FNA of Thyroid. Toward a Uniform Terminology With Management Guidelines. NCI NCI Thyroid FNA State of the Science Conference

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1 FNA of Thyroid NCI NCI Thyroid FNA State of the Science Conference Toward a Uniform Terminology With Management Guidelines Thyroid Thyroid FNA Cytomorphology

2 NCI Thyroid FNA State of the Science Conference Main Mission Support the establishment of an interdisciplinary information and educational program dedicated to thyroid FNA By means of a website and conference, to collect, analyze, and disseminate information on the diagnosis of thyroid disease via FNA to physicians, other health professionals, and the general public.

3 NCI Thyroid FNA State of the Science Conference October 22nd 23rd, 2007 Bethesda, Maryland Announcements February 28, 2008 The final Review and Conclusions document has been posted. The website will be updated to its final format shortly.

4 State of the Science Conference: Program FORUMS: Forum 1: Indications/Pre FNA requirements Forum 2: Training and Credentialing Forum 3: Technique Forum 4: Terminology and Morphologic Criteria Forum 5: Ancillary Studies Forum 6: Post-FNA Testing/Rx 2 ADDITIONAL COMMITTEES: Publications Website Atlas

5 Terminology General agreement on need for defined categories Clarity of communication Exchange of data across institutions Discussion focused on number of categories and names

6 The Bethesda Terminology Final Version Insufficient for diagnosis Benign Atypical Cells of Undetermined Significance (ACUS) Suspicious for a Follicular Neo Suspicious for a Hurthle Cell Neo Suspicious for Malignancy Malignant

7 Insufficient for Diagnosis Specimen processed and examined, but unsatisfactory for evaluation Adequacy criterion At least 6 groups, each with at least 10 benign- appearing, well-visualized follicular cells Exceptions: Thyroiditis (=Benign) Abundant colloid (=Benign) Any atypia

8 Cystic Fluid Only Should cyst fluid with only macrophages (<6 groups of follicular cells) be diagnosed as benign or non- diagnostic? Benign :: great majority prove to be benign cysts Non-diagnostic :: cannot exclude papillary carcinoma if solid portion of nodule not sampled Cystic Fluid Only category Endocrinologist can correlate result with ultrasound findings to determine if the result is representative of the lesion

9 Benign Very low risk of malignancy (<1%) This category includes Nodular goiter Chronic lymphocytic thyroiditis Hyperplastic/Adenomatoid nodule Colloid nodule Patients with a benign nodule are followed by clinical and possibly US examination

10 Benign Cellular Pattern Honeycomb sheets Macro follicle: > 15 cells, evenly distributed Small, round, uniform nuclei (size of lymphocytes or red blood cells), 7-97 u Abundant colloid Lymphocytes

11 Suspicious for a Follicular Neoplasms To be used for those cases that show significant architectural atypia (a predominance of microfollicles and/or crowded groups) Such cases raise the possibility of follicular carcinoma The distinction between follicular adenoma and carcinoma is not possible by FNA Surgery (usually lobectomy) is needed for definitive diagnosis

12 Suspicious for a Follicular Neoplasms Cellular bloody smear, syncytial or trabecular clusters, microfollicular pattern Scant or absent colloid in the background Nuclei are enlarged, crowded with coarse chromatin and prominent nucleoli Cancer rate: 20-33%

13 Suspicious for a Hurthle Cell Neoplasm Composed exclusively of Hurthle cells DDx includes medullary carcinoma, others Distinction between Hurthle cell adenoma and carcinoma not possible by FNA Surgery (usually lobectomy) required for definitive diagnosis

14 Suspicious for a Hurthle Cell Neoplasm Cellular specimen with monomorphic, oncocytic cells arranged in syncytial, cohesive clusters or dispersed single cells (Non-macrofollicular architecture) > 90% Hürthle H cells : Variable sized polygonal cells with abundant granular cytoplasm Nuclei are round, eccentrically or centrally located with finely granular chromatin and a single prominent nucleoli Scant or absent colloid Absence of lymphoid cells

15 Hürthle Cell (Oncocytic) Derived from follicular epithelium Ultrastructurally shows numerous large mitochondria Hürthle cells are not specific to any pathology Other than neoplasms, can be found in nodular goiter, Hashimoto s s thyroiditis, long standing hyperthyroidism, in thyroid of elderly persons, in the thyroid of patients who have received radiation

16 Hürthle Cell (Oncocytic) Many Hürthle H cells are present in the smears, however overall findings are equivocal for a specific diagnosis Differential diagnosis: Hürthle cell (oncocytic follicular) adenoma Hürthle cell (oncocytic follicular) carcinoma Oncocytic variant of papillary carcinoma Medullary carcinoma Hashimoto s s thyroiditis Grave s s disease Nodular goiter

17 Suspicious for Malignancy Suspicious for papillary carcinoma Suspicious for medullary carcinoma Serum calcitonin level Suspicious for lymphoma May include recommendation to repeat FNA with flow cytometry Suspicious for metastatic tumor to thyroid

18 Papillary Carcinoma Variants Malignant Medullary Carcinoma Poorly differentiated Carcinoma Anaplastic Carcinoma Lymphoma Secondary Tumor Other

19 Papillary Carcinoma Aspirates are cellular Architecture: papillary, Sheets, micro-follicles, syncytial fragments Enlarged, oval nuclei with fine chromatin, nuclear grooves and occasional intranuclear pseudoinclusion Metaplastic, squamoid cytoplasm Psammoma bodies, multinucleated cells

20 Medullary Carcinoma Dispersed cell pattern or loose aggregate Cells are variable in size and shape; round, oval to plasmacytoid, polygonal, racket-shaped, triangular or spindle-shaped shaped Nucleus : round, oval, cigar-shaped; occasional multilobated, giant, and bizarre; always eccentric; bi- or multinucleation common; stippled chromatin; inconspicuous nucleoli; intranuclear cytoplasmic inclusion Cytoplasm: pale, fibrillary, reddish granules by Diff- Quik stain Extracellular amyloid

21 Poorly Differentiated Carcinoma (Insular Carcinoma) Cellular smears with syncytial fragments, loose aggregates and single cells Cells are small and monomorphic with round nuclei (10um), granular chromatin, nuclear groove +/-, nuclear hole +/- Intense crowding and overlapping of nuclei with scant cytoplasm IHC: Thyroglobulin + Calcitonin - Cytokeratin+

22 Anaplastic carcinoma Cellular aspirates with Syncytial fragments or single cells Large, pleomorphic cells; round, oval or spindled shape with bizarre hyperchromatic nuclei, prominent single or multiple nucleoli Abundant pale, vacuolated or dense cytoplasm; leukocytophagocytosis common Mitoses and necrotic background

23 Atypical Cells of Undetermined Significance (ACUS) The I I don t t know category Cases that do not fit easily into Benign, Follicular Neoplasms, Suspicious for CA, or Malignant categories Examples: Sparsely cellular sample, but predominant microfollicles Atypical cyst lining cells Compromised specimen (obscuring blood, etc) Recommended management: repeat FNA Surgery considered for repeat atypicals

24 ACUS Authors atypical rate % FNA % of ACUS on repeat Yassa et al Yang et al

25 ACUS Authors Malignancy rate after repeated ACUS Yassa et al 24% 2007 Yang et al 19% 2007 (malignancy rate of a single ACUS probably ~5-10%)

26 ACUS Most ACUS (80-96%) resolve into benign or suspicious/malignant results after repeat FNA Malignancy rate (~5-10%) not sufficient to justify immediate surgery Avoid overuse of this category Benchmarks useful to guide laboratories in tracking their ACUS rate

27 Question Should we explicitly state the risk of malignancy associated with the interpretation we are rendering in the body of the report?

28 Conclusion Relative risk of malignancy is implicit in the proposed probabilistic classification Reporting malignancy probability values (either published literature or individual lab) on the report Optional Can be communicated verbally to the clinician

29 The Proposed Bethesda Terminology: Relationship to Clinical Algorithms Category Non-diagnostic Benign ACUS Sus for Foll Neo Sus for Hurthle Neo Sus for Malignancy Risk of Malignancy Management diagnostic? Repeat FNA Benign <1 Follow Sus for Foll Neo 20 Sus for Hurthle Neo 20 Sus for Malignancy Repeat FNA Lobectomy Lobectomy Lobectomy or total thyroidectomy Malignant Total thyroidectomy

30 Summary The NCI conference and website have succeeded in establishing and interdisciplinary informational and educational program dedicated to thyroid FNA They have allowed us to challenge some sacred assumptions and to come to agreement on a variety of issues related to thyroid FNA They provided hope for the establishment of a uniform framework for reporting results that is linked to rational management algorithms

31 The Bethesda Terminology Final Version Insufficient for diagnosis Benign Atypical Cells of Undetermined Significance (ACUS) Suspicious for a Follicular Neo Suspicious for a Hurthle Cell Neo Suspicious for Malignancy Malignant