Surgical Treatment of Recurrent or Persistent Medullary Thyroid Cancer

Because of the lack of success reported for other modalities in the treatment of persistent or recurrent MTC, surgical

FIGURE 15-5. A, Computed tomography (CT) of liver from patient with multiple endocrine neoplasia type 2A, recurrent medullary thyroid carcinoma (MTC), and elevated calcitonin levels. There is no evidence of liver metastases on the scan. B, Laparoscopic view of liver from the same patient showing multiple small raised whitish lesions on and just beneath the surface of the liver, confirmed to be metastatic MTC by biopsy. These small, multiple metastases are often not seen with routine CT scanning or other imaging modalities, including nuclear scanning. (From Tung WS, Veseley TM, Moley JF. Laparoscopic detection of hepatic metastases in patients with residual or recurrent medullary thyroid cancer. Surgery 1995;! 18:1024.)

FIGURE 15-5. A, Computed tomography (CT) of liver from patient with multiple endocrine neoplasia type 2A, recurrent medullary thyroid carcinoma (MTC), and elevated calcitonin levels. There is no evidence of liver metastases on the scan. B, Laparoscopic view of liver from the same patient showing multiple small raised whitish lesions on and just beneath the surface of the liver, confirmed to be metastatic MTC by biopsy. These small, multiple metastases are often not seen with routine CT scanning or other imaging modalities, including nuclear scanning. (From Tung WS, Veseley TM, Moley JF. Laparoscopic detection of hepatic metastases in patients with residual or recurrent medullary thyroid cancer. Surgery 1995;! 18:1024.)

reintervention has been used by several groups to attempt to control the disease. MTC is often indolent and remains in the neck for long periods of time. It is possible that removal of residual or recurrent disease in the neck will result in cure in some cases and arrest the course of the disease in others. Several groups have reported their experience with reoperation for persistent or recurrent MTC in the neck.29,73,95,96 A significant reduction in stimulated calcitonin levels after reoperation was reported in many patients, and normalization of calcitonin levels was noted in some. In 1986, Tisell and colleagues reported a series of 11 MTC patients with persistent hypercalcitoninemia after previous apparently adequate surgery.97 Tisell performed what he called a "microdissection." This involves a meticulous dissection of all lymph node and fatty tissue of the central and lateral zones of the neck, including the thyroid bed, both recurrent nerves, and nodes in the lateral neck, extending from the level of the mastoid process down to the innominate vein and subclavian arteries and out laterally to the level of the spinal accessory nerve. In several cases, a median sternotomy and resection of upper mediastinal nodes were also performed. In this series, the calcitonin levels were normalized in four patients and significantly lowered in three.

We reported two series of cervical reoperations for MTC: from 1990 to 199398 and from 1993 to 1996." In the first series, 37 operations were done in 32 patients. The patients had previously undergone total thyroidectomy and most of the patients also had previous lymph node dissections. All patients had elevated stimulated calcitonin levels. Localization studies, including selected venous catheterization, CT scanning, and physical examination, were successful in localizing tumor in half the cases. Operative morbidity was low and there were no deaths. In 28 of the 35 operations, discharge from the hospital occurred 2 to 5 days postoperatively. In nine cases (group 1), calcitonin was reduced to undetectable levels following reoperation. In 13 cases (group 2), postoperative calcitonin levels were decreased by 40% or more. In 10 cases (group 3), postoperative calcitonin levels were not improved. Patients' sex, disease, number of nodes previously resected, preoperative calcitonin levels, and preoperative localization study results were not significantly different among the three groups and therefore unlikely to predict outcome for reoperation. Previously resected tumors from patients in group 3, however, were more likely to have demonstrated invasive features (invasion of adjacent structures, extranodal or extracapsular spread) than tumors from patients in groups 1 and 2 (P < .05, Fisher's exact test).98

In this series, reoperation resulted in normalization of calcitonin levels in 28% of patients and a decrease in calcitonin levels by 40% or more in another 42% of patients. The results also suggested that determination of the degree of invasiveness of the primary tumor may help in selecting patients likely to benefit from reoperative surgery for recurrent medullary thyroid cancer.

In the second series, we sought to improve our results through better selection of patients likely to benefit from reoperation.99 This was achieved by obtaining a systematic metastatic work-up including routine staging laparoscopy, described earlier. One hundred and fifteen patients with persistent elevation of calcitonin after primary surgery for MTC were evaluated. After metastatic work-up, which revealed distant disease in 25% of these patients, and discussion of the options (including observation in patients without gross cervical disease), 52 patients elected to undergo cervical reoperation. Seven patients had palliative procedures and 45 patients had cervical re-exploration with curative intent. In the seven patients who had palliative cervical operations, one patient had persistent postoperative hypocalcemia. There were no other complications in that group. In the 45 patients who underwent reoperation with curative intent, there were no postoperative deaths and no transfusions were required. Complications included thoracic duct leak in four patients (8.9%) and hypocalcemia (2 patients [4%] at follow-up of 3 months and 2 years). Careful identification and exposure of the recurrent laryngeal nerves (RLNs) were done through a previously undissected area by the lateral, backdoor, or anterior approach. There were no permanent recurrent nerve injures.99

In the 45 patients who had reoperation with curative intent, the mean decrease in postoperative stimulated calcitonin level was 73.1% (see Fig. 15-4). In 22 of 45 patients (48%), the postoperative stimulated calcitonin level dropped more than 90% compared with the preoperative value (Fig. 15-6). Seventeen (38%) had postoperative stimulated calcitonin levels that were within the normal range (group 1), and six (13%) had no significant decrease in stimulated calcitonin levels (group 3). The remaining patients had a greater than 35% reduction in stimulated calcitonin levels (group 2). As in our earlier series, tumor invasiveness was the only parameter correlated with failure to reduce postoperative calcitonin levels to the normal range (P < .05, Fisher's exact test).99

These results indicate an improvement in outcome after reoperation for persistent or recurrent MTC. In the second

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FIGURE 15-6. Postoperative change in peak stimulated calcitonin levels. The shaded bars indicate the postoperative stimulated calcitonin levels of the 45 patients who underwent curative cervical reexploration and dissection. The postoperative calcitonin level is expressed as a percentage of the preoperative calcitonin level. One hundred percent indicates no change in calcitonin level, and 10% indicates that the stimulated calcitonin level fell by 90%. 'Postoperative levels were higher than preoperative levels. (From Moley JF, DeBenedetti MK. Patterns of nodal metastases in palpable medullary thyroid carcinoma: Recommendations for extent of node dissection. Ann Surg 1999;229:880.)

series (1992 to 1996), 38% (17 of 45) of patients had normal postoperative stimulated calcitonin levels, compared with 28% (9 of 32) in the first series. Only 13% (6 of 45) of patients had no decrease in calcitonin levels following reoperation, compared with 31% (10 of 32) in the first series (P = .07, Fisher's exact test). This improvement occurred through better preoperative selection of patients and the institution of routine laparoscopic liver examination preop-eratively, which identified metastases in 10 patients, 9 of whom had normal CT or MR imaging of the liver and who would otherwise have undergone neck reoperation with curative intent.

In this series of 115 patients, 24 decided not to have surgical intervention." If a patient with elevated calcitonin levels has had an adequate previous operation and results of imaging studies are negative, an expectant approach with routine yearly screening is appropriate in many cases.53 We do, however, believe that it is important to observe these patients closely with routine CT or MRI of the neck and chest. If central recurrence develops, resection prevents death from airway or great vessel invasion in some patients.

Tumor debulking may afford some patients relief from symptoms caused by local disease in the neck or from tumor-induced flushing and diarrhea. We treated six patients with severe, disabling diarrhea who had preoperative stimulated calcitonin levels greater than 25 ng/mL, in whom surgery reduced calcitonin levels and abolished the diarrhea (author, unpublished results).

These reports support the use of reoperation in patients with persistently elevated calcitonin levels after surgery for MTC. Although patients with highly invasive tumors are not as likely to benefit from this approach, these operations can be done safely in the majority of cases and may result in long-term survival benefit and prevention of recurrence complications in the neck. Long-term follow-up of these patients is needed to confirm the presumed benefit derived from these operations.

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