Thyroid Tumors

Match the feature with the Thyroid Tumor * * * * * * *Benign tumor with follicular differentiation that lacks evidence of capsular and vascular invasion * *

* * * * * * *Benign tumor with follicular differentiation that lacks evidence of capsular and vascular invasion: Follicular adenoma * *

A 27 year old woman was found to have a solitary thyroid nodule in her health maintenance exam. Scintigraphic scanning shows increased radio active uptake by the nodule. Which of the following is the most likely diagnosis? A Hashimoto thyroiditis B Follicular adenoma C Granulomatous thyroiditis D Medullary carcinoma E Papillary carcinoma

B Follicular adenoma 10% of follicular adenomas can be hot. Hashimoto and Granulomatous Thyroiditis have decreased uptake. Medullary and Papillary carcinoma are cold

Which of the following pathologic processes is LEAST likely to be associated with laboratory evidence for hyperthyroidism as measured by an increased serum thyroxine: A Subacute granulomatous thyroiditis B Multinodular goiter C Medullary carcinoma of thyroid D Hashimoto's thyroiditis E Follicular adenoma of thyroid

C Medullary carcinoma of thyroid Medullary carcinoma of thyroid is usually cold. All the other choices have the potential for transient hyperthyroidism (Subacute and Hashimoto) or thyroid hormone producing capability (10% of follicular adenomas may be hot)

A "lump" is felt in the neck of a 47-year-old woman. Following fine needle aspiration cytologic diagnosis of a neoplasm, a thyroidectomy is performed. Grossly, there is a 3 cm mass in the right lower pole that on sectioning is cystic and has papillary excresences. Which of the following sets of histologic findings is most typical for this lesion: A Giant cells, hypothyroidism B Amyloid stroma, calcitonin production C Cold nodule on scan, decreased TSH D Clear nuclei, lymph node metastases E Follicles, hematogenous metastases

D Clear nuclei, lymph node metastases

A 50 year old man comes to the physician for a routine health maintenance examination. Physical examination shows a firm thyroid nodule. The neoplasm is resected; histologic sections show sheets of granular cells embedded in a hyaline stroma. Immunohistochemical stains show the presence of cytoplasmic calcitonin. Which of the following is the most likely type of carcinoma? a. Anaplastic b. Follicular c. Giant cell d. Medullary e. Papillary

d. Medullary

Follicular Carcinoma

* *Peak incidence is between 40 -60 (rarely occurs in children) *More frequent in areas with iodine deficiency * *Associated with RAS mutation * *Unlike in papillary carcinoma, lymphatic spread is uncommon *Vascular/hematogenous dissemination is common (bones and lungs) **Diagnosis relies on the identification of capsular and/or lymphovascular invasion, because these tumors are in all other respects indistinguishable from follicular adenomas.* *Usually cold on scintiscans but may rarely be hot and hyperfunctional *Histologically: Characterized by relatively uniform follicles that may contain colloid *Oncocytic (Hürthle Cell) Variant of FTC has worse prognosis *Tx: *Generally good prognosis *Metastases can be treated with radioiodine *After surgery, residual follicular carcinoma may respond to TSH, so patients are given thyroid hormone to suppress TSH levels *Serum thyroglobulin is used to monitor recurrence. (Should not be detectable in normal individuals)

Histological appearance of Papillary Carcinoma

*Branching fingerlike papillae lined by cuboidal cells *The nuclei of these cells are clear and have a ground glass appearance (Orphan Annie Eye) *Intranuclear inclusions (pseudoinclusions): invaginations of cytoplasm into the nucleus *Intranuclear grooves may be present *Psammoma bodies present in 50% (very diagnostic) (look in downloads folder, saved as PTC)

Sporadic vs Familial Medullary Carcinoma

*Majority of cases are sporadic (80%) *Both sporadic and familial cases associated with MEN are caused by activating point mutations in RET *Sporadic arise later adulthood (40-50); Cases due to MEN2a/2b arise in childhood *Familial type has a better prognosis than the sporadic type *Sporadic typically present as solitary nodule; familial cases are typically bilateral and multicentric *C cell hyperplasia is a feature that is usually absent in sporadic cases and is considered a precursor lesion for familial cases

Thyroid Adenoma

*Most common benign tumor *Discrete solitary mass, derived from follicular epithelium *Hallmark of thyroid adenomas is the presence of an intact, well demarcated capsule encircling the tumor *Vast majority are nonfunctional ("cold"); can rarely cause hyperthyroidism via autonomous thyroid hormone production ("hot" or "toxic") *Approximately 10% of cold nodules progress into a follicular carcinoma. Hot nodules are rarely malignant **Absence of capsular or vascular invasion distinguishes adenoma from follicular carcinoma* *Hemorrhage, fibrosis and cystic change are common

Papillary Carcinoma

*Most common form of thyroid cancer *Account for >85% of primary thyroid malignancies *Most often occurs in ages 20-50, however may occur in any age, even in children **Prior exposure to ionizing radiation is a risk factor* *May be solitary or multifocal **Papillary carcinoma has a propensity for lymphatic spread, and thus can present with lymphadenopathy* **Most have gain of function mutations involving BRAF or RET* *Histology: Ground Glass/"Orphan Annie eye" nuclear inclusions, Nuclear grooves, Psammoma bodies,Finger like papillae with fibrovascular cores that are lined by cuboidal/columnar epithelial cells *Typically presents as a painless, palpable, nodule that may present with enlarged cervical lymph nodes *Appear as cold masses on scintiscans *Prognosis is excellent (10 yr survival > 95%) *Worse prognosis in elder men *thyroidectomy + iodine radiotherapy

Medullary Carcinoma

*Originates from parafollicular C cells of the thyroid and secrete calcitonin *Calcitonin often deposits within the tumor as amyloid (stains with Congo Red and shows apple-green birefringence under polarized light) *In some instances, may secrete Serotonin, ACTH, or VIP => (Carcinoid syndrome, Cushing, Watery diarrhea respectively) *Very rarely presents with hypocalcemia *Majority of cases are sporadic (80%) *Familial cases are associated with MEN2a/2b **Both sporadic and familial cases associated with MEN are caused by activating point mutations in RET* *Appear as cold masses on scintiscans *Histology: Solid sheets/nests of polygonal/spindle shaped cells in an amyloid stroma. Stromal amyloid deposits (due to calcitonin) that stain with congo red *Serum calcitonin can be used to aid diagnosis *Tx: Thyroidectomy is the only effective treatmen

Describe the histological appearance of Follicular Carcinomas

*Preservation of normal thyroid follicular architecture but proliferation (uniform follicles) *May invade capsule or blood vessels *Occasionally there may be Hurthle cells present (cells with abundant granular eosinophilic cytoplasm) *Whatever the pattern, they lack optically clear nuclei and nuclear grooves (differentiating from Papillary) Note the capsular invasion indicated by the arrow

Describe the histological appearance of Medullary Carcinoma

*Solid sheets/nests of polygonal/spindle shaped cells in an amyloid stroma. *Stroma has amyloid deposits (due deposition of calcitonin) that stain with congo red FIND A PICTURE

Undifferentiated/Anaplastic Carcinoma

*Undifferentiated tumors of the thyroid follicular epithelium *Most common in patients older than 65 years of age *Thought to arise by dedifferentiation of a previous low grade thyroid carcinoma such as follicular or papillary *Highly aggressive, uniformly lethal cancers; Mortality rate almost 100% (worst prognosis of all the thyroid cancers) *Histology: proliferation of bizarre spindle and giant cells, with polyploid nuclei **Present as a rapidly enlarging bulky neck mass* *Symptoms related to compression and invasion, such as dyspnea, dysphagia, hoarseness, and cough, are common

A 28-year-old girl presents to clinic with a noted change in her voice and difficulty swallowing solids. On physical exam there is a palpable, nontender swelling in the front of her neck. There is no cervical lymphadenopathy. After a non-diagnostic fine-needle aspiration biopsy of the mass, she is taken to the operating room for a hemi-possible total-thyroidectomy. Pathology of the specimen diagnoses this patient with medullary thyroid carcinoma. If this patient's cancer was secondary to an inherited germline mutation, what gene should be sequenced in this patient's family members? 1. RAS 2. RET 3. c-MYC 4. BRAF 5. NF2

2. RET Both sporadic and familial cases associated with MEN are caused by activating point mutations in RET

A 25-year-old man presents to a physician because of multiple small nodules on his lips. The clinician notes that the patient has a marfanoid habitus. Biopsy of one of these nodules demonstrates a mucosal neuroma. Which of the following screening tests is indicated? A. Pentagastrin-stimulated calcitonin B. Serum gastrin C. Serum insulin D. Serum parathyroid hormone E. Serum vasoactive intestinal peptide

A. Pentagastrin-stimulated calcitonin MEN 2B = mucosal neuroma (skin, oral, GI) + marfanoid habitus + (Medullary Thyroid Carcinoma + Pheochromocytoma)

Which type of Thyroid Cancer is associated with the worst prognosis?

Anaplastic Carcinoma

Name two common sites of metastasis for Follicular Carcinoma

Bone, Lung (Pathologic fracture may be the presenting symptom)

A 28-year-old man discovers a mass in his neck while buttoning his shirt collar. Physical examination reveals a 2 cm mass in one thyroid lobe, which is "cold" on scintiscan. Aspiration of the nodule demonstrates small "solid balls" of neoplastic follicular cells. Careful examination of these tissue balls reveals that they contain microscopic blood vessels and fibrous stroma in their centers. Which of the following is the most likely diagnosis? A. Follicular carcinoma B. Hashimoto's disease C. Medullary carcinoma D. Papillary carcinoma E. Thyroid adenoma

D. Papillary carcinoma (seems like they are describe the follicular variant of papillary carcinoma which is the most common type and is characterized by having numerous colloid balls and rosettelike follicles) The distinctive cell balls described are broken-off papillary clusters, and are considered pathognomic for papillary carcinoma of the thyroid. This is the most common form of thyroid carcinoma. It tends to present in the 3rd to 5th decade and shows a modest female predominance. Despite its propensity for local lymphatic intrusion (which may cause multifocality of tumor in the thyroid or cervical lymph node metastases), the tumor generally has an excellent prognosis with 90% 20-year survival. Follicular carcinoma (choice A) is characterized by follicular cells and colloid on aspiration, and cannot be reliably distinguished from thyroid adenoma. Distinctive features of Hashimoto's disease (choice B) on aspiration are lymphocytes, plasma cells, and macrophages. The most distinctive feature of medullary carcinoma (choice C) on aspiration is the presence of amyloid. Thyroid adenoma (choice E) shows follicular cells and colloid on aspiration, and cannot be reliably

By which mechanism, does Medullary thyroid cancer cause secretory diarrhea?

Diarrhea is caused by increased gastrointestinal secretion and hypermotility due to the hormones secreted by the tumor (calcitonin,serotonin, VIP) The mechanism by which calcitonin causes diarrhea is unclear but it is a fact that high levels of calcitonin causes diarrhea (one possible mechanism is that high levels of calcitonin => hypocalcemia => increased neuromuscular excitability => diarrhea; recall that hypercalcemia was associated with ileus/constipation)

Familial Medullary Carcinoma is usually _________ (unilateral/bilateral) Sporadic Medullary Carcinoma is usually _________ (unilateral/bilateral)

Familial: Bilateral and multicentric Sporadic: Unilateral

Can the distinction between Follicular Adenoma and Carcinoma be made by Fine Needle Aspiration?

No There is no reliable cytologic difference between follicular adenomas and minimally invasive follicular carcinomas. Making the distinction between the two requires extensive histologic sampling of the tumor-capsule-thyroid interface (requires surgical excision) to exclude capsular and/or vascular invasion

What is the most common type of Thyroid Cancer?

Papillary Carcinoma

Papillary Carcinoma has a propensity for _______________(lymphatic/hematogenous) spread Follicular Carcinoma has a propensity for _______________(lymphatic/hematogenous) spread

Papillary: Lymphatic Follicular: Hematogenous

Papillary carcinoma is associated with _______________ mutations Follicular carcinoma is associated with _______________ mutations

Papillary: RET and BRAF Follicular: RAS and PAX8/PPAR/PTEN mutations

Papillary carcinoma is more frequent in areas exposed to massive amounts of radiation (Chernobyl, Hiroshima); Which areas are more likely to have patients with Follicular carcinoma?

Papillary: Radiation exposed areas Follicular: Iodine deficient areas

Orphan Annie Eye Nuclei of Papillary Carcinoma

The nuclei of papillary carcinoma cells contain very finely dispersed chromatin, which imparts an optically clear appearance, giving rising to the designation "ground glass" or "Orphan Annie eye" nuclei

Describe the histological appearance of Follicular Adenomas

Well differentiated follicular cells containing colloid that are by surrounded by a defined capsule The follicles and follicular cells are distinct and different from the surrounding thyroid tissue which may appear compressed Picture: Adenoma (left); Capsule (center); Normal parenchyma (right)