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
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!