Parathyroid tumors

Epidemiology of parathyroid tumors

The prevalence is often said to be around 2% in postmenopausal women, and slightly lower in men and younger age groups. However, a study of premenopausal women as well as thorough analyses of larger cohorts consisting of men and women conclude that pHPT probably is much more common, with prevalence numbers up to 5-6% overall. In Sweden we operate around 900 cases a year, which means that only a minority undergo the hithertho (2013) only known cure being surgery. Median age at operation for pHPT in Sweden is 61 years, and overall more common in females (5:1). Epidemiological studies have identified an associated risk with morbidity and mortality in cardiovascular diseases, as well as certain malignancies.

Symptoms of parathyroid tumors
Tumors in the parathyroid glands usually give rise to the disease of hyperparathyroidism, which most often is primary (pHPT), but may be secondary to renal failure, malabsorption or vitamin D deficiency. PHPT classically present with symptoms from the skeleton such as bone pain or even fractures due to demineralization and low bone density or renal stones. During the last decades and in the Western world a shift towards less of these symptoms and more of so called “non-classical” symptoms have occurred. These include tiredness and fatigue, forgetfulness, mild depression including feelings of low thresholds for aggressions and of being “locked-in”, by some patients described as having a constant cloud around your head. Other symptoms may be related to factors also included in the metabolic syndrome, such as dyslipidemia, overweight, glucose intolerance, and cardiovascular problems such as arrythmias, hypertension and heart failure.

Genetics of parathyroid tumors

A fraction of patients with pHPT suffer from hereditary forms, which have an earlier onset in life. Therefore, the younger the patient is, the higher the risk for having a hereditary pHPT. The variants include multiple endocrine neoplasia type 1 (MEN-1), HRPT2 and other familial pHPT forms with unidentified mutations. Genetic studies of sporadic HPT have revealed that a fraction of these also harbor mutations in the MEN-1 gene. The majority, however, have been found to harbor cyklin D1 overepxression due to a gene transfer event or accumulation of beta cathenin as a consequence of a deletion in the surface protein LRP5 leading to activation of the Wnt pathway.

Diagnostics of parathyroid tumors


The diagnosis of pHPT is in overt cases simple by just measuring plasma or ionized calcium concomitant with plasma PTH. Milder cases may be more difficult, where also values within the upper normal range of calcium and PTH may be possible. Repeated measurements are recommended to outrule single false high values. Discrimination to familial hypocaliuric hypercalcemia (FHH) may be difficult based on biochemical plasma values only. Therefore, measurements of urinary calcium excretion should be performed. The ration between calcium and creatinine clearance is very low in FHH (<0.01), but higher in overt pHPT (>0.02). Still, many patients end up with values in between, perhaps signalling a normal mineral homeostasis. Taken together, one may conclude that overt cases are easy to biochemically diagnose, while milder ones are more difficult.

The typical examinations for localisation of parathyroid tumours are sestamibi scintigraphy (MIBI) and ultrasound. The sensitivity and specificity of both these methods vary considerably between centers, but in Uppsala we have made an effort to increase these values, and have reached internationally high sensitivity of between 80-95% for MIBI and ultrasound in patients without concomitant goiter. For a primary operation no other localisation procedures are necessary. In case of reoperation, however, we want two concordant and reliable localisation studies. To achieve that often add one or several of alternative studies. One method is selective venous sampling with quick PTH, which is a highly sensitive method. This includes selective angiography directed to areas where the qPTH identifies raised values. Also, we use positron emission tomography (PET) with methionine together with high-resolution DT scan in arterial and venous phases (so called 4D-DT) and may perform MIBI scans using different protocols which may enhance the resolution.

Treatment of parathyroid tumors
The treatment is surgical.
Cure for primary hyperparathyroidism (pHPT) is surgical. Up to now (2013), no medical compound have reached the qualifications needed to be used in this disease. Important to rule out before surgery is whether the patient harbours a risk of having multiglandular disease or only presenting a solitary parathyroid adenoma. The risk for multiglandular disease, or hyperplasia, is increased in younger patients, in Uppsala defined as being below 45 years of age, but also in older individuals with mild disease, as well as in men with recurrent renal stones. The younger patients, as well as those with a familiar history regardless of age, should before surgery undergo DNA analyses to identify possible mutations in the MEN-1 and HRPT2 genes. All patients undergo ultrasound of the neck, and in case of positive finding this is usually enugh as preoperative localisation procedures. However, patients having suspicions of possible multiglandular disease or with equivocal ultrasound examination also undergo sestamibi scintigraphy (MIBI). Patients with positive and concordant localisation are submitted to a focal surgical procedure, while others undergo classical bilateral neck exploration. In selected cases, after removal of enlarged glands, intraoperative PTH measurements are being used. We use a mimimal invasive open technique using an approximately 20 mm incision at the medial border of the sternocleidomastoideus muscle for the focal procedures. Patients with known MEN-1 mutations are always explored bilaterally. We remove all parathyroid tissue in the neck but approximately 50 mg which are left either in situ or autotransplanted to the non-dominant forearm, into the brachioradialis muscle. Which of these methods to use is somewhat arbitrary due to Intraoperative findings as well as the patient’s age, with the younger ones more commonly being autotransplanted. Our results are excellent, with an overall cure rate of approximately 98% in sporadic cases. Failures include patients with supernumerary or intrathoracic glands, or patients with mild pHPT expressing only slight enlargement of the parathyroid glands implying low-grade hyperplasia. This patient group is increasing lately, and a matter of on-going research. Results of the familial cases are also excellent, although one must bear in mind that these individuals must undergo life-long surveillance due to the remaining still genetically disturbed and pathological parathyroid tissue.

Prognosis of parathyroid tumors
The biochemical cure rate after surgery for pHPT is extremely high, reaching numbers of 98%. Effect of psychological symptoms are usually good, with a range from no effect to feelings of starting off a new life with no depression, no fatigue and no “cloud” around the head. The effect on bone mineral density is positive in patients with preoperative low density, which may be especially important in postmenopausal women. The effect on the associated symptoms of cardiovascular morbidity and mortality is somewhat more unclear, although signs of improvement different single factors are documented. These include improved dyslipidemia and reduced atherogenic index, reduced left ventricular hypertrophy, and improved peripheral endothelial function.