Thyroid Neoplasms

Question 1

The majority of solitary nodules of the thyroid are what?

Answer 1

Either benign adenomas or localized neoplastic conditions

Carcinomas only account for <1% of solitary thyroid nodules

Question 2

Clinical criteria for thyroid nodules

Answer 2

Solitary nodules are more commonly neoplastic than multiple

Nodules in very young or old (<20; >70) are more likely to be neoplastic

Nodules in males are more likely neoplastic

History of radiation exposure increases risk of thyroid malignancy

Nodules that uptake radioactive iodine in imaging studies are more likely to be benign

Question 3

What is the most definitive way to determine thyroid nodules characteristics

Answer 3

Meddle aspiration and staining

Question 4

Adenomas of the thyroid

Answer 4

Benign neoplasms that are derived from follicular epithelium

Usually are solitary and clinically are difficult to distinguish from dominant nodules

Most are nonfunctional however if they do, they always produce thyrotoxicosis via “toxic adenoma”

Question 5

Adenoma pathogenesis

Answer 5

Results from driver mutations in the TSH Rc pathway (results in toxic adenomas)

Also mutations in either:

1) TSH receptor itself (more likely)
2) a-subunit of GNAS protein (less likely)

Minority of non functioning follicular adenomas also exhibit mutations in RAS proteins (20%)

Question 6

Gross Morphology of benign and neoplastic adenomas

Answer 6

Often can look similar however usually

• benign = solitary spherical lesions with less capsule present
• neoplastic = ell-defined intact capsules

the hallmark morphological appearance of an adenoma is a well-formed capsule encircling the tumor

Question 7

Clinical features of adenomas

Answer 7

Most are painless growths with large masses

Thyrotoxicosis is often present as well as dysphagia if the growth is large enough

Question 8

Radioactive iodine and adenomas

Answer 8

Most adenomas take up iodine less than normal thyroid tissue

• termed “cold nodules”
• roughly 10% become malignant if untreated

However toxic adenomas take up iodine more than normal thyroid tissue

• termed “hot nodules”
• less than 1% become malignant if untreated

Question 9

What techniques are used in preoperative evaluation of suspected adenomas?

Answer 9

Ultrasound and fine needle aspiration

Definitive diagnosis require microscopic evaluation for a capsule
- then is pathogenomic

Question 10

Thyroid carcinomas (CA)

Answer 10

More common in females

All except medullary CAs are derived from the thyroid follicular epithelium and vast majority are well-differentiated lesions

Major subtypes:

• papillary carcinoma (>85% of cases)
• follicular carcinoma (5-15%)
• medullary carcinoma (5%)
• anaplastic carcinoma (<5%)

Question 11

Broad Thyroid carcinoma pathogenesis

Answer 11

Two pathways down streams from the growth factor receptors

1) RAS/BRAF/MAP kinase pathway
2) PI-3K/AKT pathway

Produces gain-of-function mutations in either or both of these pathways

Question 12

What is the most common genetic feature of papillary carcinomas

Answer 12

MAP kinase mutations Which do one of two things:

1) rearrangements in genes that encode the receptor tyrosine kinases RET/NTRK1
2) Activating point mutations in BRAF

Question 13

What is the most common genetic feature of follicular thyroid carcinomas

Answer 13

Both of the following:

1) Gain of function mutation in PI3K
2) Loss of function mutation in PTEN

Question 14

What is a very unique genetic abnormality seen only in follicular thyroid carcinomas

Answer 14

33-50% of follicular carcinomas possess a unique t(2;3) translocation that disrupts PAX8
- PAX8 is a homebox gene that is important for TH development in thyroid gland follicles

Also shows Peroxisome Proliferator Activated Receptor Gene (PPARG) gene mutations
- is a nuclear hormone receptor that is required for terminal differentiation of cells

Question 15

Anaplastic carcinomas

Answer 15

Aggressive tumors that can arise de novo but more commonly develop from progression of papillary or follicular carcinomas

Have all the follicular and papillary gene mutations but also present with
- loss of function in TP53

Question 16

Medullary thyroid carcinoma

Answer 16

Arises from parafollicular C-cells
- NOT follicular epithelium

Pathogenesis is from associated germ-line RET proto-oncogene mutations

• *very common in Multiple Endocrine Neoplasia type-2 (MEN-2)
• also can be sporadic

Question 17

What is the major risk factor to predisposing thyroid cancer

Answer 17

Exposure to ionizing radiation
(Especially in the first two decades)

Most common cancer caused by this is papillary carcinoma

Question 18

What cancers is deficiency of dietary iodine associated with?

Answer 18

Higher frequency of Follicular carcinomas

Question 19

What is the most common form of thyroid cancer

Answer 19

Papillary carcinoma

• can occur at any age and account for vast majority of thyroid carcinomas associated with previous ionizing radiation
• are NON-FUNCTIONAL tumors and are always painless
• if they metastasis = cervical lymph nodes always. Sometimes is also seen in lungs

Common microscopic findings

• “psammoma bodies”
• “ Orphan-Anne-eye” nuclei
• “Pseudo-inclusions”
• bringing papillae
• *There are dozens of different variants but the most common is encapsulated follicular variant
• as long as there is no evidence of inital invasion, these tumors have no potential for malignant behavior**

With radioiodine scans = cold nodules

Are indolent lesions with ten-year survival rates of >95%

Question 20

What are the main factors associated with prognosis of papillary carcinoma of the thyroid?

Answer 20

Age: >40 yrs = bad

Extra thyroid also extension found = bad

Presence of DISTANT metastasis
- cervical lymph node metastasis doesnt increase mortality

Question 21

Follicular carcinomas

Answer 21

Accounts for 5-15% of primary thyroid cancers

More common in women (3:1) and manifest with older age than papillary (40-60yrs usually)

Very heavily tied with dietary iodine deficiency

Histologically shows very small follicles and looks kinda like normal thyroid tissues
- can be widely invasive or minimally invasive (minimal = sharply demarcated lesions that look kinda similar to follicular adenomas)

Most often are solitary “cold thyroid nodules”
- rarely can be hyper functional or hot

High rates of metastasis and are more likely than papillary carcinomas to be hematogenous
- can be found in lungs/bones and liver and rarely found in cervical lymph nodes

Question 22

Prognosis and treatment of follicular carcinoma

Answer 22

Minimally invasive = 10% 10 yr

Widely invasive = 50% to yr

All are treated with surgical resection

Question 23

Anaplastic carcinoma

Answer 23

Are undifferentiated tumors of thyroid follicular epithelium and accounts for less than 5% of thyroid tumors

Only older people get this >65

25% of patients have a history of well-differentiated thyroid carcinomas and another 25% show concurrent well-differentiated tumors that are respected earlier in life

Are very bulky and rapid growing masses that grow beyond the thyroid capsule into adjacent neck structures (causes mass effect symptoms)
- histologically = highly anaplastic and looks very messy

Are very aggressive and near 100% mortality**

• even with treatment still grows
• metastasis often occurs before symptoms even arise

Question 24

Medullary carcinomas of the thyroid

Answer 24

Neuroendocrine tumors derived from parafollicular cells/ C cells of the thyroid

These tumors are functional and secrete calcitonin which needs to be monitor for diagnosis and follow-up during and after treatment
- can also secrete somatostatin, serotonin and VIP as well

70% produce sporadically
- 30% produce from familial causes such as Multiple Endocrine Neoplasia type 2A-2B (MEN) or familial medullary thyroid carcinoma without MEN

In sporadic and familial cases without MEN = occurs in 50-60s

In MEN = occurs in 20s or younger

Very commonly, sporadic cases shows mass effect symptoms such as dysphagia and hoarseness
- also shows symptoms related to excess VIP and somatostatin (diarrhea, low GH, etc.)

Question 25

Medullary carcinoma pathogenesis and morphology

Answer 25

Both familial and sporadic forms are associated with gain of function driver mutations in the RET receptor tyrosine kinase

Morphology:

• gross = solitary nodule that manifests as multiple lesions throughout thyroid lobes with time. Larger nodules show hematologic
• microscopic = composed of polygonal and spindle-shaped cells. Often looks like nests or follicles and can present with calcitonin “amyloid deposits” in stroma