al J Clin Endocrinol Metab (2014), Harrell and Bimston Endocr Pract (2014), and Lastra et al Cancer Cytopathol (2014) Negative predictive value Prevalence of malignancy varies Cytopathologists AUS/FLUS Surgical pathologists FVPTC Alexander et al N Eng J Med (2012) AUS/FLUS NPV 95%, Prev 24% Follicular neoplasm NPV 94%, Prev 25% Harrell and Bimston Endocr Pract (2014) Comparing Practice Settings Practice 1 Practice 2 AUS/FLUS rate 1% 11.5% Follicular neoplasm rate 7.7% 17.4% Afirma suspicious rate 44/60 (73%) 62/132 (47%) Afirma suspicious 5/32 (16%) 22/48 (46%) malignancy rate FVPTC rate in malignant cases 1/5 (20%) 16/22 (77%) Adapted from McIver et al J Clin Endocrinol Metab (2014) and Lastra et al Cancer Cytopathol (2014) 9

Lastra et al Cancer Cytopathol (2014) Negative predictive value Prevalence of malignancy varies Cytopathologists AUS/FLUS Surgical pathologists FVPTC Alexander et al N Eng J Med (2012) AUS/FLUS NPV

10 Afirma in the real world Be cautious with Hürthle cell lesions Understand disease prevalence in your practice setting to assess if test has desired NPV Mutation testing Moving fast Next generation sequencing gene mutation panels ThyroSeq v 2 (UPMC) Mutations in 14 genes 42 gene fusions Follicular neoplasm study [Nikiforov et al Cancer (2014)] High NPV and PPV Single institution, partially blinded study The Cancer Gene Atlas Project Detailed analysis of 496 papillary carcinomas Genomic, RNA, mirna, proteomic, DNA methylation Discovered new oncogenic driver mutations EIF1AX, PPM1D, CHEK2 and novel translocations Reduced unknown driver frequency 25% to 3.5% The Cancer Gene Atlas Research Network Cell (2014) 10

and PPV Single institution, partially blinded study The Cancer Gene Atlas Project Detailed analysis of 496 papillary carcinomas Genomic, RNA, mirna, proteomic, DNA methylation

11 The Cancer Gene Atlas Project 71 gene expression profile Broadly segregated BRAF like: Tall cell variants and classic RAS like: FVPTC, resemble follicular neoplasms The Cancer Gene Atlas Research Network Cell (2014) TERT mutations TERT: Telomerase reverse transcriptase TERT promoter activating mutations Seen in any type of follicular derived carcinoma PTC 7.5% Follicular 17.1% Poorly differentiated 29.0% Anaplastic 33.3% Associated with aggressive behavior Liu et al Endocr Relat Cancer (2013), Landa et al J Clin Endocrinol Metab (2013), Melo et al J Clin Endocrinol Metab (2014) TERT on FNA FNA study 308 pre surgery FNAs 0/179 benign 9/129 (7%) malignant 3 of 9 had indeterminate cytology 7 of 9 behaved aggressively Liu and Xing Endocrine Related Cancer (2014) 11

1% Poorly differentiated 29.0% Anaplastic 33.

12 TERT and BRAF TERT and BRAF mutations act synergistically Xing et al J Clin Oncol (2014) The risk of overdiagnosis in the US Davies and Welch JAMA Otolaryngol Head Neck Surg (2014) The risk of overdiagnosis in the US Davies and Welch JAMA Otolaryngol Head Neck Surg (2014) 12

13 The risk of overdiagnosis in the US Davies and Welch JAMA Otolaryngol Head Neck Surg (2014) The risk of overdiagnosis in the US Tumors are smaller <=1 cm: 25% 1988, 39% ,000 Americans in % total thyroidectomy US complication rate: 16.4% 2x higher in total thyroidectomy vs lobectomy ~8000 complications vs 2000 deaths Davies and Welch JAMA Otolaryngol Head Neck Surg (2014) and Hauch et al Ann Surg Oncol (2014) How can we limit overdiagnosis? Screening Diagnosis Clinical management 13

4% 2x higher in total thyroidectomy vs lobectomy ~8000 complications vs 2000 deaths Davies and Welch JAMA Otolaryngol Head

14 Screening: Revised ATA guidelines Which nodules to aspirate? None <1 cm Risk stratify based on size and ultrasound features Ultrasound Concern High Intermediate Low Very Low Benign Size >=1 cm >=1 cm >=1.5 cm >=2 cm NA Diagnosis and management: How can cytology help? Change the paradigm Risk stratify for behavior Risk for aggressive behavior (high risk) Likelihood of indolent behavior (low risk) Do not focus on malignancy risk We already risk stratify Aggressive behavior stratifies with preceding Bethesda diagnosis T stage Tumor Stage Lymphovascular Invasion Percent of Nodules Malignant Extrathyroidal Extension Suspicious for Malignancy AUS T1 T2 T3 T Malignant Suspicious for AUS Malignancy Present Absent Lymph Node Metastasis Malignant Suspicious for AUS Malignant Suspicious for AUS Malignancy Malignancy Present Absent N1 N0 NX VanderLaan et al Cancer Cytopathol (2012) Adapted from VanderLaan et al Cancer Cytopathol

5 cm >=2 cm NA Diagnosis and management: How can cytology help?

15 How can cytology help? Minimize AUS/FLUS Maximize Benign Use molecular testing wisely Use GEC to avoid surgery with low risk aspirates Use mutation testing to dictate extent of surgery Aggressive: BRAF and TERT Indolent: RAS Revise Bethesda to reflect behavioral risk rather than malignancy risk 15

avoid surgery with low risk aspirates Use mutation testing to dictate

The Role of Genetic Testing in the Evaluation of Thyroid Nodules. Thyroid Cancer and FNA. Thyroid Cancer. Pure Follicular Cancers.

Where does Molecular Analysis of FNA Specimens fit into the evaluation of thyroid nodules? The Role of Genetic Testing in the Evaluation of Thyroid Nodules Ultrasound TSH Risk factors Jill E. Langer, MD