Parathyroid carcinoma is an extremely rare but aggressive and life-threatening form of primary hyperparathyroidism (pHPT). Most hyperparathyroidism is caused by a single benign adenoma (approximately 85%) or by parathyroid hyperplasia or multiple adenomas. Parathyroid carcinoma accounts for less than 1% of cases of hyperparathyroidism.
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Photomicrograph of parathyroid carcinoma showing typical fibrotic septae. Histologic diagnosis can be difficult.
Hyperparathyroidism–jaw tumor (HPT-JT) is a rare autosomal dominant familial cancer syndrome caused by inactivating germline mutation of the Cell Division Cycle 73 (CDC73) gene. Patients with HPT-JT also have an increased risk of developing parathyroid carcinoma, ranging from 15% to 37.5% in different case series. Somatic inactivating CDC73 mutations are also strongly implicated in sporadic parathyroid carcinoma and have been found in up to 70% of such cancers.[1]
Untreated, parathyroid carcinoma leads to severe hyperparathyroidism, with signs and symptoms including hypercalcemia, bone pain, osteoporosis, fractures, and kidney stones or other renal damage. The diagnosis is often not made prior to parathyroidectomy. This results in inadequate tumor excision and a propensity to local recurrence. Regional lymph node involvement and distant metastases are usually not present at initial diagnosis.
Recurrences may be treated by local excision or ablative (eg, radiofrequency) treatments. Death is usually caused by medically refractory hypercalcemia and seldom tumor burden alone.
The parathyroids are small endocrine glands in the neck that regulate the circulating calcium level by producing and secreting parathyroid hormone (PTH), which acts to maintain homeostasis by regulating bone mineral turnover, renal calcium reabsorption, and dietary calcium absorption from the gut. PTH production is inhibited through a feedback loop when calcium binds to calcium-sensing receptors on the parathyroid cell membrane.
Hyperparathyroidism is a state of overactive parathyroid function with excessive circulating PTH. The hyperparathyroidism seen in parathyroid carcinoma is usually severe, with high serum calcium levels, severe bone disease, and renal stones. Rarely, parathyroid cancer can be nonfunctional, that is, the tumor may not produce parathyroid hormone and the sequelae of hyperparathyroidism.
Mutations of the gene encoding CDC73 (HRPT2, 1q31.2) cause hyperparathyroidism–jaw tumor syndrome, and a high proportion (15%-37.5%) of these patients develop parathyroid cancer. Many sporadic parathyroid carcinomas also exhibit defects in this gene.[2, 3]
HRPT2 encodes a protein called parafibromin. It is thought that most parathyroid carcinomas exhibit loss of parafibromin expression.[4] Parafibromin is thought to act as a tumor suppressor gene but may have several other effects, including histone modification and activation of signaling pathways.[5] HRPT2 mutations can also be seen in benign parathyroid adenomas, but carcinomas more frequently exhibit alterations in gene copy number and have large-scale chromosomal deletions.[5]
Cyclin D1 overexpression has been associated with parathyroid carcinoma.[6] Parafibromin can negatively regulate cyclin D1 and may be responsible at least in part for this.[7]
Allelic loss of the retinoblastoma protein has been shown to be associated with parathyroid carcinoma.[8]
Mutations of the MEN1 gene can occasionally be seen in parathyroid carcinomas.[9]
The etiology is unknown in most cases. Parathyroid cancer is associated with the genetic diseases hyperparathyroidism–jaw tumor (HPT-JT) and familial isolated hyperparathyroidism.[1, 10]
Parathyroid cancer is a rare disease. Data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program show an increasing annual incidence until approximately 2001. More recently the annual incidence has stabilized to a rate of approximately 11 cases per 10,000,000 persons.[11] Parathyroid cancer occurs in less than 1% of all cases of hyperparathyroidism.[12]
A large European study also demonstrated the rarity of parathyroid carcinoma, with an estimated incidence of 2 cases per 10,000,000 persons/year.[13]
No known racial predilection exists. Parathyroid cancer occurs equally in males and females.[14] Males fare slightly worse in prognosis.[14, 15] Parathyroid cancer usually occurs in patients older than 30 years. Beyond that, no predominant age association has been noted.
Survival has varied widely in the literature, with 5-year survival ranging from 20-85% and 10-year survival from approximately 15-80%.[16, 17, 18, 19, 20, 21, 22, 14, 23, 24, 25] Data from the US National Cancer Data Base showed a 5-year survival of 82% and a 10-year survival of 66%.[26] Mortality continues after 10 years however and falls below 50% by 15 years.
Median overall survival of HPT-JT ranges from 8.9 years to 14.3 years after the date of diagnosis. Risk factors associated with shorter survival include large tumor size, older age at diagnosis, and male gender. In contrast, lymph node status or performance of radical parathyroid surgery was not found to be significant in predicting survival.[1]
Hypercalcemia is found in patients with untreated or inadequately treated parathyroid carcinoma. It is often the mechanism of death in patients with metastatic disease. Postoperative hypocalcemia can be severe because of bone hunger syndrome. In patients with severe bone disease, falling presents a serious hazard due to pathologic fractures.
The prognosis associated with the disease and its relationship to hypercalcemia should be discussed with the patient. The difficulty of diagnosis should be emphasized. Discuss the long-term nature of the disease even with metastases. Make patients aware that surgery is the only effective treatment against the tumor itself even though medical therapy may alleviate the hypercalcemia.
Educate the patient and family about fall prevention. This becomes increasingly important with bone disease of increasing severity.
The presence of severe primary hyperparathyroidism and significantly elevated serum calcium and parathyroid hormone levels should trigger a high index of suspicion for parathyroid cancer and possible germline CDC73 mutation. Hyperparathyroidism–jaw tumor (HPT-JT) should be considered when the patient's family history includes benign or malignant parathyroid disease and/or fibro-osseous jaw tumors.[1]
The history should focus on symptoms of hypercalcemia plus the other symptoms of hyperparathyroidism. The onset is usually more abrupt, and the symptoms more severe, than with hyperparathyroidism due to benign disease. Manifestations include the following:
Bone pain, pathologic fracture, or other evidence of bone disease (approximately 90% of patients)
Renal stones (50-80% of patients)
Symptoms of hypercalcemia - Fatigue, weakness, confusion, depression, constipation
A palpable mass in the neck is present in approximately 50% of patients with parathyroid carcinoma. In contrast, a palpable neck mass is virtually never present with benign parathyroid adenomas or hyperplasia. Signs of hypercalcemia may also be present.
The laboratory workup for parathyroid carcinoma is the same as that for primary hyperparathyroidism. Simultaneous calcium and parathyroid hormone (PTH) levels should be determined.
Serum calcium level is usually elevated more markedly than in benign primary hyperparathyroidism.
With regard to parathyroid hormone (intact) testing, parathyroid carcinoma should produce authentic parathyroid hormone; therefore, serum parathyroid hormone levels should be elevated, usually higher than is typical for primary hyperparathyroidism.
In a retrospective chart review of 54 patients undergoing operation for primary hyperparathyroidism from 2000-2014, researchers found that parathyroid carcinoma was associated with higher parathyroid hormone (PTH) (p = 0.005) and with male sex (p = 0.002), compared with atypical parathyroid neoplasms.[27]
A mathematical model has been proposed to predict parathyroid carcinoma, taking into account the calcium and PTH levels and patient age. The model, however, has not been widely validated.[28] Differential expression of the microRNAs miR-139 and miR-30b has been proposed as a potential strategy for distinguishing parathyroid carcinomas from parathyroid adenomas.[29]
Imaging studies may be used preoperatively to determine the location of an abnormal parathyroid gland, however, no single radiological modality has sufficient sensitivity and specificity for localization of parathyroid carcinoma. See Hyperparathyroidism for the rationale of whether to obtain imaging studies for this purpose. Imaging studies may also be used for staging to determine the presence of distant metastases.
Compared with benign parathyroid lesions, parathyroid carcinomas usually display the following characteristics on ultrasound1:
Larger
More hypoechoic
Hypervascular
Heterogeneous
Lobulated, with irregular borders
Higher depth/width ratio
Greater infiltration into surrounding tissues
Hand radiographs may show subperiosteal bone resorption of the distal phalanges. Skull radiographs demonstrate a characteristic "ground glass" or "salt and pepper" appearance. In severe cases, plain films reveal the classic bone finding, osteitis fibrosa cystica, which consists of bone cysts with or without pathologic fractures. These cysts are also known as brown tumors.
Computed tomography may be helpful in detecting metastatic disease.
Positron emission tomography (PET) scanning may be helpful in staging. False-positive findings due to brown tumors have been reported.[30]
In patients with suspected or proven parathyroid cancer, genetic testing for germline CDC73 mutation should be considered to rule out HPT-JT. Besides CDC73 mutations that can be detected by conventional mutational analysis, intragenic deletion of CDC73 has also been reported in patients with familial hyperparathyroidism and parathyroid carcinoma. Therefore, intragenic and gross gene deletion should be assessed as a part of genetic analysis in patients with a high index of suspicion but negative CDC73 mutational testing. Partial or complete gene deletion can be detected by methods such as exon array comparative genome hybridization.[1]
No preoperative test is currently available to distinguish parathyroid cancer from benign primary hyperparathyroidism reliably. Fine-needle aspiration biopsy is not helpful in establishing a diagnosis and may be harmful by causing tumor dissemination.[31] Diagnosis is based on the histologic appearance of the excised parathyroid gland and clinical indicators such as recurrence or metastases.
The parathyroid glands are usually large (2-10 g).
Tumors are usually encapsulated and often have fibrous septa extending into the gland (see the image below). The majority of tumors are fibrotic. The parenchyma of the tumor usually has a predominance of chief cells. They are often larger than those typically seen in adenomas and have a bland cytologic appearance. The parenchyma may appear indistinguishable from a benign adenoma.
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Photomicrograph of parathyroid carcinoma showing typical fibrotic septae. Histologic diagnosis can be difficult.
Vascular and extracapsular invasion are common but not universal,[14]
Some degree of nuclear atypia is seen commonly, and mitotic figures are usually evident.
Proven lymphatic metastases, though uncommon, are a clear indication of malignancy.
Molecular or genetic markers may prove useful in distinguishing parathyroid cancer from other lesions. The HRPT2 gene product, parafibromin, is often but not always absent in parathyroid carcinoma.[32] Increased expression of another marker, PGP9.5, has also been shown to be highly specific for parathyroid carcinoma.[33] A preliminary study that examined a panel of 34 proteins showed promise in using protein arrays as an aid in diagnosis.[34]
Tumors that exhibit some characteristics of carcinoma but are not definitive are referred to as atypical adenoma or adenoma with suspicious features. The clinical behavior of these entities is not known.[35]
Two staging systems have been developed and externally validated to classify risk in parathyroid carcinoma.[14, 36]
The first is called the differentiated system and is reminiscent of a typical tumor, node, metastasis (TNM) staging system. It divides patients into 4 classes of risk. The second system is simpler and divides patients simply into high and low risk.
Differentiated system
T (tumor)
(Tx) - No information available
T1 - Evidence of capsular invasion
T2 - Invasion of surrounding soft tissues, excluding the vital organs of the trachea, larynx, and esophagus
T3 - Evidence of vascular invasion
T4 - Invasion of vital organs, such as the hypopharynx, trachea, esophagus, larynx, recurrent laryngeal nerve, carotid artery
N (node)
(Nx) - Lymph node not assessed
N0 - No regional lymph node metastases
N1 - Regional lymph node metastases
M (metastasis)
(Mx) - Distant metastases not assessed
M0 - No evidence of distant metastases
M1 - Evidence of distant metastases
Classes
Class I - T1 or T2 N0M0
Class II - T3 N0 M0
Class III - Any T, N1 M0, or T4
Class IV - Any N, M1
High/low risk system
Criteria are as follows:
Low risk - Capsular invasion combined with invasion of surrounding soft tissue
High risk - Vascular invasion and/or lymph node metastases and/or invasion of vital organs and/or distant metastases
The diagnosis of parathyroid carcinoma is usually not known prior to surgery. The usual indication for surgery is primary hyperparathyroidism. Unusually severe hyperparathyroidism or a palpable mass should trigger suspicion for parathyroid carcinoma. Often, however, the first indication of parathyroid carcinoma is the discovery of a hard mass during surgical exploration. Frozen section may be useful to confirm parathyroid tissue as opposed to a thyroid mass, but it is not usually sufficient to diagnosis parathyroid carcinoma.
Medical therapy is primarily geared toward management of hypercalcemia, which is often quite severe. Treatment is similar to that of hypercalcemia due to other causes. At initial presentation, and for rapid treatment of severe hypercalcemia, volume loading and diuresis with a calcium-wasting loop diuretic is the treatment of choice.
In most cases, volume expansion with normal saline and diuresis with furosemide is adequate treatment. Bisphosphonates may also be used for short-term control of the hypercalcemia but often are ineffective for long-term control in patients with metastatic disease. Calcitonin may be used for short periods, usually in conjunction with a bisphosphonate. It usually loses effectiveness rapidly.
Hypercalcemia associated with parathyroid carcinoma is often severe and refractory to medical treatment. Treatment with denosumab (120 mg/month) has been effective in controlling hypercalcemia that is resistant to bisphosphonates and cinacalcet.[37, 38] However, hypercalcemia due to parathyroid cancer is often resistant to long-term medical management and is usually the cause of death in patients with metastatic disease.
No effective medical therapy for parathyroid carcinoma is known and medical care is limited to the control of hypercalcemia (if necessary). Trials of chemotherapeutic agents have been generally disappointing. This tumor is sufficiently rare that controlled trials are impossible.
Preliminary laboratory data from archived tumor samples show that a proportion of parathyroid carcinomas exhibit tumor-infiltrating lymphocytes and are positive for programmed death ligand–1 (PDL-1). This suggests the possibility that immunotherapy might be useful in a subset of patients.[39] However, this has not been tested.
At present, resection of the parathyroid cancer is the only effective treatment.
Preoperative care
Because the hypercalcemia caused by parathyroid cancer is often severe, preoperative medical intervention to control hypercalcemia is often required. Volume expansion with isotonic saline and diuresis with furosemide is often adequate. Take care to ensure that any volume contraction is corrected before the operation.
Operative management
The goal of the initial operation is to remove the tumor en bloc with any adherent tissue, the ipsilateral thyroid lobe, and any enlarged lymph nodes. Recommendations on the precise extent of the dissection cannot be made because of the rarity of this condition, but an en bloc excision with negative margins and removal of the involved lymph nodes is standard. Prophylactic lateral neck dissection is not indicated.[40]
Because the diagnosis of malignancy is usually uncertain before the operation, the initial approach is the same as for benign primary hyperparathyroidism. Make a standard collar incision. While approaching the parathyroid, be alert for evidence of invasion into surrounding tissue or gland firmness that might indicate malignancy. If any indication of malignancy is noted, perform an en bloc excision as described above.
Regional lymph node metastases are uncommon.[12] However, if any regional lymph nodes are enlarged, perform a compartmental lymphadenectomy.
See Parathyroidectomy
Postoperative care
Postoperative care is generally the same as with surgery for benign hyperparathyroidism. Bone hunger may be quite profound and require substantial doses of postoperative calcium.
Resection of recurrence
Reoperation for local and regional recurrence is indicated and may provide substantial palliation from hypercalcemia, in some cases for many years. Resection or ablation of pulmonary or hepatic metastases also may provide palliation. Long-term cure after a recurrence is virtually unknown.
Referral to an experienced parathyroid surgeon is advised; surgical removal is the mainstay of treatment. Medical care of the hypercalcemia can be difficult and complex and should be managed by an endocrinologist. An interventional radiologist may be consulted for palliative treatment with percutaneous ablation or embolization of metastatic lesions.
External beam radiation therapy (EBRT) is controversial. Postoperative EBRT may decrease local recurrence, but the evidence for this is not strong.[18] EBRT may also be used in specific circumstances for treatment of a metastasis. In general, however, parathyroid carcinoma is relatively resistant to radiation therapy.
Germline CDC73 analysis in individuals with HPT-JT syndrome , familial isolated hyperparathyroidism or malignant parathyroid histology, and young individuals with pHPT enables optimal clinical management of pHPT as well as surveillance for development of parathyroid carcinoma.[10] First-degree relatives of patients with parathyroid cancer or HPT-JT should also be genetically screened for CDC73 mutation (when mutation is known) or periodically screened for primary hyperparathyroidism.[1]
Screening for HPT-JT associated tumors should begin in early childhood in asymptomatic patients with germline CDC73 gene mutation found through genetic testing. Screening includes biochemical testing every 6–12 months, and panoramic dental imaging and renal ultrasound every 5 years. The follow up schedule should be individualized.[1]
After surgical treatment, periodic follow-up with serum calcium determinations is mandatory. If serum calcium begins to rise, elevation of parathyroid hormone level can confirm recurrence.
Once suspected, the location of the recurrence should be determined:
Neck imaging with CT scan, MRI, or ultrasound is indicated.
PET scanning may detect distant metastases but its accuracy in this disease is not clearly defined.
A chest radiograph is indicated, but a chest CT scan may reveal pulmonary metastases missed on plain radiograph.
The 2016 American Association of Endocrine Surgeons (AAES) guidelines for definitive management of primary hyperparathyroidism (pHPT) include the following recommendations for diagnosis and treatment of parathyroid carcinoma[40] :
The diagnosis of parathyroid carcinoma should be considered in patients with pHPT, markedly elevated PTH levels and severe hypercalcemia
Patients with pHPT who present with hypercalcemic crisis should be medically managed, followed by parathyroidectomy for suspected parathyroid carcinoma
If parathyroid carcinoma is suspected, patients should be treated surgically because this is the only potentially curative treatment
Parathyroidectomy is indicated when the clinical or biochemical evidence is consistent with parathyroid carcinoma
Preoperative parathyroid fine-needle aspiration biopsy is not recommended
Histologic diagnosis relies on identification of unequivocal angioinvasion and can be assisted by biomarkers
When there is intraoperative suspicion of parathyroid carcinoma, complete resection avoiding capsular disruption offers potential cure; en bloc resection of adherent tissues may be required
There is insufficient evidence to recommend prophylactic central or lateral neck dissection
Adjuvant external beam radiotherapy is reserved for palliative care and should not be routinely performed after surgical resection
No medical treatment is available for parathyroid carcinoma except to reduce hypercalcemia. Medications used for that purpose are the calcimimetic agent cinacalcet, bisphosphonates, and calcitonin. However, hypercalcemia due to parathyroid cancer is often resistant to long-term medical management.
Clinical Context:
Directly lowers parathyroid hormone (PTH) levels by increasing sensitivity of calcium-sensing receptor on chief cell of parathyroid gland to extracellular calcium. Also results in concomitant serum calcium decrease.
These agents bind to and modulate the parathyroid calcium-sensing receptor, increase sensitivity to extracellular calcium, and reduce parathyroid hormone secretion.
Clinical Context:
Inhibits normal and abnormal bone resorption. Appears to inhibit bone resorption without inhibiting bone formation and mineralization.
Clinical Context:
Available in the United States, but not yet indicated for treatment of hypercalcemia; alendronate probably is useful for long-term prevention of recurrence of hypercalcemia following use of more conventional therapy (ie, hydration and pamidronate). Useful in preventing and treating osteoporosis, which is a complication of prolonged mild hypercalcemia.
Clinical Context:
First-generation bisphosphonate that has been shown to increase bone density at spine and femoral neck, though studies have failed to demonstrate a decrease in fractures. Acts principally by inhibiting bone resorption and does not alter renal tubular reabsorption of calcium. The effects of etidronate increase as the dose increases.
Does not affect hypercalcemia in patients with hyperparathyroidism.
Clinical Context:
Inhibits bone resorption possibly by acting on osteoclasts or osteoclast precursors. Median duration of complete response (maintaining normalized calcium levels) and time to relapse reported as 32 and 30 d, respectively.
Bisphosphonates are analogs of pyrophosphate and act by binding to hydroxyapatite in bone-matrix, thereby inhibiting the dissolution of crystals. They prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability.
Clinical Context:
Lowers elevated serum calcium in patients with multiple myeloma, carcinoma, or primary hyperparathyroidism. Can expect a higher response when serum calcium levels are high.
Onset of action is approximately 2 h following injection and activity lasts for 6-8 h. May lower calcium levels for 5-8 d by about 9% if given q12h. IM route is preferred at multiple injection sites with dose >2 mL.
Lawrence Kim, MD, FACS, FACE, Professor, Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, University of North Carolina at Chapel Hill School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Neetu Radhakrishnan, MD, Associate Professor (Adjunct) of Medicine, Division of Hematology/Oncology, University of Cincinnati Medical Center; Hematology/Oncology Medical Director, West Chester Outpatient Clinics
Disclosure: Nothing to disclose.
Additional Contributors
Sanjiv S Agarwala, MD, Chief of Oncology and Hematology, St Luke's Cancer Center, St Luke's Hospital and Health Network; Professor, Temple University Shool of Medicine
Disclosure: Received honoraria from BMS for speaking and teaching; Received consulting fee from Novartis for consulting; Received consulting fee from Merck for consulting.
Acknowledgements
Wendy Hu, MD Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center
Wendy Hu, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Blood and Marrow Transplantation, American Society of Hematology, and Physicians for Social Responsibility
Douglas L. Fraker. Chapter 44 - Cancer of the Endocrine System, Section 3: Parathyroid Tumors. Vincent T. DeVita, Jr., Theodore S. Lawrence, Steven A. Rosenberg. Cancer: Principles & Practice of Oncology. 8th. Philadelphia: Lippincott Williams & Wilkins; 2008. 1682-1690.
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