To assist in surgical planning, preoperative assessment of vocal cord function with fiberoptic laryngoscopy should be performed in all patients in whom parathyroid cancer is suspected. In patients presenting with metabolic disturbance secondary to hypercalcemia, the initial management involves the control of calcium levels with intravenous (IV) fluid resuscitation and appropriate use of loop diuretic agents before surgical intervention. Curative resection of parathyroid cancer involves removal of the primary lesion en bloc with any adjacent involved structures to ensure complete resection of disease.17 It is of paramount importance that disruption of the tumor capsule should not occur because this risks local seeding of cancer cells and local recurrence of disease.
Because of the rarity of the tumor and the high risk of recurrent disease, an oncologically complete resection should be performed for all patients with suspected parathyroid carcinoma. This is best managed by surgeons experienced in operative and reoperative parathyroid surgery at appropriately specialized institutions. Exploration of all four parathyroid glands should be performed in all cases.5 It is important to identify the ipsilateral normal parathyroid gland and remove it to achieve clearance of all parathyroid tissue from the affected side of the neck.17,18 For this reason, an ipsilateral thymectomy should also be performed from the affected side of the neck to include any supernumerary glands in this location.
As part of the operative approach to the tumor, the strap muscles overlying the region of the tumor should be resected en bloc with the lesion. An ipsilateral thyroid lobectomy, isthmusectomy, and removal of the pyramidal lobe should be performed en bloc with the primary tumor.5,17,18 In a study of 95 patients with parathyroid cancer, en-bloc thyroid lobectomy was associated with a lower rate of local recurrence and improved survival compared with simple resection of the primary tumor.13 Macroscopic invasion into surrounding structures such as the esophagus or trachea found at the time of operation requires en-bloc resection to achieve complete resection of disease, and this may require appropriate reconstruction, depending on the extent of invasion. When macroscopic invasion of the RLN is encountered during surgery, it should be sacrificed and resected en bloc.
In a review of parathyroid cancer management, Clayman and coworkers14 recommended preservation of the normally functioning RLN unless circumferential involvement of the nerve by tumor is encountered. Regional cervical lymph nodes are involved in only 6% to 8% of cases; however, removal of ipsilateral tracheoesophageal and paratracheal nodes in the central compartment adjacent to the lesion is recommended.5,14 This ensures an en-bloc resection and minimizes the risk of recurrent disease in the small percentage of patients with nodal metastases. The presence of clinically involved regional lymph nodes mandates formal dissection of the central and lateral compartment nodes. When parathyroid cancer is suspected preoperatively on clinical grounds, minimally invasive approaches to parathyroidectomy are contraindicated.
Intraoperative measurement of PTH (IOPTH) has proven useful to confirm the successful resection of all hyperfunctioning parathyroid tissue at the time of parathyroidectomy in patients with benign causes of HPT. The role of IOPTH in the resection of parathyroid cancer, however, has not been defined. Clayman and coworkers14 at the MD Anderson Cancer Center have reported their experience with IOPTH in patients with parathyroid cancer. IOPTH levels reduced at a slow rate after resection of parathyroid cancer in this report and required a longer period of time to normalize than for IOPTH performed for benign disease. Persistent elevation of IOPTH after resection of parathyroid cancer may be caused by extensive involvement of adjacent soft tissues with tumor, the presence of residual metastatic disease, or poor renal clearance of PTH in the setting of renal impairment.
The diagnosis of parathyroid carcinoma can be made with certainty when metastatic disease is confirmed or local invasion is demonstrated. When these features are not present, the diagnosis of parathyroid cancer on histopathology is difficult, particularly differentiating these malignancies from parathyroid adenoma with atypical features. Classic features that are described for parathyroid carcinoma on microscopy include trabecular cellular architecture, mitotic figures, fibrous hyaline bands, vascular invasion, and capsular invasion, yet these features are frequently absent in patients with this malignancy and are not specific for this.18 Staining for Ki-67 antigen as a marker for cellular proliferation is higher in parathyroid cancer than in benign lesions, but overlap between these two entities limits the usefulness of this technique. Immunohistochemical staining for parafibromin, the nuclear protein product of the HRPT2 gene, has been used to differentiate parathyroid carcinoma from benign lesions. Whereas parathyroid carcinoma demonstrates absent or weak nuclear staining for parafibromin in more than 90% of cases, staining is strongly positive in 98% of benign parathyroid tumors.19 All atypical parathyroid adenomas should be reviewed by an experienced tumor board, and immunohistochemical staining for parafibromin should be undertaken.
Postoperative Management and Surveillance
Serum calcium and phosphate levels should be closely monitored after resection of parathyroid cancer because of the risk for severe hypocalcemia secondary to hungry bone syndrome, which may be life threatening.5 Sudden withdrawal of high levels of PTH, the presence of severe bone disease related to HPT, and the younger age of patients with parathyroid cancer relative to those with benign disease are all factors predisposing individuals to the development of this condition. All patients should be started on oral calcium and vitamin D supplementation after surgery, and replacement therapy may be required for months after surgery to meet the demands associated with hungry bone syndrome. IV supplementation of calcium is sometimes required and should be titrated to serum calcium levels and the patient's symptoms. It is important to monitor serum magnesium and phosphate levels while replacing calcium orally and intravenously. Excessive administration of oral calcium may drive down serum phosphate because of binding within the gastrointestinal tract. For this reason, in the presence of significant hungry bone syndrome, the amount of IV and oral calcium supplementation need to be individually titrated.
Even after macroscopically complete resection of parathyroid cancer, locoregional recurrence of disease occurs in 40% to 67% of cases because of the locally aggressive nature of this tumor.3,10, 12,15 Rates of recurrence are higher where disruption of the tumor capsule occurred intraoperatively and where surgical margins are involved with tumor.6,12 External-beam radiation therapy (EBRT) is given postoperatively at some institutions with the aim of reducing the incidence of locoregional recurrence.12,14,16,20 In a series of six patients who had postoperative EBRT after macroscopically complete resection of parathyroid cancer, all patients were free of disease at a mean of 62 months follow-up.20 EBRT has also been used as primary treatment for patients with locally advanced parathyroid cancer that is not surgically resectable. Munson and coworkers12 at the Mayo Clinic reported on four patients with unresectable parathyroid cancer treated primarily with EBRT. They achieved locoregional control for all patients for periods ranging from 24 to 218 months.
Long-term surveillance of patients with parathyroid cancer is recommended because of the risk of locoregional and distant disease recurrence. The neck is the site of recurrence in 75% to 80% of cases, with mediastinal nodal involvement accounting for 25% of cases.6,15 The mean time to recurrence is 28 to 33 months, but delayed recurrence as long as 20 years after resection has been reported.5,6,12,15 Lifelong monitoring of serum calcium and PTH levels should be performed at yearly intervals, and an increase in these biochemical markers indicates disease recurrence. It should be noted that persistent elevation of PTH levels immediately after surgery may be secondary to the increased demand associated with hungry bone syndrome and that it may take months to reduce to baseline levels. Because of the slow growth rate of these tumors, an increase in biochemical markers is an early indicator of recurrence at a stage when most recurrent lesions are not detectable on imaging studies.
Management of Recurrent Disease
When disease recurrence is suspected on biochemical testing, imaging with high-resolution ultrasonography of the neck should be undertaken to assess for the presence of locoregional disease; this has a sensitivity of 69%.15 CT or MRI of the neck, thorax, and abdominal regions should be performed, looking for locoregional recurrence, mediastinal nodal disease, and distant metastases to the lungs or liver.5,15 Total-body sestamibi scanning demonstrates uptake at sites of locoregional or distant metastases with a sensitivity of 79% and has the advantage that whole-body scanning can be performed.15
Recurrent disease may also manifest clinically as a return of symptoms and complications of hypercalcemia. Surgical resection has an important role in the management of patients with both locoregional and distant recurrence because of the difficulty in achieving control of hypercalcemia with medical management alone and the poor response of patients with parathyroid cancer to systemic chemotherapy. In a study by Kebebew and coworkers,15 reoperation for recurrent disease was associated with normalization of serum calcium levels in 62% of patients, a significant reduction in serum calcium levels in 75%, and a relief of symptoms of hypercalcemia in 86%, with an acceptable rate of operative morbidity of 6.2%. In a report by Iihara and coworkers3 of 14 patients undergoing surgical resection of locoregional recurrence, successful palliation was achieved in 11 patients, and five patients were disease free after a mean 48 months of follow-up. Surgical resection of recurrent disease is rarely, if ever, curative, with most patients developing further recurrence on long-term follow-up. Reoperation can be effective in the management of such repeat recurrences.15 Recurrent disease has been associated with a mean survival duration of 28 months to 7.6 years from the time of first recurrence, and death occurs because of the eventual development of uncontrolled hypercalcemia.13,15
In patients with recurrent or metastatic disease that is not surgically resectable, control of hypercalcemia is dependent on medical therapies. Bisphosphonates, including zolendronate, pamidronate, and alendronate, are osteoclast inhibitors that may achieve control of hypercalcemia for relatively long periods with increasing dosage.5 The calcimimetic agent cinacalcet binds to calcium-sensing receptors on parathyroid tissue to reduce PTH release and has been approved by the US Food and Drug Administration for the management of patients with hypercalcemia caused by parathyroid cancer.16 So far, this agent has been shown to be effective in reducing serum calcium levels in these patients, although studies are limited.
Calcitonin, mithramycin, gallium nitrate, and corticosteroids have also been used to assist in the control of hypercalcemia from advanced parathyroid cancer. Although isolated case reports exist in the literature describing clinical response of parathyroid cancer to systemic chemotherapy for periods of 12 to 18 months, combinations of 5-fluorouracil, doxorubicin, vincrystine, carboplatin, taxols, and cyclophosphamide have been used in this setting with little therapeutic benefit.5,6,10 EBRT can be used in the palliation of painful bony metastases from parathyroid cancer.
Despite the relatively high rates of recurrent disease, parathyroid cancer is associated with 5-year overall survival rates of 77% to 85% and 10-year survival rates of 49% to 77%.12-14 In a survival analysis of patients with parathyroid cancer from the SEER database, the 10-year cancer-specific mortality rate was 12.4%.2 Older age at diagnosis, the presence of metastatic disease, and male gender were factors associated with reduced survival in this study.