Screening For Medullary Thyroid Carcinoma Research Articles

SAT309 Clinical And Genetic Profiling Of Patients With Multiple Endocrine Neoplasia Type 2 Syndrome And Screening for Medullary Thyroid Carcinoma In Asymptomatic First-degree Relatives

Abstract Disclosure: K. Kumar P: None. Y. Gupta: None. A. Goyal: None. D. Kandasamy: None. N. Tandon: None. Background: Multiple endocrine neoplasia type 2 (MEN2) syndrome is a rare disorder with autosomal dominant inheritance, characterised by the presence of two of the following three endocrine manifestations: medullary thyroid carcinoma (MTC), pheochromocytoma (PCC) and primary hyperparathyroidism (PHPT) [1-2]. There is a paucity of data on clinical and genetic profile of MEN2 syndrome in the Indian subcontinent. Objectives: We aimed to evaluate the clinical and genetic profile of patients with MEN2 syndrome and perform screening for MTC among asymptomatic family members with serum calcitonin. Materials and Methods: This was an ambispective study conducted in the Department of Endocrinology at AIIMS New Delhi, involving diagnosed patients of MEN2 syndrome between January 2016 and December 2022. Results: We evaluated a total of 24 families with MEN2 syndrome comprising 61(MEN2A, n=56; MEN2B, n=5) patients, 18 patients were diagnosed as index cases. Data were derived retrospectively for 46 patients (MEN2A, n=43 MEN2B, n=3) and prospectively for 15 patients (MEN2A, n=13; MEN2B, n=2). The mean age at presentation of MEN2A and MEN2B were 28.6 ± 13.52 years and 22 ± 4.44 years, respectively. Of the study patients, 35 (57.38%) were females, among them 32 were MEN2A. Among 18 index patients 67% were synchronously detected to have MTC and PCC while 33% had MTC preceding PCC. Among patients with MEN2A syndrome 33 (59%) had MTC, 21(38%) had simultaneous PCC and MTC and one patient had PCC as presentation. We noted PHPT in 5 (9%) patients with MEN2A syndrome. Of the 5 patients with MEN2B syndrome, 4 (80%) presented with synchronous MTC and PCC and one (20%) presented with MTC aloneMetastatic MTC was noted in six patients with MEN2A syndrome and two patients with MEN2B syndrome. Median baseline Sr calcitonin level was 42 (4-1721) pg./ml in non-Metastatic group vs 3945(928-35572) pg./ml in distant metastasis group. 1 patient had metastasis from PCC to liver. Mutational analysis data are available for 40 patients. The most common mutations in MEN2A and MEN2B groups were C634R (exon 11 of RET gene, n=21) and M918T (exon 16 of RET gene, n=4), respectively.A total of 177 eligible family members of index patients with MEN2A syndrome were contacted, of whom 83 turned up for screening and 42 (50.6%) had elevated serum calcitonin levels (>10 pg./ml). Of the 26 eligible family members of index patients with MEN2B syndrome, only 9 could be screened and all had normal serum calcitonin levels (<10 pg./ml). Discussion & Conclusion: 1) This is the largest study comprising 61 patients after screening 24 family members in India. 2) Synchronous presentation of MEN2 with PCC and MTC is 67% vs 17% in western literature in Index patients. 3) MEN2 syndrome should be suspected in patients with MTC and young-onset PCC and all first-degree relatives of index patients with this syndrome. Presentation: Saturday, June 17, 2023

Update on Calcitonin Screening for Medullary Thyroid Carcinoma and the Results of a Retrospective Analysis of 12,984 Patients with Thyroid Nodules.

We provide an update on calcitonin (Ctn) screening for the early detection of medullary thyroid carcinoma (MTC) and present the results of a large single-center analysis evaluating sex-specific cut-off-levels and long-term courses. A total of 12,984 consecutive adult patients (20.1% male and 79.9% female) with thyroid nodules who had undergone routine Ctn measurement were retrospectively analyzed. Patients with confirmed suspicious Ctn values were referred for surgery. Ctn measurements were elevated in 207 (1.6%) patients, with values below twice the sex-specific reference limit in 82% of these cases. Further clarification was possible in 124/207 cases, of which MTC could be ruled out in 108 cases. Histopathological assessment confirmed MTC in 16/12,984 patients. Our extrapolated MTC prevalence of 0.14% is significantly lower than that described in early international screening studies. The stimulation test can usually be dispensable when using a decision-making concept based on sex-specific basal Ctn cut-off values. Ctn screening is recommended even in patients with very small thyroid nodules. High quality standards in pre-analytics, laboratory measurements, and the interpretation of data must be ensured, as well as close interdisciplinary cooperation between medical disciplines.

Abstract 192

Background: Multiple endocrine neoplasia type 2 (MEN2) syndrome is a rare disorder with autosomal dominant inheritance, characterised by the presence of two of the following three endocrine manifestations: medullary thyroid carcinoma (MTC), pheochromocytoma (PCC) and primary hyperparathyroidism (PHPT). There is a paucity of data on clinical and genetic profile of MEN2 syndrome in the Indian subcontinent. Objectives: We aimed to evaluate the clinical and genetic profile of index patients with MEN2 syndrome and perform screening for MTC among asymptomatic family members of such patients. Materials and Methods: This was an ambispective study conducted in the department of Endocrinology at AIIMS New Delhi, involving diagnosed patients of MEN2 syndrome between January 2016 and November 2022. MTC screening was performed with measurement of serum calcitonin levels (normal: <10 pg/ml) among family members of index patients. Results: We evaluated a total of 23 index patients with MEN2 syndrome (MEN2A, n=18; MEN2B, n=5). Data were derived retrospectively for 18 patients (MEN2A, n=14; MEN2B, n=4) and prospectively for 5 patients (MEN2A, n=4; MEN2B, n=1). Of the study patients, 16 (MEN2A, n=13; MEN2B, n=3) were females. The mean age at presentation in the two groups was 33 years and 22 years, respectively. Among patients with MEN2A syndrome, 11 (61%) presented with PCC and were synchronously detected to have MTC, while 7 (39%) presented with MTC, of whom 5 metachronously developed PCC. We noted PHPT in 3 (16%) patients with MEN2A syndrome. A total of 177 eligible family members of index patients with MEN2A syndrome were contacted, of whom 83 turned up for screening and 42 (50.6%) had elevated serum calcitonin levels (>10 pg/ml). Of the 5 patients with MEN2B syndrome, 4 (80%) presented with synchronous MTC and PCC and 1 (20%) presented with MTC alone. Of the 26 eligible family members of index patients with MEN2B syndrome, only 9 could be screened and all had normal serum calcitonin levels (<10 pg/ml). Metastatic MTC was noted in 3 (17%) patients with MEN2A syndrome and 3 (60%) patients with MEN2B syndrome Mutational analysis data are available for 7 index MEN2A and 4 MEN2B patients. The most common mutations in MEN2A and MEN2B groups were C634R (exon 11 of RET gene, n=5) and M918T (exon 16 of RET gene, n=4), respectively. Conclusions: MEN2 syndrome should be suspected in patients with MTC and young-onset PCC and all first-degree relatives of index patients with this syndrome should be screened appropriately.

Screening for Medullary Thyroid Carcinoma with Serum Calcitonin Measurements in Patients with Thyroid Nodules in the United States and Canada

Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy with the potential for aggressive behavior. Measurement of serum calcitonin (Ct) in the thyroid nodule population is the most sensitive way to detect occult MTC. An important and controversial question is whether all patients with thyroid nodules should undergo Ct measurements to detect occult MTC. The prevalence of MTC detected by performing surgery on unselected individuals with thyroid nodules with elevated serum Ct is 0.4%. The central role of pentagastrin (PG) stimulation for triaging patients with minimally elevated serum Ct to prevent unnecessary surgery is reviewed. Data concerning a large reservoir of medullary thyroid microcarcinomas are discussed. Given the unavailability of PG in the United States and Canada, the available data argue against routine Ct measurements in all individuals with thyroid nodules in these countries because of the potential for unnecessary surgery and the uncertain benefit in diagnosing medullary microcarcinoma.

Early Diagnosis of Medullary Thyroid Carcinoma: Is Systematic Calcitonin Screening Appropriate in Patients with Nodular Thyroid Disease?

Because of its poor prognosis and high mortality rate, early diagnosis of medullary thyroid carcinoma (MTC) is a challenge. For almost two decades, routine serum calcitonin (CT) measurement has been used as a tool for early MTC diagnosis, with conflicting results. In 2006, the European Thyroid Association (ETA) recommended serum CT measurement in the initial workup of thyroid nodules, whereas the American Thyroid Association (ATA) declined to recommend for or against this approach. In late 2009, the revised ATA guidelines were published, and in June 2010 the ETA released new guidelines for the diagnosis and management of thyroid nodules that had been drafted in collaboration with the American Association of Clinical Endocrinologists and with the Associazione Medici Endocrinologi, and the picture became even more complex. The ATA still takes no stand for or against screening but acknowledges that, if testing is done, a CT value >100 pg/ml should be considered suspicious and an indication for treatment. As for the ETA, it seems to have taken a step back from its 2006 position, and it now advocates CT screening only in the presence of clinical risk factors. These new positions are more cautious and less straightforward because prospective, randomized, large-scale, long-term trial data are lacking. Are such studies feasible? Can they solve the CT dilemma? In the absence of adequate evidence, selective aggressive case finding should be pursued to improve MTC prognosis.

Comparison of Calcitonin Determinations by Polyclonal and Monoclonal IRMAs

Serum calcitonin (CT) has important diagnostic and prognostic value in patients with medullary thyroid carcinoma (MTC). Although CT can be routinely quantified by a variety of 2-site immunoassays, different assays may yield very different results. This variability, particularly at low CT concentrations, led to the recommendation to use reliable and sensitive assays in the screening of MTC and C-cell hyperplasia (1). To highlight CT variability at high concentrations, we measured 43 serum samples by use of a polyclonal IRMA and by a monoclonal IRMA. The single-step polyclonal assay used 2 different goat antibodies (as the capture and labeled antibodies), which were specific for well-defined regions of the CT molecule, with no cross-reactivity with parathyroid hormone, thyroid-stimulating hormone, CT gene–related peptide, porcine CT, or salmon CT. The reagent set was used according to the manufacturer’s instructions (Calcitonin Assay, Scantibodies Laboratory, Inc.). The …

Treatment evaluation, follow-up and familial screening of medullary thyroid carcinoma by highly specific calcitonin measurements

Calcitonin is the most sensitive and specific marker for medullary thyroid carcinoma (MTC). The aim of this study was to emphasize the role and the limits of plasma basal calcitonin (bCT) measurement in the management of Moroccan MTC patients and their relatives. This is a retrospective study on 6 MTC patients referred to our institute from January 1996 to December 2004. Serum bCT levels were measured in 36 individuals comprising six known MTC cases, 18 relatives and 12 healthy volunteers, using two-sites immunoradiometric assay method. Five of MTC patients have been followed from 12 to 96 months after surgery. Calculations were performed using SPSS 10.0 program. Data comparison was done by Student's t -test. The circulating preoperative bCT concentrations were elevated for all MTC patients (range, 44,8 -2055 pg/ml, normal <10). Recent postoperative bCT determinations varied from 24.4 to 1972 pg/ml in four patients. In one patient, the bCT value decreased to an undetectable level during a follow-up of 12 months. The mean bCT level of relatives was 4.90 +/- 3.54 pg/ml; two patients had slightly elevated bCT. Five (42%) healthy volunteers had undetectable bCT levels and all had less than 10 pg/ml; the mean bCT value was 3.06 +/- 2.51 pg/ml. Routine plasma bCT measurement still has an important place in the preoperative diagnosis and follow-up treatment of MTC.

Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas

Background. This study evaluated the outcome of total thyroidectomy and modified radical neck dissection in primary treatment of patients with medullary thyroid carcinoma (MTC). Methods. Thirty-six patients with sporadic (n = 16) and hereditary (n = 20) MTC underwent thyroidectomy and systematic central and lateral lymph node dissection (unilateral, 23; bilateral, 13) between 1994 and 2000. Postoperative serum calcitonin levels were correlated with immediate or delayed surgery, tumor categories, and lymph node metastases. Results. Sixteen of 36 (44%) patients with clinically evident MTC treated with central and lateral neck dissection exhibited normal basal and stimulated calcitonin levels at a median follow-up of 3.7 years. Lymph node involvement was detected in 75% of these patients and correlated with the TNM stages. Biochemical cure was achieved according to the T categories in 83% of the patients in stage T1, 42% in stage T2, and none of the patients in stage T4 (P =.011). Basal and stimulated calcitonin levels were found to be normal in 89% of the patients without lymph node involvement and in 30% of the patients with lymph node metastases (P =.005). Conclusions. Screening for MTC and primary treatment with total thyroidectomy and modified radical neck dissection are essential for biochemical cure of MTC. (Surgery 2001;130:1044-9.)

Impact of chromogranin A measurement in the work-up of neuroendocrine tumors

Since the development of the first immunoassay for circulating chromogranin A in 1984, a lot of studies have evaluated its clinical impact in neuroendocrine tumors. Initially studied in pheochromocytoma patients, the clinical impact of chromogranin A has rapidly extended to most neuroendocrine tumours, sometimes in combination with other eutopic or ectopic secretions. In our experience, CgA demonstrates a variable sensitivity between NET primary and a high specificity. Our results suggest that CgA should be routinely screened in foregut-derived NET and abandoned in the routine screening of medullary thyroid carcinoma. In addition, in phaeochromocytoma and ileum-NET patients, CgA demonstrates a comparable sensitivity with urinary reference markers and its impact on the follow-up will form a key point when recommending routine screening. Both tumor burden and secretory activity should be taken into account when interpreting CgA results.

Genetic analysis of seven Mediterranean families with multiple endocrine neoplasia type 2A.

Genetic analysis is now essential for the accurate screening of families with multiple endocrine neoplasia type 2 (MEN2). We present the genetic analyses by both haplotype and direct RET proto-oncogene mutation analysis in seven Mediterranean MEN 2A families and have compared these results with biochemical screening tests and pathological examinations. Total DNA was extracted from leucocytes. Linkage analysis was performed using five RFLP systems from three loci that flank the MEN2A locus (FNRB, RBP3, D10S15). RET proto-oncogene analysis was carried out by automatic DNA sequencing and adequate digestion of PCR amplified products for exons 10 and 11. Screening for medullary thyroid carcinoma or C-cell hyperplasia was performed by the pentagastrin provocation test. Adrenal medullary function was assessed by measurements of 24-hour urinary excretion of catecholamines and their metabolites. Serum calcium and phosphate measurements were the initial screen for hyperparathyroidism. Serum PTH was determined only if hyperparathyroidism was suggested by the former determinations. Genetic study was performed in 59 individuals (39 at risk) from seven kindreds of Mediterranean origin with MEN 2A. Diagnosis by linkage analysis was not possible in 30% of individuals at risk, but RET proto-oncogene analysis identified all these individuals. Mutations of the RET proto-oncogene were detected in exon 10 (codon 618) in one MEN 2A kindred and in exon 11 (codon 634) in the others. The results of direct analysis were concordant with linkage studies in each case. Three individuals from different MEN 2A kindreds, who were subsequently shown not to be gene carriers, had false positive pentagastrin stimulation tests. Biochemical tests can be replaced by direct DNA mutation analysis as the first line screening test in order to identify gene carriers of MEN 2A.

Medullary thyroid carcinoma: recent advances and management update.

Medullary thyroid carcinoma (MTC) is a malignancy of the thyroid C-cells that comprises 5-10% of all thyroid cancers. MTC occurs in both sporadic and familial forms, the latter making up 25% of all MTCs and being comprised of three distinct syndromes--multiple endocrine neoplasia type 2A (MEN 2A), multiple endocrine neoplasia type 2B (MEN 2B), and familial medullary thyroid carcinoma (FMTC). To date, screening for MTC has been performed using the pentagastrin stimulation test, which is a provocative test for calcitonin release. Germline mutations in the RET protooncogene have been identified in families manifesting these syndromes and genetic screening of individuals at risk of one of these syndromes has become integral to their clinical management. The majority of the mutations associated with MEN 2A and FMTC are tightly clustered in a cysteine-rich region of the RET receptor. A single mutation associated with MEN 2B is in the the tyrosine kinase domain of the RET receptor. Somatic mutations have been identified in the tumor tissue of individuals with sporadic MTC and may prove to be helpful markers in discerning the hereditary or sporadic nature of the MTC. There is general agreement that the primary operation for MTC should include total thyroidectomy and central neck lymph node clearance. The role of microdissection for recurrent disease awaits longitudinal evaluation. External radiotherapy, radionuclide therapy, and chemotherapy may have a role in palliation, but have not been proven to have a curative value. Prognostic factors are discussed.

Presymptomatic screening for medullary thyroid carcinoma in patients with multiple endocrine neoplasia type 2A.

Presymptomatic screening of medullary thyroid carcinoma in MEN IIA families enables the early diagnosis of this tumor with its significant morbidity. Biochemical screening consists of basal and stimulated serum calcitonin evaluation. Genetic screening is based on DNA analysis using linked DNA markers. Thyroidectomy at an occult tumor stage may be curative. Calcitonin measurement was carried out in 58 apparently unaffected family members at risk and 11 MEN IIA patients. Calcitonin elevation was detected in nine individuals. All nine underwent thyroidectomy. Histologic examination confirmed medullary thyroid carcinoma in eight patients and in one case C cell hyperplasia. Postoperatively, eight patients (89%) are clinically and biochemically tumor-free (mean follow-up 30 months). DNA screening results in one affected family are presented. DNA analysis allowed recognition of one apparently unaffected individual at risk as a MEN IIA gene carrier. One family member at risk was found not to carry the gene and may be excluded from further screening.

Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up.

Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant condition in which virtually all affected kindred members have medullary thyroid carcinoma (MTC). However, the penetrance of pheochromocytoma and hyperparathyroidism in affected kindred members is variable, and the true prevalence of these neoplasms is unclear from previous studies. Members of MEN 2A kindreds with more than 10 years of follow-up screening for MTC, pheochromocytoma, or hyperparathyroidism were studied. The diagnosis of pheochromocytoma was based on histologic examination and hyperparathyroidism on both parathyroid hyperplasia plus preoperative elevation of serum calcium levels. Eighty-six patients operated on for MTC from 12 different MEN 2A kindreds were studied, with a mean follow-up of 12.9 years of screening for pheochromocytoma (79 patients) and 15.0 years for hyperparathyroidism (78 patients). Pheochromocytomas developed in 42% of patients with MTC, with a range of 6% to 100% in different kindreds. The prevalence of hyperparathyroidism was 35%, ranging from 0% to 53% between kindreds. The average age at diagnosis of MTC, pheochromocytoma, and hyperparathyroidism was 29, 37, and 36 years, respectively. We conclude that the penetrance of pheochromocytoma and hyperparathyroidism is variable in different kindreds with MEN 2A but that the overall prevalence of pheochromocytoma approximates 40% and that of hyperparathyroidism 35%.

Calcitonin and PDN-21 as tumour markers in MEN-2 family screening for medullary thyroid carcinoma.

Calcitonin is expressed in medullary thyroid carcinomas (MTC). It is processed from a large molecular weight precursor and is flanked at its C-terminal end by a 21 aminoacid peptide (PDN-21) formed in equimolar concentrations to calcitonin by enzymatic cleavage of the prohormone. This investigation compared basal measurements of calcitonin and PDN-21 and the response of the two peptides following pentagastrin stimulation in normal controls and in family members with C-cell hyperplasia or early neoplasia. The results showed that calcitonin and PDN-21 may both be used in family screening for the MEN-2 syndrome, but the unstimulated circulating concentrations of calcitonin were higher and more influenced by C-cell hypersecretion than PDN-21 (P less than 0.01), and the increase in stimulated concentrations of calcitonin were significantly higher than for PDN-21 (P less than 0.01). These findings may be explained by differences with respect to secretion and metabolic clearance rate for the two peptides.

A COMPARISON OF CALCIUM PENTAGASTRIN AND TRH TESTS IN SCREENING FOR MEDULLARY CARCINOMA OF THE THYROID IN MEN IIA

Intravenous injections of calcium gluconate and pentagastrin (CPG) or TRH were compared as secretagogues for calcitonin (CT) in screening for medullary thyroid carcinoma (MTC) in multiple endocrine neoplasia type IIA (MEN IIA). Administration of CPG resulted in a prompt increase in plasma CT in all five patients with MTC studied, one of whom had a normal baseline value (peak 412-371,000 ng/l, 636-4847% above basal). TRH produced a rise in plasma CT levels only in MTC patients with elevated basal values; the magnitude of increase was less than that observed with CPG (peak 168-17,200 ng/l, 113-180% above basal). CT levels did not rise above 300 ng/l with either test in four unaffected first-degree relatives of MEN IIA patients, three subjects with sporadic unilateral phaeochromocytomas and five controls with essential hypertension. CPG remains the CT secretagogue of choice in screening for MTC in MEN II A.

Medullary thyroid carcinoma. The need for early diagnosis and total thyroidectomy.

Forty patients with medullary thyroid carcinoma and 3 patients with C-cell hyperplasia were studied. Seventeen (40%) cases were sporadic and 26 (60%) were hereditary. Eight patients had type lla multiple endocrine neoplasia, 7 patients had type llb multiple endocrine neoplasia, and 11 patients had familial nonmultiple endocrine neoplasia medullary thyroid carcinoma. Mean follow-up was 6.3 years, with actuarial survival of 88% and 78% at 5 and 10 years (22 and 13 patients), respectively. Seven patients died 1.5 to 10 years after the initial operation; all had advanced disease at presentation (6 with distant, 1 with lymph node metastasis). No deaths occurred in patients with familial nonmultiple endocrine neoplasia medullary thyroid carcinoma, C-cell hyperplasia, or medullary thyroid carcinoma limited to the thyroid gland. Nineteen (68%) of 28 patients diagnosed without screening had regional or distant metastases, whereas only 6 (40%) of 15 patients diagnosed by screening had metastases. Twenty-six patients treated initially with total thyroidectomy and central neck clearance required an average of one reoperation, whereas those with lesser initial procedures required an average of two reoperations. We concluded that (1) familial nonmultiple endocrine neoplasia medullary thyroid carcinoma, early medullary thyroid carcinoma or C-cell hyperplasia, and asymptomatic patients have a good prognosis; (2) screening for medullary thyroid carcinoma by measuring serum calcitonin levels results in earlier diagnosis; and (3) total thyroidectomy and central neck clearance is the procedure of choice for medullary thyroid carcinoma.

Evidence of multicentric origin of the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome) in a large family in the Netherlands: Diagnostic and therapeutic implications

The occurrence of simultaneous tumors in different organs and the multicentric localization of the tumors in each of these organs are discussed on the basis of the findings in six patients belonging to a large kindred with Sipple's syndrome and in patients with Sipple's syndrome not belonging to this kindred, as well as the data in the literature. The high number of accessory pheochromocytomas in this family and in the other patients with Sipple's syndrome was striking. Both the pheochromocytomas and the accessories were found in the form of both cortical nodules and complete adrenal glands with hyperplastic medullary tissue. The invariable occurrence of pheochromocytoma changes in accessory adrenal tissue in this family and in other cases supports and demonstrates the multicentricity of tumor development in Sipple's syndrome. The aim of surgical treatment should be to remove all the pheochromocytoma tissue identified in the adrenal glands, the celiac plexus and side chain regions, thereby reducing the chance of recurrence of the symptoms in these patients and the need for repeated surgical intervention. However, more extensive exploration of the chest, cervical area, etc., to attempt curative surgery, is too destructive to be justifiable. The medullary thyroid carcinoma, which is also multicentric in origin, is, on the contrary, a dangerous tumor for which total thyroidectomy with extensive neck exploration is obligatory, preferably in an early phase. A modified short calcium test which is especially sensitive in this early phase, is described for screening for medullary thyroid carcinoma.