Medullary Thyroid Cancer Cases Research Articles

Abstract 2761: Activating RET mutations promotes osteoblastic bone metastasis by inhibiting osteoclastogenesis and stimulating osteoblast activity via regulation of osteoprotegerin

Abstract Bone metastases (BM) are a source of increased mortality and significant morbidity in patients with medullary thyroid cancer (MTC), with ~50% survival at five years post-diagnosis. MTC causes osteoblastic, osteolytic, or mixed lesions, yet the underlying mechanisms are unknown. The RET proto-oncogene encodes a transmembrane tyrosine kinase receptor and is the driver oncogene in ~60% of MTC cases where a germline or somatic activating mutation results in ligand-independent constitutive activation of the receptor. However, the role of RET mutations in the genesis of bone metastasis lesions is unknown. We show that activating RET mutations promotes an osteoblastic phenotype in mice implanted with patient-derived MTC cells by increasing bone formation and decreasing bone resorption. We found that the radiographic appearance of osteoblastic lesions differed between the types of RET mutations (C634W and M918T). MTC cells with RETC634W mutation showed a four-fold increase in bone mineral density, trabecular bone volume, number, and thickness with a decreased number of osteoblasts compared to the non-tumor-bearing femur. TRAP staining revealed that osteoclast numbers per long bone were reduced in the injected femur compared to the control. In contrast, the MTC-RETM918T mutation showed an increased cortical thickness and porosity with reduced medullary area and increased bone formation rate compared to the non-tumor bearing femur. MTC cells formed tumors with extensive mineralized tissue, composed of bone matrix surrounded by osteoblast-like cells and osteoid. The knockdown of RET in the MTC-RETM918T model significantly reduced cortical thickness and increased the number of osteoclasts per bone surface. We observed increased osteoprotegerin (OPG) expression in MTC-bearing femurs compared to controls, suggesting decreased bone resorption. The factors secreted by MTC cells, including OPG, inhibited osteoclast formation from primary bone marrow cells and Raw264 cells. In addition, RET knockdown by shRNA in MTC cells decreased OPG expression. Moreover, the MTC-conditioned media (CM) increased osteoblast differentiation and mineralization of the primary culture of pre-osteoblasts isolated from calvarial bone, long bones, and MC3T3 cells. The conditioned media of RET-depleted cells inhibits osteoblast differentiation and mineralization. The expression of alkaline phosphatase, osteocalcin, OPG, and osterix increased in pre-osteoblast incubated with MTC-CM. Compared to primary non-metastatic tumors, the OPG expression increases in tissues of sporadic MTC bone metastases harboring RETM918T mutation. These results suggest that MTC with RET-activating mutations induces osteoblastic bone metastasis due to decreased bone resorption and increased bone formation. Citation Format: Rozita Bagheri-Yarmand, Joseph L. Kidd, Gabriel M. Pagnotti, Trupti Trivedi, Leah Guerra, Xinhai Wan, Jian Song, Sue-Hwa Lin, Theresa A Guise. Activating RET mutations promotes osteoblastic bone metastasis by inhibiting osteoclastogenesis and stimulating osteoblast activity via regulation of osteoprotegerin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2761.

Incidental 68Ga-DOTATATE uptake in thyroid nodules: Is guideline-directed management still appropriate?

BackgroundFluorodeoxyglucose uptake on positron emission tomography imaging has been shown to be an independent risk factor for malignancy in thyroid nodules. More recently, a new positron emission tomography radiotracer—Gallium-68 DOTATATE—has gained popularity as a sensitive method to detect neuroendocrine tumors. With greater availability of this imaging, incidental Gallium-68 DOTATATE uptake in the thyroid gland has increased. It is unclear whether current guideline-directed management of thyroid nodules remains appropriate in those that are Gallium-68 DOTATATE avid. MethodsWe retrospectively reviewed Gallium-68 DOTATATE positron emission tomography scans performed at our institution from 2012 to 2022. Patients with incidental focal Gallium-68 DOTATATE uptake in the thyroid gland were included. Fine needle aspiration biopsies were characterized via the Bethesda System for Reporting Thyroid Cytopathology. Bethesda III/IV nodules underwent molecular testing (ThyroSeq v3), and malignancy risk ≥50% was considered positive. ResultsIn total, 1,176 Gallium-68 DOTATATE PET scans were reviewed across 837 unique patients. Fifty-three (6.3%) patients demonstrated focal Gallium-68 DOTATATE thyroid uptake. Nine patients were imaged for known medullary thyroid cancer. Forty-four patients had incidental radiotracer uptake in the thyroid and were included in our study. Patients included in the study were predominantly female sex (75%), with an average age of 62.9 ± 13.9 years and a maximum standardized uptake value in the thyroid of 7.3 ± 5.3. Frequent indications for imaging included neuroendocrine tumors of the small bowel (n = 17), lung (n = 8), and pancreas (n = 7). Thirty-three patients underwent subsequent thyroid ultrasound. Sonographic findings warranted biopsy in 24 patients, of which 3 were lost to follow-up. Cytopathology and molecular testing results are as follows: 12 Bethesda II (57.1%), 6 Bethesda III/ThyroSeq-negative (28.6%), 1 Bethesda III/ThyroSeq-positive (4.8%), 2 Bethesda V/VI (9.5%). Four nodules were resected, revealing 2 papillary thyroid cancers, 1 neoplasm with papillary-like nuclear features, and 1 follicular adenoma. There was no difference in maximum standardized uptake value between benign and malignant nodules (7.0 ± 4.6 vs 13.1 ± 5.7, P = .106). Overall, the malignancy rate among patients with sonography and appropriate follow-up was 6.7% (2/30). Among patients with cyto- or histopathology, the malignancy rate was 9.5% (2/21). There were no incidental cases of medullary thyroid cancer. ConclusionThe malignancy rate among thyroid nodules with incidental Gallium-68 DOTATATE uptake is comparable to rates reported among thyroid nodules in the general population. Guideline-directed management of thyroid nodules remains appropriate in those with incidental Gallium-68 DOTATATE uptake.

Medullary thyroid cancer: epidemiology

Epidemiology of medullary thyroid cancer is presented in the literature review. Thyroid cancer is the most common form of endocrine oncological pathology. It accounts for 96–97 % of all malignant tumors of endocrine organs. According to the Surveillance, Epidemiology, and End Results Program (USA), the incidence of thyroid cancer in 1975–2009 increased approximately threefold, from 4.9 to 14.3 cases per 100,000 population. At the same time, the mortality rate remained low, approximately at the same level, 0.5 cases per 100,000. Such a situation can be explained to some extent by the improvement of diagnostic capabilities of the early, often preclinical, stage of thyroid tumors. Medullary thyroid cancer ranks third after papillary and follicular cancer, but surpasses them in terms of aggressiveness. It is a re­latively rare disease. This type of tumor makes up 1–9 % of all thyroid cancers. Against the background of the general tendency to increase the incidence of thyroid cancer, the absolute number of cases of medullary cancer according to various data remains relatively stable. Epidemiological characteristics of medullary thyroid cancer deserve attention in the age aspect, as well as when considering the frequency of detecting these tumors at autopsy of people who had no signs during their lifetime. In clinical practice, medullary thyroid cancer occurs in two main forms — sporadic and hereditary. The latter is represented as part of the combined syndrome of multiple endocrine neoplasia type 2 (MEN-2), which, in turn, is divided into two subtypes: MEN-2A and MEN-2B syndromes. MEN-2 syndrome is a rare combined hereditary pathology. Sporadic medullary thyroid cancer accounts for approximately 70–80 % of such tumors. It is accompanied by other types of endocrinopathies. Most cases of medullary thyroid cancer occur in the fifth decade of life. The presented data on the epidemiology of medullary thyroid cancer allow for a more detailed and in-depth study of this pathology and contain a certain amount of useful and necessary information.

Abstract #1402263: A Malignant Duo: Mixed Medullary and Follicular Variant Papillary Thyroid Cancer

Medullary thyroid cancer (MTC) is rare and only constitutes 5-10% of all thyroid malignancies. Mixed MTC and papillary thyroid cancer (PTC) are even more rare and are only found in less than 1% of MTC cases. These malignancies arise from different cell origins, follicular cells of endoderm and parafollicular C cell of neural crest. It is not clear if the coexistence of these tumors in the same patient is a coincidence or if there is a common genetic culprit. We present a case of a lady with metastatic mixed MTC and PTC. A 61-year-old woman with history of Hashimoto disease was found to have bilateral thyroid nodules, the largest (1.7cm) was in the right lobe. This nodule met fine needle aspiration (FNA) biopsy criteria and was found to have a follicular neoplasm of undetermined significance. The patient elected to pursue total thyroidectomy instead of lobectomy given presence of bilateral nodules. Postoperative pathology showed mixed medullary carcinoma (pT3b) and follicular variant papillary thyroid microcarcinoma (pT1a) involving the right lobe with positive anterior and posterior margins and lymphovascular invasion. Preoperative calcitonin was not checked. However, post-thyroidectomy calcitonin was 1599 pg/mL. She underwent central and right lateral neck dissection which showed 27 out of 35 lymph nodes were positive for malignancy. Postoperative calcitonin dropped to 38.7 pg/mL. She then established care in our endocrine clinic. Screening for pheochromocytoma and primary hyperparathyroidism was normal. She underwent external beam radiation of the neck. A year after her initial surgery, her neck ultrasound and computed tomography (CT) studies show no signs of local or distant anatomic recurrence. Her thyroglobulin level remains undetectable, CEA within normal range, and calcitonin stable at about 20 pg/mL. She is on levothyroxine 100mcg daily with TSH at suppression goal of < 0.1 mIU/L. Mixed PTC and MTC is poorly studied due to its rarity. The origin of these mixed tumors is unclear, but some suggest that they arise from neoplastic changes of remnant multipotent cells in the thyroid. While patients with PTC often have a favorable prognosis following surgical therapy, MTC has a more aggressive course. A retrospective study of 183 patients suggests that this entity is more common in patients older than 45 years and is associated with a better survival than MTC alone. We suggest monitoring patients like ours for both MTC and PTC, as if present in isolation. Our case will highlight the clinical aspects of this condition and our current knowledge of its pathophysiology.

Combination of ultrasound and serological tests for detecting occult lateral lymph node metastases in medullary thyroid cancer.

To investigate the value of ultrasound and serum marker tests in detecting lateral lymph node metastasis in medullary thyroid cancer (MTC). Data of 105 patients diagnosed with MTC and admitted to the Department of General Surgery in Peking Union Medical College Hospital from June 2010 to August 2020 were collected and retrospectively analyzed. Ultrasound examination alone had a sensitivity of 89.36% and a specificity of 70.69%. For surveillance of postoperative carcinoembryonic antigen and calcitonin, cut-off values of 7.115 ng/mL and 13.185 pg/mL, respectively, were shown to discriminate the presence of cervical lymph node metastasis. Combining ultrasound and postoperative serum levels of both carcinoembryonic antigen and calcitonin as serial tests increased the specificity to 91.38% and 87.93%, with a sensitivity of 95.45%. Multivariate logistic analysis identified the following risk factors for lateral lymph node metastasis in MTC: suspicious lymph nodes detected by ultrasound and postoperative calcitonin above 13.185 pg/mL. The combination of ultrasound and serological tests achieved higher sensitivity and specificity to identify MTC cases with potential occult lateral cervical lymph node metastasis compared with single tests.

RF11 | PSAT273 RET Gene Fusion In a Putative Case of Medullary Thyroid Cancer

Abstract Background Oncogenic RET gene fusions have been identified in non-small cell lung cancer and non-medullary thyroid cancers, whereas RET point mutations are the key genetic finding in both inherited and sporadic medullary thyroid cancer (MTC). The presence of a RET gene fusion provides a target for selective RET inhibitor drugs. We describe an unusual patient with suspected MTC and a positive RET gene fusion, with excellent response to targeted therapy. Clinical Case A 50-year-old male presented to our institution with cough, fatigue, heat intolerance, and flushing. His only remarkable history was stage IIIBS Hodgkin lymphoma treated with chemotherapy, in remission for approximately 6 years. CT chest revealed new bulky mediastinal and hilar adenopathy with bulky cervical nodes. VATS biopsy of a mediastinal node showed metastatic neuroendocrine neoplasm with plasmacytoid features that was immunoreactive for calcitonin, CEA and cytokeratin, but negative for TTF1 and PAX-8. The differential diagnosis included MTC or metastatic atypical carcinoid tumor. Next Generation Sequencing was negative, including RET and RAS point mutations. Subsequent testing for re-arrangements showed a KIF5B-RET gene fusion, an oncogene identified in lung adenocarcinoma. Biochemical findings showed a calcitonin level of 16,033 (normal &amp;lt; 10 pg/mL) and CEA 6.9 (normal &amp;lt; 4.7 ng/mL). Chromogranin A was 146.6 (normal &amp;lt; 101.16 ng/mL). ACTH and cortisol were normal. Neck US revealed a calcified 5 mm right upper pole thyroid nodule and extensive bilateral cervical nodes. A provisional diagnosis was made of MTC. Vandetanib was started. Two months later, he reported worsening orthopnea, diarrhea, and weight loss. CT chest showed marked worsening with enlarging mediastinal hilar and supraclavicular adenopathy with new moderate sized pericardial and pleural effusion. Vandetanib was discontinued and Selpercatinib started, following FDA approval. He reported prompt resolution of dyspnea and diarrhea and improved weight and energy. Calcitonin declined to &amp;lt;2 pg/mL, and CEA to1.6 ng/mL four months into treatment. CT neck showed marked shrinkage of lymph nodes with a persistent calcified thyroid nodule. CT chest showed marked shrinkage of mediastinal and hilar masses, with resolution of bronchial narrowing and right pleural effusion. Nine months after presentation, there were no chest symptoms and biochemical markers and imaging remained stable. Conclusion Approximately 25% of MTC tumors lack activating point mutations in RET or RAS genes. Analysis of actionable fusion mutations should be considered if there is metastatic disease. High serum calcitonin levels are not pathognomonic for MTC and tumor histology may overlap with neuroendocrine lung cancers, creating a diagnostic challenge. Depending on whether this patient's tumor originated in the thyroid gland, it may represent an unusual case of RET gene fusion in MTC. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m.

Medullary Thyroid Carcinoma and Associated Endocrinopathies in Slovenia from 1995 to 2021.

Background: Medullary thyroid cancer (MTC) is a rare endocrine tumour that is sporadic in 75% of cases and occurs as a part of inherited cancer syndromes in approximately 25% of cases. The aim of this study was to determine the frequency and type of RET pathogenic variants (PVs) in the Slovenian MTC patient population diagnosed between 1995 and 2021 and to elucidate the full range of associated endocrinopathies. Methods: A retrospective analysis of medical records of 266 MTC patients and their relatives seen in a tertiary centre between 1995 and 2021 was performed. Sequence analysis of exons 10, 11, 13, 14, 15, and 16 of the RET gene was analysed in most patients using Sanger sequencing. From 2017, the entire sequence of RET gene was analysed in most patients using targeted next-generation sequencing. Results: Germline PVs in the RET proto-oncogene were identified in 21.6% probands from 21 different MTC families. Of their tested relatives, 65% (67/103) were RET-positive and 35% (36/103) were RET-negative. PVs were detected in codon 618 and codon 634 in 28.6%, and in codon 790 in 23.8%. The RET-positive group consisted of 52 MTC patients, 13 patients with C cell hyperplasia and 2 individuals with neither. Associated endocrinopathies were diagnosed in 8/21 families: primary hyperparathyroidism (PHPT) in six families and pheochromocytoma (PHEO) in five families. In 62% of RET-positive families (13/21), no associated endocrinopathies were diagnosed. PHEO was most commonly associated with C634R (6/13) and PHPT with C634R (4/7). Hirschsprung’s disease appeared in one patient with RET PV in codon 618. Based on data from the Cancer Registry of Republic of Slovenia, only individual cases of common cancers with well understood environmental risk factors were discovered; lung cancer in 2/21 of families, papillary thyroid cancer in 3/21 of families, cutaneous melanoma in 2/21 of families, cervical cancer in 1/21 families, and lymphoma in 1/21 families. Conclusions: Analysis of prospectively collected MTC cases during a 27-year period revealed that 21.6% of Slovenian patients are RET PV carriers. Sixty-two percent of families had none of the associated endocrinopathies, confirming the thesis that FMTC is the most common presentation. This could suggest using risk-stratified management approaches when screening for PHEO and PHPT in RET PV carriers. However, more studies are needed to evaluate potential genetic risk modifiers as well as safety, improved quality of life, and medical cost reduction in the case of a patient-oriented approach.

Abstract #1171494: Thyroid Makes Three: Incidental Discovery of Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) is a neuroendocrine tumor (NET) arising from parafollicular or C cells and accounts for 3-4% of all thyroid cancers. MTC is either sporadic or familiar, with the sporadic form accounting for 75-80% of cases. The familial form is associated with germline mutations in the Rearranged during Transfection (RET) proto-oncogene. Most MTC cases are found during the evaluation of thyroid nodules. We report a case of incidentally discovered medullary thyroid cancer during the staging of a mucosa-associated lymphoid tissue (MALT) lymphoma of the bladder.

Calcitonin levels in washout samples vs. cytology in the detection of malignant lymph node metastasis in recurrent medullary thyroid cancer

Calcitonin level in fine-needle aspirate washout fluid (Ct-FNA) was extensively studied for thyroid nodules and lymph nodes (LN). However, the data was scarce for neck recurrences/metastases of medullary thyroid cancer (MTC). Thus, the diagnostic accuracy of Ct-FNA and cytology in the detection of neck LN metastases of recurrent MTC cases were assessed. The database of MTC patients between 2010 and 2021 was retrospectively reviewed. A total of 32 patients with recurrent MTC and suspicious LN who underwent FNA and Ct measurement from washout samples were included in this study. Preoperative serum Ct (sCt), Ct-FNA, Ct-FNA/sCt ratio, cytology data were recorded for all participants. Median sCt of 32 patients and Ct-FNA washout fluid levels of operated suspicious 44 LNs were 723 (54–9000) pg/mL and 1800 (151–9500) pg/mL, respectively. The diagnostic accuracy of Ct-FNA washout fluid was greater than cytology (95.4% vs. 86%, respectively). Using a cut-off level of >638.5 pg/mL, the Ct-FNA predicted the diagnosis of LN metastasis of recurrent MTC with a sensitivity of 80% and specificity of 94.9%. Furthermore, using a cut-off level of >1.16, the Ct-FNA/sCt ratio well predicted the diagnosis of LN metastasis of recurrent MTC with a sensitivity of 92.3% and specificity of 100%. As Ct-FNA has greater diagnostic accuracy in our study, it would be complementary to cytology results to localize metastatic LNs in recurrent MTC. Furthermore, for the first time, we demonstrated that the Ct-FNA/sCt ratio was a better predictor of metastatic LNs in recurrent MTC than a particular cut-off for Ct-FNA alone.

Active Surveillance in RET Gene Carriers Belonging to Families with Multiple Endocrine Neoplasia.

Simple SummaryMEN2 has a very high penetrance for the development of medullary thyroid cancer. However, intra- and inter-familial variabilities have been described. Accordingly, in this precision medicine era, a personalized approach should be adopted in subjects harboring RET mutations. In these subjects, we showed that thyroid surgery could be safely timed according to basal and stimulated calcitonin, especially in children who can reach adulthood, avoiding the risks of thyroid surgery and decreasing the period of a long-life hypothyroidism treatment.Multiple Endocrine Neoplasia 2 (MEN2) is a hereditary cancer syndrome for developing medullary thyroid cancer (MTC) due to germline mutations of RET gene. Subjects harboring a germline RET mutation without any clinical signs of MTC are defined as gene carriers (GCs), for whom guidelines propose a prophylactic thyroid surgery. We evaluate if active surveillance of GCs, pursuing early thyroid surgery, can be safely proposed and if it allows safely delaying thyroid surgery in children until adolescence/adulthood. We prospectively followed 189 GCs with moderate or high risk germline RET mutation. Surgery was planned in case of: elevated basal calcitonin (bCT) and/or stimulated CT (sCT); surgery preference of subjects (or parents, if subject less than 18 years old); other reasons for thyroid surgery. Accordingly, at RET screening, we sub-grouped GCs in subjects who promptly were submitted to thyroid surgery (Group A, n = 67) and who were not (Group B, n = 122). Group B was further sub-grouped in subjects who were submitted to surgery during their active surveillance (Group B1, n = 22) and who are still in follow-up (Group B2, n = 100). Group A subjects presented significantly more advanced age, bCT and sCT compared to Group B. Mutation RETV804M was the most common variant in both groups but it was significantly less frequent in Group A than B. Analyzing age, bCT, sCT and genetic landscape, Group B1 subjects differed from Group B2 only for sCT at last evaluation. Group A subjects presented more frequently MTC foci than Group B1. Moreover, Group A MTCs presented more aggressive features (size, T and N) than Group B1. Accordingly, at the end of follow-up, all Group B1 subjects presented clinical remission, while 6 and 12 Group A MTC patients had structural and biochemical persistent disease, respectively. Thank to active surveillance, only 13/63 subjects younger than 18 years at RET screening have been operated on during childhood and/or adolescence. In Group B1, three patients, while actively surveilled, had the possibility to reach the age of 18 (or older) and two patients the age of 15, before being submitted to thyroid surgery. In Group B2, 12 patients become older than 18 years and 17 older than 15 years. In conclusion, we demonstrated that an active surveillance pursuing an early thyroid surgery could be safely recommended in GCs. This patient-centered approach permits postponing thyroid surgery in children until their adolescence/adulthood. At the same time, we confirmed that genetic screening allows finding hidden MTC cases that otherwise would be diagnosed much later.

Abstract #1003222: Case Report: Medullary Thyroid Cancer as Part of the MEN2B Syndrome in an 8-year-old Male Patient

Medullary thyroid cancer (MTC) accounts for 5% of all thyroid cancers. MTC originates from the parafollicular of the thyroid, which derive from the neural crest. In children, more than 95% cases of MTC are inherited as part of the multiple endocrine neoplasia syndromes (MEN2A and MEN2B) or familial MTC. MEN2B only represents 5% of MEN2 cases and is associated with a mutation in the M918T of the RET oncogene. MEN2B is characterized by specific phenotypic features, including a marfanoid habit, a prominent jaw, ocular abnormalities, ganglioneuromas and mucosal neuromas.

Unusual case of medullary thyroid cancer

Medullary thyroid carcinomas make up 9,4% of all cancers of the thyroid gland [1]. We can divide them into sporadic and familial form. Sporadic forms are most common. The rest of medullary thyroid carcinomas are familial forms which in most cases are associated with MEN2a and MEN2b syndromes. If neoplasm is associated with MEN2a or MEN2b syndromes, other tumors can occur: pheochromocytoma or adenomas of parathyroids glands. Medullary thyroid carcinoma typically occurs as a solid tumor in the thyroid region of the neck. It can produce also: pain in thyroid region, dysphagia, hoarseness, cervical lymphadenopathy. These symptoms are caused by infiltration of adjacent tissues by neoplasm and by metastases to cervical lymph nodes. It is very rare that there is no tumor in the thyroid region, when a patient complains about signs associated with infiltration of the tumor, but in some cases lymphadenopathy can be the first sign of medullary thyroid carcinoma [2]. Rarer than that there is no tumor in thyroid gland visualized in CT scans when there are signs of cervical lymphadenopathy. In this case report we present the patient with metastases of the medullary thyroid carcinoma to the neck and no other findings in physical examination and additional testing.

The Difficulty of Post-Operative Surveillance of Calcitonin Negative Medullary Thyroid Cancer

Background: As a differentiated thyroid tumor, medullary thyroid cancer (MTC) typically maintains the secretory function of the c-cells with resultant increase in serum calcitonin level along with frequent elevations in serum chromogranin A (CgA) and carcinoembryonic antigen (CEA). Clinical Presentation: A 71-year-old female with history of multinodular goiter underwent a thyroid nodule biopsy after routine ultrasound surveillance revealed enlargement of two right lower lobe nodules compared with prior imaging. Fine needle aspiration (FNA) of one 3.1 x 1.9 x 2.7 cm right thyroid nodule revealed cellular material composed of spindle-shaped neoplastic cells, some of them with marked cytologic atypia, suspicious for a neuroendocrine tumor, specifically medullary thyroid carcinoma. A PET/CT scan was performed after injection of Gallium-68 dotatate radiotracer and revealed intense focal radiotracer activity in the approximately 2.5 x 2.1 cm right thyroid mid lower pole heterogeneous hypodense mass with tiny calcification inferiorly, consistent with the patient’s known tumor. There was no evidence of cervical octreotate avid metastatic lymphadenopathy and a chest x-ray showed no evidence of active pulmonary disease. The patient subsequently underwent a right partial thyroidectomy with isthmusectomy. Histopathology revealed a 2.8 x 1.9 x 1.9 cm neoplasm composed of spindle and polygonal cells growing in solid nests with neuroendocrine-type nuclei. Immunostains showed the tumor to be positive for AE1-AE3 cytokeratins, chromogranin, synaptophysin and CEA. It was focally positive for TTF-1 and calcitonin. Thyroglobulin and PAX-8 were negative. Using the AJCC 8th edition staging system, the tumor was staged a pT2Nx with margins uninvolved by carcinoma and no extrathyroidal extension or lymphatic invasion. Angioinvasion was present. Additional serum studies included a normal calcitonin value of <2.0 pg/ml (reference range 0-5.1 pg/ml), CEA 2.6 ng/ml (reference range <6.0 ng/ml), and a mildly elevated chromagranin A at 133 ng/ml (reference range 0-95 ng/ml). Plasma metanephrines, normetanephrines, vasoactive peptide, and glucagon levels were all unremarkable. Our patient’s surgical recovery was normal and two months later she remained asymptomatic without evidence of recurrence or metastasis. Discussion: The diagnosis and post-operative surveillance of medullary thyroid cancer is challenging; even more complicated is the rare case of calcitonin-negative MTC. The cause of calcitonin-negative MTC remains unclear. Further studies are needed for the discovery and development of novel biomarkers for post-operative surveillance and evaluation of clinical relapse.

Diagnosis of Medullary Thyroid Cancer During COVID-19 Pandemic, the Benefit of Using a Standardized Protocol

Introduction: The reported prevalence of malignancy in thyroid nodules ranges from 4% to approximately 10%, with a small percentage (~2-8%) being medullary thyroid cancer (MTC). During the COVID-19 pandemic, elective thyroid FNA was temporarily halted at our institution. In response to this, our institution has devised a new protocol to aid in the detection of MTC, which includes serum calcitonin measurement as a surrogate marker for potential MTC. A severely elevated calcitonin (>100 pg/mL) is considered for surgery even without FNA diagnosis. We present a case of MTC that was detected due to the adopting of this protocol during COVID-19 pandemic at the Phoenix VAMC. Case Presentation: 71 year old male with an incidentally noted 3.0 cm solid, hypoechoic nodule with internal calcification, TI-RADS category 5. TSH level was normal at 3.309 mIU/mL. The patient denied any personal or family history of thyroid cancer, MEN syndrome, radiation exposure, or compressive symptoms. Following established protocol published by our institution in clinical thyroidology we performed a serum calcitonin that came back elevated at 1515 pg/mL (normal < 10 pg/mL). Given the marked elevation in serum calcitonin levels and highly suspicious radiographic appearance of the thyroid nodule, we strongly suspected medullary thyroid cancer and elected to send him directly for total thyroidectomy without performing FNA. The patient underwent total thyroidectomy with central neck dissection. Pathology showed a 3.2 cm medullary thyroid carcinoma without extrathyroidal extension or perineural invasion. Lymphovascular invasion was present. 6/10 central comparement lymph nodes were positive for metastatic disease. Postoperative calcitonin level was 2 pg/mL. Discussion: Our patient had markedly elevated serum calcitonin levels in addition to a high-risk ultrasonographic features, which was highly suspicious for MTC. Per our COVID-19 protocol, we measured the serum calcitonin level to screen for MTC and then referred him directly to surgery without FNA given the high suspicion for MTC. By using this protocol, we were able to diagnose and treat MTC expeditiously. The measurement of serum calcitonin is still controversial in the U.S, with the ATA remaining equivocal on this method. We believe that our case can serve as a practical example that validates our institution’s use of calcitonin screening of thyroid nodules in diagnosing MTC during the COVID-19 pandemic.

Medullary thyroid cancer: molecular factors, management and treatment.

Medullary thyroid cancer (MTC) is an infrequent neuroendocrine tumor, which amounts to 3–5% of all thyroid malignancies. Approximately 75–80% of MTCs are sporadic neoplasms. The rest of 20–25% are familial cases that belong to multiple endocrine neoplasia (MEN) syndromes, specifically MEN2 and MEN3. These cases of familial MTC are attributed to an activating germline mutation of a tyrosine kinase receptor gene, the rearranged during transfection (RET) proto-oncogene, located on chromosome 10q11.21. These mutations are also found in some cases of sporadic MTC. This review sets forth in summary the accepted guidelines and approaches regarding diagnosis, management, and treatment of MTC. Surgical resection is the standard care, and an early, prophylactic intervention is performed in genetic cases. Further investigation and understanding of the molecular pathways involved in the growth and advancement of MTC is required in order to provide efficient therapy in cases of progressive disease.

RET Copy Number Alteration in Medullary Thyroid Cancer Is a Rare Event Correlated with RET Somatic Mutations and High Allelic Frequency.

Copy number variations (CNV) of the RET gene have been described in 30% of Medullary Thyroid Cancer (MTC), but no information is available about their role in this tumor. This study was designed to clarify RET gene CNV prevalence and their potential role in MTC development. RET gene CNV were analyzed in 158 sporadic MTC cases using the ION Reporter Software (i.e., in silico analysis) while the multiplex ligation-dependent probe amplification assay (i.e., in vitro analysis) technique was performed in 78 MTC cases. We identified three categories of RET ploidy: 137 in 158 (86.7%) cases were diploid and 21 in 158 (13.3%) were aneuploid. Among the aneuploid cases, five out of 21 (23.8%) showed an allelic deletion while 16 out of 21 (76.2%) had an allelic amplification. The prevalence of amplified or deleted RET gene cases (aneuploid) was higher in RET positive tumors. Aneuploid cases also showed a higher allelic frequency of the RET driver mutation. The prevalence of patients with metastatic disease was higher in the group of aneuploid cases while the higher prevalence of disease-free patients was observed in diploid tumors. A statistically significant difference was found when comparing the ploidy status and mortality. RET gene CNVs are rare events in sporadic MTC and are associated with RET somatic mutation, suggesting that they could not be a driver mechanism of tumoral transformation per se. Finally, we found a positive correlation between RET gene CNV and a worse clinical outcome.

Basal and stimulated calcitonin for the diagnosis of medullary thyroid cancer: updated thresholds and safety assessment

PurposeReliable cut-offs for basal (bCT) and calcium stimulated calcitonin (casCT) are needed for an early and accurate diagnosis of medullary thyroid cancer (MTC).Patients and methodsFifty-four new patients with nodular goiter were enrolled and analysed together with those previously published by our group for a total of 135 cases. bCT and casCT were measured by a highly sensitive method and the results compared with histological findings. In a subgroup of patients, cardiac rhythm was recorded before and during the calcium test.ResultsIn both females (F) and males (M), there was a significant correlation between tumor size and bCT levels (P < 0.001). The receiver operating characteristic plot analyses showed that, for bCT, the new cut-off points able to separate non-MTC from MTC patients were > 30 (F) and > 34 pg/mL (M), whereas the best casCT thresholds were > 79 (F) and > 466 pg/mL (M). bCT was shown to harbour a high accuracy, though some cases were diagnosed only upon stimulation test. Importantly, combining bCT, below or above the cut-offs, with casCT above the cut-offs, all the MTC cases were correctly identified. A reversible sinus bradycardia was observed in 9% of cases during the test.ConclusionsRefined cut-offs for bCT and casCT in patients with nodular goiter are reported. Sensitive bCT was shown to have a high accuracy, but the combination with casCT data was needed to identify all MTC cases. The reliability and safety of calcium test strongly favour the routine use of CT determination in nodular thyroid disease.

MON-490 Calcitonin-Based Thyroidectomy Is a Safe Approach in Patients with Germline RET Mutation and Permits to Delay Surgery in Children

Introduction: Medullary thyroid cancer (MTC) arises from C cells secreting calcitonin. In familial MTC cases, a germline RET mutation is discovered in 98% of cases. Nowadays, an early diagnosis and radical surgery are the only curative approach. However, thyroidectomy in children is associated with a higher rate of surgical adverse events, compared to surgery in adults. The best clinical approach in patient harboring germline RET mutation (gene carriers, GC) is still undefined. Methods and materials: since 1994 to 2018 we identified 174 GC by RET screening. 56 GC underwent total thyroidectomy and lymph node dissection for the evidence of high calcitonin levels at the first clinical evaluation, whereas 27 GC underwent surgery for high stimulated calcitonin levels during the active surveillance (median 16 months, range 13-118). 90 GC are still in follow up. Results: In the group of 27 GC patients who underwent surgery during the active surveillance, 15 GC had only C cells hyperplasia (CCH) foci and 12 were affected by MTC. These carcinomas were all confined to the thyroid, without any lymph node and distant metastasis. All these patients are still in clinical remission, after a median follow-up of 4 years (range 1-11). At time of the surgery, the patients affected by MTC were significantly older than patients harboring only CCH (median 49 vs 30 years old, respectively). Among these 27 GC, 7 were diagnosed as GC when they were younger than 18 years (median 7 years old, range 2-18) and they underwent surgery after a median period of 3 years (range 1-10 years), when they were all older than 7 years. In this group, 6 of 7 were affected by CCH and only one case by a microMTC. There were not any persistent surgical adverse events and all of them are still in clinical remission. 41 of 90 GC, who are still in active surveillance, were younger than 18 years at time of RET screening: nowadays, 10/41 are older than 18 years and 15/41 are older than 14 years, all with calcitonin still in the normal range. Conclusions: we demonstrated that the calcitonin-based thyroidectomy is a safe approach in GC. Intriguingly, this approach seems to be interesting especially in children in order to perform still an early and safe surgery but when they are older, possibly adults.

Silencing of zinc finger protein 703 inhibits medullary thyroid carcinoma cell proliferation in vitro and in vivo.

Zinc finger protein 703 (ZNF703) is a new member of the zinc finger protein family of transcription factors that plays an important role during embryogenesis in metazoans. The overexpression of ZNF703 contributes to tumorigenesis and progression of a number of malignancies by activating the Akt/mammalian target of rapamycin (mTOR) signaling pathway. This pathway is activated in medullary thyroid cancer (MTC), but its mechanism of action is not yet fully understood. The aim of the present study was to examine the role of ZNF703 and its association with Akt/mTOR activation in MTC. The present study used the phosphorylation of Akt1 protein at serine 473 (pAkt473) as an indicator of signaling activation. Immunohistochemistry (IHC) staining and western blot analyses were performed in order to examine the expression of ZNF703 in 34 cases of MTC and 12 cases of corresponding normal thyroid tissues. ZNF703 expression in MTC was significantly higher compared with the corresponding normal thyroid tissues (P<0.05). Furthermore, expression of ZNF703 was associated with tumor size, lymph node metastasis and advanced stage of disease. IHC also demonstrated that the level of ZNF703 was positively correlated with p-Akt473 in the 34 cases of MTC. The human MTC cell line TT was selected for further investigation as TT cells exhibit Akt/mTOR activation. The biological effects of silencing ZNF703 in TT cells on proliferation and apoptosis, both in vitro and in vivo were investigated in the present study. ZNF703 silencing inhibited the proliferation of TT cells in vitro and inhibited xenograft tumor growth in vivo. These effects were accompanied by the substantial decrease of pAkt473 and the induction of p53 protein. These results demonstrate that ZNF703 may play a relevant role in MTC due to its association with the Akt/mTOR signaling pathway.

Efficacy of vandetanib in the treatment of medullary thyroid cancer: literature review and case report

Medullary thyroid cancer (MTC) is a rare disorder that accounts for approximately 1.7 % of all thyroid malignancies. MTC is usually detected at early stages; however, approximately 10–15 % of patients are diagnosed with locally advanced MTC and distant metastases. Treatment of such patients is challenging due to biological characteristics of the disease and very few effective treatment approaches available. The investigation of mechanisms of carcinogenesis, as well as advances in pharmacology, allowed the development of a new group of targeted drugs, namely tyrosine kinases, which efficacy against progressive unresectable locally advanced or metastatic MTC has been demonstrated in multiple clinical trials. Vandetanib has been registered for MTC treatment in the Russian Federation. MTC is very rare, thus, each case of vandetanib use for its treatment is particularly interesting. Moreover, since the approval of this drug in 2011 by the U. S. Food and Drug Administration (FDA), new data on the clinical use of vandetanib have been accumulated. Importantly, clinical trials are usually well designed and conducted in near-ideal conditions, whereas the real conditions can be different and patients may have individual characteristics. Therefore, the aim of this study was to update the information on the efficacy and safety of vandetanib by retrospective analysis of available publications and to report a case of MTC treated with vandetanib.