Pathology of Thyroid Disease I- Dr. Vila

What are the microscopic hallmarks of papillary thyroid carcinoma?

1) *Branching papillae* having a fibrovascular stalk covered by single to multiple layers of cuboidal epithelial cells 2) Nuclei contain finely dispersed chromatin, which imparts an optically clear or empty appearance (*ground-glass* or *Orphan Annie Eye nuclei*) 3) Invagination of the cytoplasm may give the appearance of intranuclear inclusions (pseudo-inclusions) or intranuclear grooves *The dx of PTC can be made on these nuclear features, even in the presence of papillary architecture.*

What are the possible presentations of papillary thyroid carcinoma?

1) A painless, palpable nodule in a normal gland 2) A nodule with enlarged cervical lymph nodes 3) Cervical lymphadenopathy with no palpable thyroid nodule

What are the major subtypes of thyroid carcinoma?

1) Papillary carcinoma (>85%) 2) Follicular carcinoma (5-15%) 3) Anaplastic (undifferentiated) carcinoma (<5%) 4) Medullary carcinoma (5%) Most thyroid carcinomas (except medullary) are derived from the thyroid follicular epithelium.

What is a nontoxic goiter?

AKA: Simple, colloid, multinodular goiter, or nodular hyperplasia Thyroid enlargement without functional, inflammatory or neoplastic alterations. Endemic or sporadic distribution.

What is intrathoracic or plunging goiter?

AKA: retrosternal goiter Multinodular nontoxic goiter that grows behind the sternum and clavicles.

What is the histological pattern of an atypical follicular adenoma?

Abundant mitoses, excessive cellularity, nuclear atypism.

What is the precursor lesion of the familial variety of MTC?

C-cell hyperplasia. Pts. with MEN2A and MEN2B are monitored by periodic measurement of calcitonin and CEA. When these are elevated, the patient is treated by total thyroidectomy.

What are the genetic alterations in the 3 follicular cell-derived thyroid carcinomas?

*Growth factor receptor signaling pathways*. PAX8/PPARG RAS activating or Pl-3K (follicular carcinoma) Chromosomal rearragenment of the RET oncogene or mutations in BRAF (papillary carcinoma)

What is the progression and prognosis of papillary thyroid carcinoma?

-Typically invades lymphatics and spreads to regional cervical lymph nodes -Mets to cervical nodes at time of surgery do not affect prognosis -Prognosis is excellent -Fatalities are due to mets to the lungs, brain or by obstruction of the trachea or esophagus

What is the macroscopic appearance of follicular thyroid carcinoma?

-Vary in size, yellow-tan and have tick fibrous capsules -Hemorrhage and necrosis are common -Subdivided into *minimally invasive* and *widely invasive* variants

What are the risk factors for papillary thyroid carcinoma?

-First-degree relative with PTC (4-10x greater risk) -Iodine excess -External radiation to the neck -Somatic mutations: RET proto-oncogene (60% of tumors in children from Chernobyl showed this mutation. Also occurs after external radiation) -BRAF mutations -RAS mutation

What is anaplastic (undifferentiated) thyroid carcinoma?

-Highly aggressive and lethal tumors that can arise de novo or by "dedifferentiation" of a well-differentiated papillary or follicular carcinoma. -Afflicts mainly women over the age of 60 -More common in areas with endemic goiter, and at least 1/2 of pts have long-standing goiter.

What is the cause of endemic goiter?

-Impaired synthesis of thyroid hormone, which is most often the result of *dietary iodine deficiency* -*Impairment of thyroid hormone synthesis leads to a compensatory rise in serum TSH* level, which causes *hypertrophy and hyperplasia of thyroid follicular cells* and gross enlargement of the thyroid gland -The compensatory increase in functional mass of the gland overcomes the hormone deficiency, ensuring a *euthyroid metabolic state* in most individuals

What are the clinicopathological features of anaplastic thyroid carcinoma?

-Large, poorly circumscribed mass that extends into soft tissues of the neck -Histology of sarcoma-like proliferation of bizarre spindle and giant cells, polyploid nuclei, many mitoses, necrosis and stream fibrosis -present as rapidly enlarging neck masses -Dysphagia, hoarseness, dyspnea

What are lymphomas of the thyroid?

-Largely B-cell tumors -2% of thyroid malignancies -B-cell lymphomas arise in the setting of chronic thyroiditis

What are the clinical features/complications of a multinodular goiter?

-Mass effects (airway obstruction, dysphagia, compression of vessels in the neck and thorax (superior vena cava syndrome) -*Dysphagia* due to esophageal compression -*Inspiratory stridor* due to tracheal compression -Hoarseness due to compression of laryngeal nerve -Hemorrhage into nodule/cyst may lead to pain -*Most are euthyroid or have subclinical hyperthyroidism* (id'd only by low TSH levels) -Incidence of malignant transformation is <5%, but concern for malignancy arises with sudden size, shape or symptom sizes (i.e. hoarseness) -Dominant nodules can present as "solitary thyroid nodule", mimicking neoplasm

What are the epidemiologic features of follicular thyroid carcinoma?

-More common in areas with dietary iodine deficiency -Purlely follicular malignant tumor with no papillary elements -Older than 40 (peak incidence from 50-60) -F:M is 3:1

What are the microscopic features of follicular thyroid carcinoma?

-Most FTCs are composed of fairly uniform cells forming small follicles containing colloid -Reminiscent of normal thyroid -May have nests or sheets of cells without colloid -Occasionally dominated by cells with abundant granular, eosinophilic cytoplasm (Hürthle cells or oncocytic variant of FTC)

What is the morphology of multinodular nontoxic goiter?

-Multilobular, *asymmetrically* enlarged gland that can real weights of more than 2000g. -Unpredictable pattern of enlargement -May be hidden behind the trachea/esophagus -*Irregular nodules* on cut surface of thyroid, containing variable amounts of brown, gelatinous colloid -Older lesions may have hemorrhages, fibrosis, calcification and cystic change -Microscopically- colloid-rich follicles lined by flattened, inactive epithelium are follicular hyperplasia accompanied by degenerative changes

What is a thyroglossal duct cyst?

-Primitive thyroid descends to its eventual location in the lower anterior neck by elongation of its tubular attachment to the tongue (thyroglossal duct) which then atrophies around the 7th week of life. -If the thyroglossal duct fails to involute, a cystic remnant may be seen along the rout of the duct -May present at any age as cystic masses (1-4 cm) in the middle of the neck and attached to the hyoid bone or soft tissues. -Cysts can be lined by scammed or respiratory-type epithelium and contain variable amounts of thyroid tissue.

What are the clinical features of MTC?

-Symptoms related to endocrine secretion -Carcinoid syndrome (serotonin) and Cushing Syndrome (ACTH) -Watery diarrhea: secretion of VIP -Familial MTC pts may exhibit hyperparathyroidism, episodic hypertension due to catecholamine secretion by pheochromocytoma -Tumor usually presents as a firm thyroid nodule or cervical lymphadenopathy -5 year survival is 60-75%

What are the pathologic characteristics of MTC?

-Tends to arise in the superior thyroid, the area richest in C cells -MEN2 tumors are multi centric and bilateral. -MTCs are not encapsulated, but are usually circumscribed -Tumors are solid, with polygonal granular cells separated by a *vascular stroma (stream amyloid, representing deposition of procalcitonin, is conspicuous.)* -Neoplastic C cells have dense secretory granules that are positive for endocrine markers like calcitonin. -MTCs express carcinoembryonic antigen (CEA), ACTH, serotonin, substance P, glucagon, insulin and hCG. -Extend by direct invasion into soft tissues and metastasize to regional lymph nodes, lung, liver and bone

What is ectopic thyroid?

-Thyroid tissue found outside the thyroid gland, due to abnormal migration during development -Tissues are functionally normal and capable of producing thyroid hormone -Hyperplastic foci and malignant rumors can develop from displaced tissue

What is the histological pattern of a Hürthle (oncocytic) cell adenoma?

A solid tumor with oxyphil cells, small follicles and scant colloid.

What is follicular adenoma?

Adenoma of the thyroid. Typically discrete, solitary encapsulated masses, derived from follicular epithelium. *Benign neoplasm showing follicular differentiation*. Most common thyroid tumor that typically presents in euthyroid persons as a "cold" nodule that does not take up iodine. Note: In up to 90% of cases, palpable, solitary follicular lesions are just the dominant nodule in a multinodular goiter. Often mistaken for adenoma.

What is Plummer syndrome/toxic nodular goiter (TNG)?

An autonomous nodule that develops in long-standing multinodular goiter, producing hyperthyroidism. It is not accompanied by the infiltrative opthalmopathy and dermopathy seen in Graves' disease. *note: everywhere else on the web it's called Plummer's disease, bc Plummer syndrome refers to Plummer-Vinson syndrome (esophageal ulcers, koilonychia, etc.)

What are goitrogenic substances?

Anything that interferes with thyroid hormone synthesis at some level. Some cruciferous vegetables (cassava, cabbage, turnips. brussels sprouts, cauliflower)

Are functional nodules that take up iodine more likely to be benign or malignant?

Benign

Are hyperfunctioning thyroid nodules usually malignant or benign?

Benign. "Cold", nonfunctioning nodules are more frequently malignant, but may be benign.

What is the histological pattern of a fetal follicular adenoma?

Cells are similar to those of embryonal adenoma but tend to be arranges in micro follicles with little colloid.

What are psammoma bodies?

Concentrically calcified structures, usually within the cores of papillae. These structures are almost never found in follicular and medullary thyroid carcinomas.

Which type of goiter can induce cretinism?

Dyshormonogenetic goiter

What is the major predisposing risk factor for thyroid cancer?

Exposure to ionizing radiation, particularly during the first 2 decades of life. Radiation produces double-strand breaks in DNA affecting RET rearrangements.

How do you diagnose thyroid neoplasms?

Fine-needle biopsy

Deficiency of dietary iodine is linked with a higher frequency of what thyroid carcinoma?

Follicular carcinoma.

What is the histological pattern of a colloid follicular adenoma?

Large follicles with normal colloid.

What are the features of invasive follicular thyroid carcinoma?

Larger lesions may penetrate the capsule and infiltrate well beyond the thyroid capsule into the adjacent neck. Making the dx between minimally invasive FTC and invasive FTC requires extensive histologic sampling of the tumor-capsule-thyroid interface to exclude capsular and/or vascular invasion. Regional lymph nodes are rarely involves, but hematogenous dissemination is common, with mets to bone, lungs, liver, etc. Only 50% survival.

What is the histological pattern of a simple follicular adenoma?

Mature follicles with a normal amount of colloid.

Are nodules in males or females more likely to be neoplastic?

More likely to be neoplastic in males

Do follicular thyroid carcinomas have psammoma bodies, ground-glass nuclei or Orphan Annie Eye nuclei?

NO. No features of papillary carcinoma present.

What is the macroscopic appearance of papillary thyroid carcinoma?

Vary in size from microscopic to larger than a normal gland. May arise in the gland including the isthmus. Firm, solid and white-yellowish with irregular and infiltrative borders.

Are nodules in younger or older individuals more likely to be neoplastic?

Nodule in younger patients

What is endemic goiter?

Occurs is geographical areas where the soil, water and food supply contain low levels of iodine. Goiters are present in more than 10% of the population.

What is the most common thyroid cancer?

Papillary thyroid carcinoma (PTC). Up to 90% of cases in the US.

The presence of psammoma bodies in fine-needle aspiration of the thyroid is a strong indication of what?

Papillary thyroid carcinoma!

What is the hallmark of a follicular adenoma?

Presence of an intact, well-formed capsule encircling the tumor.

Mutations of what are seen in medullary carcinomas?

RET oncogene

What is the morphology of diffuse nontoxic goiter?

Range from double the normal size (40g) to hundreds of grams. 2 phases: 1) Hyperplastic Phase- thyroid gland is diffusely and symmetrically enlarges. Follicles are lined by crowded columnar cells, which may pile up a form projections similar to Graves' disease. Accumulation is not uniform through gland and some follicles are distended, while others remains small. 2) Phase of Colloid Involution- if dietary iodine increases or if demand for thyroid hormone decreases, the stimulated follicular epithelium involutes to form an enlarged, colloid-rich gland. The cut surface of the thyroid is brown, somewhat glassy and translucent. Follicular epithelium is flattened and cuboidal.

What is multinodular goiter?

Recurrent episodes of hyperplasia and involution combined to produce irregular enlargement of the thyroid. Virtually all *long-standing simple goiters convert into multinodular goiters.* Produce the most extreme thyroid enlargements and are mistaken for neoplasms. Occur in both *sporadic and endemic*, having same M:F and same origins, but *affecting older individuals bc they are late complications.*

Are solitary or multiple nodules more likely to be neoplastic?

Solitary

What is the pathologic appearance of follicular adenoma?

Solitary, well-circumscribed, 1-3cm nodule that protrudes from the surface of the thyroid and is completely surrounded by a fibrous capsule. The tumor cut surface is soft and paler than the surrounding gland (clear distinction between inside and outside the capsule). Compression of surrounding thyroid parenchyma. Hemorrhage, fibrosis and cystic changes common.

What is sporadic goiter?

Striking female preponderance and peak incidence at puberty or in young adult life. Can be caused by several conditions or by consumption of goitrogenic substances. Hereditary enzyme defects that interfere with hormone synthesis are autosomal recessive (dyshormonogenetic goiter).

What is medullary thyroid carcinoma?

The cells originate from the brachial pouches and secrete calcitonin and other peptides such as serotonin, ACTH and somatostatin. Represents 5% of thyroid cancers. Occurs in sporadic and familial forms (20% have MEN type 2B and 2A) In pts with MEN2B, tumors occur in infancy. In pts with MEN2A, tumors occur in adolescents. Somatic mutations in the RET protooncogene occur in 25-70% of sporadic MTC.

What is the histological pattern of an embryonal follicular adenoma?

Trabecular pattern with poorly-formed follicles containing little or no colloid.

What are the features of minimally invasive follicular thyroid carcinoma?

Well-defined, encapsulated tumor. On cut section it is soft, pale tan to pink and bulges from it's capsule. Hemorrhagic necrosis is common. Dx when tumor extends into, but not entirely through the capsule. 95% survival.

Are men or women more affected by thyroid tumors?

Women