Predicting Outcomes in Sporadic and Hereditary Medullary Thyroid Carcinoma over Two Decades.

Background: Medullary thyroid cancer (MTC) can be associated with significant morbidity and mortality in advanced cases. Hence, we aimed to identify factors at the time of MTC surgery that predict overall survival (OS), disease-specific survival (DSS), locoregional recurrence/persistence (LR), and distant metastases (DM). Methods: We performed a retrospective study of clinicopathologic, radiological, and laboratory data in MTC patients who underwent thyroidectomy at Mayo Clinic from January 1995 to December 2015. Results: We identified 163 patients (mean age 48.4 years, 48% males), 102 with sporadic MTC and 61 with hereditary disease (n = 46 multiple endocrine neoplasia [MEN] 2A, n = 3 MEN 2B, n = 12 familial MTC) with a median follow-up time of 5.5 years. On univariate analysis, age >55 years, male sex, DM at the time of surgery (M1), lateral neck lymph node (LN) involvement (N1b), gross extrathyroidal extension (ETE), American Joint Committee on Cancer (AJCC) stage 3/4, tumor size (T) 3/4, tumor size, and postoperative calcitonin (Ctn) and carcinoembryonic antigen (CEA) were significant predictors of worse OS and DSS. On multivariable analysis, both gross ETE (hazard ratio [HR] 4.62, 6.58) and M1 (HR 5.11, 10.45) remained significant predictors of worse OS as well as DSS, while age >55 years (HR 3.21), male sex (HR 2.42), and postoperative Ctn (HR 1.002 for every 100 pg/mL increase) were significant only for worse OS. On univariate analysis, male sex, M1, N1b, gross ETE, stage 3/4, T 3/4, tumor size, number of LNs involved, and postoperative Ctn were significant predictors of LR and DM; age >55 years was additionally significant for DM. On multivariable analysis, gross ETE (HR 3.16, 5.93) and N1b (HR 4.31, 4.64) remained significant predictors of LR and DM; ratio of resected/involved LN (HR 10.91) was additionally predictive for LR and postoperative Ctn (HR 1.003 for every 100 pg/mL increase) for DM. Conclusions: Disease burden at initial surgery, especially gross ETE, lateral neck LN involvement, and DM, as well as the biochemical response to surgery appear to be more important than demographic factors in terms of MTC prognosis. These findings highlight the importance of rigorous perioperative assessment to better predict MTC outcomes.

The RET p.G533C mutation confers predisposition to multiple endocrine neoplasia type 2A in a Brazilian kindred and is able to induce a malignant phenotype in vitro and in vivo.

BACKGROUND: We have previously described a p.G533C substitution in the rearranged during transfection (RET) oncogene in a large family with medullary thyroid carcinoma. Here, we explore the functional transforming potential of RET p.G533C mutation. METHODS: Plasmids expressing RET mutants (p.G533C and p.C634Y) and RET wild type were stable transfected into a rat thyroid cell line (PCCL3). Biological and biochemical effects of RET p.G533C were investigated both in vitro and in vivo. Moreover, we report the first case of pheochromocytoma among the RET p.G533C-carriers in this Brazilian family and explore the RET mutational status in DNA isolated from pheochromocytoma. RESULTS: Ectopic expression of RET p.G533C and p.C634Y activates RET/MAPK/ERK pathway at similar levels and significantly increased cell proliferation, compared with RET wild type. We additionally show that p.G533C increased cell viability, anchorage-independent growth, and micronuclei formation while reducing apoptosis, hallmarks of the malignant phenotype. RET p.G533C down-regulates the expression of thyroid specific genes in PCCL3. Moreover, RET p.G533C-expressing cells were able to induce liver metastasis in nude mice. Finally, we described two novel RET variants (G548V and S556T) in the DNA isolated from pheochromocytoma while they were absent in the DNA isolated from blood. CONCLUSIONS: Our in vitro and in vivo analysis indicates that this mutation confers a malignant phenotype to PCCL3 cells. These findings, in association with the report of first case of pheochromocytoma in the Brazilian kindred, suggest that this noncysteine mutation may be more aggressive than was initially considered.

Presentation of a medullary endocrine neoplasia 2A kindred with Cushing's syndrome.

Although medullary thyroid cancer (MTC) can produce adrenocorticotropic hormone (ACTH) in up to 40 per cent of cases as determined by immunohistochemistry, clinical hypercortisolism is rarely seen. We report a medullary endocrine neoplasia 2A (MEN 2A) kindred whose proband case presented with Cushing's syndrome (CS). This 51-year-old woman presented with debilitating weakness, exertional dyspnea, 50 pound weight gain, moon facies, worsening hypertension, striae, and hirsutism. A comprehensive evaluation diagnosed ectopic ACTH production from unresectable metastatic MTC to the liver. Genetic testing revealed a germline RET proto-oncogene mutation at codon 609. Further genetic testing identified six family members with the same mutation. The patient underwent palliative bilateral laparoscopic adrenalectomies with significant improvement in major comorbidities. Overall CS resulting from ectopic ACTH overproduction by MTC is rare, occurring in 0.6 per cent of all patients with medullary thyroid carcinoma. About 50 cases have been previously reported in the literature, but only three in families with MEN 2A. We describe the first case of a MEN 2A kindred presenting with CS from ectopic ACTH production by metastatic medullary thyroid carcinoma. We advocate consideration of early bilateral laparoscopic adrenalectomies in patients with symptomatic hypercortisolism from unresectable metastatic medullary thyroid carcinoma.

Identification of occult metastases of medullary thyroid carcinoma by pentagastrin-stimulated intravenous calcitonin sampling followed by targeted surgery.

BACKGROUND: High calcitonin (CT) serum levels suggest metastatic spread in medullary thyroid carcinoma (MTC) after thyroidectomy. In limited disease stages, however, morphological investigations including ultrasound, magnetic resonance imaging (MRI) and 18F-FDG positron emission tomography ([18F]FDG-PET) may often fail to identify exact tumour sites. OBJECTIVE: The aim of the present study was to establish an improved strategy to identify small cervical tumours by combining pentagastrin stimulation with bilateral cervical intravenous CT sampling followed by high-resolution ultrasound. DESIGN AND PATIENTS: Six MTC patients were examined, of whom five patients already had bilateral neck dissection. Five patients had sporadic MTC, and one patient suffered from MEN2a. RESULTS: Retrospective analysis of all patients revealed a highly sensitive positive correlation between an early calcitonin peak (20-40 s after pentagastrin injection) and site of cervical tumour affection. Postinterventional ultrasound examination of the affected regions of the neck revealed suspicious presence; in some cases small lymph nodes of less than 1 cm in size were then surgically excised. On histology, small tumours could be identified in four patients. Postsurgical examination revealed a clear decline of basal serum calcitonin levels in four patients (between -41% and -100%). In two patients CT normalized to baseline levels (< 10 pg/ml) and in another two patients CT rendered to near normal (14 and 17 pg/ml). CONCLUSION: Pentagastrin stimulation-based intravenous catheter sampling may be beneficial in the diagnostic work-up of MTC after thyroidectomy. Our data show that an early calcitonin peak (20-40 s after administration of pentagastrin) helps to identify tumour-affected regions.

RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome.

Since the establishment of a protocol for molecular analysis of hereditary medullary thyroid carcinoma (MTC) in southern Brazil, in 1997, 17 independent families with RET germline mutation have been identified. Because neither molecular diagnosis nor the pentagastrin test were available before the establishment of this protocol, we had the opportunity to observe a large number of patients in whom the disease has evolved naturally without medical intervention, namely prophylactic thyroidectomy. We observed a wide spectrum in terms of clinical presentation and natural course of the disease even among genetically related individuals. Sixty-nine individuals from 12 different families presented a codon 634 mutation, the most prevailing missense mutation in our series. The specific mutations identified were C634Y (n = 49), C634R (n = 13), and C634W (n = 7). Individuals with the C634R mutation presented significantly more distant metastases at diagnosis than subjects with the C634Y or C634W mutations (54.5% vs. 19.4% vs. 14.3%, respectively, P = 0.03). Further analysis of the estimated cumulative frequency of lymph node and/or distant metastases by Kaplan-Meier curves showed that the appearance of lymph nodes and metastases occurred later in patients with C634Y than in those with C634R (P = 0.001). Our results suggest that specific nucleotide and amino acid exchanges at codon 634 might have a direct impact on tumor aggressiveness in MEN 2A syndrome.