Chinese siblings with hereditary medullary thyroid carcinoma caused by RET mutation: implications for RET oncogene detection.

BACKGROUND: Hereditary medullary thyroid carcinoma (MTC) is mainly caused by germline mutations in the RET proto-oncogene, which accounts for 20-30% of all MTC according to foreign studies. However, no English literatures have reported Chinese hereditary MTC. Here, we reported two Chinese brothers with MTC that caused by germline RET mutation. CASE PRESENTATION: The younger brother was diagnosed with MTC at 29 years ago and suffered recurrence more than 10 years. For elder brother, the diagnosis of MTC was made by postoperative pathological examination at age 61. Both patients received total thyroidectomy and lymph node dissection. Since they had a significant family history for MTC, genetic detection was performed and identified a germline mutation in RET exon 10 (p.C620Y). This mutation was also detected in their offspring, indicating a moderate risk of MTC. CONCLUSIONS: This is the first report presenting a Chinese family with hereditary MTC caused by the RET p.C620Y variant. This case series emphasize the importance of genetic detection of RET proto-oncogene for MTC patients, and bring out managements for individuals after detection of RET mutations.

Multiple endocrine neoplasia type 2A syndrome (MEN2A) and usefulness of 68Ga-DOTATATE PET/CT in this syndrome.

AIM: The aim of this study was to evaluate a new imaging method 68Ga-DOTATATE PET/CT as an alternative method to diagnose evidence of neuroendocrine tumors or their metastasis (if any) in patient with MEN 2A. METHODS: Three patients( 2F, 1M; age 28,46 and 50 years) with MEN 2A syndrome who underwent 68Ga-DOTATATE PET/CT scan were prospectively evaluated. PET/CT images were analyzed with measurement of maximum standardized uptake value (SUVmax). RESULTS: All patients had adrenal masses with increased uptake of 68Ga-DOTATATE (first case adrenal mass SUVmax: 9,1, second case adrenal mass SUVmax: 32,4(right), 30,3(left) and third case SUVmax:12,4). All of the patients had medullary thyroid carcinoma with increased uptake of 68Ga-DOTATATE (first case SUVmax: 3,3 second case SUVmax:7,7 and third case SUVmax: left thyroid nodule: 19,4, right thyroid nodule: 21,2). Third case has a parathyroid adenoma with SUVmax: 2,8. CONCLUSIONS: New imaging method 68Ga-DOTATATE PET/CT may be an alternative method to diagnose MEN 2A patients. 68Ga-DOTATATE PET/CT can give a great opportunity to detecting the multiple neoplasia like MEN 2A with only one session. KEY WORDS: MEN 2A syndrome, 68Ga-DOTATATE PET/CT, Neuroendocrine tumors.

Use of Dexmedetomidine in a Parturient With Multiple Endocrine Neoplasia Type 2A Undergoing Adrenalectomy and Thyroidectomy: A Case Report.

Dexmedetomidine is a selective α2-agonist, frequently used in perioperative medicine as anesthesia adjunct. The medication carries a Food and Drug Administration pregnancy category C designation and is therefore rarely used for parturients undergoing nonobstetric surgery. We are reporting the use of dexmedetomidine in the anesthetic management of a parturient undergoing minimally invasive unilateral adrenalectomy for pheochromocytoma during the second trimester of pregnancy. Additionally, because of the multiple endocrine neoplasia type 2A constellation with diagnosis of medullary thyroid cancer, the patient underwent a total thyroidectomy 1 week after the adrenalectomy.

Síndromes de neoplasia endocrina múltiple: revisión radiológica / Multiple Endocrine Neoplasia Syndromes: Radiological Review

Los síndromes de neoplasia endocrina múltiple (MEN), incluyen una serie de enfermedades con alteraciones genéticas que se caracterizan por la presencia de tumores que afectan a dos o más glándulas endocrinas. Son síndromes con una herencia autosómica dominante e incluyen tres patrones: MEN 1 (síndrome de Wermer), MEN 2 (que incluye MEN 2A o síndrome de Sipple y MEN 2B o síndrome de Wagenmann-Froboese) y MEN 4. Los adenomas paratiroideos y el carcinoma medular tiroideo, son los tumores más frecuentes del MEN tipo 1 y 2 respectivamente. Esos síndromes son más comunes en pacientes jóvenes, con patología de afectación bilateral, múltiple o multifocal y, sobre todo, en pacientes con antecedentes familiares. Es necesario el trabajo en equipo de endocrinólogos, cirujanos, oncólogos y radiólogos para optimizar el tratamiento de esos pacientes.

Multiple endocrine neoplasia (MEN) encompasses a serial of familial genetically disorders in wich tumors simultaneusly occur in two or more endocrine organs. MEN síndromes are autosomal-dominant disorders categorized into three main patterns: MEN 1 (Wermer syndrome), MEN 2 (includes MEN 2A o Sipple syndrome and MEN 2B o Wagenmann-Froboese syndrome) and MEN 4. Parathyroid adenomas and medullary thyroid carcinoma are the most frecuent tumors in MEN 1 and MEN 2 respectively. These entities will be suspected in younger patients, bilateral, multiple or multifocal disease and, specially, in patients with family background. Cooperation between endocrinologist, surgeons, oncologists and radiologists is pivotal for optimizing patient treatment.

Multiple endocrine neoplasia 2A (MEN 2A) syndrome.

INTRODUCTION: In the MEN 2A syndrome, which is the most common of the three types of MEN, three endocrine systems are affected simultaneously or subsequently by the development of tumours manifested by medullary thyroid gland carcinoma, pheochromocytoma (often bilateral) and hyperparathyroidism. MATERIAL AND METHODS: 27 patients from 3 families affected by MEN 2A syndrome were examined clinically (by detecting the effects of catecholamine overproduction), biochemically (screening for metanephrine and normetanephrine in the serum), visualization (CT, MRI, MIBG, PET CT) and some of them also genetically (DNA fragment analysis obtained by PCR amplification). RESULTS: Familial incidence of pheochromocytoma was confirmed in 10 patients (4 males, 5 females and one girl) aged 6 to 54 years (average 22.8 years) . In 5 patients, the pheochromocytoma occurred on both sides, in one patient, with genetically proved MEN 2A syndrome, only one adrenal gland was affected by pheochromocytoma. In 10 patients, mutations were detected in the exon 10, 11 and 16 RET of the proto-oncogene in the centromeric region of the 10th chromosome. After proper preparation, 5 patients underwent bilateral adrenalectomy (unilateral adrenalectomy in one patient). Histological examination of the removed tumours in all cases excluded the malignant pheochromocytoma.The first of the operated patients (54 yr) died after surgery for cardiovascular failure. Others have lived 5 to 15 years after bilateral adrenalectomy without signs of local recurrence of the disease, and have no clinical signs of over-production of catecholamines. CONCLUSION: Bilateral pheochromocytoma and thyroid carcinoma are indications for detailed clinical and genetic examination of all family members. Bilateral adrenalectomy with lifetime supplementation of adrenal hormones is indicated in symptomatic patients and/or patients asymptomatic with tumours larger than 3 cm in diameter (Tab. 1, Fig. 11, Schema 1, Ref. 31).

Papillary thyroid cancer in childhood: is parental screening helpful?

BACKGROUND: Familial non-medullary thyroid cancer (FNMTC) mandates family screening with ultrasound; however, the need for screening paediatric thyroid cancer with no family history has not been addressed. METHODS: This study conducted a retrospective cohort study in a tertiary hospital. The study group is composed of patients ≤18 years undergoing surgery for papillary thyroid cancer (PTC) from 2008 to 2014. RESULTS: During the study period, 15 paediatric patients had PTC. Only one patient had a prior family history of PTC involving two second-degree relatives. Of the 30 parents, four were lost to follow-up, with the remaining 26 undergoing screening thyroid ultrasound. Nodular thyroid disease was documented in eight ultrasounds performed. Subsequently, one has not undergone fine-needle biopsy, five were benign and two underwent surgical resection: one having a benign follicular adenoma and the other a papillary microcarcinoma with nodal micrometastasis. CONCLUSIONS: Routine ultrasound screening of parents of children presenting with PTC and no family history do not demonstrate an increased incidence of FNMTC. Screening of affected families is likely to demonstrate the expected background incidence of nodular thyroid disease and incidental papillary microcarcinoma. As such, it is unlikely to be useful.

Gallium-68 Dotatate PET/CT is superior to other imaging modalities in the detection of medullary carcinoma of the thyroid in the presence of high serum calcitonin.

OBJECTIVE: Medullary carcinoma of the thyroid (MTC) is a rare neuroendocrine tumour (NET) that expresses somatostatin receptors on the cell membrane and secretes calcitonin. Surgery is the primary curative modality but is achieved only when the diagnosis is timely so there is a high rate of persistent and recurrent disease indicated by a rise in the serum calcitonin levels. Successful management of recurrent disease requires accurate localisation with cross sectional and functional imaging. The introduction of gallium-68-Dotatate ((68)Ga-Dotatate) peptides positron emission tomography/computerized tomography (PET/CT) has significantly improved the detection of NET and has been reported as a valuable adjunct in MTC localisation. We retrospectively reviewed our cases of MTC to correlate the detectability of (68)Ga-Dotatate in relation to calcitonin levels and assess suitability of inoperable patients for peptide receptor radionuclide therapy (PRRT). SUBJECTS AND METHODS: Seven patients (age range 31-66 years, M:F 3:4) with raised calcitonin (mean=7,143pg/mL) were referred for (68)Ga-Dotatate PET/CT scan for localisation of persisting recurrent MTC. Six patients were known to have MTC treated with thyroidectomy and one patient was presenting for the first time. All patients had multiple imaging including ultrasound (US), CT, magnetic resonance imaging (MRI), fluorine-18-fluorodeoxyglucose ((18)F-FDG) PET/CT and iodine-123-metaiodobenzylguanidine ((123)I-MIBG). Positive findings were defined as areas of increased uptake other than the organs of normal distribution and were correlated with results of biopsies, other imaging, long term monitoring of calcitonin and clinical follow up. RESULTS: In 6/7 patients with very high serum calcitonin (range= 672-37,180, mean=8,320pg/mL) (68)Ga-Dotatate PET/CT confirmed the presence of active disease seen on other modalities or detected hitherto unsuspected lesions. In at least 3 cases, (68)Ga-Dotatate PET/CT showed many more lesions compared to other imaging combined. In 1/7 patient (68)Ga-Dotatate PET/CT was negative in line with a relatively low calcitonin level (80pg/mL) and negative disease on fine needle aspiration. CONCLUSION: (68)Ga-Dotatate PET/CT is an effective tool for localising metastatic spread of MTC. It appears to be most effective in the presence of higher levels of serum calcitonin, probably in excess of 500pg/mL. The results of our small cohort had an impact on staging and management with the introduction of peptide receptor radionuclide therapy for inoperable disease.

Mixed medullary-papillary carcinoma of the thyroid: report of two cases and review of the literature.

Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are two distinct types of thyroid carcinoma with considerable difference in terms of cellular origin, histopathological appearance, clinical course and prevalence. The histogenetic origin and possible molecular mechanisms responsible for the development of mixed medullary-papillary carcinoma of the thyroid are still unclear. The most widely accepted hypotheses considering co-occurrence of MTC and PTC are stem cell theory, collision effect theory and hostage theory. Herein we describe two rare cases of mixed medullary-papillary thyroid carcinoma with co-occurrence of MTC and PTC which developed with concomitant MEN 2A and different sites of lymph node metastasis in the first patient, while with atypical clinical presentation in the second patient. In conclusion, co-expression of thyroglobulin, synaptophysin and chromogranin by the papillary component of mixed tumor seems to support stem cell theory in our first case, whereas positive staining for calcitonin but not for thyroglobulin in the medullary component of the tumor along with separation of these two tumors from each other by a normal thyroid tissue seem to indicates the likelihood of collision effect theory in our second case.

123I-MIBG, 18F-DOPA and 18F-FDG in a patient with MEN2 syndrome and recurrent pheochromocytoma.

Pheochromocytoma is a rare tumor located in the medulla of the adrenal gland that is characterized by high catecholamine synthesis. Surgery is the treatment of choice and is usually curative if appropriately diagnosed and excised. Imaging methods, both morphological and functional, are of great importance in presurgical evaluation. We report the case of a female patient with multiple endocrine neoplasia syndrome type 2, with bilateral adrenalectomy due to two pheochromocytomas and progressive elevation of urinary metanephrine. Magnetic resonance imaging showed a nodular image in the right adrenal fossa. The patient was referred to our unit in order to confirm suspicion of recurrence. Due to the absence of pathological findings in the (123)I-MIBG scintigraphy and high suspicion of recurrence, PET/CT imaging with (18)F-DOPA and (18)F-FDG were performed, and the diagnosis was confirmed.

Is basal ultrasensitive measurement of calcitonin capable of substituting for the pentagastrin-stimulation test?

OBJECTIVE: To evaluate a second-generation assay for basal serum calcitonin (CT) measurements compared with the pentagastrin-stimulation test for the diagnosis of inherited medullary thyroid carcinoma (MTC) and the follow-up of patients with MTC after surgery. Recent American Thyroid Association recommendations suggest the use of basal CT alone to diagnose and assess follow-up of MTC as the pentagastrin (Pg) test is unavailable in many countries. DESIGN: Multicentric prospective study. PATIENTS: A total of 162 patients with basal CT <10 ng/l were included: 54 asymptomatic patients harboured noncysteine 'rearranged during transfection' (RET) proto-oncogene mutations and 108 patients had entered follow-up of MTC after surgery. MEASUREMENT: All patients underwent basal and Pg-stimulated CT measurements using a second-generation assay with 5-ng/l functional sensitivity. RESULTS: Ninety-five per cent of patients with basal CT ≥ 5 ng/l and 25% of patients with basal CT <5 ng/l had a positive Pg-stimulation test (Pg CT >10 ng/l). Compared with the reference Pg test, basal CT ≥ 5 ng/l had 99% specificity, a 95%-positive predictive value but only 35% sensitivity (P < 0.0001). Overall, there were 31% less false-negative results using a 5-ng/l threshold for basal CT instead of the previously used 10-ng/l threshold. CONCLUSION: The ultrasensitive CT assay reduces the false-negative rate of basal CT measurements when diagnosing familial MTC and in postoperative follow-up compared with previously used assays. However, its sensitivity to detect C-cell disease remains lower than that of the Pg-stimulation test.

Ultrasonography should not guide the timing of thyroidectomy in pediatric patients diagnosed with multiple endocrine neoplasia syndrome 2A through genetic screening.

BACKGROUND: American Thyroid Association (ATA) guidelines suggest that thyroidectomy can be delayed in some children with multiple endocrine neoplasia syndrome 2A (MEN2A) if serum calcitonin (Ct) and neck ultrasonography (US) are normal. We hypothesized that normal US would not exclude a final pathology diagnosis of medullary thyroid cancer (MTC). METHODS: We retrospectively queried a MEN2A database for patients aged<18 years, diagnosed through genetic screening, who underwent preoperative US and thyroidectomy at our institution, comparing preoperative US and Ct results with pathologic findings. RESULTS: 35 eligible patients underwent surgery at median age of 6.3 (range 3.0-13.8) years. Mean MTC size was 2.9 (range 0.5-6.0) mm. The sensitivity of a US lesion≥5 mm in predicting MTC was 13% [95% confidence interval (CI) 2%, 40%], and the specificity was 95% [95% CI 75%, 100%]. Elevated Ct predicted MTC in 13/15 patients (sensitivity 87% [95% CI 60%, 98%], specificity 35% [95% CI 15%, 59%]). The area under the receiver operating characteristic curve (AUC) for using US lesion of any size to predict MTC was 0.50 [95% CI 0.33, 0.66], suggesting that US size has poor ability to discriminate MTC from non-MTC cases. The AUC for Ct level at 0.65 [95% CI 0.46, 0.85] was better than that of US but not age [AUC 0.62, 95% CI 0.42, 0.82]. CONCLUSIONS: In asymptomatic children with MEN2A diagnosed by genetic screening, preoperative thyroid US was not sensitive in identifying MTC of any size and, when determining the age for surgery, should not be used to predict microscopic MTC.

[Evaluation of efficacy and clinical impact of 18F-FDG-PET in the diagnosis of recurrent medullary thyroid cancer with increased calcitonin and negative imaging test]. / Evaluación de la eficacia y del impacto clínico de la PET-18F-FDG en el diagnóstico de recurrencia del carcinoma medular de tiroides con calcitonina elevada y pruebas de imagen negativas.

AIM: To evaluate the efficacy and clinical impact of the FDG-PET in the diagnosis of suspicion of recurrence of medullary thyroid cancer (MTC) in patients with elevated serum calcitonin and negative imaging test. MATERIAL AND METHODS: We performed a retrospective study of 31 consecutive cases from february 2001 to october 2007 of 17 women and 14 men, mean age 56.2 years (range: 26-88), with anatomical-pathology diagnosis of medullary thyroid cancer and suspicion of recurrence due to abnormal elevation of calcitonin and negative imaging tests. All of the patients underwent whole body FDG-PET scan with a dedicated PET or PET-CT 60 minutes after intravenous injection of 333-434 MBq of (18)F-FDG. Results were confirmed by pathology study in 45.2% of the patients and by clinical follow-up with a mean of 4 years (range: 16 m-8 years) RESULTS: Sensitivity was 88%, specificity 84.6%, positive predictive value 88%, negative predictive value 84.6% and diagnostic accuracy 87%. The results of the FDG PET modified the therapeutic strategy in 14 cases (45.2%). A comparison was made of the mean values of calcitonin using the Student's "t" test between positive PET studies for the disease and negative ones. No significant differences were found (P=.3). CONCLUSIONS: In patients with MTC and suspected recurrence with elevated calcitonin and negative imaging test, the FDG is the best test for the diagnosis of occult recurrence in MTC with elevated calcitonin and negative imaging techniques with elevated clinical impact. It facilitates the therapeutic management of the patients with MTC recurrence, and should be included in the diagnosis algorithm in these patients.

Diagnosis of multiple endocrine neoplasia type 2A in patients with positive thyroid imaging by iodine-131 metaiodobenzylguanidine scintigraphy.

We retrospectively analyzed iodine-131 metaiodobenzylguanidine (I-131 MIBG) scintigraphy in 320 patients (male, 108 cases; female, 211 cases; average age, 45±15 years). All patients received thyroid block before examination between 2007 and 2010 in our department. Various degrees of radioactivity were found in the thyroid glands or thyroid region after bilateral thyroid surgery, in addition to bilateral or unilateral abnormal radioactivity in the adrenal glands in 3 patients. These cases were confirmed for medullary thyroid carcinoma and adrenal pheochromocytoma by pathology after surgical removal of the glands, and the diagnosis of multiple endocrine neoplasia type 2A was established from the patients' history and genetic examination. The possibility of medullary thyroid carcinoma should be considered on the finding of abnormal radioactivity in the thyroid or thyroid region by I-131 MIBG scintigraphy after excluding normal radioactivity in the thyroid. When significant abnormal radioactivity is seen in the adrenal gland on I-131 MIBG scintigraphy, the possibility of adrenal pheochromocytoma should be considered. Adrenal pheochromocytoma cannot be excluded when adrenal uptake is increased. The possibility of multiple endocrine neoplasia type 2A should be considered taking into account the history of these patients.

Contrast-enhanced ultrasound for imaging of adrenal masses.

PURPOSE: The number of incidentally discovered adrenal masses is growing due to the increased use of modern high-resolution imaging techniques. However, the characterization and differentiation of benign and malignant adrenal lesions is challenging. This study aimed to evaluate contrast-enhanced ultrasound for the characterization of adrenal masses. MATERIALS AND METHODS: We studied 58 patients with adrenal masses detected with computed tomography, magnetic resonance imaging, or ultrasound. 7 patients had bilateral adrenal lesions. Contrast-enhanced ultrasound was performed using high-resolution ultrasound (3.5 - 7 MHz) and intravenous injection of 2.4 ml SonoVue. The contrast enhancement pattern of all adrenal lesions was documented. RESULTS: The 18 malignant adrenal tumors were significantly larger at the time of diagnosis compared to the 40 benign lesions (p < 0.03). The majority of benign adrenal lesions (37 / 40) had a nonspecific type of contrast enhancement (24 / 40) or a peripheral to central contrast filling (13 / 40) described as the iris phenomenon. Similar findings were observed in malignant adrenal tumors: most malignant lesions also showed nonspecific (6 / 18) or peripheral to central contrast filling (9 / 18). Peripheral to central contrast filling had 50 % sensitivity (26 - 74 %) and 68 % specificity (51 - 81 %) for indicating malignancy. CONCLUSION: Contrast-enhanced ultrasound facilitates the visualization of vascularization even in small adrenal masses, but it does not help to distinguish malignant and benign lesions.

PET imaging of medullary thyroid carcinoma in MEN2A transgenic mice using 6-[(18)F]F-L-DOPA.

PURPOSE: 6-[(18)F]Fluoro-3,4-dihydroxy-L-phenylalanine (6-[(18)F]F-L-DOPA) is increasingly used for PET imaging of neuroendocrine tumours. In this study, we investigated the use of 6-[(18)F]F-L-DOPA to detect and to monitor the progression of medullary thyroid carcinoma (MTC) in a genetically engineered mouse model of multiple endocrine neoplasia type 2A (MEN2A). METHODS: Dynamic [(18)F]FDG and 6-[(18)F]F-L-DOPA small animal PET scans were acquired during 60 or 90 min in 8- to 20-month-old MEN2A transgenic mice. The kinetics of 6-[(18)F]F-L-DOPA, standardized uptake values (SUV) at 60 min and tumour volumes were recorded. The detection of MTCs using PET was confirmed by autopsy and histological analysis. RESULTS: 6-[(18)F]F-L-DOPA performs better than [(18)F]FDG for MTC detection in this transgenic mouse model. Uptake kinetics of 6-[(18)F]F-L-DOPA in MTCs are very different between mice but, in all cases, high contrast could be observed. Furthermore, 6-[(18)F]F-L-DOPA can detect tumours with sizes (1.8 mm(3)) that are near the resolution limit of PET, whereas they were undetectable by autopsy at the macroscopic level. CONCLUSION: 6-[(18)F]F-L-DOPA PET imaging can monitor the progression of MTCs in a genetically engineered mouse model.