Hereditary medullary thyroid carcinoma syndromes: experience from western India.

The data from the Indian subcontinent on Medullary thyroid carcinoma (MTC) and associated endocrinopathies in hereditary MTC (HMTC) syndromes are limited. Hence, we analyzed clinical and biochemical characteristics, management, and outcomes of HMTC and other associated endocrinopathies [Pheochromocytoma (PCC) and Primary hyperparathyroidism (PHPT)] and compared with apparently sporadic MTC. The records of 97 (51 sporadic and 46 hereditary) consecutive MTC patients were retrospectively analyzed. RET mutation was available in 38 HMTC patients. HMTC group was subclassified into Multiple endocrine neoplasia (MEN) 2A index (n = 25), MEN2B index (n = 8), and MEN2A detected by familial screening (n = 12). Patients with HMTC and MEN2B index were younger at presentation than sporadic MTC. MEN2A patients detected by familial screening, but not MEN2A index and MEN2B index patients, had significantly lower serum calcitonin, smaller thyroid nodule size, more frequent early stage presentation (AJCC Stage ≤ II), and higher cure rate than sporadic MTC, which emphasizes the need for early diagnosis. RET (REarranged during Transfection) 634 mutations were the most common cause of HMTC and more frequently associated with PCC (overall 54% and 100% in those aged ≥ 35 years). Patients in ATA-Highest (HST) group had a universal presentation in stage IV with no cure. In contrast, the cure rate and postoperative disease progression (calcitonin doubling time) were similar between ATA-High (H) and ATA- Moderate (MOD) groups, suggesting the need for similar follow-up strategies for the latter two groups. Increased awareness of endocrine (PCC/PHPT) and non endocrine components may facilitate early diagnosis and management.

Current surgical management in RET mutation carriers [Aktualne postepowanie chirurgiczne u nosicieli mutacji proto-onkogenu RET].

Medullary thyroid carcinoma (MTC) still remains a rare endocrine tumor. 20-25% of MTC cases are genetically determined. The detection of the RET proto-oncogene mutation in 1993 allowed to understand the unique genotype-phenotype relationships in hereditary medullary thyroid carcinoma (HMTC) and formed the basis for therapeutic decisions based on the molecular results. Currently, prophylactic thyroidectomy is a commonly adopted and accepted therapeutic method. The decision on the time and extent of surgery should be made based on the results of molecular examination, the assessment of calcitonin (Ct) concentration and family history. Treatment of patients with HMTC requires the cooperation of a multidisciplinary team of experts and should be done in specialized centers only. The study is a review of the current guidelines for surgical management in the MEN2 syndrome.

Long-term outcome after DNA-based prophylactic neck surgery in children at risk of hereditary medullary thyroid cancer.

Advances in sequencing technology, providing unprecedented insights into cancer progression, have shifted the treatment paradigm towards precision medicine for hereditary medullary thyroid cancer (MTC), away from the 'one-size-fits-all' approach predicated on genetic risk alone. The DNA-based/biochemical concept, factoring serum calcitonin into the benefit-risk equation, optimizes biochemical cure while minimizing extent of prophylactic surgery and operative morbidity in children at risk. The transformative effect that has taking effect on medical practice has been impressive: Increasingly earlier molecular diagnosis and more limited prophylactic neck operations yielded excellent clinical outcomes at expert facilities 7-16 years postoperatively: biochemical cure rates approximating 100%; absence of residual structural disease or recurrence; and rarely any permanent operative morbidity. These excellent results, contingent on proper health care funding and pediatric surgical specialization, make a case for early prophylactic thyroidectomy in experienced hands once calcitonin serum levels exceed the upper normal limit of the assay in young gene carriers.

Prophylactic thyroidectomy in multiple endocrine neoplasia 2 (MEN2) patients with the C634Y mutation: A long-term follow-up in a large single-center cohort.

BACKGROUND: Medullary thyroid carcinoma (MTC) is the main cause of death in multiple endocrine neoplasia 2A (MEN2A) patients. It is therefore important to treat this disease at an early stage. The mutation in codon 634 is considered to be associated with an aggressive clinical course, whereas the C634Y mutation may result in a more indolent course. Prophylactic thyroidectomy is performed before thyroid disease occurs. However, controversy surrounds this disease regarding levels of calcitonin (Ct) and age. In this context, few studies have investigated this mutation over a long period. OBJECTIVE: To analyze a large cohort of patients with the C634Y mutation who received prophylactic thyroidectomy. MATERIALS AND METHODS: In a group of 110 MEN2 patients, we analyzed those with the C634Y mutation who had received prophylactic thyroidectomy (absence of clinical and radiological thyroid disease) treated in a tertiary referral hospital between 1983 and 2016. MTC is related to age and Ct. Statistical analysis was performed using the χ2 test, partial correlations, and logistic regression. RESULTS: Fifty patients with a mean age of 12 ±â€¯9 years were analyzed; 56% of these had MTC (100% stage I). There was no case of hypoparathyroidism or permanent recurrent damage. MTC was associated mainly with age (OR 1.38). One 5-year-old patient presented with MTC. Mean follow-up time was 16 ±â€¯6 years, and no cases of recurrence were observed. CONCLUSIONS: Performing prophylactic thyroidectomy in patients with the C634Y mutation allows us to cure the disease without causing long-term complications. Our results support the notion that age <5 years should be a criterion for carrying out prophylactic thyroidectomy in these patients.

A Nationwide Study of Multiple Endocrine Neoplasia Type 2A in Norway: Predictive and Prognostic Factors for the Clinical Course of Medullary Thyroid Carcinoma.

BACKGROUND: Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant syndrome caused by activating germline mutations in the RET (REarranged during Transfection) proto-oncogene. MEN 2A has a strong (>95%) and age-dependent (5-25 years) clinical penetrance of medullary thyroid carcinoma (MTC). Several major studies have analyzed the predictive and prognostic factors for MEN 2A to find indicators that predict the optimal timing of prophylactic thyroidectomy. The aims of this study were to describe all known RET positive MEN 2A patients diagnosed in Norway and to evaluate the clinical course of MTC, as well as its predictive and prognostic factors. METHODS: This nationwide retrospective cohort study included data for 65 (14 index and 51 screening patients) out of a total of 67 MEN 2A patients with the RET gene mutation who were diagnosed in Norway since 1974. Data were collected by reviewing patient files. The variables analyzed were genotype, phenotype, preoperative basal calcitonin, age at thyroid surgery, central lymph node dissection and nodal status at primary surgery, number of surgical procedures, and biochemical cure. Of the 65 patients, 60 had undergone thyroid surgery. The median follow-up period was 9.9 years. The patients were divided into pre-RET-and RET-era, which included patients who had thyroid surgery before January 1, 1994, and after, respectively. RESULTS: In index and screening patients, MTC was found, respectively, in 100% and 45% of cases, central lymph node dissection at primary surgery was done for 64% and 52% of patients, and the median total number of surgical procedures was two (range 1-6) and one (range 1-4). At primary surgery, all patients (n = 13) with lymph node metastases had preoperative basal calcitonin levels ≥68 pg/mL, and all patients (n = 17) without central lymph node dissection and preoperative basal calcitonin <40 pg/mL were biochemically cured. Multivariate analysis showed that preoperative basal calcitonin was a significant predictive factor for MTC superior to age at thyroid surgery when analyzing the entire period (p = 0.009) and the RET-era separately (p = 0.021). Prognostic factors for biochemical cure were preoperative basal calcitonin, central lymph node dissection, and nodal status at primary surgery (p = 0.037, p = 0.002, and p = 0.005) when analyzing the entire period, but only nodal status at primary surgery when the RET-era was considered separately (p = 0.006). CONCLUSIONS: Preoperative basal calcitonin alone can serve as an indicator for optimal timing and the extent of thyroid surgery for MEN 2A patients that could be considered safe. The results are consistent with previously reported data.

Clinical significance of RET mutation screening in a pedigree of multiple endocrine neoplasia type 2A.

The clinical characteristics and RET proto-oncogene (RET­PO) mutation status of a patient with multiple endocrine neoplasia type 2A pedigree (MEN2A) was analyzed with the aim of preliminarily exploring the molecular mechanisms and clinical significance of the disease. Clinical characteristics of a single MEN2A patient were analyzed. Genomic DNA was extracted from the peripheral blood of the proband and 10 family members. The 21 exons of RET­PO were PCR amplified and the amplified products were sequenced. Of the family members, 5 exhibited a C634Y (TGC→TAC) missense mutation in exon 11 of RET­PO, among which 2 family members were screened as mutation carriers, while the others did not exhibit clinical symptoms of the mutation. The screening and analysis of RET­PO mutations for the MEN2A proband and the family members suggests potential clinical phenotypes and enables assessment of the risk of disease development, thus providing useful information for determining the surgical timing of preventive thyroid gland removal.

Mild to moderate increase of serum calcitonin levels only in presence of large medullary thyroid cancer deposits.

Many open questions remain to be elucidated about the diagnosis, treatment and prognosis of medullary thyroid cancer (MTC). The most intriguing concerns the outcome of MTC patients after surgery. Great importance is usually given to serum calcitonin (Ct) and carcinoembryonic (CEA) levels. It is commonly believed that the higher are the levels of these tumor markers and their kinetics (double time and velocity of markers levels) the worst is the prognosis. However, this is not the rule, as there are huge MTC metastatic deposits characterized by low serum Ct and CEA levels, and this condition is not closely related to the outcome of the disease during post-surgical follow-up. A series is reported here of patients who have these characteristics, as well as a description of their prognosis and clinical outcome.

A cut-off value of basal serum calcitonin for detecting macroscopic medullary thyroid carcinoma.

OBJECTIVE: Serum calcitonin (CT) level is used to detect medullary thyroid carcinoma (MTC), but the cut-off level is unclear. We aimed at identifying the optimal cut-off value of basal serum CT levels for detecting MTC. DESIGN AND PATIENTS: We retrospectively enrolled patients with hypercalcitoninemia (≥2·9 pmol/l) who had undergone thyroid ultrasonography (US) and subsequent work-up between 2001 and 2013 at Asan Medical Center. We divided patients into four groups: proven MTC (group 1, n = 93), pathologically proven non-MTC after surgery (group 2, n = 57), benign single nodule by cytology (group 3, n = 68) and patients without nodules on US (group 4, n = 24). MEASUREMENT: Basal serum CT levels were evaluated. RESULTS: The median CT level of group 1 (119·5 pmol/l) was significantly higher than those of other groups (4·0, 3·8 and 3·8 pmol/l, P < 0·001). When we adopted 19·0 pmol/l of CT level as a cut-off value, the sensitivity, specificity, and positive and negative predictive values were 77·4%, 98·7%, 97·3% and 87·8%, respectively. When we compared 29·2 pmol/l (100 pg/ml) and 19·0 pmol/l (65 pg/ml) as cut-off values, 19·0 pmol/l was more sensitive and accurate than 29·2 pmol/l. Factors associated with hypercalcitoninemia in non-MTC groups were autoimmune thyroiditis, chronic kidney disease, proton pump inhibitors and other malignancies. Serum CT levels tended to decrease spontaneously in non-MTC groups. CONCLUSION: Basal serum CT levels higher than 19·0 pmol/l can be a useful cut-off value for detecting macroscopic MTC, even though values below 19·0 pmol/l cannot exclude the presence of MTC like small volume MTC or premalignant C-cell hyperplasia.

Exome sequencing reveals mutant genes with low penetrance involved in MEN2A-associated tumorigenesis.

Activating rearranged during transfection (RET) mutations function as the initiating causative mutation for multiple endocrine neoplasia type 2A (MEN2A). However, no conclusive findings regarding the non-RET genetic events have been reported. This is the first study, to our knowledge, examining genomic alterations in matched MEN2A-associated tumors. We performed exome sequencing and SNP array analysis of matched MEN2A tumors and germline DNA. Somatic alterations were validated in an independent set of patients using Sanger sequencing. Genes of functional interest were further evaluated. The germline RET mutation was found in all MEN2A-component tumors. Thirty-two somatic mutations were identified in the nine MEN2A-associated tumors, of which 28 (87.5%) were point mutations and 4 (12.5%) were small insertions, duplications, or deletions. We sequenced all the mutations as well as coding sequence regions of the 12 genes in an independent sample set including 35 medullary thyroid cancers (20 MEN2A) and 34 PCCs (22 MEN2A), but found no recurrent mutations. Recurrent alterations were found in 13 genes with either mutations or alterations in copy number, including an EIF4G1 mutation (p. E1147V). Mutation of EIF4G1 led to increased cell proliferation and RET/MAPK phosphorylation, while knockdown of EIF4G1 led to reduced cell proliferation and RET/MAPK phosphorylation in TT, MZ-CRC1, and PC-12 cells. We found fewer somatic mutations in endocrine tumors compared with non-endocrine tumors. RET was the primary driver in MEN2A-associated tumors. However, low-frequency alterations such as EIF4G1 might participate in MEN2A-associated tumorigenesis, possibly by regulating the activity of the RET pathway.

Utility of serum thyroglobulin measurements after prophylactic thyroidectomy in patients with hereditary medullary thyroid cancer.

INTRODUCTION: Prophylactic thyroidectomy can be curative for patients with hereditary medullary thyroid cancer (MTC) caused by RET proto-oncogene mutations. Calcitonin is a sensitive tumor marker used to follow patients. We suggest that thyroglobulin (Tg) levels should also be monitored postoperatively in these patients. METHODS: We reviewed patients with RET mutations who underwent prophylactic thyroidectomy between 1981 and 2011 at an academic endocrine surgery center. Patients were excluded if they had no postoperative Tg levels recorded. RESULTS: Of the 22 patients who underwent prophylactic thyroidectomy, 14 were included in the final analysis. The average age at thyroidectomy was 9.8 years (range, 4-29). Tg levels were detectable 1.5 months to 31 years postoperatively in 11 patients (79%), all of whom were <15 years old at thyroidectomy. Median thyroid-stimulating hormone (TSH) was 2.5 mIU/L and 13.4 mIU/L in patients with undetectable and detectable Tg, respectively. Of those with detectable Tg, 5 had cervical ultrasonographic examination: Two showed no residual tissue in the thyroid bed, and 3 showed remnant thyroid tissue. CONCLUSION: Tg levels can identify patients with remnant thyroid tissue after prophylactic thyroidectomy. Ultrasonography can determine whether thyroid tissue remains posterolaterally that is at risk of MTC recurrence. Maintaining normal TSH may prevent growth of remaining thyroid follicular cells.

Current understanding and management of medullary thyroid cancer.

Medullary thyroid cancer (MTC) typically accounts for 3%-4% of all thyroid cancers. Although the majority of MTCs are sporadic, 20% of cases are hereditary. Hereditary MTC can be found in multiple endocrine neoplasia 2A or 2B or as part of familial MTC based on a specific germline mutation in the RET proto-oncogene. This article discusses the current approaches available for the diagnosis, evaluation, and management of patients and their family members with suspected MTC. The disease is predominantly managed surgically and typically requires a total thyroidectomy and lymph node dissection. A review of recent guidelines on the extent and timing of surgical excision is discussed. There are not very many effective systemic treatment options for MTC, but several emerging therapeutic targets have promise.

Is the excess cardiovascular morbidity in pheochromocytoma related to blood pressure or to catecholamines?

BACKGROUND: It is generally accepted that pheochromocytoma is associated with an increased cardiovascular risk. This is however not based on studies with an appropriate control group of patients with essential hypertension. AIM OF THE STUDY: We examined whether patients with pheochromocytoma have an excess cardiovascular morbidity as compared to hypertensive patients. METHODS: In a retrospective case-control study we reviewed the medical charts of 109 pheochromocytoma patients for cardiovascular events within 5 years prior to the diagnosis. These patients were matched to control patients with essential hypertension for gender and year of birth and diagnosis. Outcome variables were ischemic heart disease, cerebrovascular accidents, and transient ischemic attacks. Classical cardiovascular risk factors were also assessed. RESULTS: A significantly higher rate of patients with pheochromocytoma suffered a cardiovascular event (13.8%; 95% confidence interval: 7.9%-21.6%) as compared to hypertensive patients (1.1%, 95% confidence interval: 0.1%-3.9%) (P < .001). Blood pressure level was lower in pheochromocytoma patients (153/91 ± 35/15 mm Hg) than in hypertensive patients (170/103 ± 18/8 mm Hg) (P < .001), even after correction for use of antihypertensive medication (P < .02). The difference in event rates could not be attributed to differences in other cardiovascular risk factors. CONCLUSIONS: Pheochromocytoma patients have a clearly higher rate of cardiovascular events than patients with essential hypertension. This cannot be attributed to differences in blood pressure or other cardiovascular risk factors. The most likely explanation for the excess event rate is the prolonged exposure to the toxic effects of tumoral catecholamines. These data underpin the importance of a timely diagnosis and treatment of pheochromocytoma.

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.

[Multiple endocrine neoplasia syndrome type 2].

Multiple endocrine neoplasia (MEN) syndrome--is a hereditary disease which is characterized by synchronous or metachronous development of benign (adenoma, hyperplasia) or malignant tumors in the endocrine organs. The presence of medullary thyroid carcinoma and pheochromocytoma are mandatory requirements of MEN 2 syndrome. The purpose of our study was to perform timely diagnosis and optimal surgical treatment of patients with MEN 2 syndrome. Over the 1999-2009 years in the clinic we have diagnosed the MEN 2 syndrome in 5 patients, of whom two women were sisters. In all patients we observed medullary thyroid carcinoma and pheochromocytoma. Two patients had bilateral pheochromocytoma, and the clinical course was characterized with mild arterial hypertension. Primary hyperparathyroidism was observed in 2 patients. In the near relatives of patients with MEN 2 syndrome it must measure calcitonin, catecholamines, calcium rate, conduct ultrasound examination of the neck and retroperitoneal space.

Failure of pentagastrin-stimulated calcitonin testing in early manifestation of familial medullary thyroid cancer.

This case report describes three generations of a family with familial medullary thyroid cancer (RET gene mutation L790F). One of the three siblings-all of them carrier of the respective mutation-exhibited the absence of pathological basal and pentagastrin-stimulated calcitonin levels in spite of multifocal medullary thyroid microcancer. This case illustrates the challenge to consider the biological diversity of RET gene mutations in the clinical management of affected gene carriers.

Could primary hyperparathyroidism-related hypercalcemia induce hypercalcitoninemia?

AIMS: To determine if primary hyperparathyroidism (pHPT) per se may be responsible of hypercalcitoninemia. pHPT induces chronic hypercalcemia that should be expected to be a potential stimulatory pathway of calcitonin (CT) secretion and to cause hypercalcitoninemia. METHOD: We studied relationships between CT and pHPT-related chronic hypercalcemia in 122 patients aged 25-83 years who underwent parathyroid surgery. CT, calcium and PTH plasma levels were measured in all patients preoperatively. CT was measured by a current immunometric assay specific of mature CT monomer. RESULTS: Of our 122 patients with pHPT-related hypercalcemia, 120 (98.4%) had normal CT values of less than 10 pg/ml and two (1.6%) exhibited a mildly increased CT above 10 pg/ml (11 and 12 pg/ml, respectively). We evidenced no relationship between CT and calcium level or PTH level. CONCLUSIONS: Chronic pHPT-related hypercalcemia per se does not cause hypercalcitoninemia. The finding of pHPT concomitant with high CT levels should raise suspicion of multiple endocrine neoplasia type 2A.

Surgical management of MEN-1 and -2: state of the art.

Multiple endocrine neoplasia syndrome type 1 (MEN-1) consists of endocrine tumors of the parathyroid, the endocrine pancreas-duodenum, and the pituitary. Surveillance and screening for the endocrinopathies is recommended in gene carriers. Surgery for MEN-1-related hyperparathyroidism is generally performed as radical subtotal parathyroidectomy, because less surgery is likely to result in persistent or recurrent disease. Multiple endocrine neoplasia syndrome type 2 (MEN-2) consists of medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. Prophylactic thyroidectomy based on DNA testing in the MEN-2 syndrome is considered one of the greater achievements in cancer treatment, because it may be performed before thyroid carcinoma development and provides cure for the patient.

Long-term clinical and biochemical follow-up in medullary thyroid carcinoma: a single institution's experience over 20 years.

OBJECTIVE: Many patients with medullary thyroid carcinomas (MTC) have reoperative surgery in different hospitals, which makes their follow-up difficult. To comprehend these complex courses and to find relevant prognostic factors we report a 20-year single center experience of 289 patients with MTC or precursor C-cell-hyperplasias. PATIENTS AND METHODS: Between April 1986 and May 2006, 289 consecutive patients with MTC or MEN2 gene carriers were treated at the Department of Surgery at the University Hospital Düsseldorf. Tumor stages were documented according to the classification of the International Union against Cancer 5th edition, 1997 (Schott. Endocr Relat Cancer. 2006;13:779-795). A system to easily comprehend operative procedures is suggested. RESULTS: There were 159 female and 130 male patients (f/m ratio 1.22). Mean age at time of diagnosis was 32 years (4-77) in the familial cases and 53 years (23-84) years in the sporadic cases. Sixty-six patients (23%) had multifocal disease. Twelve MEN2-patients had only C-cell-hyperplasia (pT0). Tumor stage was pT1 in 86 patients, pT2 in 106 patients, pT3 in 25 patients, pT4 in 52 patients and unclear in 8 patients. In the 289 patients 648 operations were performed. One hundred seventy patients had more than 1 operation (59%). Ninety-nine patients (34%) are calcitonin-negative and 91 patients (31%) live with elevated calcitonin. Median follow-up time of the surviving 211 patients was 8.9 years (range, 0.3-30.7 years). The 5- and 10-year survival of all tumor patients was 86% and 68%, respectively. CONCLUSION: The chance to achieve biochemical cure in MTC is clearly dependent on the primary tumor size. The chance for long-term biochemical cure in a pT4-tumor is almost nil even after multiple and extended reoperations, whereas a pT1 tumor can be cured in up to 67% of the patients. Long-term survival, however, can be achieved even in pT4 tumor patients in almost 50%.