Parathyroid Adenoma

Etiology

A parathyroid adenoma is part of a spectrum of parathyroid disease that also includes parathyroid hyperplasia and parathyroid carcinoma. 

The etiology of a parathyroid adenoma remains unknown for most patients. The most common genetic mutation associated with sporadic adenomas is the cyclin D1/PRAD1 gene. Alteration in the normal function of this gene affects PTH secretion. Approximately 20 to 40% of sporadic adenomas have overexpression of cyclin D1. Regarding environmental factors, some data suggest that a history of radiation therapy predisposes a patient to parathyroid disease later in life. Long-term calcium deficiency may also result in parathyroid disease due to chronic stimulation of PTH.[5]

Epidemiology

A single parathyroid adenoma is responsible for 80 to 85% of hyperparathyroidism, with double adenomas the culprit in 4 to 5%, and parathyroid hyperplasia in 10 to 12%. Parathyroid carcinomas are very rare causes of hyperparathyroidism and account for less than 1% of disease. Adenomas are most common in patients 50 to 70 years old; however, they can occur at any age. Women are affected 3-times as often as men.[6]

Pathophysiology

Parathyroid hormone plays a vital role in calcium and phosphorus metabolism by acting in the kidneys, intestine, and bone. Normally secreted in response to low blood calcium, PTH works to increase calcium absorption in the distal tubules and inhibit phosphate resorption. It also increases body calcium by indirectly stimulating osteoclasts, which results in bone resorption. Finally, PTH enhances intestinal absorption of calcium by increasing the activation of vitamin D. Pathological overproduction of PTH will cause inappropriate elevations in calcium with depletion of phosphate. It is derangements in these 2 elements that account for most of the symptoms classically seen in parathyroid disease.[7]

Histopathology

A parathyroid adenoma is primarily composed of chief cells, but it can also include oxyphil cells, oncocytes, transitional oncocytes, or a mixture of these cell types. There may also be a rim of normal parathyroid tissue surrounding the adenoma. Microadenomas tend to be unencapsulated; however, larger tumors may have a thin fibrous capsule present with cystic degeneration seen within the tumor. Characteristics such as thick fibrous capsule, adherence to surrounding tissues, vascular and capsular invasion, tumor necrosis, and increased mitotic activity should not be seen in benign adenoma and are more suggestive of carcinoma.

History and Physical

Many patients with a parathyroid adenoma are asymptomatic, with hypercalcemia incidentally discovered on routine lab work. Symptomatic parathyroid disease will most commonly manifest as symptoms of hypercalcemia such as bone pain, fatigue, polyuria, nephrolithiasis, constipation, and neuropsychiatric disturbance. More extreme elevations in calcium can cause complications such as cardiac arrhythmias, coma, and death. A patient is unlikely to have outward physical signs of a parathyroid adenoma. The pathologic gland itself is rarely palpable, and an obvious neck mass is more suggestive of thyroid pathology or parathyroid carcinoma.

Evaluation

Hypercalcemia seen on routine lab work performed for other purposes is the most common initial sign of hyperparathyroidism. In most patients, this hypercalcemia is mild and may even be intermittent and is usually less than 1.0 mg/dL above normal upper limits. Unexplained hypercalcemia on a repeated set of lab work warrants further investigation. PTH level should be subsequently measured, and it may be elevated or even within normal limits, although inappropriately so given the patient’s hypercalcemia. Twenty-four-hour urinary calcium may also be measured, but it is not essential for diagnosis.[8][9][10]

The next step in evaluation is radiographic imaging. Imaging is essential because it not only guides operative planning but distinguishes a single adenoma from a multi-gland hyperplastic disease.

Normal parathyroids are generally too small to be seen on ultrasound; therefore, visualization of this gland should raise suspicion for a pathologic process. If an adenoma identifiable on ultrasound, it should appear as a homogeneously hypoechoic extrathyroidal oval mass with a fat plane separating it from normal thyroid tissue. A feeding artery may also be visualized entering the superior or inferior pole of the adenoma. Ultrasound alone has a sensitivity of only 60 to 80% because it is operator-dependent. It may be used as an adjunct nuclear imaging.

The gold standard of parathyroid localization is single-radioisotope scintigraphy with technetium-99m (99mTc) combined with single-photon emission computed tomography (SPECT) imaging. SPECT is a 3-dimensional sestamibi scan that improves the visualization of parathyroid glands. The combination of these methods has a 91 to 98% sensitivity for identifying parathyroid adenomas.

An alternative is dual-radioisotope imaging, in which both 99mTc pertechnetate and thallium-201 (201Tl) are given. Thallium is taken up by both the thyroid and parathyroid, while pertechnetate only has avidity for the thyroid. Subtraction imaging is then used to visualize the glands. Drawbacks to this method include the necessity of a subtraction program, long imaging times, and limited views.

Four-dimensional CT and MRI have also been used in parathyroid imaging. However, they are only 75% and 40% to 85% sensitive, respectively. For that reason, nuclear imaging for preoperative localization. Four-dimensional CT and MRI may have a more beneficial role in localizing ectopic glands after failed parathyroidectomy. In a study of 45 patients who had undergone previous neck exploration, 4-dimensional CT had 88% sensitivity for abnormal parathyroid glands compared with sestamibi SPECT or neck ultrasound (54% and 21%, respectively).

Treatment / Management

Traditionally, bilateral 4-gland exploration was the procedure of choice for hyperparathyroidism. However, because a single adenoma causes 85% of the disease, minimally invasive parathyroidectomy is emerging as the gold standard for parathyroid adenoma.[11][12][13](A1)

Due to the short half-life of PTH, the Miami criteria dictates that the PTH level should decrease by at least 50% within 10 minutes of adenoma removal. If this value is not met, further exploration is warranted. Missing glands can be found in the retropharyngeal or retro-esophageal planes, posterior mediastinum, thymus, mediastinum, inside the thyroid capsule or gland, or in the carotid sheath.[14]

Differential Diagnosis

Perhaps the most important alternative diagnosis to be considered when a patient presents with hypercalcemia is a malignancy. Hyperparathyroid and malignancy combined account for 90% of cases of hypercalcemia. However, hypercalcemia of malignancy tends to present with much higher concentrations of the ion than a benign parathyroid disease.

Another differential diagnosis is familial hypocalciuric hypercalcemia (FHH). Up to 20% of patients with this disease will also have an elevated PTH level, which can make differentiation difficult. However, patients with FHH characteristically have a low urine calcium excretion and calcium/creatinine (Ca/Cr) clearance ratio, which is not a feature of parathyroid adenomas.

Two medications that can cause elevated calcium levels are thiazide diuretics and lithium. The medication history of any patient presenting with elevated calcium should first be checked for either of these medications.

Complications

An untreated parathyroid adenoma could cause complications related to hypercalcemia. A rare clinical phenomenon is a parathyroid crisis, which is characterized by extremely high calcium levels, usually more than 15 mg/dL. Symptoms include changes in mental status leading to nervous system failure and coma.

Complications can also arise with resection of the parathyroid adenoma. Injury to the recurrent laryngeal nerve is a serious complication of endocrine surgery and has consequences of hoarseness (unilateral damage) or airway occlusion (bilateral damage). Direct trauma to the nerve due to clipping, grasping, or stretching can cause damage. Indirect deleterious effects on the nerve include skeletonization, thermal injury, or compression. The damage may be transient in cases of compression or stretching and may resolve in 4 to 6 weeks. However, if improvement in function is not seen after 6 to 12 months, the damage should be presumed to be permanent. If the damage is recognized intraoperatively, immediate primary repair or grafting should be performed.