Context: Preoperative neck ultrasonography may yield false-negative findings in more than one-third of medullary thyroid cancer (MTC) patients. If not cleared promptly, cervical lymph node metastases may emerge subsequently. Reoperations entail an excess risk of surgical morbidity and may be avoidable. Objective: This comprehensive investigation aimed to evaluate in a head-to-head comparison the clinical utility of pretherapeutic biomarker serum levels (basal calcitonin; stimulated calcitonin; carcinoembryonic antigen) for indicating extent of disease and providing biochemical stratification of pretherapeutic MTC risk. Design: This was a retrospective analysis. Setting: The setting was a tertiary referral center. Patients: Included were 300 consecutive patients with previously untreated MTC. Interventions: The intervention was compartment-oriented surgery. Main Outcome Measure: Stratified biomarker levels were correlated with histopathologic extent of disease. Results: Higher biomarker levels reflected larger primary tumors and more lymph node metastases. Stratified basal calcitonin serum levels correlated better (r = 0.59) with the number of lymph node metastases than carcinoembryonic antigen (r = 0.47) or pentagastrin-stimulated calcitonin (r = 0.40) levels. Lymph node metastases were present in the ipsilateral central and lateral neck, contralateral central neck, contralateral lateral neck, and upper mediastinum, respectively, beyond basal calcitonin thresholds of 20, 50, 200, and 500 pg/ml. Bilateral compartment-oriented neck surgery achieved biochemical cure in at least half the patients with pretherapeutic basal calcitonin levels of 1,000 pg/ml or less but not in patients with levels greater than 10,000 pg/ml. Conclusions: Most newly diagnosed MTC patients, i.e. those with pretherapeutic basal calcitonin levels greater than 200 pg/ml, may need bilateral compartment-oriented neck surgery to reduce the number of reoperations.

Early lymphatic and systemic dissemination of tumor cells is the hallmark of medullary thyroid cancer, a sometimes elusive neoplasm of neural crest derivation. Medullary thyroid cancer cells arise from parafollicular cells and have retained the capability of secreting calcitonin as a neuroendocrine peptide and carcinoembryonic antigen (CEA) as a serum protein. Unlike absolute calcitonin or CEA levels, serial measurements of calcitonin and CEA doubling times correlate well with tumor progression and survival.¹

In medullary thyroid cancer (MTC), there is a concordance between central and lateral neck involvement, but this relationship has not been assessed quantitatively. After compartment-oriented lymphadenectomy for untreated MTC, the numbers of central lymph node metastases with ipsilateral (195 patients) and contralateral (185 of 195 patients) lateral lymph node metastases were analysed retrospectively. With one to three positive central lymph nodes, involvement of the ipsilateral lateral neck increased from 10·1 per cent (with no central node involvement) to 77 per cent, and from a mean of 0·6 to 3·7 nodal metastases (P < 0·001). With four or more central nodes, the rate was 98 per cent, with 10·7 nodal metastases (P = 0·001). A weaker increase was observed in the contralateral lateral neck: with one to nine positive central nodes, contralateral lateral neck involvement increased from 4·9 to 38 per cent, and from a mean of 0·6 to 2·3 nodal metastases (P = 0·011). With ten or more positive central nodes, the rate rose to 77 per cent, with 6·2 nodal metastases (P = 0·009). With one exception, contralateral lateral nodal metastases coexisted with metastases in the central and ipsilateral lateral neck. These data may lay the groundwork for more informed decision-making regarding dissection of the lateral neck compartments.

Objective: This institutional study aimed at quantifying a medullary thyroid cancer (MTC) patient's risk of lung, liver, or bone metastasis. Background: Without quantitative information regarding risk factors for lung, liver, and bone metastasis, risk stratification is liable to be haphazard, resulting in poor cost-effectiveness of screening programs. Methods: Included in this study were 715 patients with MTC for whom histopathologic information was available for each lymph node removed. Results: Seventy-two patients (10.1%) were diagnosed with lung metastasis, 58 patients (8.1%) with liver metastasis, and 34 patients (4.8%) with bone metastasis. Multivariate analyses were limited to patients revealing no more than 1 type of distant metastasis to avoid confounding by other distant metastasis. Extrathyroidal extension and 1 to 10 involved nodes indicated a small risk of lung metastasis [3%–4%; odds ratio (OR) 3–4], tumors greater than 40 mm and 11 to 20 involved nodes implied an intermediate risk (13%; OR 6), and more than 20 involved nodes entailed a high risk (26%–30%; OR 14–16). In the multivariate logistic regressions on liver and bone metastasis, in which the number of involved nodes was omitted on statistic grounds, extrathyroidal extension signified a strong risk of liver metastasis (19%, OR 23), whereas no clinical-pathologic variables were significantly associated with bone metastasis. Cumulative rates of lung, liver, and bone metastasis, plotted against the number of lymph node metastases, were similar. Discussion: N categories encompassing 1 to 10 (N1), 11 to 20 (N2), and more than 20 (N3) lymph node metastases are important prognostic classifiers that should be incorporated into MTC staging systems for better risk stratification.

Objective: This study sought to define the need for lymph node dissection in Rearranged during Transfection (RET) carriers at risk for hereditary medullary thyroid cancer. Summary Background Data: Controversy surrounds the need for lymph node dissection to complement thyroidectomy in RET carriers. Methods: Integration of molecular, biochemical, histopathologic, and clinical information from 308 RET carriers referred for (re-)operation to a specialist surgical center. Results: The carriers differed significantly in age at thyroidectomy when stratified by histopathology (tumor-free thyroid, node-negative, and node-positive medullary thyroid cancer) and mutated codon (611, 618, 620, 634, 768, 790, 804, 891, and 918). The wide overlap among the 3 histopathologic groups compromised individual predictions based on age alone. There was a significant relationship between the presence of lymph node metastases and increased pretherapeutic basal calcitonin levels. All 46 carriers with node-positive medullary thyroid cancer, who harbored 1 to 68 positive nodes, exhibited increased pretherapeutic basal calcitonin levels (91.4 pg/mL or higher). Conversely, 74 (44%) of 168 carriers with normal thyroids, C-cell hyperplasia, or node-negative medullary thyroid cancer displayed normal pretherapeutic basal calcitonin levels (negative predictive value 100%). Prediction of lymph node metastasis was better in carriers of codon 918 mutations (positive predictive value, PPV, 80%–100%) and those older than 20 years of age (PPV, 50%). Discussion: In the absence of clinical evidence to the contrary, RET carriers with normal pretherapeutic basal calcitonin levels may forgo lymph node dissection. The usefulness of calcitonin thresholds to break down the block of carriers with increased calcitonin levels should be explored further.