Elevated Serum Calcitonin Levels Research Articles

C-Cell Hyperplasia and Cystic Papillary Thyroid Carcinoma in a Patient with Type 1B Pseudohypoparathyroidism and Hypercalcitoninaemia: Case Report and Review of the Literature.

Hypercalcitoninaemia has been described in patients with pseudohypoparathyroidism (PHP) type 1A and 1B. Elevated calcitonin levels are thought to result from impaired Gsα receptor signaling, leading to multiple hormone resistance. Evidence on the risk of medullary thyroid carcinoma (MTC) or C-cell hyperplasia in PHP patients with hypercalcitoninaemia is lacking. A 43-year-old Caucasian man was referred to our endocrinology clinic for chronic hypocalcemia associated with elevated serum parathormone levels and a single cystic thyroid nodule. The patient did not show skeletal deformities, and screening for concomitant hormone resistances was negative, except for the presence of elevated serum calcitonin levels. The workup led to a molecular diagnosis of sporadic PHP1B. Fine needle aspiration of the thyroid nodule was not diagnostic. The calcium stimulation test yielded an abnormal calcitonin response. Given the scarcity of data on the risk of thyroid malignancy in PHP and calcium stimulation test results, total thyroidectomy was performed. Histological examination revealed cystic papillary thyroid cancer in a background of diffuse C-cell hyperplasia. To our knowledge, we are the first to describe a rare form of thyroid cancer combined with C-cell hyperplasia in a patient with PHP and hypercalcitoninaemia. In the present case, a mere receptor resistance might not fully explain the elevated calcitonin levels, suggesting that hypercalcitoninaemia should be carefully evaluated in PHP patients, especially in the case of concomitant thyroid nodules. Further studies on larger cohorts are needed to elucidate this topic.

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

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

Ectopic Cushing's syndrome from a corticotropin-releasing hormone-secreting medullary thyroid carcinoma: a rare pitfall of inferior petrosal sinus sampling.

This case report describes a rare presentation of ectopic Cushing's syndrome (CS) due to ectopic corticotropin-releasing hormone (CRH) production from a medullary thyroid carcinoma (MTC). The patient, a 69-year-old man, presented with symptoms of muscle weakness, facial plethora, and easy bruising. An inferior petrosal sinus sampling test (IPSS) demonstrated pituitary adrenocorticotrophic hormone (ACTH) secretion, but a whole-body somatostatin receptor scintigraphy (68Ga-DOTATOC PET/CT) revealed enhanced uptake in the right thyroid lobe which, in addition to a grossly elevated serum calcitonin level, was indicative of an MTC. A 18F-DOPA PET/CT scan supported the diagnosis, and histology confirmed the presence of MTC with perinodal growth and regional lymph node metastasis. On immunohistochemical analysis, the tumor cell stained positively for calcitonin and CRH but negatively for ACTH. Distinctly elevated plasma CRH levels were documented. The patient therefore underwent thyroidectomy and bilateral adrenalectomy. This case shows that CS caused by ectopic CRH secretion may masquerade as CS due to a false positive IPSS test. It also highlights the importance of considering rare causes of CS when diagnostic test results are ambiguous. Medullary thyroid carcinoma may secrete CRH and cause ectopic CS. Ectopic CRH secretion entails a rare pitfall of inferior petrosal sinus sampling yielding a false positive test. Plasma CRH measurements can be useful in selected cases.

The Role of 18F-FDOPA PET/CT in Recurrent Medullary Thyroid Cancer Patients with Elevated Serum Calcitonin Levels.

To evaluate the diagnostic performance of 18F-dihydroxyphenylalanine (FDOPA) positron emission tomography/computed tomography (PET/CT) in the detection of medullary thyroid carcinoma (MTC) recurrence in patients with elevated calcitonin levels. The patients who had undergone 18F-FDOPA PET/CT imaging for elevated calcitonin levels after primary surgery of MTC were included in the study. addition, if available 18F-fluorodeoxyglucose (FDG) PET/CT and Gallium-68 (68Ga)- DOTATATE PET/CT images of the patients were evaluated retrospectively. The sensitivity and diagnostic performance of 18F-DOPA PET/CT were investigated. A total of 14 patients (9 F and 5 M; median age: 45) were included in the analysis. Three patients had MEN IIA syndrome and 1 patient had MEN IIB syndrome, 10 patients had a diagnosis of sporadic MTC. Median calcitonin levels of the patients were calculated as 757.5 (min-max: 28.5-7911) pg/mL. Nine patients and 5 patients had undergone ultrasound and contrast-enhanced computed tomography (ceCT) of the neck, respectively, before 18F-FDOPA PET/CT imaging. 18F-FDOPA PET/CT revealed pathological uptake in the thyroid bed, lymph nodes, and distant organs in three, five and two patients, respectively. Median maximum standardized uptake value for the recurrent or metastatic lesions were calculated as 6.4 (min-max: 1.9-18.4). The sensitivity of 18F-FDOPA PET/CT in the detection of recurrent disease was calculated as 64%. Eight patients had 68Ga-DOTATATE PET/CT and 7 of them had 18F-FDG PET/CT within 3 months period before 18F-FDOPA PET/CT. 18F-FDOPA PET/CT revealed recurrent disease in 4 of 5 and 2 of the 5 patients who had negative 18F-FDG PET/CT and negative 68Ga- DOTATATE PET/CT, respectively. 18F-FDOPA PET/CT can detect recurrence in about two- thirds of patients with elevated calcitonin levels after primary surgery for MTC. Due to variable differentiation degree, different receptor status, and clinical behavior of MTC, all three radiopharmaceuticals can be beneficial and are complementary to each other in patient management.

PSAT387 An Unusual Case of Sporadic Metastatic Medullary Thyroid Cancer Without a Primary Tumor Presenting with Paraneoplastic Cushing's Syndrome

Abstract Introduction Medullary thyroid carcinoma (MTC) accounts for 5-10% of all thyroid cancers and up to 30% of MTCs are hereditary. Only 0.6% of MTCs are associated with a paraneoplastic ACTH-dependent Cushing's syndrome (CS) (PMID: 16029131). Even rarer are MTCs without a primary intra-thyroidal tumor. Here we describe a patient with metastatic MTC without a known primary intrathyroidal tumor presenting with paraneoplastic ACTH-dependent CS. Clinical Case A 47-year-old Ukrainian man was referred to our center for management of metastatic MTC. During evaluation of refractory diarrhea two years earlier, an elevated serum calcitonin (1758 pg/mL, normal: <11.5) led to the diagnosis. Thyroid ultrasound revealed a normal thyroid with bulky cervical lymphadenopathy. Cervical lymph node biopsy revealed metastatic MTC with positive calcitonin, synaptophysin, and chromogranin-A on immunohistochemistry (IHC) and RET protooncogene M918T pathogenic variant on molecular testing. Germline testing for RET pathogenic variants was negative. Prior to referral, the patient was on octreotide to control diarrhea and vandetanib for a few months, but they were discontinued due to financial stress. At our center, patient complained of 4-6 watery bowel movements daily. Physical examination revealed facial plethora, dorsocervical fat pad, central adiposity, wide purple striae, and pustular acne on the chest wall and proximal muscle weakness. Biochemical testing revealed elevated serum calcitonin (158,535 pg/mL, normal: <14.3), carcinoembryonic antigen (3,634 ng/mL, normal: 0.8–6.2), and chromogranin-A (5504 ng/mL, normal<93) levels. Morning serum cortisol (40.4 mcg/dL, normal: 3.7–19.4), and plasma ACTH (116.0 pg/mL, normal: 5.0-46.0) levels were elevated, along with markedly elevated 24-hour urine free cortisol levels (12,460.8 mcg/24-hour, normal: 35-45.0), consistent with ACTH-dependent Cushing's syndrome. Further IHC testing of the tumor biopsy sample revealed mild ACTH positivity. A pituitary MRI was normal. Stool osmolality studies showed a secretory diarrhea pattern. Computed tomography (CT) of neck and torso demonstrated bulky cervical, retroperitoneal, and inguinal lymphadenopathy, and extensive liver metastasis, all of which were strongly avid on an 18-fluorodeoxyglucose positron emission tomography CT scan, but poorly avid on a gallium-68 DOTATATE scan. Sodium fluoride bone scan revealed multiple osseous metastases in the spine, ribs, pelvis, and in the right femoral shaft. An adrenal CT scan revealed bilateral adrenal hyperplasia. The patient was unfortunately not eligible for any ongoing local clinical trials on RET-mutated cancer therapies. After extensive discussion with the patient, a palliative approach was pursued. The cervical lymphadenopathy and right femoral shaft metastasis were treated with external beam radiation. Diarrhea was controlled with loperamide. Cushing's syndrome was initially managed with metyrapone and ketoconazole, followed by bilateral adrenalectomy and hydrocortisone and fludrocortisone replacement. Conclusion Sporadic metastatic MTC can rarely present without an intrathyroidal primary tumor and may originate from ectopic C-cells. Paraneoplastic syndromes such as Cushing's syndrome can be observed in MTC due to ectopic-ACTH production. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Evaluation of F-18 DOPA PET/CT in the detection of recurrent or metastatic medullary thyroid carcinoma: comparison with GA-68 DOTA-TATE PET/CT.

PET imaging with F-18 DOPA (FDOPA) and Ga-68 DOTATATE (TATE) shows the most promising results to detect medullary thyroid cancer (MTC) recurrence. We performed this comparative study to detect the site of recurrent or metastatic disease in MTC patients with elevated serum calcitonin (Ctn) and/or carcinoembryonic antigen (CEA) levels. We studied 46 MTC patients (25 women, 21 men) with elevated Ctn and/or CEA levels during follow-up who had both FDOPA and TATE PET/CT scans for re-staging purposes. FDOPA PET imaging yielded an overall sensitivity of 86.8%, specificity of 100%, PPV of 100%, NPV of 61.5%, and accuracy of 89.1%, while TATE PET scan had the same values as 84.2%, 87.5%, 96.9%, 53.8%, and 84.6%, respectively, and there was no statistically significant difference between the two modalities with the exception of the specificity value that was higher for FDOPA imaging. In a subgroup of patients with overt Ctn or CEA elevation, sensitivity of FDOPA increased significantly, whereas TATE sensitivity did not change. FDOPA PET imaging was significantly superior in detecting liver and regional lymph node (LN) metastases, while TATE PET scan was significantly better in the skeletal metastases. Early FDOPA demonstrated 11 invisible lesions on late FDOPA. Both FDOPA and TATE PET/CT imaging are useful to localize recurrences in MTC patients. While TATE imaging is superior to reveal skeletal disease, FDOPA seems better in liver and regional LN metastases; therefore, the two modalities appear complementary in monitoring MTC patients with elevated serum Ctn and/or CEA levels.

GHRH secretion from a pancreatic neuroendocrine tumor causing gigantism in a patient with MEN1.

SummaryA male patient with a germline mutation in MEN1 presented at the age of 18 with classical features of gigantism. Previously, he had undergone resection of an insulin-secreting pancreatic neuroendocrine tumour (pNET) at the age of 10 years and had subtotal parathyroidectomy due to primary hyperparathyroidism at the age of 15 years. He was found to have significantly elevated serum IGF-1, GH, GHRH and calcitonin levels. Pituitary MRI showed an overall bulky gland with a 3 mm hypoechoic area. Abdominal MRI showed a 27 mm mass in the head of the pancreas and a 6 mm lesion in the tail. Lanreotide-Autogel 120 mg/month reduced GHRH by 45% and IGF-1 by 20%. Following pancreaticoduodenectomy, four NETs were identified with positive GHRH and calcitonin staining and Ki-67 index of 2% in the largest lesion. The pancreas tail lesion was not removed. Post-operatively, GHRH and calcitonin levels were undetectable, IGF-1 levels normalised and GH suppressed normally on glucose challenge. Post-operative fasting glucose and HbA1c levels have remained normal at the last check-up. While adolescent-onset cases of GHRH-secreting pNETs have been described, to the best of our knowledge, this is the first reported case of ectopic GHRH in a paediatric setting leading to gigantism in a patient with MEN1. Our case highlights the importance of distinguishing between pituitary and ectopic causes of gigantism, especially in the setting of MEN1, where paediatric somatotroph adenomas causing gigantism are extremely rare.Learning pointsIt is important to diagnose gigantism and its underlying cause (pituitary vs ectopic) early in order to prevent further growth and avoid unnecessary pituitary surgery. The most common primary tumour sites in ectopic acromegaly include the lung (53%) and the pancreas (34%) (1): 76% of patients with a pNET secreting GHRH showed a MEN1 mutation (1).Plasma GHRH testing is readily available in international laboratories and can be a useful diagnostic tool in distinguishing between pituitary acromegaly mediated by GH and ectopic acromegaly mediated by GHRH. Positive GHRH immunostaining in the NET tissue confirms the diagnosis.Distinguishing between pituitary (somatotroph) hyperplasia secondary to ectopic GHRH and pituitary adenoma is difficult and requires specialist neuroradiology input and consideration, especially in the MEN1 setting. It is important to note that the vast majority of GHRH-secreting tumours (lung, pancreas, phaeochromocytoma) are expected to be visible on cross-sectional imaging (median diameter 55 mm) (1). Therefore, we suggest that a chest X-ray and an abdominal ultrasound checking the adrenal glands and the pancreas should be included in the routine work-up of newly diagnosed acromegaly patients.

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.

Calcitonin Levels in Thyroid Disease Are Not Affected by Autoimmune Thyroiditis or Differentiated Thyroid Carcinoma

Introduction: Association between hypercalcitoninemia and pathological conditions such as autoimmune thyroiditis (AIT) or differentiated thyroid carcinoma (DTC) has been addressed, with conflicting results. We evaluated the prevalence and the clinical relevance of elevated basal serum calcitonin (CT) levels in non-neoplastic (nodular goiter [NG] and AIT) and neoplastic thyroid diseases (DTC). Methods: We retrospectively evaluated 3,250 consecutive patients with thyroid nodular disease who underwent fine-needle aspiration cytology with adequate sample. After exclusion of medullary thyroid cancer (MTC) patients were divided according to the presence/absence of thyroid autoimmunity into NG or nodular autoimmune thyroiditis (N-AIT) and, according to cytological results, in benign or suspicious/malignant nodules. Results: One hundred ninety-seven/3,250 patients (6.0%) showed CT level >10 pg/mL. In 11/3,250 (0.3%) cases, a final histological diagnosis of MTC was made, while the remaining 186/3,250 patients (5.7%) had non-MTC-related hypercalcitoninemia (CT > 10 pg/mL). According to cytological diagnosis, the rate of hypercalcitoninemia was similar in class II and class V–VI groups (5.4 vs. 6.9%, p = 0.4). The occurrence of hypercalcitoninemia was significantly higher in patients with NG (166/2,634 [6.3%]) than in patients with N-AIT (20/605 [3.3%]) (p = 0.004). However, after matching by sex, no difference was found between the 2 groups (NG and N-AIT). These results were confirmed in 598 patients submitted to surgery. Conclusions: AIT and DTC seem not to affect serum CT levels in patients with thyroid nodules. Therefore, hypercalcitoninemia, in these patients, should be submitted to the same diagnostic workup than patients without AIT or DTC.

Considerations for Thyroid Fine Needle Aspiration (FNA) Biopsies During the COVID-19 Pandemic

Considerations for Thyroid Fine Needle Aspiration (FNA) Biopsies During the COVID-19 Pandemic

F-18-Dopa Positron Emission Tomography/Computed Tomography Is More Sensitive Than Whole-Body Magnetic Resonance Imaging for the Localization of Persistent/Recurrent Disease of Medullary Thyroid Cancer Patients.

Background: Elevated postoperative serum calcitonin (Ctn) level indicates persistent/recurrent disease in patients with medullary thyroid carcinoma (MTC). Its location is a challenge. The aim of our study was to compare the disease detection rates of F-18-Dopa (fluoro dihydroxyphenylalanine) positron emission tomography (PET)/computed tomography (CT), whole-body (WB) magnetic resonance imaging (MRI), F-18-FDG (fluorodeoxyglucose) PET/CT, WB CT scanning, neck ultrasonography, and bone scintigraphy in MTC patients with increased Ctn levels and unknown localization of the source. Methods: We compared the independent reading of each imaging procedure with a reference assessment for structural disease defined by pathology or concordance between two imagings or with subsequent follow-up. The detection rate of each imaging modality was determined in per patient, per organ, and per lesion analysis. Results: Thirty-six consecutive patients (21 females, mean age: 57 years, sporadic MTC in 26 cases, median serum Ctn level: 760 pg/mL; range: 21-10,121) were analyzed. The reference assessment localized disease in 24 (64%) patients with 74 lesions detected in the thyroid bed (8), in neck lymph nodes (15), mediastinal lymph nodes (6), lungs (1), liver (2), bones (3), and other site (1). At the patient level, the detection rates were 64% (CI 0.48-0.80) for F-18-Dopa PET/CT with early acquisitions, 40% (CI 0.24-0.56) for F-18-FDG PET/CT, 40% (CI 0.24-0.56) for WB MRI, and 48% (CI 0.31-0.66) for WB CT scan. Conclusions: In MTC patients with increased Ctn and no known distant metastases, F-18-Dopa PET/CT is more sensitive to detect structural disease than any other imaging modality, including WB MRI.

RET S409Y Germline Mutation and Associated Medullary Thyroid Carcinoma.

Background: Inherited medullary thyroid carcinoma (MTC) is primarily caused by RET mutations that are commonly localized in exons 5, 8, 10, 11, and 13-16. In this study, we report pedigrees for individuals with MTC that harbor a germline S409Y variant within exon 6 of the RET proto-oncogene. Methods: Targeted sequencing was used to diagnose four apparently sporadic MTC index cases carrying the germline RET S409Y (c.1226 C>A) variant. Subsequently, 27 relatives of these individuals underwent clinical and genetic assessments and/or thyroid surgery. Furthermore, in silico analyses and in vitro assays were performed to predict or verify the potential oncogenic activity of the S409Y variant. Results: Overall, 15 of 31 participants were found to carry the RET S409Y variant. Of these, 6 presented with isolated MTC (mean age 50.2 years; range 41-75 years), of which 3 presented with neck lymph node metastases and 2 presented with distant liver or lung metastases. Among the remaining 9 carriers, 3 (mean age 56 years; range 41-76 years) had elevated serum calcium-stimulated calcitonin (sCtn) or concurrent marginally elevated serum calcitonin (Ctn) levels, whereas the other 6 (mean age 37.5 years; range 14-52 years) exhibited typical Ctn/sCtn levels (p < 0.05). None of the 15 carriers in these 4 families presented clinical evidence of pheochromocytoma, hyperparathyroidism, or Hirschsprung's disease. In silico analyses revealed that S409Y was a "possibly damaging" mutation that could affect the RET protein inter-domain interface. An in vitro assay revealed that the phosphorylation level of RET tyrosine 905 was relatively higher in the RET S409Y mutant than in wild-type (WT) RET. Moreover, transfection of HEK 293 cells with S409Y enhanced the phosphorylation activity of AKT, ERK pathways, and it increased cell proliferation compared with WT RET, but to a lesser degree than that for the RET C618Y and C634Y mutations. Conclusions: This study demonstrates that the novel germline RET S409Y variant is likely pathogenic and is associated with lower penetrance of MTC than that for the C618Y and C634Y mutations. Individuals with S409Y should be managed using a personalized approach, and additionally, "at-risk" family members should be evaluated. Additional studies are needed to elucidate the correlation between the S409Y mutation and multiple endocrine neoplasia type 2-specific tumors.

18F]DOPA PET/ceCT in diagnosis and staging of primary medullary thyroid carcinoma prior to surgery

PurposeMedullary thyroid carcinoma (MTC) is characterized by a high rate of metastasis. In this study we evaluated the ability of [18F]DOPA PET/ceCT to stage MTC in patients with suspicious thyroid nodules and pathologically elevated serum calcitonin (Ctn) levels prior to total thyroidectomy and lymph node (LN) dissection.MethodsA group of 32 patients with sonographically suspicious thyroid nodules and pathologically elevated basal Ctn (bCtn) and stimulated Ctn (sCtn) levels underwent DOPA PET/ceCT prior to surgery. Postoperative histology served as the standard of reference for ultrasonography and DOPA PET/ceCT region-based LN staging. Univariate and multivariate regression analyses as well as receiver operating characteristic analysis were used to evaluate the correlations between preoperative and histological parameters and postoperative tumour persistence or relapse.ResultsPrimary MTC was histologically verified in all patients. Of the 32 patients, 28 showed increased DOPA decarboxylase activity in the primary tumour (sensitivity 88%, mean SUVmax 10.5). Undetected tumours were exclusively staged pT1a. The sensitivities of DOPA PET in the detection of central and lateral metastatic neck LN were 53% and 73%, in contrast to 20% and 39%, respectively, for neck ultrasonography. Preoperative bCtn and carcinoembryonic antigen levels as well as cN1b status and the number of involved neck regions on DOPA PET/ceCT were predictive of postoperative tumour persistence/relapse in the univariate regression analysis (P < 0.05). Only DOPA PET/ceCT cN1b status remained significant in the multivariate analysis (P = 0.016, relative risk 4.02).ConclusionThis study revealed that DOPA PET/ceCT has high sensitivity in the detection of primary MTC and superior sensitivity in the detection of LN metastases compared to ultrasonography. DOPA PET/ceCT identification of N1b status predicts postoperative tumour persistence. Thus, implementation of a DOPA-guided LN dissection might improve surgical success.

Patients with papillary thyroid carcinoma associated with high stimulated serum calcitonin levels.

Among various substances produced by C-cells, the most important one is calcitonin (CT) that is used for detection, post-operative follow-up and evaluation of individuals at risk of developing medullary thyroid carcinoma (MTC). However, the role of serum CT measurement in the evaluation of thyroid nodules has been widely discussed, and there is still no consensus about the role of CT in the initial evaluation of all thyroid nodules. Two patients with thyroid nodules whose fine-needle aspiration results were compatible with benign cytology besides having mildly elevated basal serum calcitonin levels were reported. Calcitonin responses (peak levels were 313 and 229 pg/mL, respectively) to calcium stimulation test were compatible with the possible diagnosis of MTC. However, the final diagnosis was papillary thyroid carcinoma of the thyroid gland. There are limited numbers of case reports showing such an increased serum calcitonin responses to calcium stimulation test associated with papillary or follicular thyroid carcinoma of the thyroid. We suggest to measure serum CT level once and in case of normal levels, no further CT measurement is necessary. Physicians should keep in mind that thyroid carcinomas other than MTCs may also be associated with high serum CT levels.Learning points:Although serum calcitonin is a valuable tumor marker for MTC, it is well known that mild elevations may be seen in some other diseases such as Hashimoto thyroiditis, neuroendocrine tumors or due to medications such as proton pump inhibitors, calcium salts, beta blockers and glucocorticoids.Those two cases indicate that high calcitonin responses to calcium stimulation test, mimicking MTC, may also be seen in patients with papillary thyroid carcinoma although the mechanism is not clear.

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Case Presentation: A 19-year-old female with multiple endocrine neoplasia type 2A secondary to a p.C634R mutation in the RET proto-oncogene presented for ongoing evaluation of persistent medullary thyroid carcinoma (MTC). She had a total thyroidectomy with central and bilateral lateral neck dissections at the age of 16 years at an outside institution. Final surgical pathology demonstrated a bilateral MTC (largest focus 3.7 cm in the right lobe), and 2 of 53 lymph nodes were positive. Final cancer staging was stage IVA (T2N1bM0). Postoperatively, the patient was identified to have a persistently elevated serum calcitonin level. At the initial visit to the University of Texas MD Anderson Cancer Center, no cervical lymphadenopathy was palpated, and the patient's calcitonin and carcinoembryonic antigen levels were 788 pg/mL (normal, ≤5 pg/mL) and 2.7 ng/mL (normal range, 0.0 to 3.0 ng/mL), respectively. Neck ultrasound (US) did not identify any pathologic lymphadenopathy, and a computed tomography (CT) chest and abdomen did not reveal distant metastases or adrenal mass. A contrast-enhanced CT scan of the neck documented a 1.5-cm right-sided enhancing mass in the retropharyngeal space (Fig. 1). What is the diagnosis?

Normalization of Hypercalcemia Following Successful Treatment of Bilateral Pheochromocytomas Due to A MAX Gene Mutation

ABSTRACT Objective: Pheochromocytoma (PCC) is one of the most heritable tumors known. Currently, 14 gene mutations have been linked with familial PCC. This report describes a novel mutation in one of these known PCC-predisposing mutations. Methods: A patient was diagnosed with bilateral PCCs following discovery of elevated 24-hour urine catecholamines and an abdominal computed tomography scan demonstrating bilateral adrenal masses. Pre-operatively, the patient was found to have elevated serum calcium and calcitonin levels, raising the possibility of multiple endocrine neoplasia (MEN) type 2. The patient underwent a bilateral total adrenalectomy. Postoperative genetic testing was performed. Results: Genetic testing for mutations in the RET proto-oncogene was negative. Serum calcium and calcitonin levels returned to the normal range postoperatively. Repeat genetic testing at a later date revealed a novel heterozygous MYC-associated factor X (MAX) gene mutation (c.3G>A). Conclusion: Testing for mutations in ...

Metastatic Moderately Differentiated Neuroendocrine Carcinoma Of The Larynx Mimicking Medullary Thyroid Cancer

ABSTRACT Objective: The objective of this report is to describe a case of metastatic moderately differentiated neuroendocrine carcinoma (MDNC) of the larynx with markedly elevated serum calcitonin levels mimicking medullary thyroid carcinoma. Methods: We present the clinical, laboratory, and radiologic findings in a patient with an unusual clinical course of metastatic MDNC of the larynx, as well as a review of the relevant literature. Results: A 72-year-old male presented with an enlarging right neck mass. Positron emission tomography–computed tomography of the neck revealed enlarged right level III lymph nodes with compressive effect on the right internal jugular vein. Surgical resection of the lymph nodes was consistent with metastatic medullary carcinoma. Immunohistochemical staining was positive for cytokeratin, synaptophysin, chromogranin, and calcitonin, but negative for thyroid transcription factor-1 (TTF-1). No focus of medullary thyroid cancer or evidence of C-cell hyperplasia was identified aft...

Calcitonin-Secreting Pancreatic Neuroendocrine Tumor in a Patient with Multiple Endocrine Neoplasia Type 1

ABSTRACT Objective: To present a patient with multiple endocrine neoplasia type 1 (MEN1) syndrome recently diagnosed with a calcitonin-secreting pancreatic neuroendocrine tumor. Methods: Clinical and diagnostic evaluation, along with intervention, is presented. The relevant literature is reviewed. Results: The patient was a 52-year-old Caucasian man with a history of known MEN1 who had a right parathyroidectomy 10 years prior to admission, completion parathyroidectomy and total thyroidectomy for C cell hyperplasia 3 years prior, and removal of a pituitary adenoma 4 years prior. He was asymptomatic but had persistently elevated serum calcitonin levels. Venous sampling and positron emission tomography–computerized tomography indicated several lesions in the pancreas as the most likely cause of ectopic calcitonin secretion. The patient underwent pylorus-sparing pancreaticoduodenectomy (Whipple procedure). Several well-differentiated neuroendocrine lesions of the pancreas were noted, with lymphatic invasion a...

Vandetanib induces a marked anti-tumor effect and amelioration of ectopic Cushing's syndrome in a medullary thyroid carcinoma patient.

SummaryA 55-year-old woman diagnosed with sporadic MTC underwent total thyroidectomy 20 years ago. After the first surgery, elevated calcitonin levels in parallel with local disease persistence were noted and therefore she underwent repeated neck dissections. During follow-up, multiple foci of metastatic disease were noted in the neck and mediastinal lymph nodes, lungs and bones; however, the disease had an indolent course for a number of years, in parallel with a calcitonin doubling time of more than two years and without significant symptoms. During a routine follow-up visit 2 years ago, findings suggestive of Cushing’s syndrome were observed on physical examination. The biochemical evaluation demonstrated markedly elevated serum calcitonin level, in parallel with lack of cortisol suppression after an overnight 1 mg dexamethasone suppression test, lack of cortisol and ACTH suppression after high-dose IV dexamethasone 8 mg, elevated plasma ACTH up to 79 pg/mL (normal <46 pg/mL) and elevated 24-h urinary free cortisol up to 501 µg/24 h (normal 9–90 µg/24 h). After a negative pituitary MRI, she underwent IPSS, which was compatible with EAS. Whole-body CT demonstrated progressive disease at most of the tumor sites. Treatment with vandetanib at a dosage of 200 mg/day was commenced. The patient showed a significant, rapid and consistent clinical improvement already after two months of treatment, in parallel with biochemical improvement, whereas a decrease in tumor size was demonstrated on follow-up CT.Learning points:Ectopic Cushing’s syndrome due to ectopic ACTH secretion (EAS) by MTC is an uncommon and a poor prognostic event, being associated with significant morbidity and mortality.We demonstrate that vandetanib is effective in controlling the signs and symptoms related to the EAS in patients with advanced progressive MTC.We demonstrate that vandetanib is effective in decreasing tumor size and in inducing tumor control.

Calcitonin-Secreting Neuroendocrine Carcinoma of Larynx with Metastasis to Thyroid.

Primary neuroendocrine tumors of the larynx are rare, with moderately differentiated neuroendocrine carcinoma (MDNC) being the most frequent histologic type. We report a MDNC in a 57-year-old gentleman with an enlarging right-sided neck mass. Flexible fiberoptic exam revealed a right arytenoid lesion. Histology from excisional biopsy was concerning for medullary thyroid carcinoma (MTC) versus NET of the larynx. Immunohistochemistry was diffusely positive for calcitonin and CEA and focally positive for TTF-1. Serum calcitonin was elevated. Thyroid ultrasound was unremarkable. The patient underwent laryngectomy, thyroidectomy, and neck dissection. Pathology showed neuroendocrine carcinoma of right arytenoid with positive cervical lymph nodes. A 4 mm deposit of NET was present in right thyroid with adjacent intravascular tumor consistent with thyroidal metastasis from a primary laryngeal NET (MDNC). MDNC and MTC can be microscopically indistinguishable. Both tumors can stain positively for calcitonin and CEA. TTF-1 staining has been useful to help distinguish these tumors as it is strongly and diffusely positive in MTC, but usually negative (or only focally positive) in MDNC. We report the fourth case of primary neuroendocrine carcinoma of the larynx associated with elevated serum calcitonin level and the first such case associated with metastasis to the thyroid.