Case #1. Ed Stelow, MD University of Virginia

Case #1 Ed Stelow, MD University of Virginia

Imagine, If You Will It s 4:30 on Friday Last cytology case A thyroid FNA from outside that did not have any onsite interpretation It is from a 45-year old woman with a 2.5 cm left thyroid nodule You open the tray there are 20 slides that all look bloody, you cannot grossly see any colloid and there are very few dots from your screener

No one will know if you leave it for whomever is on service Monday!

What You Have Blood, a lot 15-20 groups of follicular cells no microfollicles, occasional sheets No nuclear features of papillary CA A little colloid, probably Some siderophages

What are we doing? Screening and diagnostic test Generally we are trying to tell the clinicians which thyroids do notneed to be resected Definitive diagnoses of some lesions help guide therapy (e.g., the diagnosis of papillary carcinoma can lead to a complete thyroidectomy)

What does this mean? Aiming for a high overall sensitivity for the detection of thyroid malignancy Compromise of overall specificity

Assessment of Adequacy Not just so many groups of so many cells!

Assessment of Adequacy (1) All thyroid FNAs must be technically adequate with wellpreserved and well-prepared tissue for interpretation. (2) Any cytological atypia precludes the interpretation of inadequateand, although adequacy can be deemed limited, an interpretation of the atypia must be rendered. (3) An interpretation of an inflammatory process such as thyroiditis does not require a minimum number of follicle cells. (4) An interpretation of a colloid nodule in which there is abundant, thick colloidpresent on the slide(s) does not require a minimum number of follicle cells. (5) In solid nodules producing a follicular cell population with less than abundant colloid, a minimum number of 5-6 groups with a least 10 cells is recommended.

Non-diagnostic Rate Very important although we don t exactly know what it should be Toyota Production System process redesign (adoption of a standardized diagnostic terminology scheme and an immediate interpretation service) The false-negative rate decreased from 41.8% to 19.1% (P =.006) The specimen nondiagnostic rate increased from 5.8% to 19.8% (P <.001) The sensitivity increased from 70.2% to 90.6% (P <.001) Am J Clin Pathol 2006; 126: 585-92.

The Bethesda System for Reporting Thyroid Cytopathology: Implied Risk of Malignancy and Recommended Clinical Management Diagnostic Category Nondiagnostic or Unsatisfactory Risk of Malignancy (%) Usual Management Repeat FNA with ultrasound guidance Benign 0-3% Clinical follow-up Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance Follicular Neoplasm or Suspicious for a Follicular Neoplasm ~ 5-15% Repeat FNA 15-30% Surgical lobectomy Suspicious for Malignancy 60-75% Near-total thyroidectomy or surgical lobectomy Malignant 97-99% Near-total thyroidectomy

ROC Curve for Thyroid FNA Suspicious for Follicular / Hurthle Cell Neoplasm Suspicious Malignancy Benign Atypical / Non-diagnostic Sens sitivity Malignancy 1-Specificity

Criteria / Benign Nodular hyperplasia (Do you want to subclassify?) Thyroiditis (Mostly lymphocytic thyroiditis but includes granulomatous (subacute), etc)

Colloid Nodule Colloid, thick and thin Degeneration with macrophages, hemosiderin macrophages, rare fibrosis, degeneration of follicular cells Usually fewer follicular cells than with a neoplasm and follicles are variably sized (i.e., one will see microfollicles, larger follicles and sheets of follicular cells) Follicular cells will often show Hurthle cell change Smaller, bland nuclei (no features of papillary ca)

Criteria / Atypical Many previously used descriptive diagnoses here Obviously no steadfast criteria, will not be reproducible between observers Adequacy criteria are technically met and the diagnostician thinks it may be benign but is not sure

Re-aspiration of atypical cases Final cytologic diagnosis % Positive for malignancy 1-2 Suspicious for papillary carcinoma 1-13 Suspicious for a follicular neoplasm 6-17 Atypical cells of undetermined 19-31 significance No malignant cells 49-54 Insufficient for diagnosis <1-7 Cancer Cytopathol 2007; 111: 508-16 Cancer Cytopathol 2009; 117: 195-202

Moving Cases from the Atypical Category Cyto Diagnosis Benign Follicular Neoplasm Papillary Carcinoma Benign 8 2 5 Susp for FN 3 6 0 Susp for Mal 0 0 1 Malignancy 0 0 0 Total 11 8 6 Cancer Cytopathol 2009; 117: 298-304.

Criteria / Suspicious for Follicular Neoplasm Follicular or Hurthle cell carcinoma cannot be excluded No nuclear features of papillary carcinoma

Suspicious for Follicular Neoplasm High Cellularity (85%) Paucity of other cell types, i.e, no lymphocytes, no degenerative cells, etc. Uniform follicle size (90% microfollicular) Not too much colloid Cytoplasm moderate amount (low N/C ratios) Delicate cytoplasm with indistinct cell borders

Suspicious for Follicular Neoplasm Occasional granules and vacuoles Nuclei small and round devoid of features of papillary carcinoma Smooth contours Occasional nuclear overlap Occasional small nucleoli

Problem Colloid nodule vs follicular neoplasm

Colloid Nodule VS Follicular Neoplasm Colloid Cells Colloid Nodule Follicular Neoplasm

Colloid Nodule Co olloid Black Hole of Thyroid Aspirations Suspicious for Follicular Neoplasm Follicular Cells

Favor Colloid Nodule Clinical - enlarged thyroid, multiple nodules Cytology lower cellularity, more colloid, degeneration (hemorrhage, macrophages, etc.), variable follicle size

How well do we draw the line? Case # Observer 1 Observer 2 Observer 3 Observer 4 Observer 5 1 Colloid Nod Colloid Nod Colloid Nod F Lesion Colloid Nod 2 Colloid Nod Colloid Nod Colloid Nod Colloid Nod Colloid Nod 3 F Neoplasm F Lesion F Neoplasm F Lesion F Neoplasm 4 Colloid Nod Colloid Nod Colloid Nod Colloid Nod Colloid Nod 5 Colloid Nod Colloid Nod Colloid Nod F Lesion F Lesion 6 Non-dx F Lesion Colloid Nod F Lesion Colloid Nod 7* F Neoplasm F Neoplasm F Neoplasm Papillary CA Papillary CA 8 Non-dx F Lesion F Neoplasm F Lesion F Lesion 9 F Neoplasm F Neoplasm F Neoplasm F Lesion Colloid Nod 10 Colloid Nod Colloid Nod Colloid Nod Colloid Nod Colloid Nod 11 Colloid Nod Colloid Nod Colloid Nod Colloid Nod Non-dx 12 F Lesion F Neoplasm F Neoplasm F Lesion F Neoplasm 13 F Neoplasm F Lesion F Neoplasm F Lesion F Lesion 14 Colloid Nod Colloid Nod Colloid Nod Colloid Nod Colloid Nod 15 F Lesion F Neoplasm F Neoplasm F Lesion F Lesion 16 F Lesion F Lesion Colloid Nod Colloid Nod F Lesion 17 Colloid Nod Colloid Nod Colloid Nod Colloid Nod Non-dx 18 Colloid Nod Colloid Nod Colloid Nod Colloid Nod Colloid Nod 19 Colloid Nod Colloid Nod Colloid Nod Colloid Nod Colloid Nod 20 Non-dx F Lesion Colloid Nod Colloid Nod Colloid Nod *The 3 observers for case 7 who diagnosed it as follicular neoplasm noted features suspicious for papillary carcinoma. Black- Cases deemed to not require resection. Red- Cases deemed to require resection. Am J Clin Pathol 2005; 124: 239-44

IV was somewhat poor before data was collapsed (kappa=0.35). When data was collapsed based on triaging, IV was relatively good (kappa=0.65) Number of follicular cells and amount of colloid correlated with triage recommendation (p<0.05)

Is there a real difference and can it be recognized histologically?? Adenomatoid Nodule Goiter Can be solitary Follicular adenoma Single Nodule Can occur in goiter Different from surrounding thyroid Fibrotic Follicular pleomorphism Can be rather monomorphic Degeneration May not be prominent Hyperplasia Up to 70% clonal Encapsulated Follicular monomorphism Can be pleomorphic Was it FNA d? Clonal neoplasm

Can the difference be recognized even Interobserver agreement. histologically? Am J Surg Pathol 2002; 26: 1508-14.

Colloid / Hyperplastic Nodule Follicular Neoplasm Increased Cellularity Decreased Colloid Other features, e.g., lack of degeneration, abundance of microfollicles, etc

How do we do? Cancer Cytopathol 2000;90:357-63.

Follicular Variant of Papillary Carcinoma 12/15 dx d as FVPTC were found to be so by histology 12/13 cases of FVPTC were dx d by cytology Overlap Grooves Inclusions Nucleolus 1 Thick Colloid 2 Giant Cells Psammoma 13/13 13/13 2 3 /13 2/13 8/13 3/13 0/13 1 2 cases had prominent nucleoli; All other had inconspicuous nucleoli. 2 Described as blobs or chunks. 3 The single case with a lymph node metastasis had nuclear pseudoinclusions. Cancer Cytopathol 1998; 84: 235-44.

What does the diagnosis of suspicious for follicular neoplasm mean? With strict criteria in place for the diagnosis of follicular carcinoma and the exclusion of papillary carcinoma, follicular carcinoma had come to represent less than 5% of thyroid malignancies. Dx (n) Non-neoplastic Adenoma Follicular CA Papillary CA Yang 1 FN (147) 21.8% 62.6% 10.2% 5.4% Aguilar-Diosdado 2 FP (40) 40% 15% 15% 30% Baloch 3 FN (122) 47% 23% 9% 20% Goellner 4 FN (202) 4% 96% Ravetto 5 FN (888) 30% 58% 9% 3% Yassa 6 SFN (268) 10% 14% Everts 7 FN (336) 16% 71% 5% 7% FN: Follicular Neoplasm; FP: Follicular Proliferation; SFN: Suspicious for Follicular Neoplasm. 1. Cancer Cytopathol 2003;99:69-74. 2. Acta Cytologica 1997;41:677-82. 3. Diagn Cytopathol 2002;26:41-4. 4. Acta Cytologica 1987;31:587-90. 5. Cancer Cytopathol 2000;90:357-63 6. Cancer Cytopathol 2007; 111: 508-16 7. Cancer Cytopathol 2008; 111: 395A

Cyst Fluid 76 cyst fluids with follow-up; 10 with malignancies > 1 cm (about 1% of all cases labeled as cyst fluid) Of 66 benign cases, 49 had inadequate numbers of follicular cells and 2 had atypia Of 10 malignant cases, 5 had inadequate numbers of follicular cells and 3 had atypia Colloid, macrophages, siderophages, and blood not helpful for predicting malignancy Cancer Cytopathol 2009; 117:305-10.

Papillary / Follicular Carcinoma Galectin-3 CK19 HBME1 CC44v6 RET Other

Galectin-3 and HBME1 Disease Galectin-3 HBME1 Normal 0% 0% Nodular Hyperplasia 0-55% 0-27% Chronic Lymphocytic Thyroiditis 50-100% Follicular Adenoma 0-47% 0-27% Papillary Thyroid Carcinoma 64-100% 55-100% Follicular Thyroid Carcinoma 44-95% 50-100%

Molecular Studies BRAF RAS (NRAS, KRAS, HRAS) RET/PTC PAX8/PPARgamma

Nikiforov, Y. E. et al. J Clin Endocrinol Metab 2009;94:2092-2098

J Clin Endocrinol Metab 2009; 94: 2092-8

What You Have Blood, a lot 15-20 groups of follicular cells no microfollicles, occasional sheets No nuclear features of papillary CA A little colloid, probably Some siderophages

My Diagnosis Colloid Nodule (see note) Note: This study is LIMITED BY obscuring blood and scant cellularity. Re-aspiration could be considered if the lesion is clinically worrisome.

Thank You

Case #1 Ed Stelow, MD Introduction Thyroid fine needle aspiration (FNA) specimens are some the most commonly seen samples at institutions with busy FNA clinics. The purpose, in general, is to diagnose patients with benign disease so that they can avoid surgery. Thus, it functions mostly as a screening test. Here, it works quite well. It is estimated that at one time less than 20% of resected thyroid glands had malignancies and now more than 50% do! The problem It is estimated that more than 30,000,000 people in the United States have thyroid nodules greater than 1 cm in size. On the other hand, there are less than 30,000 thyroid malignancies found in the US each year and less than 2,000 die of thyroid malignancy. 30,000,000 Patients with Nodules >1cm 30,000 Thyroid Malignancies <2,000 Deaths to Thyroid C ancer The incidence of thyroid malignancy has nearly double in the last 20 years. This likely has to do with the increased use of thyroid ultrasound and pathologists increased diagnosis (recognition) of follicular variant of papillary carcinoma. What Are We Doing? Screening and diagnostic test Generally we are trying to tell the clinicians which thyroids do not need to be resected Definitive diagnoses of some lesions help guide therapy (e.g., the diagnosis of papillary carcinoma can lead to a complete thyroidectomy) Thus Aiming for a high overall sensitivity for the detection of thyroid malignancy 1

Compromise of overall specificity Case #1 Ed Stelow, MD Adequacy Adequacy will differ from center to center based on many factors More passes, more adequacy Assessment of Adequacy Not just so many groups of so many cells! (1) All thyroid FNAs must be technically adequate with well-preserved and well-prepared tissue for interpretation. (2) Any cytological atypia precludes the interpretation of inadequate and, although adequacy can be deemed limited, an interpretation of the atypia must be rendered. (3) An interpretation of an inflammatory process such as thyroiditis does not require a minimum number of follicle cells. (4) An interpretation of a colloid nodule in which there is abundant, thick colloid present on the slide(s) does not require a minimum number of follicle cells. (5) In solid nodules producing a follicular cell population with less than abundant colloid, a minimum number of 5-6 groups with a least 10 cells is recommended. (6) Thyroid cysts with little to no follicular cells should be interpreted as unsatisfactory / non-diagnostic; a recommendation for correlation with the cyst size and complexity and a disclaimer about the possibility of cystic papillary carcinoma Nomenclature The Bethesda System for Reporting Thyroid Cytopathology: Implied Risk of Malignancy and Recommended Clinical Management Diagnostic Category Nondiagnostic or Unsatisfactory Risk of Malignancy (%) Usual Management Repeat FNA with ultrasound guidance Benign 0-3% Clinical follow-up Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance Follicular Neoplasm or Suspicious for a Follicular Neoplasm ~ 5-15% Repeat FNA 15-30% Surgical lobectomy Suspicious for Malignancy 60-75% Near-total thyroidectomy or surgical lobectomy Malignant 97-99% Near-total thyroidectomy 2

Case #1 Ed Stelow, MD Criteria Benign: Nodular Hyperplasia VS Colloid, thick and thin Degeneration with macrophages, hemosiderin macrophages, rare fibrosis, degeneration of follicular cells Usually fewer follicular cells than with a neoplasm and follicles are variably sized (i.e., one will see microfollicles, larger follicles and sheets of follicular cells) Follicular cells will often show Hurthle cell change Smaller, bland nuclei (no features of papillary ca) Suspicious for Follicular Neoplasm High Cellularity (85%) Paucity of other cell types, i.e, no lymphocytes, no degenerative cells, etc. Uniform follicle size (90% microfollicular) Not too much colloid Cytoplasm moderate amount (low N/C ratios) Delicate cytoplasm with indistinct cell borders Occasional granules and vacuoles Nuclei small and round devoid of features of papillary carcinoma Smooth contours Occasional nuclear overlap Occasional small nucleoli Differential Diagnoses Colloid / Hyperplastic Nodule Follicular Neoplasm Increased Cellularity Decreased Colloid Other features, e.g., lack of degeneration, abundance of microfollicles, etc 3

Case #1 Ed Stelow, MD OR Conclusions To distinguish cases of benign hyperplasia and suspicious for follicular neoplasm we use amount of colloid and number of follicular cells Often we have to us other criteria including degeneration and heterogeneity of follicular size Don t be afraid to call cases non-diagnostic! 4

Case #1 Ed Stelow, MD References: 1. Baloch Z, Layfield LJ: Quest for a uniform cyto-diagnostic approach to thyroid aspirates: a consensus proposal. Diagn Cytopathol 2006, 34:85-6 2. Baloch ZW, Cibas ES, Clark DP, et al.: The National Cancer Institute Thyroid fine needle aspiration state of the science conference: a summation. Cytojournal 2008, 5:6 3. Baloch ZW, Fleisher S, LiVolsi VA, et al.: Diagnosis of "follicular neoplasm": a gray zone in thyroid fine-needle aspiration cytology. Diagn Cytopathol 2002, 26:41-4 4. Baloch ZW, LiVolsi VA, Asa SL, et al.: Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: a synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008, 36:425-37 5. Cibas ES, Ali SZ: The Bethesda system for reporting thyroid cytopathology. Am J Clin Pathol 2009, 132:658-65 6. Clark DP, Faquin WC: Thyroid Cytopathology. New York, Springer, 2005 7. Franc B, de la Salmoniere P, Lange F, et al.: Interobserver and intraobserver reproducibility in the histopathology of follicular thyroid carcinoma. Hum Pathol 2003, 34:1092-100 8. Goellner JR, Gharib H, Grant CS, et al.: Fine needle aspiration cytology of the thyroid, 1980 to 1986. Acta Cytol 1987, 31:587-90 9. Hirokawa M, Carney JA, Goellner JR, et al.: Observer variation of encapsulated follicular lesions of the thyroid gland. Am J Surg Pathol 2002, 26:1508-14 10. Ravetto C, Colombo L, Dottorini ME: Usefulness of fine-needle aspiration in the diagnosis of thyroid carcinoma: a retrospective study in 37,895 patients. Cancer 2000, 90:357-63 11. Stelow EB, Bardales RH, Crary GS, et al.: Interobserver variability in thyroid fine-needle aspiration interpretation of lesions showing predominantly colloid and follicular groups. Am J Clin Pathol 2005, 124:239-44 12. Yang J, Schnadig V, Logrono R, et al.: Fine-needle aspiration of thyroid nodules: a study of 4703 patients with histologic and clinical correlations. Cancer 2007, 111:306-15 5

Case #1 Ed Stelow, MD 13. Yassa L, Cibas ES, Benson CB, et al.: Long-term assessment of a multidisciplinary approach to thyroid nodule diagnostic evaluation. Cancer 2007, 111:508-16 14. http://thyroidfna.cancer.gov/pages/conclusions/ 6