Parathyroid carcinoma is a rare, malignant neoplasm involving 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.
In most cases, the 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 are the oxiphil cells. Their function is unknown, but they tend to be rich in mitochondria. Parathyroid glands with high concentrations of oxiphil cells tend to function abnormally.
The cause of parathyroid carcinoma is unknown. There is a rare correlation of patients with parathyroid carcinoma who have a history of radiation to the neck. 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 is hypothesized that parathyroid carcinoma may arise in the presence of primary parathyroid hyperplasia.
Mutation of HRPT2 (CDC73), tumor suppressor gene, has been described to play a role in the molecular pathogenesis of parathyroid carcinoma. This gene is located on chromosome 1 and encodes for a 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.
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. The mean age of onset is 44 to 54 years of age, and it is equal to males and females.
Parathyroid carcinomas tend to be large tumors, and most are palpable pre-operatively. They are typically hard, firm, and adherent to surrounding tissues. Their average size is around 3 cm. They tend to present with widespread local invasion into adjacent structures including the thyroid, trachea, strap muscles and recurrent laryngeal nerve. Regional metastases are rare and distant metastases are also rare, but they may occur to the lungs, bone, mediastinal nodes, liver and kidney. Patients with parathyroid carcinoma tend to have higher PTH and serum calcium levels compared to patients with benign primary hyperparathyroidism.
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.
A thorough head and neck evaluation should be done. Fifty percent of patients with parathyroid carcinoma present with a palpable central neck mass, kidney stones, or osteoporosis. A palpable neck mass in combination with hyperparathyroidism or hypercalcemia is suggestive of parathyroid carcinoma.
Laboratory evaluation is similar to that of primary hyperparathyroidism, which includes parathyroid hormone and serum calcium. Parathyroid hormone and calcium levels tend to be higher in parathyroid carcinoma compared with primary hyperparathyroidism. A PTH three times the upper limit of normal is suspicious but a PTH of 10 times the upper limit of normal has a positive predictive value of 84% for parathyroid carcinoma.
X-rays of the hand a skull may be performed to evaluate for osteoporosis. Plain films of the hand may reveal subperiosteal bone resorption of the distal phalanges. Plain films of the skull may reveal a salt and pepper appearance. Other plain films may demonstrate bone cysts or brown tumors due to osteitis fibrosa cystica. CT and PET scans may be helpful in determining metastasis and staging respectively. 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.
Fine-needle aspiration is contraindicated in the workup for parathyroid carcinoma. These are not helpful in establishing a diagnosis and may seed the tumor.
Diagnosis of parathyroid carcinoma is generally made at the time of surgery to correct for severe hyperparathyroidism.
Surgery is the preferred treatment for parathyroid carcinoma. If there is a high suspicion for parathyroid carcinoma preoperatively, parathyroidectomy or en bloc resection of the parathyroid tumor and adjacent tissues that have been invaded should be performed. When the diagnosis is made postoperatively, the patient should be taken back to the operating room for ipsilateral thyroidectomy. In the instance where pathology evaluation reveals positive margins, the patient should be taken back to the operating room to achieve negative margins.
When parathyroid carcinoma is no longer resectable due to widespread dissemination, medical management is recommended to control hypercalcemia. 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.
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.
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.
Radiation therapy is not routinely used for adjuvant therapy in cases of parathyroid carcinoma because it is difficult to differentiate parathyroid adenoma from carcinoma without pathological evaluation. Radiation will also distort and scar the tissues in the neck making a second neck surgery more difficult.
Chemotherapy is not routinely used in parathyroid carcinoma. Due to the rarity of parathyroid carcinoma, there are no prospective randomized studies in evaluating chemotherapy in parathyroid carcinoma.
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.
The prognosis of parathyroid carcinoma depends on the presence of invasion into adjacent structures and metastasis. In about 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.
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.
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.
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. Although parathyroid carcinoma is rare, there should be high suspicion in patients with a neck mass who also have elevated parathyroid hormone levels and hypercalcemia.
There should be high suspicion for parathyroid carcinoma in patients with a neck mass who also have elevated parathyroid hormone and hypercalcemia. These patients should undergo surgical exploration and excision of the parathyroid tumor for pathological examination and definitive diagnosis.
Because parathyroid cancer is rare and presents with vague signs and symptoms, it is best managed by a multidisciplinary team that includes a radiologist, ENT surgeon, general surgeon, internist and an endocrinologist. While the treatment for localized lesions is surgery, in many cases the cancer has spread and medical management is recommended. Even in those who undergo resection, recurrences are common.
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.
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