Continuing Education Activity

Parathyroid carcinoma is a rare, malignant neoplasm originating from the parathyroid gland. The clinical presentation can mimic primary parathyroid adenoma or other causes of hyperparathyroidism, from which it must be distinguished. This activity reviews the cause, pathophysiology, and presentation of parathyroid cancer and highlights the role of the interprofessional team in its management.

Objectives:

• Review the presentation of parathyroid cancer.
• Describe the pathophysiology of parathyroid cancer.
• Summarize the treatment options for parathyroid cancer.
• Explain modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by parathyroid cancer.

Introduction

Parathyroid carcinoma is a rare, malignant neoplasm originating from the parathyroid gland. The normal weight and size of the parathyroid glands vary. The average weight is about 60 mg. The average dimensions of each gland are 5 mm in length by 3 mm in width and 1 mm in thickness. The color of normal parathyroid glands is a yellow-brown color. There are generally 4 parathyroid glands, 2 superior and 2 inferior glands; they are located on the posterior and lateral surface of the thyroid gland. The location of the glands may vary based on the embryological descent during development. The inferior parathyroids and the thymus both develop from the third branchial pouch, whereas the parafollicular C cells and the superior parathyroids develop from the fourth branchial pouch. The superior parathyroid glands are frequently found near the cricothyroid junction, just superior to the intersection of the recurrent laryngeal nerve and the inferior thyroid artery. The superior parathyroids are closely associated with the posterior capsule of the superior thyroid pole. The inferior parathyroids have a more variable location, and greater than 50% are located at the inferior thyroid pole, but they can be located in the anterior mediastinum along the thyrothymic ligament. Rarely there is the presence of a supernumerary gland. The association of the parathyroid glands to the recurrent laryngeal nerve is an important anatomical relationship. The superior parathyroids are deep to the recurrent laryngeal nerve, and the inferior parathyroids are superficial.[1][2][3]

In most cases, each parathyroid gland's arterial supply is derived from the inferior thyroid artery, which is a branch of the thyrocervical trunk.  In 20% of cases, it may derive its blood supply from the superior thyroid artery, which is a branch from the external carotid artery. There is generally rich anastomosis between the parathyroids, larynx, pharynx, esophagus, and trachea. The venous drainage parallels the arterial vessels and drains into the internal jugular. The lymphatics of the parathyroid drain into the deep cervical and pretracheal lymph nodes, similar to the lymphatic drainage of the thyroid gland. 

The major functional cells of the parathyroid are the chief cells, which contain many cytoplasmic secretory granules. These are responsible for producing parathyroid hormone. The second cell type that makes up the parathyroid parenchyma is the oxyphil cell. Their function is unknown, but they tend to be rich in mitochondria. Parathyroid glands with high concentrations of oxyphil cells may be more prone to hyperfunction[4]. 

As with all malignancy, parathyroid carcinoma is a result of the uncontrolled or unregulated growth of the parathyroid cells, and most parathyroid carcinomas are functional - meaning they secrete parathyroid hormone (PTH)[5]. Parathyroid carcinoma can occur in any of the parathyroids and does not appear to have a predilection for either the superior or inferior glands (or supernumerary glands), though the rarity of the disease precludes any definitive conclusions. The hallmark characteristic is a very high serum PTH level, often into the thousands, which is rare in benign hyperparathyroidism.[6]

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.

Postoperative and Rehabilitation Care

Postoperatively, patients' serum calcium should be monitored closely, and calcium supplementation should be given if needed. Patients with very high serum calcium levels preoperatively are at risk for developing hungry bone syndrome after parathyroidectomy and will require calcium supplementation intravenously. PTH and serum calcium are monitored closely postoperatively, and elevation in either is an indication for further workup for possible persistence or metastasis.

Consultations

An otolaryngologist or another experienced surgeon should be consulted for parathyroidectomy. Endocrinology consultation may be needed to manage hypercalcemia due to its complexity in parathyroid carcinoma. Interventional radiology consultation may be necessary for percutaneous ablation of metastatic lesions for palliative care.

Deterrence and Patient Education

Patients with a family history of hyperparathyroidism-jaw tumor syndrome should be instructed to follow up with their primary care physicians for routine physical exams and blood work, as well as with medical genetics. Similarly, patients discovered to have a MEN syndrom will require further endocrinologic and genetic workup. Although parathyroid carcinoma is rare, there should be high suspicion in patients with a neck mass who also have extremely elevated parathyroid hormone levels and hypercalcemia.

Pearls and Other Issues

There should be high suspicion for parathyroid carcinoma in patients with a neck mass who also have extremely elevated parathyroid hormone and hypercalcemia.

Enhancing Healthcare Team Outcomes

Because parathyroid cancer is rare and presents with vague signs and symptoms, it is best managed by an interprofessional team that includes a radiologist, ENT surgeon, internist, geneticist, and an endocrinologist. While the treatment for localized lesions is surgery, in some cases the cancer has spread and medical management is recommended.

Early, small, tumors are resectable with apparently good outcomes. The prognosis is generally poor with widely disseminated 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. Overall, this cancer is very aggressive and most patients are dead within 3 years.[18]