1. Thyroid Pathology Last Updated Oct. 5, 2006 Jamie Tibbo Reviewed with Dr. Jane Thomas

2. Overview Benign Pathology –Hashimoto’s Thyroiditis –Grave’s Disease –Multi-nodular goiter –Follicular Adenoma Malignant Pathology –Papillary Carcinoma –Follicular Carcinoma –Medullary Carcinoma –Anaplastic Carcinoma

3. Normal thyroid tissue Normal thyroid tissue with follicles filled with colloid. Thyroid cells form follicles, spheres of epithelial cells (always single-layered in health, usually more-or-less cuboidal, variably tall or short). The C-cells (parafollicular cells) of the thyroid are visible between the follicles

4. Normal thyroid tissue

5. Hashimoto’s Thyroiditis an autoimmune disease in which the immune system reacts against a variety of thyroid antigens overriding feature of is progressive depletion of thyroid epithelial cells (thyrocytes), which are gradually replaced by mononuclear cell infiltration and fibrosis

6. Hashimoto’s-Pathogenesis Sensitization of autoreactive CD4+ T-helper cells to thyroid antigens appears to be the initiating event. The effector mechanisms for thyrocyte death include the following: –CD8+ cytotoxic T cell-mediated cell death: CD8+ cytotoxic T cells may cause thyrocyte destruction by one of two pathways: exocytosis of perforin/granzyme granules or engagement of death receptors, specifically CD95 (also known as Fas) on the target cell –Cytokine-mediated cell death: CD4+ T cells produce inflammatory cytokines such as IFN-γ in the immediate thyrocyte milieu, with resultant recruitment and activation of macrophages and damage to follicles. –Binding of antithyroid antibodies (anti-TSH receptor antibodies, antithyroglobulin, and antithyroid peroxidase antibodies) followed by antibody-dependent cell-mediated cytotoxicity (ADCC) Reference: Kumar: Robbins and Cotran: Pathologic Basis of Disease, 7th ed., Copyright © 2005 Saunders

7. Hashimoto’s- Pathogenesis Reference: Kumar: Robbins and Cotran: Pathologic Basis of Disease, 7th ed., Copyright © 2005 Saunders

8. Hashimoto’s Thyroiditis Lymphocytic infiltrate in the thyroid, with lymphoid follicle formation and fibrosis. Presence of oncocytes-always has oncocytic metaplasia

9. Hashimoto’s Thyroiditis Reference: Kumar: Robbins and Cotran: Pathologic Basis of Disease, 7th ed., Copyright © 2005 Saunders

10. Grave’s Disease

12. Multi-nodular Goiter

14. Follicular Adenoma adenomas are not forerunners of cancer except in rare instances small proportion produce thyroid hormones and cause clinically apparent thyrotoxicosis Typically a solitary, spherical, encapsulated lesion that is well demarcated from the surrounding thyroid parenchyma

15. Follicular Adenoma Gross Specimen

16. Follicular Adenoma Microscopic Microscopically, the constituent cells often form uniform-appearing follicles that contain colloid The follicular growth pattern within the adenoma is usually quite distinct from the adjacent non-neoplastic thyroid –distinguishing feature b/w adenomas and MNG- nodular and uninvolved thyroid parenchyma may have similar growth patterns

17. Follicular Adenoma Microscopic Mitotic figures are rare papillary change is not a typical feature of adenomas and, if extensive, should raise the suspicion of an encapsulated papillary carcinoma Occasionally, the neoplastic cells acquire brightly eosinophilic granular cytoplasm (oxyphil or Hürthle cell change)

18. Follicular adenoma H/E preparation x 100 Follicular carcinoma account for less than 10% Follicular Adenoma Microscopic

19. well-differentiated follicles resembling normal thyroid parenchyma Follicular Adenoma Microscopic

20. Follicular Adenoma with Oncocytic or Hurthle Cell Change Also known as: –Hurthle Cell Adenoma Occasionally, the neoplastic cells acquire brightly eosinophilic granular cytoplasm (oxyphil or Hürthle cell change) –Eosinophilic granules due to enlarged, bizarre mitochondria

21. Follicular Adenoma with Oncocytic or Hurthle Cell Change

22. Thyroid Neoplasms with Follicular Architecture Non-Neoplastic: –Hyperplastic nodule in Goiter Neoplastic: –Follicular adenoma –Follicular carcinoma –Follicular variant Papillary carcinoma

23. Papillary Thyroid Carcinoma solitary or multifocal lesions Some tumors well-circumscribed and encapsulated; others infiltrate the adjacent parenchyma with ill-defined margins may contain areas of fibrosis and calcification and are often cystic

24. Papillary Thyroid Carcinoma can contain branching papillae having a fibrovascular stalk covered by a single to multiple layers of cuboidal epithelial cells NUCLEI of papillary carcinoma cells contain finely dispersed chromatin, which imparts an optically clear or empty appearance, giving rise to the designation ground glass or Orphan Annie eye nuclei invaginations of the cytoplasm may in cross-sections give the appearance of intranuclear inclusions ("pseudo-inclusions") or intranuclear grooves

25. Papillary Thyroid Carcinoma the diagnosis of papillary carcinoma is based on these nuclear features even in the absence of papillary architecture. Concentrically calcified structures termed psammoma bodies are often present within the lesion, usually within the cores of papillae –These structures are almost never found in follicular and medullary carcinomas, and so, when present, they are a strong indication that the lesion is a papillary carcinoma –whenever a psammoma body is found within a lymph node or perithyroidal tissues, a hidden papillary carcinoma must be considered

26. Papillary Thyroid Carcinoma Foci of lymphatic invasion by tumor are often present, but involvement of blood vessels is relatively uncommon Metastases to adjacent cervical lymph nodes are estimated to occur in up to half the cases ???

27. Papillary Thyroid Carcinoma

28. Papillary Thyroid Cancer calcified sphere, or psammoma body Papillary thyroid carcinoma accounts for about 80% of all thyroid carcinomas

29. Papillary Thyroid Cancer Psammoma body within a papillary cancer. large clear areas within the nuclei which look like "Little Orphan Annie" eyes are circled in blue. Although these nuclear features are characteristic of papillary carcinoma, they are not pathognomonic Papillary cancer (low resolution). Notice the frond- like projections.

30. Papillary Thyroid Carcinoma Ground Glass Nuclei

31. Papillary Thyroid Carcinoma Psammoma Body

32. Papillary Thyroid Cancer- Variants Encapsulated variant –constitutes about 10% of all papillary neoplasms –has an excellent prognosis Follicular variant –has the characteristic nuclei of papillary carcinoma but has an almost totally follicular architecture Tall cell variant –tall columnar cells with intensely eosinophilic cytoplasm lining the papillary structures –Occur in older individuals and are usually large with prominent vascular invasion, extrathyroidal extension, and cervical and distant metastases

33. Papillary Thyroid Cancer- Variants Diffuse sclerosing variant –occurs in younger individuals, including children. These tumors do not present with a mass, but rather with a bilateral goiter –nodal metastases are present in almost all cases Hyalizing trabecular tumors –includes both adenomas and carcinomas, have recently been reconsidered as a variant of papillary carcinomas, based on the presence of ret/PTC gene rearrangements in 30% to 60% of these tumors

34. Follicular Thyroid Carcinoma 2nd most common thyroid cancer –10% to 20% of all thyroid cancers tend to present in women, and at an older age than do papillary carcinomas –peak incidence in the forties and fifties incidence increased in areas of dietary iodine deficiency, suggesting that in some cases, nodular goiter may predispose to the development of the neoplasm high frequency of RAS mutations in follicular adenomas and carcinomas suggests that the two may be related tumors

35. Follicular Thyroid Carcinoma Gross Specimen Tumor has light-tan appearance Contains small foci of hemorrhage

36. Follicular Thyroid Carcinoma Microscopic Features Most composed of fairly uniform cells forming small follicles containing colloid  appearance of normal thyroid In other cases, follicular differentiation may be less apparent –may be nests or sheets of cells without colloid Occasional tumors are dominated by cells with abundant granular, eosinophilic cytoplasm (Hürthle cells). nuclei lack the features typical of papillary carcinoma psammoma bodies are NOT present

37. Follicular Thyroid Carcinoma Microscopic Features Follicular lesions with nuclear features typical of papillary carcinomas should be treated as papillary cancers Nuclear features NOT helpful in distinguishing follicular adenomas from minimally invasive follicular carcinomas –Requires extensive sampling of the tumor-thyroid capsule interface to exclude capsular or vascular invasion. the presence of tumor plugs within intratumoral blood vessels has little prognostic significance Unlike in papillary cancers, lymphatic spread is distinctly uncommon in follicular cancers

38. Follicular Thyroid Carcinoma

39. Follicular Adenoma No Capsular invasion Compressed normal thyroid usu. present external to capsule Follicular Carcinoma Capsular invasion present May have vascular invasion

40. Medullary Thyroid Cancer (MTC) arise from the parafollicular C cells in the thyroid Familial medullary thyroid carcinomas occur in multiple endocrine neoplasia type 2 (MEN-2) and are associated with germ-line RET protooncogene mutations RET mutations are detectable in approximately 95% of families with MEN-2; in the remaining few cases, the mutations may arise in hard-to-detect promoter sequences or intronic sites. RET mutations are also seen in nonfamilial (sporadic) medullary thyroid cancers. Chromosomal rearrangements involving RET, such as the ret/PTC translocations reported in papillary cancers, are not seen in medullary carcinomas.

41. Medullary Thyroid Carcinoma Gross Specimen Solid pattern of growth Do not have connective tissue capsules

42. Medullary Thyroid Carcinoma Microscopic Features Immunohistochemical anti-calcitonin antibody stain of a medullary carcinoma showing strong red positivity

43. Medullary Thyroid Carcinoma Microscopic Features composed of polygonal to spindle-shaped cells –may form nests, trabeculae, and even follicles Small, more anaplastic cells are present in some tumors and may be the predominant cell type Acellular amyloid deposits, derived from altered calcitonin molecules, are present in the adjacent stroma in many cases Electron microscopy reveals variable numbers of membrane-bound electron-dense granules within the cytoplasm of the neoplastic cells.

44. Medullary Thyroid Carcinoma Microscopic Features Familial medullary cancers –presence of multicentric C-cell hyperplasia in the surrounding thyroid parenchyma, a feature that is usually absent in sporadic lesions

45. Medullary Thyroid Carcinoma Microscopic Features Amyloid stroma

46. Medullary Thyroid Carcinoma Microscopic Features

48. Anaplastic Carcinoma undifferentiated tumors of the thyroid follicular epithelium aggressive tumors mortality rate approaching 100% fewer than 5% of all thyroid cancers Mean Age = 65 yrs half of the patients have a history of multinodular goiter 20% of the patients with these tumors have a history of differentiated carcinoma 20% to 30% have a concurrent differentiated thyroid tumor, frequently a papillary carcinoma

49. Anaplastic Thyroid Carcinoma Microscopic Features highly anaplastic cells, which may take one of several histologic patterns: 1.large, pleomorphic giant cells, including occasional osteoclast-like multinucleate giant cells 2.spindle cells with a sarcomatous appearance; 3.mixed spindle and giant cells; and 4.small cells resembling those seen in small cell carcinomas arising at other sites.

50. Anaplastic Thyroid Carcinoma Microscopic Features Anaplastic carcinoma histology H/E preparation x 200