It is often difficult to diagnose parathyroid cancer prior to surgery as the clinical features are very similar with benign disease. On the other hand, PHP can easily be established with an abnormal level of total calcium and an inappropriate or high level of PTH. As part of the differential diagnosis of PHP, it is important to exclude benign familial hypercalcemic hypocalciuria. This disease will present with hypercalcemia, usually normal PTH levels, and hypocalciuria with calcium to creatinine clearance ration <0.01. Genetic testing is also available for evaluation of CASR mutations.
Making a preoperative diagnosis of parathyroid cancer as the cause of PHP is often difficult. As said before, there is no single laboratory finding that is pathognomonic of parathyroid cancer. Findings of severe hypercalcemia (calcium levels usually >14 mg/dL), extreme elevated levels of PTH (5 to 10 times the upper limit of the normal range), and a palpable neck mass may suggest the diagnosis. About 60% to 65% of patients present with a calcium level >14 mg/dL.14,39,44 Patients with parathyroid cancer often have elevated alkaline phosphatase and low serum phosphorus levels. Some tests like human chorionic gonadotropin and N-terminal parathyroid hormone can be ordered, but they can also be elevated in benign parathyroid disease.45–47
Patients that present with severe hypercalcemia, metabolic complications (like bone and renal), and a neck mass have a higher likelihood of parathyroid cancer. Preoperative imaging may help with tumor localization but cannot reliable distinguish benign and malignant disease. A heterogeneous mass with irregular borders may increase the suspicious of malignancy, but these characteristics are not always present in parathyroid cancers.48 Fine needle aspiration should be avoided in patients with suspected parathyroid cancer because of the possibility of cutaneous seeding along the needle track.49
Parathyroid cancer remains a diagnostic dilemma. There are no definitive histologic diagnostic criteria, and the diagnosis can only be made in a patient who has either locoregional or distant metastasis at the time of initial neck exploration. A patient presenting with severe symptoms, a palpable mass, and metabolic complications has a higher likelihood of having parathyroid cancer, but this is not pathognomonic.11
At the present time, there is a lack of a TNM (tumor, node, metastases) staging system available for parathyroid cancer. Shaha and Shah50 have proposed a staging system in the past taking in consideration the size of the tumor, invasion to adjacent tissues, lymph node involvement, and distant metastases (Table 83.2). Talat and Schulte17 in 2010 suggested an anatomy-based TNM system that showed that patient prognosis could be predicted with their model. They used the same principles established for other endocrine tumors.17
MANAGEMENT OF PARATHYROID CANCER
Surgery is the treatment of choice for parathyroid cancer. It is helpful to have a high index of suspicion prior to the surgical procedure to better enable the surgeon to perform the appropriate operation, including a complete resection with microscopically negative margins as this offers the best chance of cure. An en bloc resection of the tumor and the involved structure(s) has been associated with decreased risk of recurrent disease. At the very least, the surgical resection should include en bloc removal of the tumor without compromising the tumor capsule. Systemic chemotherapy, embolization, and radiofrequency ablation have been attempted but in general are not effective in patients with parathyroid cancer.
Hypercalcemia can be very challenging to manage and correction of electrolyte imbalance is paramount to avoid irreversible cardiac and renal complications. Several therapies may be instituted including rehydration, repletion of electrolytes, and loop diuretics after adequate hydration to improve urinary excretion of calcium.11 Other treatment options include calcitonin and bisphosphonates in an attempt to lower calcium levels. Less common treatment includes amifostine (agent that inhibits PTH release) but use has been limited due to side effect profile.51 A new drug called cinacalcet (a calcimimetic) is more effective in lowering serum calcium levels and with fewer side effects. This medication is preferred when compared to the older drugs.
Surgical Treatment
As patients are often not assessed for the risk of parathyroid cancer, the initial surgery may not completely address the need for wide resection. If during the resection the adenoma shows suspicious features like a large mass, whitish capsule, and adherence to adjacent structures, an en bloc resection of the tumor and adjacent structures involving the neck, including the ipsilateral thyroid lobe with gross clear margins should be attempted.18,50,52
En bloc resection is the modality of choice and is associated with improved outcome.11 It includes removal of the parathyroid lesion with avoidance of capsular disruption (rupture can cause tumor spread leading to parathyromatosis)53 and resection of all involved tissues, including the ipsilateral thyroid lobe, trachea, and esophageal wall. Suspicious ipsilateral regional lymph nodes should also be removed. Patients with untreated hypercalcemic crisis should have their surgery delayed until the electrolyte imbalance is corrected. Those with diffuse metastatic disease are less likely to benefit from surgical resection.
Common surgical complications include recurrent laryngeal nerve (RLN) injury, esophageal and tracheal injury, neck hematoma, and infection. If the patient presents with a hoarse voice, invasion of the RLN should be suspected. Preoperative laryngoscopy can confirm vocal cord paralysis. It is appropriate to resect the nerve in symptomatic patients or the ones at high risk of RLN invasion, as the risk of recurrence outweighs the benefit of preserving the nerve.54
Patients with poor outcome usually are the ones with incomplete resection, tumor seeding, and a history of recurrence. The finding of positive surgical margins predicts recurrence.55 Studies have shown that patients with local excision rather than en bloc resection have poor outcomes.56 For localized recurrent tumors, a cervical and/or mediastinal exploration with wide resection is recommended.42 Radical surgical procedures will reduce the risk of local recurrence but will not prevent distant metastasis secondary to vascular invasion.
Lymph node metastasis occurs in up to 8% of patients with parathyroid cancer but can be as high as 17% to 32% (see Table 83.1).38,44,57 If cervical nodes are involved, a modified neck dissection should be performed. Prophylactic neck dissection does not seem to improve survival and has increased morbidity.58 En bloc resection has an 8% local recurrence rate and long-term overall survival rate of 89%.18 Usually, parathyroid carcinoma will recur 2 to 5 years after surgery with a local recurrence rate of 33% to 82% at 5 years.11 Metastases may occur via lymphatic spread or hematogenously; the most common sites include lung and liver (40% and 10% incidence, respectively).37,52,59
Radiotherapy
Usually, parathyroid cancer is radioresistant and radiation treatment as primary therapy has not been shown to have any significant effect either locally or at distant sites. External-beam adjuvant radiotherapy therapy may be considered in high-risk patients or those with positive surgical margins.60 One study showed that the local recurrence rate is lower with radiation independent of the surgical procedure or stage, in addition to improved disease-free survival. These findings, however, were not statistically significant.43 Another study showed that patients with aggressive tumors who received radiation postsurgery achieved better locoregional disease control, but all patients had negative margins.60 Patients with parathyroid cancer have been treated with doses as high as 70 Gy.42 The efficacy of radiotherapy is difficult to evaluate as the current evidence in the literature is scarce and most of the studies have a small number of patients. In addition, parathyroid cancer is a rare diagnosis. Resection in bloc with negative margins is still the best chance of cure in parathyroid carcinoma, and the use of adjuvant radiotherapy should be decided on an individual basis. Adjuvant radiation therapy does not affect the survival of patients with parathyroid cancer.
Chemotherapy
There is no standard chemotherapy regimen for parathyroid carcinoma, and such treatment usually is ineffective. Most of the experience comes from a limited number of case reports without randomized clinical trials.13,15,37,39 Regimens used include dacarbazine as monotherapy; a combination of fluorouracil, cyclosphosphamide, and dacarbazine; or a combination of methotrexate, doxorubicin, cyclophosphamide, and lomustine. There is no survival benefit associated with chemotherapy in patients with parathyroid cancer.
Other Treatment Modalities of Parathyroid Cancer
Patients with parathyroid cancer will usually succumb to the complications of severe hypercalcemia. The primary goal in patients with metastatic disease is controlling the PTH-driven hypercalcemia. Some of the drugs that may be used include bisphosphonates, calcitonin, glucocorticoids, mitramycin, plicamycin, and gallium nitrate as well as hemodialysis in addition to generous hydration. These medications help decrease the calcium levels in the short term, but long-term remission rarely is seen.61 Studies with intravenous pamidronate and zoledronate have shown good calcium response in the short term, but gradually the effect diminishes with subsequent infusions.61–63 Oral bisphosphonates are not effective.
A new drug called cinacalcet (a calcimimetic) is more effective in lowering serum calcium levels and with less side effects. This drug is preferred when compared to the other drugs. Cinacalcet modulates calcium receptors on the surface of parathyroid cells directly decreasing PTH synthesis and secretion, consequently lowering serum calcium levels. It usually is started at a dose of 30 mg twice daily.64–67
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