Sylvia L. Asa, MD, PhD Pathologist-in-Chief Medical Director Laboratory Medicine Program University Health Network, Toronto

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1 Minimizing in Thyroid Grey Zones Pathology Sylvia L. Asa, MD, PhD Pathologist-in-Chief Medical Director Laboratory Medicine Program University Health Network, Toronto

2 Controversies Nodules in Thyroiditis Sporadic Nodular Goitre/Follicular nodular disease Papillary adenomas Follicular Variant Papillary Carcinoma/Follicular carcinoma Capsular Invasion Extrathyroidal Extension Vascular invasion

3 Controversies Nodules in Thyroiditis Sporadic Nodular Goitre/Follicular nodular disease Papillary adenomas Follicular Variant Papillary Carcinoma/Follicular carcinoma Capsular Invasion Extrathyroidal Extension Vascular invasion

4 Hashimoto s Thyroiditis: Morphology Lymphoplasmacytic infiltrate with follicle formation

5 Hashimoto s Thyroiditis: Cytology Oncocytic or Hürthle cell metaplasia

6 Hashimoto s Thyroiditis: Cytology Oncocytic or Hürthle cell metaplasia With atypia! IS THIS DYSPLASIA?

7 Nodules in Thyroiditis

8 Not encapsulated Cellular Bland cytology? Due to TGI? Destruction of follicular epithelium ± regeneration Hyperplasia in Thyroiditis

9 Carcinoma in Thyroiditis Nuclear features of papillary carcinoma

10 Controversies Nodules in Thyroiditis Sporadic Nodular Goitre/ /Follicular nodular disease Papillary adenomas Follicular Variant Papillary Carcinoma/Follicular carcinoma Capsular Invasion Extrathyroidal Extension Vascular invasion

11 Sporadic Nodular Goiter Multinodular colloid goiter Occasionally associated with hyperthyroidism Plummer s disease Etiology and pathogenesis NOT understood

12 Thyroid Morphology Multifocal, bilateral, assymetrical nodularity variable architecture and cytology 1 3 2

13 Follicular Nodular Disease Colloid-rich, variable architecture & cytology, Sanderson s polsters Focal degeration, stellate scar, hemorrhage & hemosiderin

14 ollicular Nodular Disease: s It Hyperplasia?

15 Adenomatoid Nodule Encapsulated Uniform architecture B land cytology Different from surrounding gland Compresses surrounding gland Is it adenoma?

16 Definitions: Hyperplasia vs Neoplasia An increase in the number of cells in an organ or tissue that is induced by known stimuli A controlled process that stops when the environmental stimulus is removed A proliferation of cells that exceeds and is uncoordinated with that of normal tissues An uncontrolled process that persists independent of environmental stimulation

17 Classical Criteria: Hyperplasia vs Neoplasia Multiple Poorly encapsulated Architectural heterogeneity Cytological heterogeneity Comparable areas in adjacent gland No compression of surrounding gland Solitary Encapsulated Uniform architecture Cytological homogeneity Different from surrounding gland Compresses surrounding gland

18 ClonalityPatterns in Sporadic Nodular Goiter: Multiple Monoclonal Nodules Apel et al; Diagn. Mol. Pathol. 1995; 42:

19 Clonality of Nodules in Sporadic Nodular Goiter Polyclonal OR Monoclonal i.e. hyperplastic OR neoplastic Nodules may show LOH or aberrant methylation i.e. features of neoplas sia Multiple nodules from a single goiter exhibit activation of the same allele? predisposition?diagnostic criteria? Hyperplasia-neopla asia sequence Apel et al; Diagn. Mol. Pathol. 1995; 42:

20 Terminology When Not Goiter: Follicular Nodular Disease Avoids controversy Avoids misunderstanding Clarifies lack of understanding

21 Follicular Nodular Disease: Pearls Follicular nodular disease is common Some may be hyperplasia, but much is multifocal neoplasia Nodules in FND/SNG are usually benign Nodules in FND/SNG may be malignant! Watch out for generation, but.. Watch out for cancer!

22 Controversies Nodules in Thyroiditis Sporadic Nodular Goitre/Follicular nodular disease Papillary adenomas Follicular Variant Papillary Carcinoma/Follicular carcinoma Capsular Invasion Extrathyroidal Extension Vascular invasion

23 Follicular Adenoma with Papillary Architecture: Papillary Adenoma Hot nodules on scan Biologically benign Papillary architecture but benign cytology Solitary or Plummer s Molecular features: monoclonal activating mutations of TSH receptor or Gsα

24 G-Protein Activation and Action Ligand OFF α β γ Receptor GDP Effector GTP α β γ Receptor GTP Effector GDP β γ α Receptor Effector GDP GTP Receptor β γ α GTP Effector ON

25 Controversies Nodules in Thyroiditis Sporadic Nodular Goitre/Follicular nodular disease Papillary adenomas Follicular Variant Papillar ry Carcinoma/Follicular carcinoma Capsular Invasion Extrathyroidal Extension Vascular invasion

26 Follicular Adenoma or Papillary Carcinoma?

27 The Answer: 5 Years Later Do we overcall many to catch this one? Do we undercall many and miss this one? Do we find scientific markers to predict behavior?

28 Follicular Adenoma A follicular neoplasm that: does NOT exhibit invasive features and does NOT have nuclear features of papillary carcinoma

29 Follicular Adenoma vscarcinoma Distinguished by features of invasion

30 Follicular Variant PTC A follicular neoplasm of thyroid defined by the presence of a unique set of nuclear features: 1. Enlarged, overlapping nuclei 2. Pale vacuolated nucleoplasm with peripheral margination of chromatin 3. Irregular nuclear membrane 4. Nuclear grooves 5. Nuclear pseudoinclusions

31 3D-Reconstruction of PTC Nuclei Virchows Arch (2004) 444:

32 Emerin Identifies Nuclear Features Asioli et al Histopathology. 2009;54:571-9 Asioli et al Virchows Archiv 2010:457:43-51

33 FVPTC vsfollicular Carcinoma Both differentiated thyroid malignancy Both follicular architecture Similar biologic behavior Similar genetic profiles Are they really the same thing? Are the criteria wrong? Does the distinctionn matter?

34 Markers of Thyroid HBME-1 Malignancy: Monoclonal antibody Unknown epitope Unknown significance Identified in 60% of thyroid malignancies, not in normal or benign lesions

35 Markers of Thyroid Malignancy: Galectin-3 31kD β-galactosidebinding lectin High percentage of malignant thyroid tumors, not in normal or benign lesions

36 Markers of Papillary Carcinoma: CK19 one of many keratins identified diffusely in 60% of papillary carcinomas also seen in reactive nontumorous thyroid Raphael et al, Mod Pathol. 1995;8(8):870-2

37 Controversies Nodules in Thyroiditis Sporadic Nodular Goitre/Follicular nodular disease Papillary adenomas Follicular Variant Papillary Carcinoma/Follicular carcinoma Capsular Invasion Extrathyroidal Extension Vascular invasion

38 Capsules in Endocrine Tissues The pituitary and adrenals have capsules

39 Capsules in Endocrine Tissues The thyroid and parathyroid don t The pancreatic islets, adrenal medulla and other dispersed endocrine cells don t

40 Normal Thyroid Histology Mete et al, Ann Surg Oncol 2010, 17(2): 386

41 Capsules in Thyroid Tumors Thyroid tumors may NOT have a capsule Capsular invasion cannot be evaluated Invasion must be assessed as infiltration into surrounding parenchyma, perineural or vascular involvement

42 Capsular Invasion by Thyroid Neoplasms Refers to TUMOR capsule Generally accepted as evidence of malignanc cy IF there is a capsule in thyroid follicular neoplasms

43 Definitions: Capsular Invasion Nests, cords or cells in capsule Islands in capsule associated with perpendicular rupture of collagen In capsule beyond bulk of lesion Total thickness into adjacent parenchyma?? Artefactual trapping?? postfna

44 Capsular Invasion Most agree with Yes Many agree with No Few agree with Not yet FROM: Chan JKC. The thyroid gland. In: Fletcher CDM, ed. Diagnostic Histopathology of Tumours. 3rd ed. Edinburgh; Churchill Livingstone Elsevier; 2007:1018.

45 Classification of Thyroid Carcinoma Minimally invasive carcinoma up to 100% 10 year survival Widely invasive carcinoma 25-45% 10 year survival What is Minimally vs Widely Invasive? -You can see wide invasion grossly!

46 Controversies Nodules in Thyroiditis Sporadic Nodular Goitre/Follicular nodular disease Papillary adenomas Follicular Variant Papillary Carcinoma/Follicular carcinoma Capsular Invasion Extrathyroidal Extension Vascular invasion

47 Extra-Thyroidal Invasion Since the thyroid has no capsule and normal thyroid can be found in fat: Skeletal Muscle invasion is the hallmark of ETE in the lateral lobes The interpretation of ETE is problematic in the isthmus because of the normal proximity of muscle and thyroid follicles (Soemmering muscle)

48 What is the Significance of Extra-Thyroidal Invasion? Primary Tumor (pt) ptx: Cannot be assessed pt0: No evidence of primary tumor pt1: Tumor size 2 cm or less, limited to thyroid pt1a: Tumor 1 cm or less in greatest dimension limited to the thyroid. pt1b: Tumor more than 1 cm but not more than 2 cm in greatest dimension, limited to the thyroid pt2: Tumor more than 2 cm, but not more than 4 cm, limited to thyroid pt3: Tumor more than 4 cm limited to thyroid or any tumor with minimal extrathyroid extension (eg, extension to sternothyroid muscle or perithyroid soft tissues) pt4a: Moderately advanced disease. Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus or recurrent laryngeal nerve pt4b: Very advanced disease. Tumor invades prevertebralfascia or encases carotid artery or mediastinal vessels Maybe because this is not really ETE??

49 Controversies Nodules in Thyroiditis Sporadic Nodular Goitre/Follicular nodular disease Papillary adenomas Follicular Variant Papillary Carcinoma/Follicular carcinoma Capsular Invasion Extrathyroidal Extension Vascular invasion

50 PseudoVascularInvasion by Thyroid Neoplasms 1 1. Tumor cells bulging into an endothelial-lined lumen 2. Intravascular tumor nests covered with endothelium 3. Tumor casts within vessel lumen 3? artificial implantation 2 Mete and Asa, Modern Pathol Dec 2011

51 True Vascular Invasion by Thyroid Neoplasms Intravascular tumor associated with thrombus Rigid criteria predict high likelihood of metastasis EVEN in differentiated thyroid carcinoma Mete and Asa, Modern Pathol,Dec 2011

52 Angioinvasionin Differentiated Thyroid Carcinoma Must be defined properly Must be distinguishedd from lymphatic invasion The term lymphovascular invasion should be discarded in this field! * Is predictive of aggressive behavior * the CAP worksheets need to be revised

53 Controversies in Thyroid Pathology Controversyis a state of prolonged public dispute or debate, usually concerning a matter of opinion It is time for some science!

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