The parathyroid glands are four tiny, rice-sized glands located in the neck, typically situated just behind the thyroid gland. Their primary function involves tightly controlling the body’s calcium levels, which is necessary for proper nerve, muscle, and bone function. A parathyroid tumor represents an abnormal growth within one or more of these glands. This growth often leads to a condition called primary hyperparathyroidism, where the body’s calcium regulation mechanism is disrupted.
The Role of Parathyroid Glands and Hyperparathyroidism
The parathyroid glands produce parathyroid hormone (PTH), which acts to raise calcium levels in the bloodstream by signaling the bones to release calcium and the kidneys to conserve it. When a tumor develops, the affected parathyroid gland loses its ability to sense and respond to normal calcium levels. It begins to secrete PTH continuously and without regulation. This excessive, uncontrolled PTH production forces too much calcium into the blood, resulting in a state of hypercalcemia.
The vast majority of these growths are non-cancerous, called adenomas. This overactivity causes serious health concerns over time, including the weakening of bones and the formation of kidney stones. The primary issue is the overproduction of PTH, which upsets the body’s mineral balance, defining primary hyperparathyroidism.
Primary Cause: Sporadic Parathyroid Adenoma
The most frequent cause of parathyroid tumors, accounting for 80% to 85% of all cases, is the sporadic parathyroid adenoma. The term “sporadic” indicates that the tumor arises randomly in an individual without any clear family history or inherited genetic predisposition. In these instances, the tumor is almost always a solitary, benign adenoma affecting only one of the four parathyroid glands.
The development of a sporadic adenoma begins with a random somatic mutation in a single parathyroid cell. This alteration in DNA occurs after conception and is therefore not passed down from a parent. For example, some tumors show alterations in genes like CCND1 or inactivation of tumor suppressor genes. The majority of individuals developing a sporadic adenoma are women over the age of 60.
Genetic Predisposition and Inherited Syndromes
A smaller percentage of parathyroid tumors arise due to inherited causes, which involve germline mutations passed down through families. These familial cases are distinct because the genetic alteration is present in every cell of the body from birth. The tumors in these syndromes often present as hyperplasia, meaning an enlargement of multiple parathyroid glands, rather than a single adenoma.
Multiple Endocrine Neoplasia Type 1 (MEN1) is the most common familial cause, resulting from a mutation in the MEN1 tumor suppressor gene. MEN1 predisposes individuals to tumors in the pituitary gland, parathyroid glands, and pancreas. Another condition is Multiple Endocrine Neoplasia Type 2A (MEN2A), which is caused by a mutation in the RET proto-oncogene and is associated with parathyroid tumors, medullary thyroid cancer, and pheochromocytoma.
Hyperparathyroidism-Jaw Tumor Syndrome (HPT-JT) is a rare, severe inherited disorder linked to germline mutations in the CDC73 gene. This syndrome causes parathyroid tumors that have a higher risk of being malignant, along with fibrous tumors of the jaw bones.
Environmental and Acquired Risk Factors
Certain external factors are associated with an increased risk of developing parathyroid tumors. Exposure to therapeutic radiation directed at the head and neck region is a recognized acquired risk factor. This exposure, which often occurred decades earlier, can lead to the later development of a parathyroid adenoma. The risk is generally related to the dose of radiation received.
Long-term treatment with the medication lithium is also linked to an increased risk. Lithium can interfere with the parathyroid gland’s ability to regulate calcium, potentially stimulating cell growth and leading to a parathyroid adenoma or multiple gland hyperplasia.