Goiter caused by thyroid follicular hyperplasia is the most common cause of thyroid enlargement
Graves disease is the most common cause of hyperthyroidism and Hashimoto is the most common cause of hypothyroidism
Hyperparathyroidism is much more common than hypoparathyroidism
Follicluar adenomas are the most common benign thyroid tumors, whereas papillary carcinomas are the most common malignant tumors
Hypoparathyroidism is most often caused by accidental removal of parathyroids during surgery
Histo: Colloid in the middle surrounded by follicular cells and C cells can be seen via IHC stain
What is cretinism?
Lack of iodine during development leading to severe developmental deficiencies including mental retardation
What is this? Describe the prominent histologic features.
-Many germinal centers with follicle destruction
-Hurthle cell change
NOTE: In all variants of Hashimoto's, the patient will start out hyperthyroidic and then will become hypothyroid in the long term AND the goiter will be PAINLESS
Give an overview subacute granulomatous thyroiditis
Uncommon self-limiting (6-8 weeks) virally-induced autoimmune (cytotoxic T-cell mediated) disease common in women in 40-60s that presents clinically as diffuse thyroid pain and flu-like symptoms and clinically as mild hyperthyroidism which is usually followed by a period of hypothyroidism.
What is this?
Subacute granulomatous thyroiditis marked by acute inflammation as well as lymphocytes, macrophages, and giant cells and follicular destruction
Describe Subacute Lymphocytic Thyroiditis –
Aka painless thyroiditis – variant of Hashimotos
An autoimmune disease of middle aged women with Abs against thyroid peroxidase that presents as mild, painless goiter or hyperthyroidism, and most patients recover while a small percentage progress to hypothyroidism (1/3rd)
NOTE: By definition excludes women who have a painless thyroiditis syndrome within one year after a delivery, abortion, or miscarriage (aka post-partum thyroditis)
What is happening here?
In subacute lymphocytic thyroiditis, there is more follicle destruction seen but less inflammation, germinal centers, and fibrosis than Hashimoto's
Notes about subacute lymphocytic thyroiditis and postpartum thyroditis
These are variants of Hashimoto's thyroiditis and thus are most associated with painless thyroiditis and may evolve to hypothyroidism (more common in postpartum than subacute) and look like Hashimotos under the scope – so you can’t really distinguish them histologically
Rule of thumb: If the patient presents within a year of birth go with postpartum thyroiditis. Also, if therapy is needed it will be tapered since most of these patients recover (both variants recover)
Describe postpartum thyroiditis
The classic description of postpartum thyroiditis includes thyrotoxicosis followed by hypothyroidism. The thyrotoxic phase occurs 1-4 months after delivery of a child, lasts for 1-3 months and is associated with symptoms including anxiety, insomnia, palpitations (fast heart rate), fatigue, weight loss, and irritability.
It is much more common for women to present in the hypothyroid phase, which typically occurs 4-8 months after delivery and may last up to 9 –12 months. Typical symptoms include fatigue, weight gain, constipation, dry skin, depression and poor exercise tolerance.
Most (80%) women will have return of their thyroid function to normal within 12-18 months of the onset of symptoms and the remaining 20% will remain hypothyroidic
What is this?
Riedel Thyroiditis- characterized by extensive fibrosis in the thyroid and possibly other parts of the body and may be IgG4 related
Image: Fibrosis laden with lymphocytes and hyperplastic germinal centers so clinically the thyroid is going to be extremely hard and non-mobile
What is this? HLA association?
Graves' Disease- the most common cause of hyperthyroidism. An autoimmune disease with autoantibodies (TSH and thyroid growth-stimulating immunoglobulins-TSI- (seen in 90% of patients and is specific to Graves') to TSH receptors that mimic the actions of TSH
•Association with HLA-DR3 and a strong genetic predispostion
Image: Thyroid hyperplasia characterized by papillary infoldings
How does Graves disease present?
Common in women aged 20-40. Labs will show decreased TSH and increased T4/T3 and clinically you will see symmetrical enlargement of the thyroid gland due to follicular cell hypertrophy with varying degrees of hyperthyroidism, bulging eyes (aka infiltrative ophthalmopathy), followed by infiltrative dermatopathy (aka pertibial myxedema) from GAGs and lymphocyte deposition
NOTE: Radioiodine scans will show a diffusely increased uptake of iodine
What is pretibial myxedema (aka localized myxedema)?
An autoimmune manifestation of Graves' disease (It also occasionally occurs in Hashimoto's thyroiditis) caused by Abs against TSH binding to fibroblast receptors (All patients with localized myxedema have high serum concentrations of TSH receptor antibodies, indicating the severity of the autoimmune condition) causing increased deposition of GAGs and typically occurring after the onset of ophthalmopathy and is usually only a cosmetic concern
. Cytokines such as TNFa and y-IFN induce GAG release from fibroblasts, and may be secreted by Th1 type T cells activated by TSH receptor antigen
What causes goiter (enlargement of the thyroid)?
Caused by impaired synthesis of thyroid hormone (most commonly due to dietary iodine deficiency) that leads to a compensatory rise in serum TSH levels causing hypertrophy of the gland
NOTE: The compensatory increase in functional mass of the gland overcomes the hormone deficiency, ensuring a euthyroid metabolic state in most individuals
What are goitrogens?
substances that can be ingested that interfere with thyroid hormone synthesis at some level, such as cabbage, cauliflower, brussel sprouts, and turnips
What are the main causes of goiter?
-Diffuse Nontoxic (simple) Goiter
Describe Simple Goiter. What are the subtypes?
This goiter causes enlargement of the entire gland without producing nodularity (Because the enlarged follicles are filled with colloid, it is aka colloid goiter)
Endemic and Sporadic
Describe Endemic goiter
A geographic phenomenom in parts of the world with low dietary iodine and frequent ingestion of goitrogens that starts as diffuse thyroid enlargement, but generally progresses to a multinodular state
Describe Sporadic goiter
A more rare phenomenom with a female preponderance and a peak incidence at puberty or in young adult that may be caused by goitrogens or may be due to congential enzymatic defects that interfere with thyroid hormone synthesis OR thyroid development (mostly AR)
Describe multinodular goiter
These are most commonly due to progression of simple goiters that are due to variations in growth patterns of indidvidual follicles
What is this?
Multinodular goiter lacking a capsule. Notice how the thyroid tissue is being squished
Neoplasms of the Thyroid Notes
Benign neoplasms outnumber thyroid carcinomas by a ratio of nearly 10:1 but there are still about 15,000 new cases of thyroid carcinoma per year in the United States
Most of these cancers are indolent; more than 90% of affected patients are alive 20 years after being diagnosed
What are some clues that a thyroid nodule is neoplastic?
Risk factors: Solitary nodule, young patient, male, Hx of radiation treatment
(All more likely to be neoplastic than multiple nodules, in older patients, and those found in females)
T or F. Functional nodules that take up radioactive iodine in imaging studies (hot nodules) are much more likely to be benign than malignant.
What is this?
Follicular adenoma- neoplasms derived from follicular epithelium that are grossly solitary and encapsulated and mostly considered nonfunctional (except for a small percentage that are toxic adenomas, aka thyroid hormone producing) and are not considered a forerunner to carcinoma, but there are shared genetic alterations
Describe what is happening here
Follicular adenomas tend to compress adjacent nonneoplastic thyroid tissue and contain a well-defined capsule (as opposed to mutlinodular goiters which dont do either of these).
The neoplastic cells show little variation in cell size, cell shape, or nuclear morphology and compress the normal follicular anatomy. These can show Hurthle cell transformation (below) (may be called a hurthle cell adenoma)
NOTE: Nonfunctioning Adenomas take up radioactive iodine less avidly than normal tissue and thus are considered cold and toxic adenomas appear hot. Cold adenomas are more likely to be malignant than hot adenomas
Tx: Requires careful histo examination of the resected specimen to look for a capsule
What causes toxic follicular adenomas?
Most often Gain of function mutations of the gene encoding the TSH receptor (TSHR) or the α-subunit of Gs (GNAS) cause follicular cells to secrete thyroid hormone independent of TSH stimulation (“thyroid autonomy”) leading to symptoms of hyperthyroidism and produces a functional “hot/toxic” nodule on imaging.
NOTE: TSHR and GNAS mutations are rare in follicular carcinomas (the main difference between follicular adenomas and carcinomas is that adenomas stay in the capsule while carcinomas result once they expand from the capsule)
A minority (less than 20%) of nonfunctioning follicular adenomas have mutations of RAS or PIK3CA, genetic alterations that are shared with follicular carcinomas.
What are the major subtypes of thyroid carcinomas?
•Papillary carcinoma (>85% of cases)- follicular derived
•Follicular carcinoma (5% to 15% of cases)- follicular derived
• Medullary carcinoma (5% of cases)- C cell derived
•Anaplastic (undifferentiated) carcinoma (5% of cases)- follicular derived
What is this?
Papillary carcinoma- These are common from 25-50 yo, have a good prognosis, and are most often associated with MAP kinase pathway mutations (RET/PTC fusion proteins (common in these occuring after radiation) or NTRK1, or BRAF)
In this image you can see Psammoma bodies (middle, dark pink) which are laminated calcifications and distinct nuclear features.
What nuclear features are diagnostic of papillary carcinomas?
-Optically clear, ground glass nuclei (can see white)
-empty, intranuclear grooves
-pseudoinclusions (invaginations into the nucleus)
-dense fibrovascular cores (unlike Graves disease)
The diagnosis is made based on these features!!
How common is metastasis in papillary carcinomas? How? progression?
up to 50% to adjacent cervical lymph nodes
These are indolent and have a great prognosis even with lymph metastasis
What is this?
Tall cell variant of papillary carcinoma- cells twice as tall as wide comprise 50% of tumor, have abundant eosinophilic cyotplasm aand papillary nuclear features
This variant is VERY aggressive
What is this showing specifically?
Optically clear nuclei in a papillary thyroid cancer
What patient populations are common for follicular carcinomas? Mutations?
Follicular carcinomas account for 5% to 15% of primary thyroid cancers, but are more frequent in areas with dietary iodine deficiency, where they constitute 25% to 40% of thyroid cancers.
They are more common in women (3 : 1) and present more often in older patients (40-60) than do papillary carcinomas
Mutation: PI-3K/AKT signaling pathway (gain of function of RAS or PIK3CA, and loss of function of PTEN), PAX8/PPARG fusion proteins
How can follicular adenomas be differentiated from follicular carcinomas?
Follicular adenoma (left) - no capsular invasion and adjacent tissue compression
carcinoma (right) = capsular invasion can be minimal or extensive and lead to vascular invasion into the neck tissue
How do follicular carcinomas typically present?
These are typically solitary, slowly enlarging painless, cold nodules
Prognosis for follicular carcinoma?
The prognosis depends largely on the extent of invasion and stage at presentation. Widely invasive follicular carcinoma often presents with systemic metastases (via blood to sites like the lungs, bone, and liver), and as many as half of affected patients succumb to their disease within 10 years.
This is in sharp contrast to minimally invasive follicular carcinomas, which have a 10-year survival rate of greater than 90%.
NOTE: Unlike papillary carcinomas, regional lymph metastasis is uncommon
Where do medullary carcinomas arise from? Mutations?
These are neuroendocrine tumors deriving from C cells in the thyroid and secrete calcitonin
Mutations: RET activation (but not fusion proteins like in papillary carcinomas)
Are medullary carcinomas of the thyroid sporadic or genetic?
70% of tumors arise sporadically, the rest are associated with:
◦MEN syndrome 2A or 2B. Cases associated with MEN types 2A or 2B occur in younger patients, and may even arise during the first decade of life. OR
◦As familial tumors without an associated MEN syndrome (familial medullary thyroid carcinoma, or FMTC). In contrast, sporadic as well as familial medullary carcinomas are lesions of adulthood, with a peak incidence in the 40s and 50s.
Recall that activating point mutations in the ________ play an important role in the development of both familial and sporadic medullary carcinomas.
What is this?
Medullary carcinoma- Composed of polygonal to spindle-shaped cells, which may form nests, trabeculae, and even follicles.
Calcitonin is readily demonstrable within the cytoplasm of the tumor cells
What is this showing?
Acellular amyloid deposits derived from calcitonin polypeptides are present in the stroma in many cases of medullary carcinomas
Describe anaplastic carcinomas. Mutations?
These are extremely aggressive, rapidly progressing, undifferentiated tumors of the thyroid follicular epithelium that are almost 100% mortal. These are primarily found in older patients who often have a history of a well-differentiated papillary or follicular thyroid carcinoma that progresses or harbor a concurrent well-differentiated tumor in the resected specimen.
Mutations: RAS or PIK3CA albeit at a higher rate with TP53
What is this showing?
(1)large, pleomorphic giant cells, including occasional osteoclast-like multinucleate giant cells;
(2)spindle cells with a sarcomatous appearance
NOTE: Although widespread metastasis is common, death usually occurs within 1 yr due to local destruction of structures
The most frequent thyroid malignancy (_____) is also the one with the best prognosis.
papillary thyroid carcinoma
And the least common one (anaplastic thyroid carcinoma) has the worst prognosis.
Best to worst thyroid carcinoma prognosis
What is this?
Ectopic Thyroid: Thyroglossal Duct Cyst
Describe Thyroglossal Duct Cysts
These are usually apparent at birth or in childhood and present in the midline, between isthmus of thyroid and hyoid bone. They are Not hormonally active but do tend to get removed due to increased risk of repeated infections
What is this?
Ectopic Thyroid: Struma Ovarii
What are Struma Ovarii?
monodermal teratoma of ovary, composed mainly (>50%) of adult thyroid tissue May functionally cause thyrotoxicosis
Adenomas are common; 5% are malignant
The 2 inferior parathyroids develop from the _______, which also gives rise to the thymus.
third branchial pouch
The 2 superior parathyroids develop from the fourth branchial pouch.
Note: Normally, there are 4 parathyroids, but up to 8 parathyroids can occur.
Normally, the 4 parathyroids are located posterior to the thyroid at the upper and lower poles, but they sometimes reside in the thyroid, or below it, even as low as in the mediastinum.
What is the most common cause of asymptomatic hypercalcemia?
Primary hyperparathyroidism (Most cases are from an adenoma, and some sporadic hyperplasia)
Secondary hyperparathyroidism is most commonly from what?
Parathyroid carcinoma is exceedingly rare
NOTE: Parathyroid carcinoma is exceedingly rare
What is this?
What is this?
Parathyroid adenoma- notice the lack of fat
What is this?
Parathyroid Adenoma (Cause of 85 to 95% of cases of hyperparathyroidism)
How does hyperparathyroidism present?
In most cases, the tumors are found when routine blood test reveal elevated blood calcium and PTH levels. In more serious cases, the bone density will diminish and kidney stones can form. Other non-specific symptoms include depression, muscle weakness, and fatigue.
Mneomic: Groans (depression), moans (GI pain), bones, and stones
What is the most common cause of hypoparathyroidism?
Less common, typically due to surgical interventions
T or F. Hot thyroid nodules are mainly benign
What causes the infiltrative ophthalmopathy seen in Grave's disease?
-infiltration of the retroorbital spaces by T cells
-accumulation of GAGs such as hyaluronic acid in these spaces
-increased adipocyte density
All of these push the eyeball forward