Lipophages In Thyroid

There have been multiple descriptions of the histo-logic appearance of parathyroid carcinoma (Figures 7-4 and 7-5). The cells appear to have a tendency to form pseudorosettes around capillaries. The nuclei of the cells are typically enlarged; occasionally, this results in the presence of macronuclei. Mitotic figures

Figure 7-4. Intermediate power view of parathyroid carcinoma illustrating rosette formation (hematoxylin and eosin).

can be seen. It may be difficult to distinguish parathyroid carcinoma from medullary thyroid carcinoma or other neuroendocrine-derived carcinomas (small cell carcinoma of the lung or esophagus or pheochromo-cytoma). These other entities tend to exhibit the presence of argyrophillic granules. Parathyroid carcinomas tend to be associated with the presence of lipophages (cells that have a high lipid content). One can exclude thyroid carcinoma and small cell carcinomas when lipophages are detected in the specimen. On electron microscopy, parathyroid carcinoma cells tend to have an almost round and central nucleus that has a prominent nucleolus. Most tumor cells also are loosely packed with multiple mitochondria spread throughout the cytoplasm. Immunohistochemical stains for parathyroid hormone can help identify the

Figure 7-5. Parathyroid carcinoma, low-power view, illustrating invasion into surrounding structures (hematoxylin and eosin).

tumor as being of parathyroid origin. However, the presence of a positive parathyroid hormone stain does not distinguish between a benign adenoma and a malignant carcinoma. One can also aspirate the presumed parathyroid tissue and determine the level of parathyroid hormone concentration in the tissue. It should be markedly increased (> 1,500 ng/L) in parathyroid neoplasm, in contrast to low or absent levels in nonparathyroid neoplastic tissue. Finally, immunohistochemical staining for RB protein or the cell cycle-associated antigen Ki-67 may prove useful in distinguishing parathyroid carcinoma from benign parathyroid disease.26,27,36

Over the years, there has been some debate concerning criteria to establish an accurate diagnosis of parathyroid carcinoma. The tumors themselves are firm, grayish-white, and frequently lobulated, with adherence to adjacent tissues. Most authors agree that one should note the presence of fibrous trabec-ulae, associated with vascular invasion, neovascular-ization, and mitotic figures. At least 50% of parathyroid carcinoma tumors are surrounded by a dense fibrous capsule, which reveals microscopic invasion by the neoplastic cells. In addition, there is frequent invasion of the tumor cells into contiguous structures such as the thyroid, strap muscles, recurrent laryngeal nerve, esophagus, or trachea. Schantz and Castleman established a set of histologic criteria for parathyroid carcinoma including uniform sheets of chief cells in a lobular pattern with fibrous trabecu-lae, evidence of capsular or vascular invasion, and mitotic figures within tumor parenchymal cells.35

The presence of metastatic deposits to either regional lymph nodes or distant organs confirms the diagnosis. Local recurrence with spread to contiguous structures in the neck is common. Approximately one-third of parathyroid carcinomas will present with distant metastases, most typically to the lungs (40%) (Figures 7-6 and 7-7), cervical lymph nodes (30%), and liver (10%) and less commonly to the bones (Figure 7-8), pleura, pancreas, or pericardium.

The diagnostic workup of patients for persistent or recurrent parathyroid carcinoma includes sestamibi radioactive scanning. Parathyroid cells contain a great deal of mitochondria that will preferentially concentrate sestamibi. Single-photon emission computed tomography with radioactive sestamibi gives a good

Figure 7-6.

metastases.

Posteroanterior chest radiograph of pulmonary

Figure 7-6.

metastases.

Posteroanterior chest radiograph of pulmonary three-dimensional view of the location of the parathyroid tumor. Magnetic resonance imaging (MRI) of the neck can also be used to help explore anatomic relationships and tissue planes in the neck (Figure 7-9). One should also consider including a computed tomographic scan of the chest to look for the presence of pulmonary or mediastinal metastases (see Figure 7-7). An example of multiple resected pulmonary metastases is seen in Figure 7-10.

Staging definitions for parathyroid carcinoma have not been determined clearly. The typical tumor, node, metastasis schema used for most tumors does

Figure 7-7. Computed tomography scan appearance of pulmonary metastases from parathyroid carcinoma.
Figure 7-8. Positron emission tomograph demonstrating intense uptake in a parathyroid cancer metastasis located in the right humoral head.

not lead to clear correlations with survival in parathyroid carcinoma. It would appear that the extent of resection and the inherent biology of the underlying disease are more important determining factors. The natural history of the disease is determined by the severity of the underlying hyperparathyroidism and the underlying hypercalcemia. Uncontrolled hyper-calcemia will result in severe end-organ damage, which will result in life-threatening complications.

Treatment for parathyroid carcinoma is largely surgical, and the most effective therapy is complete resection at the initial operation. There is some controversy as to the ideal extent of the resection that should be employed. All four parathyroid glands should be carefully explored and examined. Most authors agree that the primary surgery should

Figure 7-9. Magnetic resonance image of parathyroid mass.

remove the whole tumor en bloc, with the associated ipsilateral lobe of the thyroid and isthmus, as well as any structures that are directly invaded by the tumor, including the recurrent laryngeal nerve if neces-sary.13 The capsule of the tumor should remain intact as rupture increases the likelihood of local seeding. The extent of nodal dissection remains controversial. Some authors feel that an extensive lymph node dissection should be undertaken. Most authors feel that because lymph node involvement is relatively uncommon in this disease, a prophylactic or extensive lateral lymph node dissection is not warranted.37 An ipsilateral central neck dissection as well as resection of all abnormal nodes should be performed. If the diagnosis of parathyroid carcinoma is made postoperatively, with evidence of vascular or capsular invasion or persistent hypercalcemia, the neck should be re-explored with complete resection and ipsilateral central neck dissection.

Postoperatively, patients should have careful monitoring of serum calcium and parathyroid hormone every 3 months. Symptomatic hypocalcemia should be treated with supplemental calcium and vitamin D as necessary until recovery of normal remaining parathyroid glands. Recurrent hypercalcemia is evaluated promptly with localizing studies including neck ultrasonography and technetium Tc 99m sestamibi scanning. MRI is helpful for recurrent disease in the chest and mediastinum, and selective venous catheterization is useful for suspected

Figure 7-10. Gross specimen of resected metastases.

recurrence when localizing studies are negative. Recurrent tumor should be widely resected. Significant palliation of hypercalcemia may be provided by resection of distant metastases.38

The rarity of parathyroid carcinoma has not permitted the formal studying of either radiation therapy or chemotherapy as treatment modalities for the management of this diagnosis. The literature has several case reports of attempts at controlling parathyroid carcinoma with either single agents or combinations of agents. With rare exceptions, these reports suggest that parathyroid carcinoma is not sensitive to older chemotherapeutic agents.39,40 Case reports have shown some partial responses to different regimens of dacarbazine, 5-fluorouracil, cyclophosphamide, methotrexate, doxorubicin, and lomustine.41-43 The effectiveness of newer agents released in the past 5 years or so has not been formally evaluated.

The effectiveness of radiation therapy has not been formally evaluated in parathyroid carcinoma. Here, too, most of our information is gleaned from individual case reports. Once again, we are left with the general impression that radiation therapy is not particularly effective.4,35 Newer techniques such as intraoperative radiation and three-dimensional conformal planning have not been evaluated to date. The role of these newer techniques may be worth studying further.

Hypercalcemia associated with parathyroid carcinoma must be managed aggressively. Once the diagnosis of hypercalcemia is made, the first step in management is to restore the depleted intravascular volume and to induce a sodium diuresis. For that purpose, patients should be treated agressively (200 to 300 cc/hour) with normal saline intravenous hydration. The use of loop diuretics such as furosemide should be postponed until the intravas-cular volume has been restored.

To achieve a fairly rapid reduction in the serum calcium, one can administer calcitonin (3 to 6 U/kg subcutaneously every 12 hours) and glucocorticoids (300 mg hydrocortisone). Calcitonin inhibits osteo-clast-mediated bone resorption and increases urinary calcium excretion. Glucocorticoids inhibit gastrointestinal calcium absorption. The use of calcitonin by itself is unlikely to correct the calcium imbalance fully, but it will decrease the serum calcium by 2 to

4 mg/dL rapidly, allowing for initial stabilization. The long-term use of calcitonin to control hypercalcemia is limited by the development of tachyphylaxis. Glu-cocorticoids have a fairly delayed onset of action so that they are limited in the short term but help prevent or ameliorate the calcitonin tachyphylaxis.

One of the more effective ways to manage hyper-calcemia is to use an intravenous bisphosphonate compound such as pamidronate. The bisphosphonate compounds bind competitively to the bony matrix and interfere with osteoclast-induced bone resorption. Pamidronate is quite effective at a dose of 90 mg intravenously. The effects of pamidronate are noted within the first 24 hours. If the serum calcium fails to decline after a first dose of pamidronate, it can be repeated. More recently, zoledronic acid has been compared with pamidronate in the management of hypercalcemia of malignancy. Double-blind, randomized clinical trials have shown that a 4 to 8 mg rapid infusion (over 8 minutes) of zoledronic acid is equivalent to a 2- to 4-hour 60 to 90 mg infusion of pamidronate.

The prognosis of parathyroid carcinoma remains reasonable. The National Cancer Database recently reported 5-year survival rates of 85% and 50% at 10 years.7 The best prognosis is achieved with early diagnosis and complete resection during the initial operation. The median time to local recurrence is 3 years.13 Although these numbers are optimistic, their accuracy remains to be verified in formal clinical trials. Such trials will need to involve many institutions with an interest in this disease to enrol sufficient numbers of patients with this rare but debilitating and sometimes lethal disorder.

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