Parathyroid Carcinoma

Synonyms and related keywords: parathyroid gland, parathyroid carcinoma, parathyroid gland malignancy, hyperparathyroidism, bone disease, high serum calcium level, renal stones, hypercalcemia


INTRODUCTION

Background: Parathyroid carcinoma is a rare malignancy of the parathyroid glands. These tumors usually secrete parathyroid hormone, thereby producing hyperparathyroidism, which is usually severe. Parathyroid carcinoma may be suspected, but it usually cannot be confirmed prior to operation. This complicates the treatment strategy.

Pathophysiology: Parathyroid carcinomas cause hyperparathyroidism (see Hyperparathyroidism). The hyperparathyroidism is usually severe, with high serum calcium level, severe bone disease, and renal stones.

Frequency:

• In the US: Parathyroid carcinoma is found in fewer than 1% of patients with primary hyperparathyroidism, although some series report that as many as 5% of cases of hyperparathyroidism are due to parathyroid carcinoma.

• Internationally: No geographic variation in prevalence is known.

Mortality/Morbidity:

• Reported overall 5-year survival rate ranges from approximately 50-75%.

• A significant number of patients die of recurrent disease 5 years or longer after the initial treatment.

• Only 30% of patients have a long-term cure.

Race:

• No known racial predilection

Sex:

• Occurs equally in males and females

Age:

• Parathyroid carcinoma usually occurs in patients older than 30 years. After that, no predominant age association has been noted.

CLINICAL

History: 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 hyperparathyroidism due to benign disease.

• 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

Physical:

• Palpable mass in the neck (approximately 50% of patients)

• A palpable mass is virtually never present with benign parathyroid adenomas or hyperplasia.

• If a mass is palpated, parathyroid carcinoma should be suspected.

• Signs of hypercalcemia

Causes: The etiology is unknown in most cases. It may be associated with the genetic disease hyperparathyroidism - jaw tumor syndrome. It also may be associated with a history of neck irradiation.

• Several genetic defects have been reported to be associated with parathyroid cancer. Mutations of the HRPT2 gene (1q25-31) have been described in this disease, most commonly in association with the hyperparathyroidism - jaw tumor syndrome. However, many sporadic parathyroid carcinomas exhibit defects in this gene. The gene codes for a tumor suppressor protein called parafibromin, whose function is not yet known.

• Allelic loss in several chromosomes has been noted, but other than HRPT2, no gene has definitively been associated with parathyroid carcinoma.

DIFFERENTIALS

Hypercalcemia
Hyperparathyroidism
Paraneoplastic Syndromes
Thyroid Nodule


WORKUP

Lab Studies:

• Laboratory workup is the same as for primary hyperparathyroidism. Simultaneous calcium and PTH levels should be determined.

• Serum calcium level usually is elevated more markedly than in benign primary hyperparathyroidism.

• Parathyroid hormone (intact): Parathyroid carcinoma should produce authentic parathyroid hormone; therefore, serum parathyroid hormone levels should be elevated, usually markedly.

Imaging Studies:

• No imaging tests are specifically required for parathyroid carcinoma. See Hyperparathyroidism for the rationale of whether to obtain imaging studies.

• Radiographs

• Hand films may show subperiosteal bone resorption of the distal phalanges.

• Skull films have a characteristic "ground glass" or "salt and pepper" appearance.

• In severe cases, plain films reveal the classic bone finding, osteitis fibrosa cystica. It consists of bone cysts with or without pathologic fractures. These cysts are also known as brown tumors.

• CT scanning may be helpful in detecting metastatic disease.

Other Tests:

• Fine-needle aspiration biopsy is not helpful in establishing a diagnosis and may be harmful by causing tumor dissemination.

Procedures:

• No preoperative test currently is available to reliably distinguish parathyroid cancer from benign primary hyperparathyroidism.

• Diagnosis is based on the histologic appearance of the excised parathyroid gland and clinical indicators such as recurrence or metastases.

Histologic Findings:

• The parathyroid glands are usually large (2-10 g).
• Tumors usually are encapsulated and often have fibrous septa extending into the gland.
  • 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.
• The most reliable histologic finding in carcinoma is extracapsular invasion by the tumor, but this is seen in only two thirds of cases.
• Some degree of nuclear atypia is seen commonly, and mitotic figures are usually evident.
• Molecular or genetic markers may prove useful in distinguishing parathyroid cancer from other lesions.

Staging:

• Parathyroid cancer is sufficiently rare that no staging systems have been established.

TREATMENT

Medical Care: No effective medical therapy for parathyroid carcinoma is known. Trials of chemotherapeutic agents have been disappointing. Patients often present with severe hypercalcemia that initially requires medical management. 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.

Surgical Care: 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 often is 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.
• 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.

• If any regional lymph nodes are enlarged, remove them.

• 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 probably adequate.

• Postoperative care

• Postoperative care is generally the same as for benign hyperparathyroidism.
• Bone hunger may be quite profound and require substantial doses of postoperative calcium.

• Resection of recurrence

• Re-operation 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.

Consultations:

• Experienced surgeon - Surgical removal is the only effective treatment.

• Medical endocrinologist - Medical care of the hypercalcemia can be difficult and complex.

• Radiation oncologist - External beam radiation is controversial. It may decrease local recurrence when used in the adjuvant setting postoperatively. It may also be used in specific circumstances for treatment of a metastasis.

No medical treatment is available for parathyroid carcinoma except to reduce hypercalcemia. However, hypercalcemia associated with parathyroid carcinoma is often severe and refractory to medical treatment.

Drug Category: Calcimimetic agent -- Binds to and modulates the parathyroid calcium-sensing receptor, increases sensitivity to extracellular calcium, and reduces parathyroid hormone secretion.

Drug Name	Cinacalcet (Sensipar) -- 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.
Adult Dose	30 mg PO qd initially; titrate q2-4wk as needed to normalize calcium levels by sequential doses of 30 mg bid, 60 mg bid, 90 mg bid, and 90 mg tid/qid Take with meals or immediately following; do not crush, chew, or cut tablets
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Strong CYP450 2D6 inhibitor; may increase serum levels of CYP 2D6 substrates (eg, flecainide, vinblastine, thioridazine, tricyclic antidepressants); coadministration with CYP450 3A4 inhibitors (eg, ketoconazole, erythromycin, itraconazole) may decrease clearance
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Serum calcium reduction may cause lowered seizure threshold, paresthesia, myalgia, cramping, and tetany; monitor calcium and phosphorus levels closely within 1 wk following initial dose or dose changes, and then monthly (secondary hyperparathyroidism) and q2mo (parathyroid carcinoma); do not initiate treatment if serum calcium level below 8.4 mg/dL; adynamic bone disease may occur if iPTH levels suppressed below 100 pg/mL; caution with hepatic impairment; common adverse effects include nausea and vomiting

Drug Category: Bisphosphanate -- Analogs of pyrophosphate and act by binding to hydroxyapatite in bone-matrix, thereby inhibiting the dissolution of crystals. Prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability

Drug Name	Pamidronate -- Inhibits normal and abnormal bone resorption. Appears to inhibit bone resorption without inhibiting bone formation and mineralization.
Adult Dose	Moderate hypercalcemia: 60-90 mg IV as a single dose infused over 2-24 h Severe hypercalcemia: 90 mg IV as a single dose infused over 2-24 h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hypocalcemia
Interactions	None reported
Precautions	Monitor hypercalcemia-related parameters, such as serum levels of calcium, phosphate, magnesium, and potassium, once treatment begins; adequate intake of calcium and vitamin D is necessary to prevent severe hypocalcemia; caution when administering bisphosphonates in patients with active upper GI problems; do not coadminister with alendronate for osteoporosis in postmenopausal women; renal toxicity decreases with IV infusions >2 h

Drug Name	Alendronate (Fosamax) -- 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.
Adult Dose	Not established; usual starting dose is 40 mg PO qam
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hypocalcemia, abnormalities of the esophagus, inability to stand upright for 30 min
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Must be taken at least 30 min before first food, beverage, or medication of the day and should be taken with large amounts of water; caution in renal impairment

Drug Name	Etidronate disodium (Didronel) -- 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.
Adult Dose	7.5 mg/kg/d IV diluted in approximately 250 mL of sterile NS over period of approximately 2 h for 3 d; hypocalcemia may occur when administered > 3 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; hypocalcemia, renal impairment
Interactions	Coadministration with calcium containing products and other multivalent cations decrease absorption
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor hypercalcemia-related parameters (eg, serum levels of calcium, phosphate, magnesium and potassium); maintain adequate intake of calcium and vitamin D to prevent severe hypocalcemia; caution if active upper GI problems; do not administer with alendronate for osteoporosis in postmenopausal women

Drug Name	Zoledronic acid (Zometa) -- 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.
Adult Dose	4 mg IV over at least 15 min qmo; hydrate patient prior to infusion; may repeat treatment if serum calcium does not return to desired level after 7 d CrCl >60 mL/min: 4 mg CrCl 50-60 mL/min: 3.5 mg CrCl 40-49 mL/min: 3.3 mg CrCl 30-39 mL/min: 3 mg
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Concurrent administration with loop diuretics may increase risk of hypocalcemia
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal insufficiency (hold dose with increased CrCl); risk of renal deterioration increased with less than 15 min IV infusion; flu-like syndrome (fever, arthralgias, myalgias, skeletal pain), gastrointestinal reactions, anemia, insomnia, dyspnea, electrolyte and mineral disturbances (eg, low serum phosphate, calcium, magnesium, and potassium) may occur

Drug Category: Human calcitonin analogs -- These agents promote the renal excretion of calcium, making them suitable for the treatment of hypercalcemia.

Drug Name	Calcitonin (Miacalcin, Osteocalcin) -- 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.
Adult Dose	4 IU/kg IM/SC q12h Increase dose to 8 U/kg q12h if response is not satisfactory after 1-2 d and 8 IU/kg q6h if response remains unsatisfactory > 2 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Precautions	Hypocalcemia may occur; examine urine sediment during prolonged therapy.

FOLLOW-UP

Further Inpatient Care:

• Inpatient care usually is limited to the perioperative period, or to treating refractory hypercalcemia.

• Occasionally, other complications such as pathologic fractures may require hospitalization.

Further Outpatient Care:

• 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.

• Chest radiograph is indicated, but a chest CT may reveal pulmonary metastases missed on plain radiograph.

In/Out Patient Meds:

• Medical therapy is limited to the control of hypercalcemia (if necessary).

• Most of the time volume expansion with normal saline and diuresis with furosemide is adequate treatment.

• The bisphosphonates may also be used for short-term control of the hypercalcemia but often are ineffective in 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.

Transfer:

• Because parathyroid carcinoma is rare, transfer to a tertiary care facility is warranted. This concentration of experience may hasten our understanding of this rare disease.

Deterrence/Prevention:

• No preventive measures to guard against this disease are known.

Complications:

• See complications outlined in Hyperparathyroidism.

• 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.

• Pathologic fractures: In patients with severe bone disease, falling presents a serious hazard.

• Injury to the recurrent nerve at the time of operation may be unavoidable in some cases because of direct invasion by the tumor.

Prognosis:

• Recurrence and death are quite common. Disease recurs after the initial operation in more than two thirds of patients. Recurrence often is delayed, sometimes for more than 20 years.

• Overall, 5-year survival rate is between 50% and 70%, but many die after 5 years. Often, death from other causes intervenes so death from parathyroid carcinoma may be relatively uncommon.

Patient Education:

• Discuss the prognosis associated with the disease and its relationship to hypercalcemia.

• Make patients aware that surgery is the only effective treatment against the tumor itself even though medical therapy may alleviate the hypercalcemia.

• Emphasize the difficulty of diagnosis. Discuss the long-term nature of the disease even with metastases.

• Educate the patient and family about fall prevention. This is more important as bone disease is more severe.

MISCELLANEOUS

Medical/Legal Pitfalls:

• One of the greatest difficulties in parathyroid carcinoma is diagnosis.

• Often even the resected specimen cannot be identified clearly as malignant by pathologic features, and only after the lesion recurs or metastasizes can the diagnosis be made.

• If a patient presents with recurrent parathyroid carcinoma after resection of a presumed adenoma, the argument could be made that the physicians failed to make the correct diagnosis. Both the surgeon and pathologist must be alert to findings that might suggest parathyroid cancer. However, many carcinomas give no indication of malignancy until recurrence or metastasis appears. Therefore, failure to make the diagnosis initially cannot be criticized unless clear indicators of malignancy have been ignored.

• Widespread use of molecular techniques to differentiate the genetic abnormalities identifying carcinoma from adenoma may someday better elucidate the diagnosis.