Mutations In RET Proto-oncogene Research Articles

Misrepresented multiple endocrine neoplasia 2: Do the British Thyroid Association guidelines accurately predict thyroid cancer risk in high-risk groups with multiple endocrine neoplasia 2? A case series

Introduction: The incidence of thyroid nodules in the general population is around 40%. The British Thyroid Association U-grading has high sensitivity for identifying the common thyroid cancer subtypes (papillary and follicular). However, ultrasound features of the rarer medullary thyroid cancer differ, with lower sensitivity for ultrasound detection. Hereditary medullary thyroid cancer accounts for 25% of cases, forming part of the multiple endocrine neoplasia syndromes (multiple endocrine neoplasia 2) and is associated with RET proto-oncogene mutation, for which gene testing is increasingly available. This study aims to evaluate British Thyroid Association U-grading for thyroid cancer risk stratification in this high-risk population. Case report: This was a retrospective review of four multiple endocrine neoplasia 2 patients referred for thyroid ultrasound. A total of 10 thyroid nodules were graded as part of routine evaluation, taken from an endocrine and genetics tertiary referral centre. Patients with identifiable RET mutation from March 2017 to February 2023 were reviewed. Discussion: Six patients had 10 thyroid nodules, of which 8 were graded as U2, 2 graded U3–5 and 8 confirmed as medullary thyroid cancer. However, two patients had no pathology data at the time of writing. For this cohort, U-grading and genetics were discordant, with RET gene testing more effective than ultrasound in cancer detection. All nodules should be considered high risk for medullary thyroid cancer, regardless of U-grade. Conclusion: Our data demonstrate that British Thyroid Association U-score has limited value for medullary thyroid cancer detection in this high-risk group and cannot be used for risk stratification or surveillance. As a rarer thyroid cancer subtype, medullary thyroid cancer and the high-risk multiple endocrine neoplasia 2 population are under-represented in British Thyroid Association 2014 guidance and deserve consideration in future editions.

SAT540 A Case of Simultaneous Medullary Thyroid Cancer (MTC) And Papillary Thyroid Cancer (PTC) In a Patient With Germline RET Mutation

Abstract Disclosure: N. Vaghasia: None. G. Jaiswal: None. Introduction: There are only handful of cases reported of concurrent MTC and PTC in a patient with germline RET proto-oncogene mutation. Case: A 41 year old female with no PMH presented to Endocrine clinic for evaluation of recently diagnosed RET mutation. Patient’s nephew passed away at 5 weeks of age from abnormal organogenesis of heart and brain. Genetic testing showed germline RET mutation. Subsequently her brother and his two children was tested positive for RET mutation. Patient underwent genetic testing which was positive for RET mutation. Patient was found to be heterozygous for p.V804M (c.2410G>A) mutation reported as moderate risk mutation in the RET gene. The result was consistent with an increased risk for RET-related cancers. No family history of MTC, pheochromocytoma or primary hyperparathyroidism was identified. Patient was asymptomatic on presentation and no previous symptoms concerning for any RET mutation related disease. Her physical examination was normal. Patient underwent testing for pheochromocytoma and hyperparathyroidism which was unremarkable. Patient’s calcitonin level was also normal. Patient had US thyroid done to evaluate for nodule and was found to have 1.62 x 0.97 x 1.50 cm mixed solid cystic, hypoechoic, irregular margins and punctate echogenic foci right sided nodule. No abnormal cervical lymph nodes. Patient underwent FNA of the suspicious nodule which was reported as benign based on Bethesda classification. Patient’s calcitonin level was undetectable <0.2 pg/ml (0.0-5.0). Patient underwent total thyroidectomy and on surgical pathology had three papillary microcarcinomas, classic type, 0.4 cm (right lobe), 0.3 cm (left lobe) and 0.1 cm (right lobe). Patient had medullary microcarcinoma 0.2 cm on left lobe. Background thyroid with C-cell hyperplasia. No lymphovascular invasion, no extrathyroidal extension and margins cleared. Discussion: Association of simultaneous MTC-PTC have been reported in few case reports in patient with germline RET mutation. There has been no risk factors or specific patient phenotype identified in previous cases to suggest any association between the two. One important feature in our case is the presence of highly suspicious thyroid nodule which on FNA was benign. This raise an important question on whether the co-existence of MTC and PTC in germline RET mutation decreases sensitivity of FNA. Also it is yet unknown if specific mutation like in our case p.V804M (c.2410G>A) is associated with higher incidence of multi-tumor pathology or not. Finally, our patient had normal calcitonin level despite having MTC which is unusual. Conclusion: Coexistence of MTC and PTC in germline RET mutation is an uncommon association and more information is required to understand common features, risk factors, phenotype and cancer aggressiveness in these patients. At this point it cannot be concluded that the association is a mere coincidence. Presentation Date: Saturday, June 17, 2023

Multiple Endocrine Neoplasia 2a: Case Report and Review of Literature

Multiple endocrine neoplasia is a hereditary, autosomal dominant disease. It is created predominantly by RET germline mutations and is considered rare, with a frequency of 1 in 30,000 people. In particular, medullary thyroid cancer associated to this pathology presents at a younger age in relation to sporadic cases. Pheochromocytoma is linked to metastatic disease in only 4% of cases and it is a disease which requires high clinical suspicion. The age of presentation when related to multiple endocrine neoplasia is lower than that of the general population, 38 and 47 years of age respectively. RET proto-oncogene mutation on Codon 634 in exon 11 is the most frequent genetic alteration, present in 85% of cases of MEN2A. Its penetrance for pheochromocytoma is 25% at 30 years and 88% at 77. The objective of this article is to present a case of a patient with MEN2A with bilateral pheochromocytoma and medullary thyroid cancer, discovered in a hypertensive man as an incidental finding.

PSAT013 Elevated Plasma Free Metanephrines with No Evidence of Pheochromocytoma in a Patient with Multiple Endocrine Neoplasia Type 2A

Abstract Background Adrenal medullary hyperplasia (AMH) is arbitrarily defined by adrenal medullary proliferation measuring less than 1 cm while larger lesions are considered pheochromocytoma. Some patients with MEN2 present with adrenal medullary hyperplasia (AMH), which is a precursor of pheochromocytomas. Clinical Case A 22-year-old female with a past medical history of MEN2A. She is positive for germline mutation in RET proto-oncogene at 10q11.2 exon 11, position 634 from cysteine to arginine. She was evaluated for a 1cm left thyroid nodule, which required total thyroidectomy for Medullary Thyroid Cancer. Pathology revealed a 0.5cm deposit on the largest dimension, clear margins, and no angiovascular, or lymphovascular invasion, surgery was complicated by hypoparathyroidism. She complained of intermittent anxiety and fatigue but was otherwise asymptomatic. Physical examination is unremarkable except for thyroidectomy scar and multiple exostoses. On 8/5/2011 plasma-free metanephrines were elevated at 83 pg/ml (<57pg/ml) and Free normetanephrine was 45 pg/ml (<145pg/ml). Over the next years, her plasma-free metanephrine levels have been checked approximately every 6 months ranging between 63-106pg/ml with free plasma normetanephrine in normal ranges (30-81pg/ml). However, on 2/2021, her plasma normetanephrine level increased to 304pg/ml. More recently, on 11/30/2021 her free normetanephrine levels reached 671pg/ml and free Metanephrine 131pg/ml. She had two MRIs of the abdomen and pelvis over the years and both showed unremarkable adrenal glands. NM I-123 MIBG scintigraphy reported physiologic symmetric activity in the adrenal glands. Finally, she had GA-68 DOTATATE PET/CT with no suspicious radiotracer avid lesion in the abdominopelvic organs. Given the persistent elevation on plasma metanephrines, we decided to start the patient on Doxazosin prophylactically while we continue biochemical and imaging surveillance. Conclusion Our patient has a persistent elevation in plasma-free metanephrines with no evidence of pheochromocytoma in abdominal imaging. The earliest abnormality in the adrenal medulla in patients with MEN 2 is diffuse hyperplasia with a reduction in the cortical/medullary ratio (1). This hyperplasia is considered to be a precursor of pheochromocytoma in patients with MEN 2 and in our case the most likely explanation for the progressive elevation in plasma-free metanephrines (1). There is a strong molecular relationship between AMH and Pheochromocytoma (2), close monitoring for progression to pheochromocytoma is necessary for all patients with AMH. The presence of markedly elevated plasma metanephrines in an asymptomatic patient with no evidence of pheochromocytoma poses a therapeutic dilemma for preemptive use of alpha blockade and the potential need for a medical alert bracelet. References (1) Cho, K et al "Adrenal Medullary disease in Multiple Endocrine Neoplasia II". AJR 134: 23-29. (2) Korpershoek, E et al "Adrenal Medullary Hyperplasia Is a Precursor Lesion for Pheochromocytoma in MEN2 Syndrome". Neoplasia. 2014 Oct; 16(10): 868–873 Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

The trends in early precision diagnosis and treatment strategies of multiple endocrine neoplasia type 2

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant hereditary neuroendocrine cancer syndrome characterized by medullary thyroid carcinoma, in combination or not with pheochromocytoma, hyperparathyroidism and extra-endocrine features, and two forms subtyped as MEN2A and MEN2B. Based on the correlation between RET proto-oncogene mutation and MEN2 phenotype, MEN2 could be prevented through prenatal diagnosis and preimplantation genetic testing. Integrating the detection of RET mutation with measurement of serum calcitonin, plasma or urinary metanephrine/normetanephrine, and serum parathyroid hormone levels could accurately predict the progression of MEN2, and then facilitating implementation of personalized precision treatment. In addition, increased awareness of MEN2 is needed, which requires participation of physicians, patients/family members, and relevant organizations, supplemented by psychological support, which could promote the comprehensive management of MEN2. The "5P" strategies for MEN2 represents a paradigm of precision medicine, which could effectively avoid or reduce the clinical adverse outcomes, improve the prognosis and quality of life of MEN2 patients.

CRISPR/Cas9 RET Gene Knockout in Medullary Thyroid Carcinoma Cell-lines: Optimization and Validation.

Medullary Thyroid Cancer (MTC) is a very aggressive type of thyroid carcinoma. Mutation in RET proto-oncogene is demonstrated in MTC development. We aimed to knock-out of RET-oncogene using CRISPR/Cas9 genome editing method in MTC cell-lines. This research was conducted in Shahid Beheshti University of Medical Sciences, Tehran, Iran during 2019-2020. Four different sgRNAs were designed to target exons one, two, and four of RET-oncogene in TT and MZ-CRC-1 cell-lines using bioinformatics tools, then the CRISPR/Cas9 constructs was made. About 72-hours after cell transfection, T7EI method and DNA sequencing were used to confirm the knock-out of RET-oncogene. Expression of RET, Calcitonin genes and RET protein were evaluated by Real-time PCR and ELISA, respectively. The results of T7E1, and DNA sequencing of transfected cells confirmed RET gene knock-out by CRISPR/Cas9. There was a significant decrease in RET gene expression and RET protein in transfected TT and MZ cells compared to controls. The rate of cell apoptosis in transfected cells was significantly increased. Calcitonin gene expression was also significantly reduced in transfected cells. p-RET, p-PI3K, p-AKT, p-MEK, p-ERK protein levels were significantly reduced in TT and MZ transfected cells. For the first time, knock-out of RET gene was performed and confirmed using CRISPR/Cas9. Inhibition of this gene leads to inhibition of the tyrosine kinase RET signal transduction pathway. Therefore, it can be one of the most effective and specific therapeutic goals in the field of Personalized Medicine in the treatment of diseases caused by over activity of RET molecular pathway.

Sclerosing Paragangliomas: Correlations of Histological Features with Patients' Genotype and Vesicular Monoamine Transporter Expression.

Paragangliomas and pheochromocytomas are rare neuroendocrine tumors, carrying a germ-line mutation in 40% patients. Sclerosis is a rare histological feature in these tumors. We investigated the possible correlations between histological findings, first sclerosis, immunoreactivity for vesicular catecholamine transporters (VMAT1/VMAT2) and patients' genotype in a consecutive series of 57 tumors (30 paragangliomas and 27 pheochromocytomas) from 55 patients. The M-GAPP grading system, sclerosis (0-3 scale) and VMAT1/VMAT2 (0-6 scale) immunoreactivity scores were assessed. Germ-line mutations of Succinate Dehydrogenase genes, RET proto-oncogene and Von Hippel Lindau tumor suppressor gene were searched. A germ-line mutation was found in 25/55 (45.5%) patients, mainly with paraganglioma (N = 14/30, 46,66%). Significant (score ≥ 2) tumor sclerosis was found in 9 (16.1%) tumors, i.e., 7 paragangliomas and 2 pheochromocytomas, most of them (8/9) from patients with a germ-line mutation. M-GAPP score was higher in the mutation status (in 76% of patients involving the SDHx genes, in 12% the RET gene and in the remaining 12% the VHL gene) and in tumors with sclerosis (p < 0.05). Spearman's rank correlation showed a strong correlation of germ-line mutations with M-GAPP (p < 0.0001) and sclerosis (p = 0.0027) scores; a significant correlation was also found between sclerosis and M-GAPP scores (p = 0.029). VMAT1 expression was higher in paragangliomas than in pheochromocytomas (p = 0.0006), the highest scores being more frequent in mutation-bearing patients' tumors (p < 0.01). VMAT2 was highly expressed in all but two negative tumors.Sclerosis and VMAT1 expression were higher in paragangliomas than in pheochromocytomas; tumor sclerosis, M-GAPP and VMAT1 scores were associated to germ-line mutations. Sclerosis might represent a histological marker of tumor susceptibility, prompting to genetic investigations in paragangliomas.

Never Forget the Family History: MEN2A Syndrome Presenting as Metastatic Medullary Thyroid Cancer and Bilateral Pheochromocytoma

Abstract Introduction: MEN 2A is an autosomal dominant hereditary syndrome considered part of the medullary thyroid carcinoma (MTC) syndromes. This is characterized by MTC, pheochromocytoma, and parathyroid hyperplasia or adenomas causing primary hyperparathyroidism (PHPT). Clinical Case: A 34 year old female was referred to our clinic for multi-nodular goiter diagnosed during routine gynecologic evaluation. A thyroid ultrasound revealed a heterogeneous right thyroid lobe with a hypoechoic 2.5 cm nodule, associated macro calcifications and increased vascularity; and a left nodule measuring 2.3 cm with the same characteristics. Bilateral thyroid nodule biopsies were performed, resulting in MTC confirmed by positive calcitonin staining. Pre-operative studies revealed serum calcitonin and carcinoembryonic antigen (CEA), both of which are considered serologic markers of MTC activity, at 4,340 pg/ml (n &amp;lt;= 5) and 276.2 ng/mL (n &amp;lt;= 2.5 in non-smokers) respectively. The patient reported father with history of unspecified thyroid cancer, and paternal uncle with history of pheochromocytoma with a p.Cys634Trp mutation in RET proto-oncogene. Due to her family history, pre-operative screening for primary hyperparathyroidism (PHPT) resulted in a calcium 10 mg/dL (n 8.6-10.2), PTH 34 pg/mL (n 14-64). Additionally, screening for pheocromocytoma revealed an elevated 24 hour urine metanephrines of 2,276 (n &amp;lt;= 49-290) ug/24h, plasma metanephrines, including fractionated metanephrine (MN) at 163 (n &amp;lt;= 57) pg/ml, fractionated nor-metanephrine (NMN) at 182 (n &amp;lt;= 148) pg/ml, and total, Free (MN+NMN) metanephrines at 345 (n &amp;lt;= 205) pg/ml. CT abdomen revealed bilateral adrenal nodules, right measuring 1.4 x 3.3 cm and left 2.4 x 3.3 cm. The patient underwent posterior retroperitoneoscopic adrenalectomy with cortex sparing prior to thyroidectomy. Adrenal pathology resulted in bilateral pheochromocytoma with peri-adrenal adipose tissue microscopic involvement, and positive synaptophysin and S-100 stain. Subsequently, she underwent total thyroidectomy with extensive cervical lymph node resection, with pathology resulting in MTC with lymph node metastasis, involving 5/18 cervical lymph nodes. Post-operative labs revealed serum calcitonin &amp;lt;= 2 pg/ml, CEA 26.8 ng/mL, MN &amp;lt; 25 pg/ml, NMN 102 pg/ml, and MN+NMN of 102 pg/ml, which suggested initial surgical success. Post-operative genetic test evaluation revealed abnormal RET oncogene testing compatible with MEN 2A, variant 1: c.1902C&amp;gt;G (p.Cys634Trp). Conclusion: This case illustrates that patients presenting with MTC and reporting family history of thyroid cancer should be screened for familial MTC syndrome. Patients with RET mutation should be screened for pheochromocytoma prior to surgery for MTC to prevent life-threatening hypertensive crisis.

Occurrence of sporadic medullary thyroid carcinoma in Graves’ disease in association with a RET proto-oncogene mutation

ABSTRACT Background Graves’ disease may be associated with thyroid cancer, particularly differentiated thyroid cancer. Medullary thyroid cancer (MTC) is less common. The occurrence of sporadic MTC in Graves’ disease in the presence of a RET proto-oncogene has never been reported. Clinical presentation A 63-year-old woman was referred for Graves’ disease. A thyroid ultrasound disclosed five nodules, one of which was classified as Eu-Tirads 5 with a size of 6.7 × 6.5× 11 mm. Fine needle aspiration was reported as Bethesda class IV follicular neoplasm of a Hürthle cell subtype. Calcitonin level was found to be elevated. A total thyroidectomy confirmed the diagnosis of MTC and a bilateral cervical lymphadenectomy was performed, with four lymph nodes being infiltrated by MTC. Genetic testing revealed a M918T mutation in the RET proto-oncogene. Conclusion MTC may occur in Graves’ disease, especially if a nodule is present. In this case, genetic testing should always be performed even if MTC is sporadic. Increased incidence of thyroid cancer in autoimmune thyroid diseases, as well as the link existing between autoimmunity, inflammation and carcinogenesis, leads us to hypothesize that the association here reported is not coincidental.

Generation and characterization of iPSC lines (BCH001) from a boy with intron 14 mutation in the ret proto-oncogene (RET) gene

Congenital central hypoventilation syndrome (CCHS) is characterized by an alteration of the ventilatory response to hypercapnia and hypoxia, and is classically presented in neonates with abnormalities of the autonomic nervous system. Here, we generated human induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) isolated from a male patient clinically diagnosed with CCHS. These iPSC lines carry a heterozygous RET mutation (c.2608-125C > T), express pluripotency markers, have the capacity to differentiate into the normal teratoma tissue, retain the RET mutation and display the normal karyotype, which will also provide a useful resource to study the pathogenesis of CCHS.

Profiling Oncogenic Germline Mutations in Unselected Chinese Lung Cancer Patients.

IntroductionEmerging evidence has suggested that inherited factors are also involved in lung cancer development. However, most studies focused on well-elucidated cancer predisposition genes, the majority of which are tumor suppressor genes. The profile of germline mutations in oncogenic driver genes remains unrevealed, which might also provide potential clinical implications for lung cancer management.MethodsSequencing data from 36,813 unselected lung cancer patients who underwent somatic mutation profiling were retrospectively reviewed. All recruited patients had matched white blood cell samples sequenced in parallel using a capture-based panel including eight key lung cancer driver genes (epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), MET proto-oncogene, receptor tyrosine kinase (MET), Kirsten rat sarcoma viral oncogene homolog (KRAS), Erb-B2 receptor tyrosine kinase 2(ERBB2), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), ret proto-oncogene (RET), and B-Raf proto-oncogene, serine/threonine kinase (BRAF)). Likely pathogenic/pathogenic (LP/P) variants were called according to the classification criteria of the American College of Medical Genetics and Genomics. Variants of uncertain significance (VUS) located in the kinase domains of driver genes and occurring recurrently (n ≥3) were also included for further analyses.ResultsSeven different LP/P variants in EGFR, MET, or RET were identified in 0.03% of lung cancer patients (n = 14) and 25 different VUS in the kinase domains of seven driver genes (except KRAS) were found with a prevalence of 0.3% (n = 117).Collectively, germline mutations were most frequently seen in ROS1 (n = 31, 0.084%), followed by MET (n = 23, 0.062%), EGFR (n = 22, 0.06%), ALK (n = 22, 0.06%) and RET (n = 17, 0.046%). LP/P variants and VUS fell the most commonly in EGFR (n = 10, 72%) and ROS1 (n = 31, 26%), respectively. Of the 10 patients with EGFR LP/P germline mutation, 70% also acquired somatic EGFR driver mutation exon21 p.L858R or exon19 deletion at baseline; while the three patients with pathogenic germline RET mutation displayed distinct baseline somatic profiles of rare EGFR mutation or KRAS exon2 p.G12C. We discovered 11 germline mutations that also occurred somatically, including four LP/P variants and seven VUS.ConclusionWe present the first study to systemically characterize the germline mutation in oncogenic driver genes in a large cohort of unselected patients with lung cancers.

Significance of chromogranin A and synaptophysin in medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a rare thyroid carcinoma of C-cell deviation that produces and secretes calcitonin (CT) and chromogranin A (CgA) into the blood. Thus, CT and CgA are immunohistochemical and serum markers for MTCs. MTC occurs in sporadic and inheritable forms. The hallmark of inheritable cases in multiple endocrine neoplasm 2 (MEN2) is MTC. MEN2 cases represent 30% through germline RET proto-oncogene mutation and occur in younger ages involving bilateral thyroid lobes. Sporadic cases are 70% and occur in older ages. CgA and synaptophysin (SPY) are the two most widely used and reliable immunohistochemical markers for neuroendocrine tumors, including MTCs. This study aimed to detect different immunohistochemical staining patterns for CgA and SPY between non-symptomatic small lesions and invading larger aggressive tumors in both MEA2 cases and sporadic cases. There was different CgA and SPY immunostaining in MEA2 cases where small tumors (≤0.3 cm) were lesser immunostained for CgA and SPY, despite intense staining for CT, compared to the larger (≥0.5 cm) tumors, stronger immunostained for CgA. There was also different CgA and SPY immunohistochemical staining in sporadic cases between small lesions (≤0.5 cm) and larger tumors (≥1.0 cm). One small sporadic tumor (0.5 cm × 0.3 cm) was strongly and weakly, patchy stained for CgA and SPY, respectively, while larger sporadic tumors were diffusely and strongly stained for CgA and SPY. Therefore, stronger CgA and SPY immunostaining for larger tumors in both MEA2 and sporadic cases may be used as independent, aggressive immunohistochemical markers for MTCs.

The clinical significance of RET gene fusion among Chinese patients with lung cancer.

BackgroundThe incidence of lung cancer is growing fast in China, however, the prognosis remains dismal due to the limited therapeutic approaches. The “ret proto-oncogene mutation” (RET) fusions have been proven to be the driver gene in lung cancer development and the therapeutic target of several multi-target tyrosine kinase inhibitors.MethodsWe applied formalin-fixed, paraffin-embedded (FFPE) samples of 39 patients with non-small cell lung cancer (NSCLC) using the Lung Plasma panel covering 168 cancer-associated genes and performed capture-based targeted deep sequencing to identify the RET fusion partners and concurrent gene mutation with Miseq. The log-rank test was used to compare the survival difference of patients according to treatment strategies. Statistical analyses and graphs were performed using R language and GraphPad Prism.ResultsMost of the samples were advanced (stage IIIb and IV) lung adenocarcinomas (80.77%). KIF5B-RET fusions were identified in 52% of the samples and K15-E12 was the most common variant. 6 (15%) samples harbored concurrent TP53 mutation and 3 samples were positive with EGFR mutation including a mutation in exon 19. Of these patients included, ten received cabozantinib, two received anlotinib, and one received crizotinib. Two (20%; 0–45) samples achieved stable disease and two were progressed in the cabozantinib treated group. Median progression-free survival (PFS) was 4 months (95% CI: 3.2–4.8) and median overall survival (OS) was 25 months (95% CI: 1.5–48.5). Three (11.54%; 0–24) samples achieved partial response in patients without RET inhibitor treatment and 4 (15.38%; 2–29) were stable disease. The median PFS was 11 months (95% CI: 1.2–20.8). There was no significant difference in PFS and OS between groups with or without RET inhibitors treatment.ConclusionThis study provided insight into the RET fusions patients treatment. The survival benefit of current RET inhibitors was limited. More precise and potent RET inhibitors should be developed in the near future.

RET gene mutation analysis and long-term clinical outcomes of medullary thyroid cancer patients.

Medullary thyroid carcinoma is a rare, potentially aggressive tumour, with relatively worse prognosis than well-differentiated thyroid cancer. We evaluated the long-term outcomes and prognosis of medullary thyroid carcinoma patients at a single institution in India and compared outcomes based on results of RET protooncogene mutation analysis. Data were retrieved through a prospectively maintained thyroid cancer database from 1998 to June 2019, and medullary thyroid carcinoma patients were recruited. RET gene mutation status (exon 10-16) was assessed. Patient with a minimum follow-up of 12 months was eligible to be part of the long-term outcome analysis. Out of 149 peripheral blood samples, 42 were positive for RET gene mutation (prevalence of 28.1%). The median follow-up duration was 48 months, ranging from 12 to 240 months. Long-term clinical outcomes of 113 patients were assessed. Two deaths were noted in this series. Both 5- and 10-year survival was cent per cent. Overall survival was 98.2% (97.3% in RET positive and 98.7% in RET negative group). Progression-free survival was 55.4% in total (60% in RET positive and 53.3% in RET negative group). No statistically significant difference was found between RET positive and RET negative groups concerning overall survival (P = 0.6011) and progression-free survival (P = 0.5140). Univariate analysis revealed high calcitonin (>10 pg/mL), stage IV disease, and presence of lymph nodal metastasis to be significant predictors of disease recurrence, however, multivariate analysis demonstrated the presence of lymph node metastases as the only significant predictor of recurrence (P = 0.0005). Medullary thyroid carcinoma patients had relatively favourable long-term outcomes. Long-term survival was similar irrespective of RET mutation status. Presence of lymph node metastases appeared to be the strongest predictor of overall and progression-free survival, followed by Calcitonin level and stage of the disease.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: Early thyroidectomy in multiple endocrine neoplasia: a four decade experience.

Forty years ago, physicians caring for the J-kindred, a 100+ member family with multiple endocrine neoplasia type 2A (MEN2A), hypothesized that early thyroidectomy based on measurement of the biomarker calcitonin could cure patients at risk for development of medullary thyroid carcinoma (MTC). We re-evaluated 22 family members with proven RET proto-oncogene mutations (C634G) who underwent thyroidectomy and central lymphadenectomy between 1972 and 1994 based on stimulated calcitonin abnormalities. Current disease status was evaluated by serum calcitonin measurement and neck ultrasound in 18 of the 22 prospectively screened patients. The median age of the cohort at thyroidectomy was 16.5 years (range 9-24). The median duration of follow-up at the time of examination was 40 years (range 21-43) with a median current age of 52 years (range 34-65). Fifteen of the 18 patients had no detectable serum calcitonin (<2 pg/mL). Three had detectable serum calcitonin measurements, inappropriately elevated following total thyroidectomy. None of the 16 patients imaged had an abnormal ultrasound. Survival analysis shows no MTC-related deaths in the prospectively screened patients, whereas there were many in prior generations. Early thyroidectomy based on biomarker testing has rendered 15 of 18 MEN2A patients (83%) calcitonin-free with a median follow-up period of 40 years. There have been no deaths in the prospectively screened and thyroidectomized group. We conclude that early thyroidectomy and central lymph node dissection is an effective prophylactic treatment for hereditary MTC.

A New MEN2 Syndrome with Clinical Features of Both MEN2A and MEN2B Associated with a New RET Germline Deletion

Background Multiple endocrine neoplasia type 2 (MEN2) is a hereditary cancer syndrome caused by RET proto-oncogene mutation. Two different clinical variants of MEN2 are known (MEN2A and MEN2B): medullary thyroid carcinoma (MTC) almost always present and associated with pheochromocytoma (Pheo), and primary hyperparathyroidism (HPTH) in MEN2A and with Pheo and other nonendocrine diseases in MEN2B. Case Report. A 7-year-old girl, previously treated for a pelvic plexiform neurofibroma, arrived at our observation with a peculiar MEN2B syndrome and with HPTH. The neck ultrasound showed bilateral thyroid nodules, local lymph node lesions, and a suspicious left hyperplastic parathyroid. The CT scan showed a megacolon and described the persistence of the pelvic tumor. A new RET germline deletion in exon 11 (c.1892_1899delCGAGCT; p.Glu632_Leu633del) was found. She underwent total thyroidectomy, central compartment and latero-cervical lymph node dissection, and neck exploration for primary HPTH. The histology confirmed bilateral MTC, multiple lymph node metastases, a hyperplastic parathyroid, and a parathyroid adenoma. Conclusions This is the first case of a complex syndrome characterized by peculiar features of MEN2B, without Pheo but with a pelvic plexiform neurofibroma and with HPTH, which is typical of MEN2A. A “de novo” new germline RET deletion located in exon 11 was found.

Medullary Thyroid Cancer - Feature Review and Update on Systemic Treatment.

SUMMARYMedullary thyroid carcinoma (MTC) is a rare malignancy that originates from parafollicular (C cells) of the thyroid and accounts for 2-4% of all thyroid malignancies. MTC may be sporadic or inherited, the latter as part of the MEN 2 syndromes. Germline mutations in the RET proto-oncogene (REarranged during Transfection) are driver mutations in hereditary MTC, whereas somatic RET mutations and, less frequently, RAS mutations, have been described in tumor tissues of sporadic MTC. Genetic screening for germline mutations in RET proto-oncogene identifies gene carriers of germline mutations. That enables primary prevention (the avoidance of disease onset by total prophylactic thyroidectomy), or at least secondary prevention (early detection) of the disease. Radical surgery with complete tumor resection is still pivotal in attaining cure for MTC. Despite recent advances, the treatment of advanced, metastatic, and progressive MTC remains challenging. Metastatic MTC can have an indolent clinical course; therefore, it is necessary to assess which patient to cure and when to initiate the treatment. Multidisciplinary boards of various specialists involved in the diagnostics and therapy of the patients with MTC in highly specialized centers with a high volume of patients provide optimal patient management. Multikinase inhibitors (MKI) vandetanib and cabozantinib were approved for the treatment of progressive or symptomatic metastatic/unresectable MTC. Although these treatments have been shown to improve progression-free survival (PFS) with higher overall response rates (ORR) compared with placebo, no MKI has been shown to increase the overall survival (OS) yet, except in the subgroup of patients with RETM918T-mutations on cabozantinib therapy. As these drugs are nonselective, significant off-target toxicities may occur. Recently, next-generation small-molecule tyrosine kinase inhibitors (TKIs) have been developed. These highly selective RET-inhibitors are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. The selective RET-inhibitor selpercatinib has been very recently registered for the treatment of RET-mutated thyroid cancer.

Perspective Summary of Brief Report on Thyroid Disease of Post Glaciations Quaternary Is Endocrinology of Ecology System in Centre Marc Sankale Setting in Dakar

Reflexions about immunoradiometric Tsh and Trh test during on Optimal thyroid hormonal therapy (Optimal dosages and overdosages) as Pionnary Auto-immune Primary Hypothyroidism in Dakar [Senegal] gives us A Propose of Whitaker Syndrome Case Report and THYROID GLAND AND ITS PEPTIDES OR ACTUALITYOF GENERAL ENDOCRINOLOGY. Many peptides by their cell molecular metabolism in the thyroid gland are involved: mutations of TSH receptor is linked to hormone resistance with congenital hypothyroidism; a new oroxigenic peptide, Ghrelin is widespread in endocrine tissues; tachykinine is another novel peptide with endocrine paracrine effect. PTTG and FGF-2 are prognostic markers of differentiated cancers; CRIF1 is a novel protein of nucleus interacting with Gadd45 and could negatively regulate cycle cell progression and cell growth; mutations of RET protooncogene is now the best CMT biomarker in the place of calcitonin in addition with CGRP, CGRPβ and Amylin; regulating proteins of CAMP, protein G, Gi alpha 1, MAL proteolipid are identified near immunologic antigens involved in Grave’s disease, autoimmune polyendocrinopathies. These peptides by their diversity of function support the concept of general endocrinology equivalent of medical sciences. Bastenie P. A. classification is a bio-clinical semeiology that could be reviewed by doing the integration of obesity as the incipient stage of epigenetic thyroid turnover of deiodinase realizing an inactive TSH. Thus primary hypothyroidism in an historical-technically point of view can recognize since Bastenie: -1 Atrophic thyroid myxedema with: low T4 and low T3 and High TSH and TRH positive. -2 Mild hypothyroidism where only TSH is High and TRH Test positive. -3 Infra-clinic hypothyroidism where only TRH Test is positive. -4 Compensated thyroiditis where only auto-antibodies are positive. -5 Common obesity where deiodinase turnover is only disturbed. Iodine regulates nutritional metabolism probably via the microbiome. Thyro-diabetes has concerned clinicians. Endocrine disruptors have come to recall us if necessary that thyroid gland is a gate keeper of the environment which in our approach is the testimony of primordial role of mineral iodine in the majority of living beings. Here are the perspectives of General Practitioner of Endocrine Diseases and Clinical Medicine Department.

The mismatch repair system is not affected in medullary thyroid carcinoma independent of stromal desmoplasia or ret proto-oncogene mutation

IntroductionMedullary thyroid carcinoma (MTC) is an aggressive neuroendocrine neoplasia of the thyroid with 10 year overall survival of 50% and limited therapeutic options. High tumor mutational burden because of microsatellite instability (MSI) seems to be a predictor of response to immune checkpoint inhibitor therapy in different tumors. Therefor in 2017 the U.S. Food and Drug Administration (FDA) permitted the therapy of solid tumors with proven Microsatellite instability (MSI) with PD1 antibody Pembrolizumab independently of their origin. As little is known about MSI in MTC and new therapeutic strategies would be eligible we tried to find out, if therapy with PD1-inhibitors could be promising. Material and methodsWe performed MSI-analyses of 38 cases of MTC. Included were MTCs with and without stromal desmoplasia and with/without lymph node metastases. We also checked the immunhistochemical expression of PD-L-1 and performed next generation sequencing for genetic alterations. ResultsAll cases revealed stable conditions of the microsatellites and showed immunohistochemically positive staining of the four mismatch repair proteins. PD-L-1- Immunostaining was negative in all cases. DiscussionOur data show there is no MSI in MTCs, irrespectively of their status of desmoplasia, metastases and/or ret-mutation. Therefore a positive effect of PD1 inhibitors, because of MSI-associated high tumor mutational burden, seems to be unlikely.

Hopeful Waiting Before Disappointment: Vocal Cord Paralysis After Thyroidectomy

Vocal cord paralysis (VCP) is a well-known complication after thyroidectomy operation which may occur due to direct or indirect injury to the recurrent laryngeal nerve (RLN). Indirect damage to the RLN may be due to compression or stretch of the nerve and usually results in transient VCP. Here, we report a case of bilateral VCP developed after total prophylactic thyroidectomy due to RET proto-oncogene mutation. The patient was successfully extubated after 3 days of waiting with anti-edema treatment. Despite protective measures, thyroidectomy may result in injury to LRN leading to VCP. A trial of waiting period with anti-edema treatment seems to be a reasonable approach in patients with temporary VCP.