Parathyroid Cancer

Etiology

Most parathyroid carcinomas are idiopathic and sporadic, though there are well-documented syndromic associations with Multiple Endocrine Neoplasia (MEN) syndrome types I and IIa, as well as with hyperparathyroidism-jaw tumor syndrome (HPT-JT). It is reported that parathyroid carcinoma is the cause of primary hyperparathyroidism in 0.1% to 5% of cases. It is uncertain whether parathyroid carcinoma begins as benign parathyroid lesions, but it has been hypothesized by some that parathyroid carcinoma may arise in the presence of primary parathyroid hyperplasia, though the potential for malignant transformation remains theoretical[6]. 

Mutation of HRPT2 (CDC73), a tumor suppressor gene, has been described in the molecular pathogenesis of parathyroid carcinoma. This gene is located on chromosome 1 and encodes for the protein parafibromin, which is involved in the inhibition of cell proliferation. The HRPT2 mutation is found in hyperparathyroidism-jaw tumor syndrome and sporadic parathyroid carcinoma. Patients with hyperparathyroidism-jaw tumor syndrome develop ossifying fibromas of the jaw, cysts, and neoplasms of the kidneys. They are at an increased risk for parathyroid carcinoma. Studies show 15% of patients with hyperparathyroidism-jaw tumor syndrome develop parathyroid carcinoma.[7][8][9]

The MEN syndromes are described in detail elsewhere in StatPearls, please reference these articles for further discussion of MEN I and MEN IIa.

Epidemiology

Parathyroid carcinoma is extraordinarily rare with an incidence of 1.25 cases per 10,000,000 people. In the United States, it occurs in less than 1% of all cases of hyperparathyroidism, and the total number of cases reported in the literature numbers only in the hundreds. The mean age of onset is 44 to 54 years of age, and it is equal to males and females.[10]

Pathophysiology

Parathyroid carcinomas often present with a palpable neck mass and hyperparathyroid laboratory values. This presence of a palpable mass is an important finding that should alert the astute clinician that malignancy may be present[10]. They are typically hard, firm, and adherent to surrounding tissues. Their average size at presentation is around 3 cm, as they are often otherwise asymptomatic. They tend to present with local invasion into adjacent structures, especially the ipsilateral thyroid. Invasion of the trachea, strap muscles, and recurrent laryngeal nerve are possible in more advanced disease, but are rare presenting findings. Regional metastases are rare and distant metastases even more so, but if present can occur in the lungs, bone, mediastinal nodes, liver, and kidney. Patients with parathyroid carcinoma tend to have extremely high PTH levels compared to patients with benign primary hyperparathyroidism, and almost always have a refractory, elevated, serum calcium also.[11][12][13]

Histopathology

Microscopic diagnosis of parathyroid carcinoma can be difficult because it is very similar to parathyroid adenoma histologically. Parathyroid adenomas may also show increased mitotic activity and capsular invasion. The entire gland is generally traversed by broad fibrous bands that originate from the capsule and extend to the tumor, which results in a lobulated appearance. The cells may be clear, oxyphilic, uniformly bland, or show metaplasia and are arranged in nests or trabeculae. The cells with minimal atypia may be difficult to differentiate from parathyroid adenoma. Mitotic figures are a primary factor in diagnosing parathyroid carcinoma, but they are also present in adenoma and hyperplasia. Thus, their absence does not rule out carcinoma. Extra-glandular spread is a hallmark but is not necessary for the diagnosis of early parathyroid carcinoma.

History and Physical

A thorough head and neck evaluation is essential. Fifty percent of patients with parathyroid carcinoma present with a palpable central neck mass in addition to systemic signs of hypercalcemia and hyperparathyroidism. These include kidney stones, arrhythmias, and osteoporosis. A palpable neck mass in combination with hyperparathyroidism or hypercalcemia is suggestive of parathyroid carcinoma. It is important to obtain a very detailed endocrine history and family history of any endocrine diseases or malignancies (to screen for occult MEN syndromes). Any history of prior ionizing radiation to the head and neck should be obtained, as there have been rare reports of parathyroid carcinoma after radiation[14].

The physical examination should include a thorough oral, jaw, and neck examination. The lateral and central neck should be palpated for masses and lymphadenopathy, with particular attention to palpation of the thyroid at rest and with deglutition. Attention should be paid to the character and strength of the voice, and there is a low threshold to perform flexible laryngoscopy or stroboscopy to evaluate the function of the vocal folds for subtle weakness.

Evaluation

Laboratory evaluation is similar to that of primary hyperparathyroidism, which includes parathyroid hormone and serum calcium. Parathyroid hormone and calcium levels tend to be much higher in parathyroid carcinoma compared with primary hyperparathyroidism (and frequently read in the thousands of pg/mL). A PTH three times the upper limit of normal is suspicious for malignancy, while a PTH of 10 times the upper limit of normal has a positive predictive value of 84% for parathyroid carcinoma[15].

Computed tomography (CT) scan is the imaging study of choice for a newly discovered neck mass and may reveal a peri-thyroid mass and potential thyroid invasion. This has the advantage of concurrently evaluating the remaining neck compartments for invasion or lymphadenopathy suspicious for metastasis. Positron-emission tomography (PET) scans may be helpful in determining metastasis and staging, though the reliability of PET in parathyroid carcinoma is unknown. Sestamibi scans may be used to detect hyperactive parathyroid glands but will not specifically identify carcinoma. Ultrasound may also be utilized to help characterize parathyroid tumors but cannot definitively diagnose parathyroid carcinoma, and a recent study has described some characteristics on ultrasound that may aid in diagnosing parathyroid malignancy[16]. X-rays of the hand a skull may be performed to evaluate for osteoporosis, but are extremely nonspecific and are not recommended as a screening examination.

Ultrasound-guided fine-needle aspiration has been reported, but the ability to distinguish benign hyperplastic parathyroid from malignant parathyroid remains in question.

Treatment / Management

Surgery (parathyroidectomy, often including ipsilateral thyroidectomy) is the preferred treatment for parathyroid carcinoma. If there is a high suspicion for parathyroid carcinoma preoperatively, parathyroidectomy with en bloc resection of the ipsilateral thyroid and any adjacent tissues that have been invaded should be performed. If positive margins are documented on final histopathology, re-resection with the aim of clearing the margins is recommended. Of note, this subsequent resection can be quite involved, potentially involving tracheal and esophageal resection, and potential sacrifice of the recurrent laryngeal nerve.  The surgeon and patient must be prepared for this, as well as the required reconstructive procedures.

When parathyroid carcinoma is no longer resectable due to widespread dissemination, medical management is recommended to control hypercalcemia and manage symptoms in a palliative manner. The prognosis is generally poor with widely disseminated or otherwise unresectable parathyroid carcinoma, but survival can be prolonged with adequate control of serum calcium. Intravenous hydration and bisphosphonates are recommended for the treatment of hypercalcemia. In episodes of hypercalcemia refractory to bisphosphonates, cinacalcet may be attempted to aid in serum calcium reduction.

In cases of local or regional recurrence, surgical excision is indicated and will provide palliation from hypercalcemia. Long-term cure after recurrence is unknown. In cases with metastasis to the lungs or liver, surgical excision of these areas has been described for palliative care, but long-term survival data are lacking.[17]

Differential Diagnosis

Parathyroid carcinoma presents similarly to primary hyperparathyroidism with elevated levels of parathyroid hormone and serum calcium. Paraneoplastic syndromes may also present similarly with elevated serum calcium levels but will be distinguishable with elevated levels or parathyroid hormone-related peptide. Thyroid nodules may be difficult to distinguish from parathyroid neoplasms but both present with a palpable mass in the neck.

Differential diagnosis:

• Parathyroid adenoma
• Parathyroid hyperplasia
• Paraneoplastic syndrome (lung or head and neck primary)
• Thyroid nodule
• Primary thyroid malignancy
• Brown's tumor

Staging

There is no standardized TNM staging system of parathyroid carcinoma. The American Joint Cancer Committee acknowledges in the 2017 edition for the TNM cancer manual that staging for parathyroid carcinoma would be premature at this point.

Prognosis

The prognosis of parathyroid carcinoma depends on the presence of invasion into adjacent structures and metastasis. In approximately 33% of cases, the cancer is well demarcated without extension into adjacent tissues or distant metastasis, and the likelihood of total resection with clear margins is high, thus establishing a very good prognosis. In 33% of cases, the disease will recur after an extended disease-free survival. In these cases, reoperation provides a cure. However, in 33% of cases, there is a short and aggressive course that leads to death.