Localization of Persistent or Recurrent Medullary Thyroid Carcinoma

Computed Tomography and Ultrasonography

A number of methods have been used to localize residual or recurrent disease in patients with persistent or recurrent calcitonin elevation after surgery for MTC. Careful physical examination may reveal adenopathy in the jugular and para-tracheal regions. Patients with advanced metastatic disease may acquire subcutaneous tumors of the trunk and extremities. Imaging studies that have been reported to be successful in localization include ultrasonography with fine-needle biopsy, computed tomography (CT) scanning, magnetic resonance imaging (MRI), selective venous catheterization (SVC), and nuclear imaging studies. Van Heerden and colleagues reported on high-resolution (10-MHz) ultrasonography with ultrasound-guided fine-needle aspiration biopsy in patients with a negative clinical examination.53 In a study of 47 patients with elevated calcitonin levels after primary surgery for MTC, Raue and associates evaluated ultrasonographic examination of the neck as well as physical examination, CT scan, SVC, fine-needle biopsy, and combinations of these modalities in localization of metastatic MTC.7' After reoperation in 14 patients, calcitonin levels were normalized in 2 patients. In a subsequent study they reported that SVC correctly localized tumor tissue in 89% of patients compared with 38% with CT scan and only 28% with ultrasonography.72

Selective Venous Catheterization

SVC facilitates detection of occult foci of metastatic MTC by determining basal or stimulated calcitonin levels in samples of venous blood drawn from sites in the neck, chest, and abdomen. This technique was used successfully by Norton and coworkers in seven patients.73 They reported that SVC correctly localized tumor to a surgically resectable area of the neck in every case. In a study by Mrad and colleagues,74 localized disease in the neck was identified by SVC in six patients. In two patients the calcitonin levels were normal after operation guided by SVC data.74

In a study from France in 1994, SVC was performed in 19 patients, and calcitonin elevations suggestive of distant metastases were found in 5 patients.75 All five eventually acquired clinically apparent distant disease, recommending the usefulness of this technique in identifying distant metastases. In another series from Norway, elevated hepatic vein stimulated calcitonin levels were believed to indicate the presence of hepatic metastases. In this series, however, only three patients were demonstrated to have hepatic metastases by other means, and the significance of this finding is unclear.76

In our series, eight patients with hepatic vein calcitonin gradients were not found to have evidence of liver metastases by CT scanning and laparoscopy with liver biopsy.77 These patients underwent resection of metastatic MTC in the neck and two of the eight had subsequent normalization of stimulated calcitonin levels, indicating that the hepatic vein elevations may have been spurious. We no longer routinely use SVC in patients with occult MTC. The technique of SVC varies depending on the institution. At our institution, catheters are simultaneously placed in the right and left jugular veins and also in the left innominate vein and in a hepatic vein. Peripheral blood is drawn from a femoral catheter. After obtaining baseline values from these locations, a standard injection of calcium and pentagastrin is performed. Samples for calcitonin levels are drawn at 1,3, and 5 minutes from each of these locations. Values obtained are compared with simultaneously obtained baseline and stimulated peripheral values. Other authors do not use calcium-pentagastrin stimulation during SVC but rather use sample basal levels from multiple sites in the neck, chest, and abdomen and determine gradients by comparing these with peripheral levels.75

Nuclear Imaging Studies

A number of different radiopharmaceuticals have been described to localize metastatic MTC. Thallium 201 (20IT1) chloride and technetium 99m dimercaptosuccinic acid (99mTc DMSA) have been shown to be useful in evaluating hypercalcitoninemic patients.78-80 Iodine 131 metaiodoben-zylguanidine (MIBG) scintigraphy can be used to image MTC but is not consistent.81,82 Octreotide scans with indium 111 ("'In) have been used to localize metastatic disease, but these scans do not detect small liver metastases.83,84

Monoclonal anti-CEA antibodies labeled with iodine 131 (13II) or iodine 123 (123I), 11'In, and 99mTc have been evaluated for localization of MTC.85,86 Juweid and colleagues reported the largest series with 26 patients, but only 9 of those were identified as patients with occult disease.87,88 Single-photon emission CT (SPECT) with labeled monoclonal anti-CEA antibodies was compared with ultrasonographic examination and CT scan, and in four of nine patients imaged metastatic foci were confirmed by operative results.88 The value of monoclonal antibodies in localization of occult MTC remains to be proved. Anticalcitonin monoclonal antibodies have also been evaluated in a small number of cases but have never gained broad attention.89

In addition, studies have examined the imaging of cholecys-tokinin B receptors, which have been demonstrated in a high percentage of MTCs in vitro in patients with MTC.90,91

Radioimmunoguided surgery is a technique designed to facilitate the intraoperative detection of metastases. After systemic administration of tumor-specific radiolabeled monoclonal antibodies, a hand-held gamma counter is used to scan the operative field. Areas of increased activity are explored, and soft tissue and nodes from these areas are resected. In five patients in whom immunoscintigraphy using an anti-CEA monoclonal antibody was applied, all previously identified metastases could be visualized. According to the authors, the technique detected tumor foci missed by intraoperative inspection and palpation in three of five patients. Radioimmunoguided surgery did not identify two small (10 mm x 10 mm) lesions that were resected and found to contain microscopic cancer.86 In a case report, intraoperative scanning after "'In pentetreotide administration was used to localize metastatic sites. Plasma calcitonin levels fell remarkably after surgery but were not reduced to normal values.92 Although these results are promising, surgical cures were not noted, and a compartment-oriented resection or observation may also be considered in asymptomatic patients.93

Fluorodeoxyglucose (FDG) positron emission tomography (PET) has been evaluated by our group in the staging of MTC. From January to December 1996, 10 consecutively treated patients (7 men and 3 women) with elevated serum calcitonin levels after primary operative treatment for MTC were included in the study. FDG-PET images were compared with CT and MRI images, and suspected metastatic foci were assessed by correlation with intraoperative and histopathologic findings.94 FDG-PET imaging proved to be more sensitive but less specific in detecting cervicome-diastinal metastatic lesions compared with CT or MRI, respectively. Two patients with liver metastases detected by laparoscopy only, however, had no evidence of abnormal liver FDG uptake on PET imaging.94

Diagnostic Laparoscopy

MTC metastatic to the liver often has a miliary appearance, with multiple small (1 to 3 mm), white, raised nodules on the liver surface, which are easy to see with the laparoscope but may not be detected by CT scan, MRI, or other imaging techniques. We have routinely used diagnostic laparoscopy to look for liver metastases in patients with elevated calcitonin levels after primary surgery for MTC (Fig. 15-5).77 In a series of 41 patients, liver metastases were demonstrated in 8 patients, 7 of whom had negative CT imaging. In an update of this series, 136 patients had direct inspection of the liver by laparoscopy (126) or open procedure (10). Liver metastases were identified in 29 patients (21.3%).77

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