Image Diagnosis of Medullary Cancer

All patients with a preoperative diagnosis of medullary cancer of the thyroid should be tested for a ret protoonco-gene germline point mutation and also be screened for pheochromocytoma and hyperparathyroidism (see other chapters regarding medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism). Medullary cancer secretes calcitonin and carcinoembryonic antigen (CEA) and occasionally neuron-specific enolase, serotonin, chromogranin, gastrin-releasing peptide, substance P, pro-opiomelanocortin-derived products, and somatostatin. Among them, calcitonin and CEA are used as tumor markers for following patients for persistent disease or recurrent disease. Calcitonin is the most sensitive biochemical marker for predicting the presence of tumor. A steep slope with rapidly rising CEA levels indicates that the patients have rapidly progressive tumor. A normal CEA level or a flat slope indicates that patients may be cured or they have only slowly progressive disease.63 64 Decrease of the calcitonin/CEA ratio indicates dedifferentiation of medullary thyroid cancer.

Ultrasonography

Medullary cancer is a considerably rare disease, constituting only 4% to 9% of all thyroid cancers. Ultrasonography is the most recommended helpful modality for detecting primary tumor as well as localizing cervical metastases in the central or lateral neck nodes, particularly those associated with multiple endocrine neoplasia (MEN) type 2A. Ultrasonography is superior to radionucleotide scanning for detecting cancer foci within the thyroid or in the cervical lymph nodes. One can identify primary tumors as small as 3 mm by high-resolution ultrasonography. Lymph node metastases are common in patients with MEN 2A and familial medullary cancer. Pathologic examinations of the lymph nodes during primary staging revealed cervical lymph node involvement in 31% to 33% of the pTl cases,65'66 in 53% of the pT2 cases,66 and in 100% of the pT3 and pT4 patients. Ultrasonographic features include hypoechoic nodules with disseminated or focal echogenic calcifications that may cast an acoustic shadow and smooth or irregular delimited nodules with pseudopod-like projections (Fig. 16-8). These features are found both in primary tumors as well as in lymph node metastases. Since these ultrasonographic findings are nonspecific and may be present in adenomatous nodular goiters, one should interpret the ultrasonographic findings with the serum calcitonin levels.67-68 Serum calcitonin levels are highly specific for medullary thyroid cancer and are helpful for both preoperative planning and postoperative evaluation. Most patients with mild increases in calcitonin have metastatic tumors only in the cervical lymph nodes. Some of these metastatic nodes are too small to detect by palpation but may be detected by ultrasound scanning. Ultrasonography therefore is the first choice as a localization test. It is inexpensive and there is no radiation hazard. An experienced ultrasonographer, however, is essential for good results.

MIBG

Three years after the advent of l32I-metaiodobenzylguani-dine (MIBG) as an imaging agent for pheochromocy-tomata,69 it was noted that some medullary thyroid cancers also could be identified by MIBG scanning. This is also true for metastases.70 From these observations it was expected that MIBG might be a helpful therapeutic agent.71 Unfortunately, due to the poor sensitivity of MIBG scintigraphy in medullary thyroid cancer, this agent is not suitable for initial diagnosis but can be used when internal radiation therapy with 131I-MIBG is planned. I31I-MIBG has been used for treatment of pheochromocytoma, paraganglioma, and medullary cancer when MIBG scanning is positive. Symptomatic control was achieved in all patients treated with 131I-MIBG alone, including hormonal improvement and tumor regression or stabilization in patients with

FIGURE 16-8. Calcification of medullary thyroid cancer (A) and of part of a multinodular goiter (B).

FIGURE 16-8. Calcification of medullary thyroid cancer (A) and of part of a multinodular goiter (B).

metastatic tumors with minimal adverse effects.72 Also, in many other articles, no important adverse effect is mentioned.73"78 However, in one article, a patient with metastatic pheochromocytoma to the lung, liver, and paraaortic lymph node was treated with 3.7 GBq (100 mCi) of 13II-MIBG. The metastatic nodes in the lung and liver disappeared, and the secretion of catecholamine levels decreased to normal. Major but temporary untoward responses were hypertension and hyperglycemia.79

Anti-CEA Monoclonal Antibody

Medullary cancer contains and secretes CEA as well as calcitonin. l3lI-labeled or luIn-labeled CEA unfortunately detects only relatively large metastases (>10 mm3) as occurred in 5 of 11 patients with medullary thyroid cancer.80 Initially, radiolabeled CEA monoclonal antibodies were reported to be specific but not very sensitive. Subsequent investigation demonstrated nonspecific uptake of radiolabeled CEA in the spleen, kidneys, bone marrow, and liver, presumably due to the poor specificity of the antibody that was used.81 Hoefnagel,82 Zanin,83 and their associates suggested that l31I-labeled monoclonal antibody might be used therapeutically in patients with medullary thyroid cancer. In 1997, Juweid and colleagues84 reported that anti-CEA monoclonal antibodies were excellent agents for imaging recurrent, residual, or metastatic medullary thyroid cancer. The high lesion sensitivity in patients with known lesions, combined with the ability to detect disease, may make these agents ideal for staging patients, monitoring disease preoperatively or postoperatively, and especially for evaluating patients with recurrent or persistent elevated calcitonin or CEA levels after primary surgery.84 Sensitivity of anti-CEA radiolabeled antibody technique seems to be dependent on the quality of monoclonal antibody.85 Combined therapy using 13iI-labeled CEA with conventional chemotherapy of medullary thyroid cancer has been reported in animals.86 Behr and coworkers reported that 30 patients with small-volume metastatic colorectal cancers have been treated with l31I-labeled anti-CEA as an adjuvant setting.87

99mTc( V)-Dimercaptosuccinic Acid and Somatostatin Analog

Ohta and associates first reported the use of DMSA for imaging medullary cancer of the thyroid in 1984.88 Four patients with medullary cancer showed clear and specific tumor uptake in primary and/or metastatic foci. DMSA uptake was subsequently noted in the nasopharynx, axial skeleton, breast, liver, spleen, heart, kidney, urinary bladder, great vessels, and skeletal muscles.89 There was no DMSA uptake in the male breast. Positive uptake was seen in only one of three subjects younger than 15 years of age, in 16 of 23 patients (70%) between 15 and 50, and in 7 of 25 (28%) older than 50.90 The overall sensitivity of DMSA ranged from 57% to 95%.91"96 The differences in sensitivity may depend on the method of preparing pentavalent DMSA since the pH of the mixture has to be high (7.5) for highest activity. When the pH is low, trivalent DMSA is synthesized, which makes DMSA sensitivity low.97 Unfortunately, most subsequent studies have not found DMSA to be sensitive enough to recommend it for routine use in patients with medullary thyroid cancer. Kwekkeboom and colleagues98 have reported tumor localization in 11 of 17 patients (65%) with luIn-octreotide with medullary thyroid cancer. They reported that neither serum calcitonin nor CEA levels differed significantly between patients whose tumor accumulated labeled octreotide in vivo and those tumors that did not. Numerous authors have subsequently presented their experience using octreotide scintigraphy for the localization of recurrent medullary cancer.99107 When somatostatin scintigraphy was compared with MRI scanning in nine patients, the same 17 lesions were seen by both methods; however, 13 additional suspicious lesions were seen with somatostatin scintigraphy. Histologic confirmation was available from 19 metastases; MRI was positive in 13 (68%) and somatostatin receptor scintigraphy was positive in 18 (95%).99'100 Comparison of mIn-octreotide and DMSA has also been done. Three papers concluded that octreotide is superior; however, the sensitivity of DMSA is relatively low.91102 108 Another investigation suggests that both '"In and DMSA are relatively that insensitive.103

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