1. Tumors of the Thyroid Gland
Noel A. Brownlee, M.D., Ph.D.
Go from common to rare in presentation

2. Outline Solitary thyroid nodules
The role of fine needle aspiration biopsy in clinical work-up
Follicular adenoma
Thyroid cancer
Papillary carcinoma - Metastatic tumors
Follicular carcinoma
Medullary carcinoma
Anaplastic carcinoma
Insular carinoma

3. Solitary thyroid nodules

4. Solitary thyroid nodules
A palpable, discrete swelling within an otherwise apparently normal thyroid gland.
Estimated incidence: 1-10% in U.S., but significantly higher in goitrous regions (endemic iodide deficiency areas)
Single nodules are approximately 4 x more common in women than men.
Incidence increases with age.

5. Benign or Malignant
The majority of solitary nodules are benign and include multinodular goiter, simple cysts, or foci of thyroiditis
Less than 1% of solitary thyroid nodules are malignant, but nearly 15,000 new cases of thyroid carcinoma are diagnosed each year in U.S.
Most carcinomas are indolent: up to 90% survival at 20 years.
Anaplastic and medullary Nodules have a lower survival

6. Clinical Evaluation of Thyroid Nodules
In general, solitary nodules are more likely to be neoplastic than are multiple nodules.
Nodules in younger patients tend to be more likely neoplastic than in older patients.
Nodules in men are more likely to be neoplastic than those in women.
A history of radiation therapy to neck region is associated with an increased incidence of thyroid malignancy
Neoplastic in women are more likely to be malignant

7. Clinical Evaluation of Thyroid Nodules
“Hot” nodules (i.e. functional nodules) that take up radioactive iodine in imaging studies are significantly more likely to be benign than malignant.
“Cold” nodules are more likely to be malignant.
Ultimately, fine needle aspiration biopsy or thyroid resection provides most definitive information.

8. Nuclear Medicine Thyroid Scan Nuclear Scintigraphy with I-123
Hyperplastic (high metabolic activity) will light up as red or black on regular film
Cold would take up less radioactive iodin

9. Laboratory Evaluation
Evaluating TSH, T4, and T3 is helpful in assessing for hypo- and hyperthyroidism.
In most cases of solitary thyroid nodules, the TSH level is normal.

10. Fine Needle Aspiration Biopsy
Useful in distinguishing between benign and malignant thyroid nodules by examination of cytologic features microscopically.
Plentiful colloid, regular appearing follicular cells, and macrophages favor benign
Cell clusters with minimal colloid and cells with nuclear enlargement, nuclear irregularity (grooves), and intracytoplasmic nuclear inclusions consistent with papillary thyroid carcinoma (nuclear detail best assessed on Pap stains).
Pap smear does well with thyroid tissue

11. Thyroid Fine Needle Aspiration

12. Thyroid FNA – Diff Quik stained slide
Not great to look at nuclear change

13. Thyroid FNA – Papanicolaou stained slide
Orderlyness here (suggest benign)

14. Follicular Adenoma of Thyroid Gland
Benign, encapsulated (hints at benign) tumor
Follicular cell differentiation
Resembles normal thyroid tissue
Typically a cold nodule
Typically seen in euthyroid adult
The most common thyroid neoplasm
Females are more commonly affected than males. F:M ratio = 7:1.
Most commonly encountered in 4th and 5th decades

15. Follicular Adenoma Gross pathology

16. Follicular Adenoma Microscopic pathology
Back to back arrangement of follicles
Relatively decreased colloid, but colloid still present
No significant nuclear atypia

17. Thyroid Cancer - Overview
Accounts for <1% of all new malignant diagnoses in U.S.
Most common endocrine malignancy
Incidence peaks in 3rd and 4th decades of life
External radiation to the cervical region linked to thyroid carcinoma

18. Papillary Carcinoma Arises from follicular cells of the thyroid gland.
Most common form of thyroid carcinoma (almost 90% of primary thyroid malignancies).
Most commonly occur between 30 and 50 years of age (3rd to 5th decade of life).
Some tumors associated with exposure to ionizing radiation.
M:F ratio = 1:3

19. Papillary Carcinoma Gross pathology
Tumor is going out
Firm compared to follicular adenoma (which is more fleshy)

20. Papillary Carcinoma Microscopic pathology
Papillary, follicular variants
Nuclear grooves,
Optically clear nuclei – dispersed chromatin
Intranuclear cytoplasmic inclusions – “Orphan Annie” nuclei
Psammoma bodies  calcifications
Follicular variant of papillary carcinoma not uncommonly encountered

21. Papillary Carcinoma, Tall Cell Variant
Pretty good survival
Tall Variant
Histological evidence for poor prognosis
More eosinophilic molecules

22. Papillary Carcinoma Molecular pathology
RET-PTC rearrangements: RET is proto-oncogene encoding membrane-bound tyrosine kinase receptor (RET is placed under control of genes constitutively expressed in thyroid follicular epithelium)
Resulting activation of serine/threonine kinase pathway including Ras, B-raf, and mitogen-activated protein kinase (MAP-K) drives cellular proliferation
Mutation of B-RAF gene present in up to 30-50% of papillary thyroid carcinoma. Point mutations lead to activation mimicking phosphorylated form of B-raf.
- Can be with or without RET gene

23. Papillary Carcinoma Treatment
Primary treatment is surgical resection (total thyroidectomy) with or without regional lymph node dissection
4-6 weeks after surgery: radioactive iodine therapy
Generally good prognosis: up to 95% 10-year survival
Prognosis poorer if entension to adjacent structures, positive lymph nodes, certain histologic variants such as the tall cell variant

24. Follicular Carcinoma
Like papillary carcinoma, this tumor arises from follicular cells of thyroid gland
Purely follicular malignant tumors
Account for 5% of primary thyroid carcinoma
More common in women (M:F= 1:3)
Usually presents as painless solitary nodule (like papillary)
Present at an older age than do papillary carcinoma
Mean age at diagnosis is 50 years +
Must establish capsular or vascular invasion for diagnosis
If not call it a follicular adenoma
Nuclei lack classic features of papillary carcinoma; lack psammoma bodies
Distinction between follicular adenoma and follicular carcinoma difficult
May need a follow up and genetics can help
Less common than papillary carcinoma

25. Follicular Carcinoma Gross pathology
Well circumscribed. More hemorrhagic in the middle

26. Follicular Carcinoma Microscopic pathology
Frank invasion
Tongue of tumor

27. Follicular carcinoma Molecular pathology
- Yellow and green show FSH rearrangement
PAX8-PPARG rearrangement: translocation involving chromosome 2 and 3 results in chimeric molecule activating gene expression
Chimeric protein acts in dominant negative fashion interrupting the differentiating and growth inhibiting actions of PPAR agonists
Rearrangements occur with increased frequency in tumors detected post-radiation
Rearrangement in up to 60% of follicular carcinomas
Other mutations: Ras mutation, PI3K/AKT pathway mutations
PAX8 can cause issues because of growth. In development, cause normal growth and then shut off.

28. Follicular Carcinoma Treatment
If tumor less than 1 centimeter and only microinvasion, unilateral lobectomy usually sufficient
If greater than 1 centimeter and gross capsular or vascular invasion, total thyroidectomy preferred.
Radioactive iodine treatment 4-6 weeks after surgery
Metastasis usually hematogenous in follicular carcinoma (papillary goes through lymph nodes) in contrast to lymphatic spread in papillary carcinoma
Prognosis is largely dependent on extent of invasion and stage at presentation
Hypocalcaemia if parathyroid is taken out by mistake.

29. Medullary Carcinoma
Sporadic medullary carcinoma occurs in older patients (>50 years); younger patient with multiple endocrine neoplasia (MEN)
Associated with MEN 2A and 2B (mainly 3rd decade of life)
5% of thyroid gland tumors; 80% sporadic
Associated with C-cell hyperplasia (considered precursor to tumor), production of calcitonin
Calcitonin- can depress calcium levels by inhibiting osteoclastic activity
Can also secrete carcinoembryonic antigen (CEA), serotonin, and vasoactive intestinal peptide (VIP)
Use radioactive antibody for calcitonin. If area lights up, then calcitonin issue make be the answer

30. Medullary Carcinoma Gross pathology
Look like follicular carcinoma, maybe more hemorrhagic

31. Medullary Carcinoma Microscopic pathology
Variable histology – trabecular, follicular patterns
Produces amyloid
Both neoplastic cells and extracellular amyloid stain for calcitonin on immunohistochemistry

32. Medullary carcinoma – electron microscopy highlights secretory granules
Not usually used for diagnosis of things but here it is useful.

33. Medullary Carcinoma Molecular pathology
RET mutation in both MEN patients non-MEN familial carcinomas
97% of patients with MEN 2A, 95% of MEN 2B, and 86% of patients with familial medullary carcinoma have germline point mutation in RET proto-oncogene
RET proto-oncogene codes for a transmembrane tyrosine kinase receptor  mutation increases kinase activity which drives cellular proliferation

34. Medullary Carcinoma Treatment
Surgical treatment
Total thyroidectomy and lymphatic dissection of anterior compartment of neck  STANDARD OF CARE
Because tumor does not concentrate iodine, radioactive iodine treatment has no place in treatment of this tumor
After thyroidectomy, patient calcitonin levels monitored
Overall prognosis for patients with medullary carcinoma is worse than that for patients with papillary and follicular carcinomas
Reported 10-year survival rate is 65% overall

35. Anaplastic Carcinoma Most aggressive form of thyroid carcinoma
Rapidly enlarging neck mass; hoarseness, dyspnea, pain
Bc of recurrent laryngeal nerve
Approximately 50% of patients have metastatic tumors (lung, bone, liver)
Almost uniformly rapid and lethal clinical course
Accounts for 1% of thyroid carcinomas
Up to 40% of deaths from thyroid carcinoma
Anaplastic tumors thought to represent transformation from a benign or low grade thyroid neoplasm (may harbor a concurrent well-differentiated tumor).
Peak incidence is 6th to 7th to 8th decades of life
M:F ratio = 3:1
Thought to come from other carcinomas and just has changed so much

36. Anaplastic Carcinoma Clinical / Gross pathology features
Fat all around it!
Tumor in adipose tissue  BAD

37. Anaplastic Carcinoma Microscopic pathology
Bizarre, hyperchromatic cells
Brisk mitotic rate
Necrosis

38. Anaplastic Carcinoma Molecular Pathology
Some of same mutations seen in other thyroid tumors: Ras, RET/PTC
Mutations of tumor suppressor p53
Mutation of p53 thought to play pivotal role in transformation of well-differentiated thyroid tumor to anaplastic carcinoma
P53 mutations may explain anaplastic carcinoma insensitivity to the majority of chemotherapeutic agents

39. Anaplastic Carcinoma Treatment
Treatment mostly palliative
Combined multimodality therapy: surgical resection, systemic chemotherapy, radiation therapy
Overall 5-year survival is less than 10%
Most patients do not live longer than a few months after diagnosis
Former Chief Justice of U.S. Supreme Court

40. Thyroid Gland – Metastatic tumors
Malignant melanoma
Carcinomas: non-small cell carcinomas of the lung
Others