History Of Medullary Thyroid Carcinoma Research Articles

Diagnostic dilemma in a patient with history of medullary thyroid carcinoma and abnormal serum liver enzymes; a case report with six years follow up

BackgroundMedullary thyroid carcinoma (MTC) is a neuroendocrine tumor that originates from parafollicular C-cells. Calcitonin (Ctn) and carcinoembryonic antigen (CEA) are useful biomarkers for monitoring MTC cases.Case presentationHere, we describe a 48-year-old woman, who presented in 2014 with bilateral thyroid nodules. Report of fine needle aspiration was suspicious for MTC; initial laboratory evaluation showed serum Ctn level of 1567 pg/mL. After excluding type 2 multiple endocrine neoplasia syndrome clinically, total thyroidectomy and neck lymph node dissection were performed. The final histopathological diagnosis was right lobe MTC with neither vascular invasion nor lymph node involvement. On regular follow-up visits, Ctn and CEA levels have been undetectable, and repeated cervical ultrasonographic exams were unremarkable from 2014 to 2021. As liver enzymes became elevated in 2016, the patient was further evaluated by a gastroenterologist. Abdominopelvic ultrasonography revealed a coarse echo pattern of the liver parenchyma with normal bile ducts. A liver fibroscan showed a low fibrosis score (7kPa). The patient was recommended to use ursodeoxycholic acid. According to the progressive rise of liver enzymes with a cholestatic pattern in October 2020, a liver biopsy was performed that showed tiny nests of neuroendocrine-like cells with a background of primary biliary cholangitis (PBC). Immunohistochemical stainings were positive for chromogranin A (CgA), and synaptophysin and negative for Ctn, CEA, and thyroglobulin. Further imaging investigations did not reveal any site of a neuroendocrine tumor in the body. Considering normal physical exam, imaging findings, as well as normal serum levels of Ctn, CEA, CgA, and procalcitonin, the patient was managed as a PBC.ConclusionIn follow-up of a patient with MTC, we reported progressively increased liver enzymes with a cholestatic pattern. Liver biopsy revealed nests of neuroendocrine-like cells with a background of PBC, the findings that might suggest acquiring neuroendocrine phenotype by proliferating cholangiocytes.

The occurrence of adrenocorticotropic hormone-independant Cushing's syndrome in a woman with the history of medullary thyroid carcinoma: a case report

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Type 2 diabetes in youth: Rationale for use of off-label antidiabetic agents.

Dr. Kelsey has been a site PI for clinical trials related to youth-onset type 2 diabetes sponsored by Janssen, Boehringer-Ingelheim, Merck, and Daiichi-Sankyo; Dr. Zeitler has been site PI for clinical trials related to youth-onset type 2 diabetes sponsored by Janssen and is a consultant on research design and oversight for clinical trials related to youth-onset type 2 diabetes sponsored by Janssen, Merck, Daiichi-Sankyo, Boehringer-Ingelheim, Novo-Nordisk, and Eli Lilly. Dr. Shah has been a site PI for clinical trials related to youth-onset type 2 diabetes sponsored by Takeda, Daiichi-Sankyo, and Eli Lilly; Dr. Nadeau does not have any conflicts of interest to disclose. The peer review history for this article is available at https://publons.com/publon/10.1111/pedi.13350. Data sharing is not applicable to this article as no new data were created or analyzed in this study. FIGURE S1: The supplementary figure provides a more detailed suggested algorithm for medication adjustment, based on the ST2OMP treatment algorithms, with each panel representing a different in-clinic scenario at the time of HbA1c measurement: (a) Patient has been on metformin monotherapy for at least 2 months. Of note, the threshold for starting insulin is higher in these patients due to a greater opportunity to achieve glycemic control by adding multiple non-insulin agents; (b) Patient is prescribed metformin and one additional non-insulin agent; (c) Patient is prescribed metformin and 2 other non-insulin agents; (d) Patient is prescribed metformin, 2 or more non-insulin agents, and insulin; (e) Patient is being treated for presumed type 1 diabetes based on presentation and has a revised diagnosis of type 2 diabetes. Of note, it is critical to assess adherence and reinvigorate current treatment if suspicion that doses are being missed prior to adding new agents, with the exception that insulin needs to be added regardless of adherence if evidence of metabolic decompensation. Also, we recommend to schedule for a nurse certified diabetes educator visit for patients with HbA1c ≥ 11% 1 month after insulin is added. Second tier agent considerations: GLP-1 agonist (liraglutide, exenatide, exenatide XR, dulaglutide, semaglutide): Consider if patient is overweight and/or needs appetite suppression. Caution if history of pancreatitis or family history of medullary thyroid carcinoma. Thiazolidinedione (pioglitazone): TODAY study outcomes suggest better glycemic outcomes in girls than boys when thiazolidinediones are used as add-on to metformin. There is evidence for improvement of NAFLD with pioglitazone. Discuss risks for edema, especially if on insulin. SGLT2 inhibitor (canagliflozin, empagliflozin, dapagliflozin, ertugliflozin): Consider if daytime/post-prandial hyperglycemia. Caution in patients with low reliability or metabolic decompensation due to risk for euglycemic diabetic ketoacidosis.2 If well-tolerate and insurance allows, consider switching to SGLT2i-metformin combination medication. Caution in patients with history of chronic/recurrent UTI. DPP-4 inhibitor (sitagliptin, saxagliptin, linagliptin): Little utility unless required as 2nd line by insurance. Long-acting insulins: Detemir, glargine, degludac, NPH, if insurance does not cover others. Rapid-acting insulins: Aspart, lispro, regular if insurance does not cover others. aPioglitazone can be used as alternative agent for patients not tolerating metformin; bIn absence of significant adverse effects, new agent should be titrated up each visit to maximal dose; cThese agents would typically be added sequentially, 3 months apart; d Patients with HbA1c ≥11% will also be scheduled for a CDE visit 1 month after insulin is added. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Ectopic Cushing’s Syndrome and Severe Hypocalcemia Due to Medullary Thyroid Cancer Responsive to Selpercatinib

Introduction: Cushing’s syndrome (CS) due to ectopic ACTH production from medullary thyroid carcinoma (MTC) is characterized by rapid progression of disease, leading to hyperglycemia and hypokalemia. However, hypercortisolemia leading to hypocalcemia is rarely seen. Initiation of selpercatinib greatly improved hypocalcemia and ectopic CS in this case. Clinical Case: A 41-year-old man with a history of MTC (variant RET p.M918T) post thyroidectomy in 2018 developed progressive weight gain, lower extremity edema, weakness, new onset diabetes, severe refractory hypocalcemia and hypokalemia requiring multiple hospitalizations. On initial presentation to our institution, he was lethargic, had multiple ecchymoses, peripheral edema and proximal myopathy. Laboratory evaluation revealed Ca 5.4 mg/dL (NR 8.9 - 10.3), albumin 3 g/dL (NR 3.5 - 5.1), iPTH 1.4 pmol/L (NR 1.6 - 6.9), 25-OH vitamin D 23 pg/mL (NR 25–80) while taking elemental calcium 1500 mg every 6h, calcitriol 0.25 mcg/d and vitamin D3 1000 IU/d. Serum cortisol measured at 9:30 pm was 136 ug/dL (NR 2.5–11.9), ACTH 1,145 pg/mL (NR 7.2–63.3) and 24-h UFC 27,629 ug/d consistent with CS due to ectopic ACTH production. Calcitonin and CEA were 18,687 pg/mL (NR 0–7.5) and 3,766 ng/mL (NR 0–4.7). CT abdomen revealed numerous bilateral liver lesions and bilateral adrenal hyperplasia. In addition to high doses of oral calcium and calcitriol, he required calcium drip up to 1.5mg/kg/hr for about 1 week. He simultaneously began cabozantinib, ketoconazole and metyrapone. Hospital course was complicated by infections and recurrent scrotal bleeding, so he was switched to selpercatinib. Two days after starting selpercatinib, ketoconazole was discontinued, and metyrapone has been gradually reduced. Most recent calcitonin was 149 pg/mL, CEA 97.8 ng/mL and 24-h UFC 10 ug/d on metyrapone 250 mg twice daily. Similarly, refractory hypocalcemia greatly improved, last serum Ca was 8.3 mg/dL on elemental calcium 480 mg/d. He has made significant clinical gains and has returned home from rehab. Clinical Lesson: Hypocalcemia is rarely described as a complication in patients with CS. Our patient had underlying hypoparathyroidism and vitamin D deficiency; however, hypocalcemia was initially refractory to high doses of calcium and calcitriol and only improved with treatment of CS. We suspect hypercortisolemia impaired 25 to 1,25 D activation, thereby reducing calcium absorption, and likely inducing hypercalciuria. These deleterious effects of severe hypercortisolemia combined with underlying hypoparathyroidism led to severe and refractory hypocalcemia requiring repeated admissions, and only improved once his ectopic CS due to MTC was recognized and controlled. The RET kinase inhibitor, selpercatinib, induced a rapid decline in calcitonin, CEA and ACTH levels, and with metyrapone, enabled control of hypercortisolemia and its complications.

SUN-032 Exome Sequencing Reveals that Pathogenic RET Variants Occur at Higher Prevalence Than Previously Recognized: Data from a US Health System Biobank

Background: Multiple Endocrine Neoplasia Syndrome Type 2 (MEN2) is an inherited endocrine disorder characterized by the development of pheochromocytoma, medullary thyroid carcinoma (MTC) and parathyroid neoplasia. MEN2 is autosomal dominant and occurs from activating missense variants in the RET proto-oncogene. The estimated prevalence of MEN2 is thought to be 1 per 30,000 in the general population, and although rare, the identification of MEN2 can aid with early screening and prevention for patients and their families. Aim: The aim of our study was to investigate the prevalence and clinical manifestations of pathogenic RET variants in the multi-ethnic BioMe Biobank. Methods: We used exome sequencing and electronic health record (EHR) data from BioMe Biobank participants, who are recruited from primary care and specialty clinics across a single U.S. Health System. We evaluated exome sequence data from 30,000 BioMe participants for RET variants designated as pathogenic for MEN2 according to the clinical genetics database ClinVar. We reviewed EHR data for carriers of pathogenic RET variants. Results: In the BioMe Biobank, 5 ClinVar pathogenic variants were identified in the RET gene. Fifteen participants were heterozygous carriers of these variants; 5 were of self-reported African ancestry, 5 of Hispanic/Latino ancestry, 2 of European ancestry, and 3 of other or unknown ancestry. The age range of carriers was 23-78 years, and 60% were female. The estimated prevalence of pathogenic RET variant carriers in BioMe was ~1 in 2000. Based on EHRs, only 3 carriers (20%) were identified from usual clinical care as having the diagnosis of MEN2A. All 3 carriers with diagnosed MEN2A had the 10:43114500:T:C variant (rs75076352) and had a history of MTC and pheochromocytoma. One of the 3 carriers had a history of elevated parathyroid hormone levels and renal calculi without hypercalcemia. Two of the 3 carriers had a documented family history of MEN2A. Of the 12 pathogenic RET variant carriers without known MEN2, 9 (75%) were diagnosed with hypertension. 7 (58%) carried the 10:43119548:G:A variant (rs79658334). Of these 7 carriers, one had a thyroid nodule, three had autoimmune thyroid disease, one had an adrenal cortical adenoma with primary hyperaldosteronism and hypokalemic periodic paralysis, and two had no known endocrine conditions. Conclusions: These results from the BioMe Biobank reveal a higher prevalence of pathogenic RET variants than previously recognized. Carriers of pathogenic RET variants demonstrate highly variable expressivity for traits for which earlier diagnoses might improve outcomes; these findings have implications for cascade testing of family members. Genomic screening for pathogenic RET variants will likely improve our understanding of MEN2 on a more molecular basis.

SUN-596 A Rare Case of Metastatic Medullary Thyroid Carcinoma to Pituitary Gland

Background: Metastasis to the hypothalamus & pituitary gland account for 1-2% of sellar masses. Pituitary metastasis of medullary thyroid carcinoma (MTC) accounts for only 6 published cases in the literature. Imaging alone cannot diagnose metastasis & requires resection for histochemical identification. We describe a case of metastatic MTC presenting with 3rd nerve palsy & pituitary lesion. Case Presentation: 63 y.o. man with 1-month history of bilateral retro-orbital headache, diplopia & left eye ptosis presented to the hospital for second evaluation. He had history of MTC (5 x 3 x 2.5 cm), h/o thyroidectomy 5 years prior & known metastatic non-progressive lung lesions on CT. Medications included levothyroxine & citalopram. He had no personal or family history of MEN syndromes. 2 weeks prior he went to another hospital for same complaints. Initial MRI of head found a parasellar 1.6 cm mass extending to sella. Neurosurgery did not recommend intervention at that time. At our hospital, dedicated pituitary MRI this time showed a primary intrasellar lesion displacing normal pituitary gland, without bony erosion, favoring a pituitary macroadenoma with bilateral cavernous sinus invasion. No optic optic chiasm involvement was noted. Calcitonin level was 2582 pg/mL (1580 pg/mL 10 months ago), CEA 17.0 ng/mL [<3.0 ng/mL]. Hormonal workup did not indicate functional adenoma - instead showed partial hypopituitarism, with LH 1.0 mIU/mL [1.24-8.62 mIU/mL], FSH 2.90 mIU/mL, am free testosterone 7.9 pg/mL [35 - 155 pg/mL], total testosterone 522 ng/dL [250-1100 ng/dL], TSH 0.059 [ 0.28-3.89 uIU/mL], free T4 0.72 ng/dL [0.58-1.64 ng/dL], IGF-1 230 [41-279 ng/mL], am cortisol of 8.4 mcg/dL [6.7-22.7 mcg/dL]. Ophthalmology consult revealed CN III palsy with left ptosis, without visual field deficits, indicating mass compression of CN III. Due to persistent headache, 2nd neurosurgical opinion was sought & transphenoidal resection performed. Initial frozen section suggested pituitary adenoma. Gross pathology demonstrated calcitonin, chromogranin A & synaptophysin immunoreactive cells consistent with metastatic MTC. Post operative MRI demonstrated only small residual right sellar & cavernous component. Daily local conventional fractionated radiation was started with Rad/Onc. Tyrosine kinase inhibitor therapy will be considered after post-radiation MRI & genetic testing for RET mutations. Discussion: Our patient’s clinical presentation of severe headache & rapid onset of diplopia was not consistent with pituitary adenoma, and the MRI result was a confounder. Conclusion: Although pituitary metastasis is rare, it should be considered in the differential in the appropriate clinical context. For MTC, active surveillance with imaging and biochemical markers is critical for management. Doubling time of calcitonin <1 year and rising CEA levels should prompt suspicion for disease progression.

All in the family? Analyzing the impact of family history in addition to genotype on medullary thyroid carcinoma aggressiveness in MEN2A patients.

Several guidelines for patients with multiple endocrine neoplasia 2A (MEN2A) take into account genotype and family history of medullary thyroid carcinoma (MTC) disease aggressiveness. We sought to determine if an association exists independent of genotype, which could provide important information for counseling MEN2A patients in management of their MTC. Pedigrees of patients with ≥5 family members with MEN2A were retrospectively reviewed. Analysis was performed among kindreds with the most frequently observed codon mutation (RET 634). Familial MTC disease aggressiveness was evaluated using: (1) mean age at diagnosis of MTC, (2) current mean age of carriers without MTC, (3) proportion of kindred with MTC with metastatic disease at diagnosis, (4) proportion of kindred with MTC with metastasis/death from MTC as worst outcome, and (5) proportion of kindred with disease progression. 170 affected patients from 12 different MEN2A kindreds met inclusion criteria. The number of affected family members available for study per kindred ranged from 8 to 43 individuals. A difference in mean age of MTC diagnosis was found in screened patients (p=0.01); mean age of MTC-free patients did not differ (p=0.93). No differences were noted among kindreds in disease stage at presentation, worst outcome, or progression; marked variation in these measures was noted within families. In conclusion, a difference in age of MTC diagnosis among different RET 634 kindreds was identified. In contrast, notable intra-familial variability in disease aggressiveness was observed. Based on these findings, we recommend counseling patients with codon 634 mutations that their MTC disease course cannot be predicted by that of their relatives.

Usefulness of Serum Calcitonin in Patients Without a Suspicious History of Medullary Thyroid Carcinoma and with Thyroid Nodules Without an Indication for Fine-Needle Aspiration or with Benign Cytology.

This study evaluated the usefulness of serum calcitonin (Ctn) in subjects without a suspicious history of medullary thyroid carcinoma (MTC) and with nodular thyroid disease without an indication for fine-needle aspiration (FNA) or with benign cytology. This was a prospective study that evaluated 421 patients with nodular disease without an indication for FNA and 602 patients with benign cytology. Patients with basal Ctn>10 pg/ml were submitted to calcium stimulation testing. Patients with stimulated Ctn>100 pg/ml were submitted to total thyroidectomy. Basal Ctn was<10 pg/ml in 1001 patients (97.8%). Among patients with basal Ctn>10 pg/ml, 16/22 exhibited stimulated Ctn>100 pg/ml. Two of these 16 patients had MTC. The 2 patients with MTC had undetectable basal Ctn 6 months after surgery. Using a cut-off of 30 pg/ml in women and 60 pg/ml in men for basal Ctn, the 2 cases of MTC of our series would have been identified and there would have been no false-positive case. It should be noted that 14/16 patients with stimulated Ctn>100 pg/ml were false-positive cases. Although uncommon, even subjects without a suspicious history and with nodular thyroid disease without an indication for FNA or with benign cytology can have MTC. The measurement of Ctn permits the diagnosis of these cases. Our results favor the hypothesis that basal Ctn could be superior to stimulated Ctn.

My, How Things Have Changed in Multiple Endocrine Neoplasia Type 2A!

The history of medullary thyroid carcinoma (MTC) has been characterized by several distinct phases. The initial descriptive phase originated with the 1961 report from John Sipple describing the association of thyroid carcinoma and pheochromocytoma (1). Subsequent investigators correctly identified the thyroid malignancy as MTC, showed that the tumor produced the newly discovered hormone calcitonin, and further categorized this syndrome into its two major subtypes—multiple endocrine neoplasia (MEN) types 2A and 2B (2–4). The second phase began in the late 1960s with the use of serum calcitonin measurements to identify MTC and successful treatment of the malignancy by total thyroidectomy and lymph node dissection. In the 1970s and 1980s, investigators questioned whether MTC could be identified in children at risk for inheriting the disease through the use of provocative calcitonin testing and treatment by early thyroidectomy (5, 6). These studies identified well-defined kindreds with MEN2, an essential resource for the genetic linkage analysis to map the causative gene. The third phase began in 1993 with the identification of RET proto-oncogenemutations inMEN2and theuseof this information to identify affected children (7, 8). The fourth phase began in 2002 with the recognition that small organic molecules that inhibit phosphorylation of RET (and other kinase receptors) have therapeutic efficacy for treatment of metastatic MTC (9), leading to recent Food and Drug Administration approval of two agents for this purpose (10, 11). Machens and Dralle (12), in their insightful report published in this issue, summarize their substantial lifetime contributions to this field and, through their experience, chronicle the changes that have occurred over the past 50 years. Perhaps the most significant observation made by the authors in their report has been the impact of early thyroidectomy on the presence of disease and identifiable metastasis, assessed by histological evaluation of the thyroid gland and lymph nodes removed for treatment of MTC. For those non-index patients with American Thyroid Association (ATA)-labeled level C (high-risk) mutations (13), the percentage with MTC found in the thyroid gland at thyroidectomy has fallen from 100% in the 1985–1989 period to 19% in the 2010–2014 period. This dramatic decrease was caused initially by provocative testing that lowered the age of thyroidectomy to an average of 13 years, with a drop from 100% MTC to approximately 50% in the series of cases that encompassed the period from 1971–1988 (6). The decline was further accelerated by the rapid adoption of genetic testing and the acceptance of the recommendation that children with level C mutations undergo thyroidectomy by age 5 or 6 years. Interestingly, there has not been a comparable decline in the MTC or node positivity in the level A or B mutations, a point to which we will return later. Another important observation, highlighted by their data, is the shift in frequency of specific mutations over the past 20 years. In the classic report by Eng et al (14) in 1996, approximately 80% of mutations identified in MEN2 occurred at codon 634 of the RET proto-oncogene (Figure 1). Sipple’s syndrome, or classic MEN2A, the association of MTC, pheochromocytoma, and hyperparathyroidism caused most commonly by a codon 634 RET mutation, came to attention in 1961 (1) because it is a “noisy” syndrome with as many patients initially identified based on the presence of hypercalcemia or pheochromocytoma as MTC, facilitating its identification in the pregenetic era. Subsequent reports by Yip et al (15) in 2003 and Frank-

Novel tandem germlineRETproto-oncogene mutations in a patient with multiple endocrine neoplasia type 2B: Report of a case and a literature review of tandemRETmutations within silicoanalysis

Multiple endocrine neoplasia type 2B (MEN2B) is the rarest and most aggressive form of MEN2. MEN2B cases usually carry either an M918T or A883T mutation of the RET, but to date, there are 3 atypical MEN2B caused by tandem mutations. A 32-year-old woman with no family history of medullary thyroid carcinoma (MTC) presented with a neck tumor and multiple mucosal nodules. She was diagnosed with MEN2B. Genetic analyses of RET revealed that she had 2 mutations, Q781R and V804M. Subclone and genetic analyses revealed that Q781R was on the paternal allele and V804M was a de novo. In silico analysis of the tandem mutations showed a high prediction score. We describe a novel combination of tandem RET mutations (Q781R/V804M) in a MEN2B-like patient. In silico analysis showed a high prediction score, which was compatible with the clinical phenotype in the present case.

La TEP-TDM à la 18F-Dopa aurait-elle un rôle dans le suivi postopératoire des patients atteints de carcinome médullaire de la thyroïde ? Résultats préliminaires de l’expérience strasbourgeoise et revue de la littérature

Aim Retrospective study to assess the value of fluorine-18 dihydroxyphenylalanine ( 18F-Dopa) positron emission tomography (PET)/computed tomography (CT) in the post-surgical follow-up of patients with history of medullary thyroid carcinoma (MTC) and biological suspicion of disease relapse. A review of the literature was also performed. Patients and methods Ten patients (23–71 years) with MTC previously treated by surgery were examined by at least one 18F-Dopa PET/CT. All patients presented with elevated serum calcitonin (130–9076 ng/l) and/or CEA (1.2–518 ng/ml) levels. 3D whole body PET/CT was performed 45 and 120 minutes after intravenous injection of 4 MBq/kg of 18F-Dopa. Scintigraphic images were visually interpreted. For quantitative analysis, maximum standardized uptake value (SUV max) per focus was employed. PET results were compared with histological findings and/or with the results of all other imaging procedures. Results Seven patients (70%) had a positive 18F-Dopa PET/CT. Twenty-five focal tracer accumulations were described. Histopathological confirmation of metastatic disease was obtained in four of the seven patients with pathologic 18F-Dopa PET/CT. No scintigraphic abnormalities were evidenced in the three other patients, whose conventional morphological imaging procedures were also negatives. Delayed PET/CT examinations didn’t increase sensitivity. No correlation between 18F-Dopa PET/CT results and both serum calcitonin and CEA levels was achieved. Conclusion Our results are in accordance with the existing literature, showing the potential role of 18F-Dopa PET/CT in the clinical management of patients with history of MTC and biological suspicion of relapse during post-surgical follow-up. Prospective studies including larger patient series are necessary to confirm the future place of 18F-Dopa PET/CT in follow-up of MTC.

GLP-1 and Calcitonin Concentration in Humans: Lack of Evidence of Calcitonin Release from Sequential Screening in over 5000 Subjects with Type 2 Diabetes or Nondiabetic Obese Subjects Treated with the Human GLP-1 Analog, Liraglutide

Serum calcitonin (CT) is a well-accepted marker of C-cell proliferation, particularly in medullary thyroid carcinoma. Chronic glucagon-like peptide-1 (GLP-1) receptor agonist administration in rodents has been associated with increased serum CT levels and C-cell tumor formation. There are no longitudinal studies measuring CT in humans without medullary thyroid carcinoma or a family history of medullary thyroid carcinoma and no published studies on the effect of GLP-1 receptor agonists on human serum CT concentrations. The aim of the study was to determine serum CT response over time to the GLP-1 receptor agonist liraglutide in subjects with type 2 diabetes mellitus or nondiabetic obese subjects. Unstimulated serum CT concentrations were measured at 3-month intervals for no more than 2 yr in a series of trials in over 5000 subjects receiving liraglutide or control therapy. Basal mean CT concentrations were at the low end of normal range in all treatment groups and remained low throughout the trials. At 2 yr, estimated geometric mean values were no greater than 1.0 ng/liter, well below upper normal ranges for males and females. Proportions of subjects whose CT levels increased above a clinically relevant cutoff of 20 ng/liter were very low in all groups. There was no consistent dose or time-dependent relationship and no consistent difference between treatment groups. These data do not support an effect of GLP-1 receptor activation on serum CT levels in humans and suggest that findings previously reported in rodents may not apply to humans. However, the long-term consequences of GLP-1 receptor agonist treatment are a subject of further studies.

Medullary Thyroid Carcinoma: Molecular Signaling Pathways and Emerging Therapies

Research on medullary thyroid carcinoma (MTC) over the last 55 years has led to a good understanding of the genetic defects and altered molecular pathways associated with its development. Currently, with the use of genetic testing, patients at high risk for MTC can be identified before the disease develops and offered prophylactic treatment. In cases of localized neck disease, surgery can be curative. However, once MTC has spread beyond the neck, systemic therapy may be necessary. Conventional chemotherapy has been shown to be ineffective; however, multikinase inhibitors have shown promise in stabilizing disease, and this year will probably see the approval of a drug (Vandetanib) for advanced unresectable or metastatic disease, which represents a new chapter in the history of MTC. In this paper, we explore newly understood molecular pathways and the most promising emerging therapies that may change the management of MTC.

New drugs: Liraglutide, dalfampridine, and abobotulinumtoxinA

Antidiabetic agent Liraglutide (Victoza—Novo Nordisk) is an analog of glucagon-like peptide-1 (GLP-1) and acts as a GLP-1 receptor agonist. Its properties are most similar to those of exenatide (Byetta), and both agents are administered subcutaneously. Liraglutide and exenatide reduce blood glucose concentrations via several mechanisms that include increased insulin release in the presence of elevated glucose concentrations, decreased glucagon secretion, and delayed gastric emptying. Liraglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes and may be used as monotherapy or in conjunction with one or more oral antidiabetic drugs, such as metformin, glimepiride, or a thiazolidinedione. However, it is not recommended as first-line therapy for patients inadequately controlled on diet and exercise, whereas the labeling for exenatide does not include this limitation. The effectiveness of liraglutide was demonstrated in studies in which it was used alone or in patients also treated with metformin and/or glimepiride or with metformin and rosiglitazone (Avandia). In the study in which liraglutide monotherapy was compared with glimepiride monotherapy, the new drug provided significantly greater reductions in glycosylated hemoglobin (A1C; –0.8% and –1.1% with daily doses of 1.2 and 1.8 mg liraglutide, respectively, compared with –0.5% with 8 mg daily glimepiride, after 52 weeks). In one study, either liraglutide (1.8 mg once a day) or exenatide (10 μg twice a day) was added to a regimen of metformin and/or glimepiride. After 26 weeks, patients receiving liraglutide achieved a significantly greater reduction in A1C from baseline (–1.2%) compared with 0.79% in patients receiving exenatide. Liraglutide also provided significantly greater reductions in fasting plasma glucose, but patients treated with exenatide experienced a greater reduction in postprandial glucose after breakfast and dinner. As with exenatide, many patients treated with liraglutide lose weight (~3 kg on average); this is an added benefit for these medications, which are often used in patients who are overweight. In contrast, use of glimepiride and other sulfonylureas is often associated with weight gain. The adverse events reported most often in the study in which liraglutide was used as monotherapy included nausea (28%), diarrhea (17%), vomiting (11%), constipation (10%), upper respiratory tract infection (10%), and headache (9%). As with exenatide, pancreatitis has been reported infrequently. Caution should be exercised in patients with a history of pancreatitis, particularly when treatment is initiated and following increases in dosage. If symptoms suspected to be associated with pancreatitis develop, treatment should be discontinued. If pancreatitis is confirmed, liraglutide should not be resumed. Liraglutide has been reported to cause malignant thyroid C-cell tumors in rodents, and this is the subject of a boxed warning in the labeling for the drug. Although whether liraglutide causes such tumors, including medullary thyroid carcinoma (MTC), in humans is unknown, the new drug is contraindicated in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2. The labeling for exenatide does not address this problem, although recent observations suggested the possibility of an increased cancer risk with its use. Many of the patients in the clinical studies were tested for the presence of anti-liraglutide antibodies at the end of treatment. These antibodies were detected in approximately 9% of those tested, but the potential for significant neutralization of the clinical benefit was not assessed. Although experienced infrequently, immunogenicity-related events, including urticaria, were reported more often in patients treated with liraglutide (0.8%) than with other antidiabetic agents. Liraglutide is classified in Pregnancy Category C and should only be used during pregnancy if the anticipated benefit justifies the risk to the fetus. Whether the drug is excreted in human milk is not known, and a decision should be made whether to discontinue nursing or not use the drug. The effectiveness and safety of liraglutide in pediatric patients have not been established. Liraglutide is not likely to cause hypoglycemia. However, serious hypoglycemia may result when it is used concurrently with an insulin secretagogue such as a sulfonylurea. The risk of hypoglycemia may be reduced by decreasing the dosage of the latter agent when treatment with liraglutide is initiated. Because liraglutide delays gastric emptying, a potential exists for altered absorption of oral medications used concurrently. Although interactions of this type were not reported in the clinical studies, the potential for changes in absorption and activity of orally administered drugs should be monitored. Liraglutide is administered subcutaneously in the abdomen, thigh, or upper arm. Following administration, maximum concentrations are attained within 12 hours, and the absolute bioavailabil-

Mixed Medullary‐Papillary Carcinoma of the Thyroid: A Case Report

With fewer than 40 cases described in the otolaryngology literature, mixed medullary papillary thyroid carcinoma represents a rare but phenotypically distinct tumor. While isolated medullary carcinoma may be admixed with normal follicular structures, true mixed carcinoma displays morphological and immunological characteristics of medullary and papillary carcinoma within a single lesion. We report the case of a 73-year old woman initially evaluated for a multinodular thyroid goiter. The patient denied a family history of medullary thyroid carcinoma or other endocrine neoplasms. Fine needle aspiration of a nodule of the thyroid isthmus suggested a follicular neoplasm with abundant Hurthle cells and colloid present. Considering these findings, the patient underwent a left thyroid lobectomy with isthmusectomy. Histopathological analysis of the surgical specimen revealed a medullary thyroid carcinoma measuring 0.4 cm in size. Within this lesion, a distinct focus of papillary thyroid carcinoma, follicular variant, measuring 0.1 cm was also identified. Mixed medullary-papillary thyroid carcinoma is a rare clinical entity but merits consideration in the differential diagnosis of thyroid nodules particularly in patients with a family history of thyroid malignancy. The foundation of treatment of this lesion is total thyroidectomy with central compartment node dissection in the clinically N0 neck and dissection of levels II-VII in the node-positive neck.

Bilateral pheochromocytoma during the postpartum period

Pheochromocytoma manifesting during pregnancy is uncommon but it is responsible for a high maternal and fetal mortality rate, especially when unrecognized. Most cases of pheochromocytoma are sporadic but they can be part of hereditary autosomal dominant syndromes. We describe a case of bilateral pheochromocytoma in a term-pregnant patient with a previous history of medullary thyroid carcinoma (MTC). Her genetic study revealed a heterozygous mutation, c.1900T>C, in the RET proto-oncogene which confirmed the diagnosis of multiple endocrine neoplasia type 2A (MEN2A). Unrecognized, the tumors caused a crisis with fatal outcome in the mother during the postpartum period. This event might have been prevented if the tumor had been detected previously. MEN2A affected pregnancy is an unusual condition. This syndrome should be suspected when a pregnant patient has a history of MTC. Early detection and appropriate management can prevent serious maternal and fetal complications. We also reviewed the literature of MEN2A-affected pregnancies.

Long-Term Octreotide Treatment is an Alternative to Adrenalectomy in Patients With Bilateral Pheochromocytoma in the Multiple Endocrine Neoplasia Type 2A Syndrome

Abstract: Pheochromocytoma, a rare tumor arising from catecholamine-producing chromaffin cells in the adrenal medulla, can appear sporadically or be a part of a tumor syndrome, including multiple endocrine neoplasia type 2 (MEN 2). MEN 2 is a rare disorder characterized by the presence of medullary thyroid carcinoma (MTC) with pheochromocytoma and/or primary hyperparathyroidism. Clinical presentation requires biochemical confirmation of catecholamine oversecretion, followed by anatomic localization methods (computed tomography, magnetic resonance) and functional diagnostic procedures (metaiodobenzylguanidine scintigraphy, In–111-labeled octreotide), allowing the possibilities for radiotherapy in some cases. Laparoscopic adrenalectomy is the “standard” treatment for benign pheochromocytoma, including the bilateral forms. We present a case of a 35-year-old woman patient with a history of MTC and giant bilateral pheochromocytomas (left adrenal tumor: 11 × 9 cm, right adrenal tumor: 4 × 3 cm in size on magnetic resonance, respectively). She had multiple endocrine neoplasia type 2A confirmed by genetic testing. Because of religious reasons, patient refused surgical treatment. In–111-labeled scintigraphy was performed, which suggested the use of subcutaneous octreotide as an alternative to surgical therapy. We report 24 months of successful treatment with octreotide, which improved symptoms, decreased hormone secretion, and slightly induced a reduction in size of the tumor. Our case shows that an octreotide treatment of pheochromocytoma can be an acceptable alternative to surgery when operation is not possible.

S138 – Treatment Controversy Incidental Micro-Medullary Carcinoma

Objectives 1) Investigate the controversial management dilemma of microscopic foci of medullary thyroid carcinoma found incidentally. 2) Describe appropriate treatment strategies for this rare scenario after critically reviewing the literature. Methods This case is a 33-year-old Caucasian female with a history of a multinodular goiter seen as a referral from an endocrinologist. She had no previous history of parathyroid disease, pheochromocytoma or MEN syndrome. She also had no family history of medullary thyroid carcinoma. The patient underwent total thyroidectomy for multiple nodules with an uneventful operative course and recovery. Results The thyroid was sent for permanent section and evaluated microscopically with an H&amp;E stain. Final microscopic evaluation revealed multiple adenomatous nodules, a 2mm focus of papillary thyroid carcinoma, and a 2 mm focus of medullary thyroid carcinoma. The patient underwent no further surgical treatment. She has undergone chromosomal analysis, evaluation for possible multiple endocrine neoplasia, and serial calcitonin measurements. She is currently disease-free. Conclusions Medullary thyroid carcinoma is a well-described form of thyroid malignancy that typically mandates aggressive surgical treatment; however, there is a paucity of information in the literature concerning sporadic, microscopic foci of medullary thyroid carcinoma. We review the literature and describe appropriate treatment strategies for this rare scenario.

Role of FNA cytology and immunochemistry in the diagnosis and management of medullary thyroid carcinoma: Report of six cases and review of the literature

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine thyroid malignancy. This study retrospectively reviewed 10 fine-needle aspiration samples from six MTC patients. Aspirated specimens were from thyroid (3), cervical lymph nodes (5), left lung (1), and anterior chest wall (1). Cytomorphology consisted predominantly of plasmacytoid cells (3 cases), spindle cells (2 cases), and epithelioid cells (1 case). However, all specimens had a mixture of other cell types and "salt and pepper" chromatin. Only one specimen showed Congo-red-positive amyloid. Calcitonin was expressed in 7/7 specimens. Four patients underwent surgical excision and MTC was confirmed in all four. Follow-up studies included serum calcitonin (3/6 cases) and imaging (2/6 cases). One patient had MTC associated with multiple endocrine neoplasia IIA syndrome and one had familial MTC with a history of MTC in mother. In conclusion, the cytomorphology of MTC is typical and calcitonin immunostain is a reliable method for confirming primary or metastatic MTC. Early cytological diagnosis of MTC positively impacted patient management. Follow-up with serum calcitonin and imaging is helpful in the early detection of recurrences.

Multiple endocrine neoplasia 2A syndrome presenting as peripartum cardiomyopathy due to catecholamine excess

We report the case of a 24-year-old female with a history of medullary thyroid carcinoma who presented at 38 weeks gestation with acute chest pain and shortness of breath. She was found to be in pulmonary edema and respiratory failure. An emergency cesarean section was performed. Subsequently, an echocardiogram revealed an ejection fraction of 10%. After medical therapy with digoxin, milrinone, captopril and diuretics, her condition improved rapidly and a repeat echocardiogram showed that the left ventricular function had normalized. Diagnosis of pheochromocytoma was made by urine and plasma catecholamine measurements. Magnetic resonance imaging revealed a 3.7 cm left adrenal mass. Increased uptake activity was seen in the same region by an (131)I-metaiodobenzylguanidine (MIBG) scan. The patient underwent successful surgical resection of the pheochromocytoma. Subsequent DNA analysis revealed that the patient had a mutation of the RET proto-oncogene. The same mutation was also found in several of her family members. In summary, we report a case of multiple endocrine neoplasia 2A presenting as peripartum cardiomyopathy and cardiovascular collapse. Pheochromocytoma should be considered as a potential cause of peripartum cardiomyopathy.