philippe vielhmd, phd, fiac zone.pdf · 15-30% of fnac are difficultto beclassifiedand have a...

The grey zone

Philippe Vielh MD, PhD, FIAC

Director of CytopathologyDeputy Director of Anatomic Pathology

National Health Laboratory of LuxembourgPast President of the International Academy of Cytology

philippe.vielh@lns.etat.lu

Conflict of interest: no disclosure

OUTLINE

� Thyroid fine-needle aspiration (FNA)

� diagnostic and screening capacities

� the PSC initiative and the NCI meeting

� Challenges for morphologists

� Today & tomorrow

� Conclusions

THYROID FNA

� Most widely used method for the preoperativediagnosis and screening of thyroid nodules

� Recommended by national and international associations

� American Thyroid Association (revised) recommendations C

� Cooper DS, et al. Thyroid 2009;19:1167-1214

THYROID FNA

� Diagnostic method

� for tumors with clearly defined cytologic features(classical papillary, medullary, and anaplasticca…)

� Screening method

� for follicular carcinomas and

� other carcinomas with less distinct nuclearfeatures

THYROID FNA

Spectrum of follicular nuclear size and amount of colloid in follicular lesions of the thyroid. (modified from Cervino JM, Paseyro P, Grosso O, et al. La exploracion citologica de la glandula tirodes y sus correlaciones anatomoclinicas. In, Thyroid Cytopathology: an atlas and text. Kini SR, 2008.

THYROID FNA

� Great success

� the majority of thyroid FNAC can be classified as benign (>450,000 annually in the USA)

� Big shortcoming

� 15-30% of FNAC are difficult to be classified and have a variable risk of malignancy, while beingmostly benign on histology.

THYROID FNA

� Before 2007� Huge variability in reporting and classifying (4-6tier)

as well as in defining some thyroid lesions (« greyzone ») before the Papanicolaou Society of Cytopathology (PSC) initiative

� Interobserver variability� Stelow EB, et al. Am J Clin Pathol 2005;124:239-244

� PSC initiative started in 2006� NCI Thyroid Fine-Needle Aspiration State of the

Science Conference (2007)

� The Bethesda System for Reporting ThyroidCytopathology (TBSRTC): standardization

THYROID FNA

TBSRTC: terminology and criteria

Diagn Cytopathol 2008;36(6):425-437

THYROID FNA

TBSRTC: diagnostic categories

Cibas ES & Ali SZ. Am J Clin Pathol 2009;132:658-665

THYROID FNA

TBSRTC: images

THYROID FNA

TBSRTC : risk & management

Cibas ES & Ali SZ. Am J Clin Pathol 2009;132:658-665

THYROID FNA

TBSRTC : 28 members from 14 European countries

Kocjan G, et al. Cytopathology 2010;21:86-92

CHALLENGES

� TBSRTC: 3 categories (“grey” zone vsindeterminate)

� Atypia/follicular lesion of undeterminedsignificance (AUS/FLUS)

� Suspicious for a follicular neoplasm/ follicularneoplasm (SFN/FN)

� Suspicious for malignancy (SM): typicallypapillary carcinoma

CHALLENGES: AUS/FLUS (1)

Ali SZ & Cibas ES book

CHALLENGES: AUS/FLUS (1)

� Nondiagnostic/unsatisfactory

� Fewer than 6 groups of well-preserved, well-stained follicular cell groups with 10 cells each

CHALLENGES: AUS/FLUS (1)

CHALLENGES: AUS/FLUS (1)

� Nondiagnostic/unsatisfactory

� Fewer than 6 groups of well-preserved, well-stained follicular cell groups with 10 cells each

� Follicular variant of papillary carcinoma

CHALLENGES: SFN/FN (2)

microfollicles trabeculae

Ali SZ & Cibas ES book

CHALLENGES : SFN/FN (2)

CHALLENGES : SFN/FN (2)

� Follicular carcinoma

CHALLENGES: SFN/FN (2)

CHALLENGES : SFN/FN (2)

� Follicular carcinoma

� Follicular variant of papillary carcinoma

CHALLENGES : SFN/FN (2)

� Follicular carcinoma

� Follicular variant of papillary carcinoma

� Poorly differentiated carcinoma

CHALLENGES: SFN/FN (2)

Ali SZ & Cibas ES book

CHALLENGES: SFN/FN (2)

+

Ali SZ & Cibas ES book

CHALLENGES : SFN/FN (2)

� Benign lesion

� Mix of benign follicular cells + Hürthle cells

CHALLENGES : SFN/FN (2)

CHALLENGES : SFN/FN (2)

� Benign lesion

� Mix of benign follicular cells + Hürthle cells

� Hashimoto thyroiditis

CHALLENGES : SFN/FN (2)

CHALLENGES : SFN/FN (2)

� Benign lesion

� Mix of benign follicular cells + Hürthle cells

� Hashimoto thyroiditis

� Oncocytic tumor (benign/malignant)� Auger M. Cancer (Cancer Cytopathology) 2014;122:241-249

CHALLENGES: SM (3)

Ali SZ & Cibas ES book

CHALLENGES: SM (3)

Ali SZ & Cibas ES book

CHALLENGES: other (4)

CHALLENGES: other (4)

� Acute inflammation vs undifferentiated(anaplastic) carcinoma

� Papillary thyroid carcinoma + Hashimoto thyroiditis

CHALLENGES: general (5)

� Intra- and interobserver variability in thyroid cyto- and histopathology

� Stelow EB, et al. Am J Clin Pathol 2005;124:239-244

� Elsheikh TM, et al. Am J Clin Pathol 2008;130:736-744

� Cibas ES, et al. Ann Intern Med 2013;159:325-332

� Some agressive variants of follicular cell-derived thyroid carcinomas (papillaryvariants, poorly differentiated, anaplastic)

� Lastra RR, LiVolsi VA, Baloch ZW. Cancer (Cancer Cytopathol) 2014;122:484-503

TODAY & TOMORROW

� Immunocytochemistry

� Panel : CK19, HMBE-1, Galectin-3, Ki-67

� Anti-BRAF (V600E) monoclonal antibody (VE1) : plump +/- sickle-shaped nuclei

� Liquid-based cytology

� Molecular cytopathology

� BRAF mutation; « rule-in » and/or « rule-out » tests

� Next generation sequencing (NGS) on cytologyspecimens

TODAY & TOMORROW

� Thyroid Imaging and Reporting Database System (TI-RADS)

� The Bethesda System for reporting ThyroidCytopathology update ?

� British (Cross 2011) & Italian (Nardi 2013) classifications

� WHO 2004 update !

TODAY & TOMORROW

� Primary or secondary detection of radioactive iodine-refractory differentiatedthyroid cancer

� Schlumberger M, et al. Lancet Diabetes Endocrinol 2014;2:356-358

� Study of pathways (MAPK and PI3K-AKT-mTOR) implicating druggable kinases (kinase inhibitors)

� Xing M, Haugen BR, Schlumberger M. Lancet 2013;381:1058-1069

CONCLUSIONS

� Grey (gray?) zone still exists

� Increased incidence of small low riskthyroid cancer

� Evolution of terminology (indolent lesion of epithelial origin: IDLE) ?

� Esserman LJ, et al. Lancet Oncol 2014;15:e234-e242

CONCLUSIONS

Primum non nocere!

The origin of this phrase is uncertain. The Hippocratic Oathincludes the promise « to abstain from doing harm ».

Perhaps the closest approximation in the HippocraticCorpus is in Epidemics: "The physician must ... have two special objects in view with regard to disease, namely, to do good or to do no harm" (book I, sect. 11, trans. Adams).

According to Gonzalo Herranz, Professor of Medical Ethicsat the University of Navarre, this sentence was introducedinto American and British medical culture by Worthington Hooker, in his 1847 book Physician and Patient, whoattributed it to the French pathologist and clinician Auguste François Chomel (1788-1858).

12th-century Byzantine manuscript of the Hippocratic Oath

� Grazie!