22. Pathology of Parathyroid Flashcards
What cells are contained in the Parathyroid Gland and what do they contain? Also, what tissue aside from glandular tissue significantly comprises a normal Parathyroid gland?
Chief Cells - Polygonal cells with glycogen and secretory granules containing PTH
Oxyphil Cells - Larger than Chief Cells, they have abundant nuclei and minimal to no secretory granules
Adipose tissue in the gland reaches a max of 25% by age 25
What does Parathyroid Hormone (PTH) do and what stimulates its release?
Decreased serum calcium stimulates PTH release. PTH increases:
- Renal reabsorption of Calcium
- GI absorption of Calcium
- Conversion of vitamin D to D3 (active form)
- Urinary excretion of Phosphate
What is the pathway through which general malignancies may cause Hypercalcemia?
Some neoplasms can secrete PTH-related protein (PTHrP), which will decrease Osteoprotegerin secretion by Osteoblasts. Osteoprotegerin normally removes RANKL, a ligand on Osteoblasts that binds to RANK on Osteoclast progenitor cells and causes their maturation. Thus with increased PTHrP, there will be increased Osteoclast proliferation, activity, and bone resorption.
What are the causes of Primary Hyperparathyroidism? And what is the most common cause?
Causes include:
- Adenomas
- Primary Hyperplasia
- Parathyroid Carcinoma (rare)
The MOST COMMON cause of Primary Hyperthyroidism is a Solitary Parathyroid Adenoma.
What genetic syndromes are associated with Primary Hyperparathyroidism? Also, describe the mutations involved in these syndromes.
- MEN-1: inactivation of the MEN-1 gene on chromosome 11q13 in parathyroid adenomas and parathyroid hyperplasia
- MEN-2: syndrome caused by activating mutation in the tyrosine kinase receptor, RET, on chromosome 10q. In parathyroid hyperplasia.
- Familial Hypocalciuric Hypercalcemia: autosomal dominant - inactivating mutations in parathyroid calcium sensing receptor (CASR) gene on chromosome 3q. Causes decreased sensitivity to extracellular calcium -> increases PTH secretion.
What are the mutations that cause Sporadic Parathyroid Adenomas?
- Cyclin D1 gene inversions on chromosome 11 - places Cyclin D1 gene next to PTH gene. Causes overexpression of Cyclin D1 protein, leading cells to proliferate.
- MEN-1 mutations: some of these tumors might not cause MEN syndrome, but will have mutations in both copies of the MEN gene
How do Parathyroid Adenomas present? Also, what is an Oxyphil Adenoma?
Parathyroid Adenomas present as nodular enlarge of ONE parathyroid gland, with the remaining glands being normal or slightly shrunken. Grossly, the adenomas:
- Are often solitary, well circumscribed, with a capsule
- Have a homogenous cut surface
- Are soft, tan, or reddish-brown
- Have minimal fat present (unlike normal parathyroid tissue)
The adenomas contain uniform Chief cells. Pleomorphic cells, if present, don’t change the benign nature of the adenoma. There are also nests of larger Oxyphil cells.
Oxyphil Adenomas are adenomas composed entirely of Oxyphil cells.
What are the characteristics of Primary Parathyroid Hyperplasia?
All four glands are typically involved, compared to an adenoma which usually only involves one gland.
Primary hyperplasia usually results from Chief Cell hyperplasia, either in a diffuse or multinodular pattern. These are difficult to palpate, and fat is minimal (unlike normal parathyroid tissue).
Primary hyperplasia may occur sporadically or as part of a MEN syndrome.
Describe the skeletal changes that occur in patients with Hyperparathyroidism.
- Increased number of osteoclasts - leads to erosion of bone matrix, especially in the metaphysis of long bones.
- Increased osteoblast activity is also seen, and the formation of new boney trabeculae (despite common sense).
- Osteitis Fibrosa Cystica - the marrow will contain masses of fibrous tissue with foci of hemorrhage and cyst formation, along with thinning of the cortical bone
Describe the tissue changes that are seen in patients with Hyperparathyroidism.
- Brown Tumors: localized aggregates of osteoclasts, hemorrhage, and giant cells. A reactive change that may resemble a neoplasm.
- Renal stones: form in response to hypercalcemia. Calcification of the renal tubules and interstitium may also be seen.
- Metastatic calcification of the stomach, lungs, myocardium, and blood vessels may occur.
What is the difference between Metastatic calcification and Dystrophic calcification?
Metastatic calcification occurs in normal tissue and is a result of hypercalcemia.
Dystrophic calcification occurs in abnormal tissue, often with normal serum calcium levels.
What are the characteristics of Parathyroid carcinomas?
They are often well circumscribed with a dense capsule. They often involve one parathyroid gland with an irregular mass and a trabecular pattern. The cells are uniform and may resemble normal cells.
They may appear similar to adenomas, or may be clearly invasive. But invasion of the surrounding tissues and/or metastasis must be established to make the Dx of malignancy!
What causes asymptomatic hyperparathyroidism, and how is it diagnosed?
Primary hyperparathyroidism is the most common cause. The asymptomatic form is often detected during routine blood work as hypercalcemia. If detected early, clinical manifestations may not be seen.
While both cause hypercalcemia, what difference would you see in PTH levels between Primary Hyperparathyroidism and Nonparathyroid Neoplasms/diseases?
In Primary Hyperparathyroidism, serum PTH will be inappropriately high for the level of serum calcium. This high level of PTH is associated with hypophosphatemia.
In Nonparathyroid Neoplasms/Diseases, PTH levels will be low or undetectable. This is because the high levels of PTHrP will lead to a decrease in PTH levels.
What are the signs and symptoms seen with Symptomatic Primary Hyperparathyroidism?
- Bone pain with fractures - from bone weakening by osteoporosis and osteitis fibrosa cystica.
- Nephrolithiasis: pain and obstructive uropathy.
- GI Disturbances: constipation, nausea, peptic ulcers, pancreatitis, and gallstones.
- CNS: depression, lethargy, and seizures.
- Neuromuscular abnormalities: weakness and fatigue.
- Cardiac involvement: calcifications on the aortic or mitral valve.
A good phrase: “Painful bones, renal stones, abdominal groans, and mental moans.”
