SUN-351 Clinical Features And Outcomes Of Medullary Thyroid Cancer Based On Different Bethesda Cytology Categories

The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.

Medullary thyroid carcinoma (MTC) is a rare malignancy originating from aggressive parafollicular C cells that causes 8-13% of thyroid cancer-related deaths despite its low incidence. Calcitonin and carcinoembryonic antigen (CEA) are considered to be important indicators for the diagnosis of MTC, while serum inflammatory markers have been shown to be valuable in the diagnosis and evaluation of a variety of malignant tumors, but the amount of research literature on MTC is still limited. This article aims to assess the value of serum inflammatory markers, CEA and calcitonin in the differential diagnosis of MTC from papillary thyroid carcinoma (PTC), and to explore the risk factors affecting lateral zone lymph node metastasis of MTC and the clinical features that can be predictive of disease-free survival (DFS). We retrospectively analyzed 883 patients with PTC and 128 patients with MTC who received care at West China Hospital Sichuan University. The data of clinical characteristics and follow-up results were collected. In our cohort, after performing propensity score matching (PSM), there were 117 patients in the MTC group and 436 in the PTC group. Compared with PTC, MTC patients had higher neutrophil-lymphocyte ratio (NLR) (P=0.008), neutrophil-monocyte-platelet-to-lymphocyte ratio (NMPLR) (P=0.03), and CEA values (P<0.001), and no significant differences were found between the remaining baseline characteristics, with CEA having the largest area under the curve (AUC) in the differential diagnosis of PTC and MTC at 0.898 [95% confidence interval (CI): 0.862-0.934, P<0.001]. Univariate and multivariate logistic regression analyses showed that the occurrence of extrathyroidal extension (ETE) [P=0.002, odds ratio (OR): 4.159, 95% CI: 2.734-5.584], calcitonin level >1,000 pg/mL (P=0.002, OR: 4.785, 95% CI: 3.220-6.350) and CEA level (P=0.04, OR: 1.005, 95% CI: 1.000-1.010) were significantly correlated with lateral zone lymph node metastasis in MTC, while platelet-to-lymphocyte ratio (PLR) was a predictor of DFS. Preoperative blood inflammatory indexes, CEA, and calcitonin level may be able to initially identify MTC and PTC. Meanwhile, ETE, CEA, and calcitonin levels are independent risk factors for lymph node metastasis in the lateral zone of the MTC; therefore, surgeons should consider more carefully planning surgery in conjunction with imaging in patients who have these risk factors at the initial visit.

Serum levels of calcitonin (CT) and carcinoembryonic antigen (CEA) were evaluated in a group of 41 patients with histologically proven medullary thyroid carcinoma (MCT) before and sequentially after treatment for a period up to 7 years. Before thyroidectomy, CT levels were high in all patients, and significantly more elevated when metastases were present. On the other hand, CEA levels were high in most but not all the patients, and they also were found more frequently to be elevated in patients with metastases. After treatment, most of the patients without metastases showed persistently normal basal and pentagastrin stimulated CT and CEA levels. In some patients either without or with local metastases, postoperative CT levels, although considerably reduced, remained persistently above normal limits, whereas CEA levels became completely normal. This pattern may be due to the persistence of minute occult foci of the tumor, not sufficient to produce measurable amounts of CEA, which is not synthesized by all tumor cells. Most of the patients with metastases at diagnosis, showed still elevated CT and CEA levels after treatment. In the nonprogressive cases both markers decreased after adjunctive treatment or remained unchanged. In patients with progressive disease, an increase of CEA levels in the absence of a parallel increase of CT levels, which even decreased, was often observed. In one patient with progressive disease high CEA levels were seen for the first time when liver metastases had occurred. These data seem to suggest that, even though CEA production is not recognizable in all patients with MCT, in the CEA positive cases CEA levels may follow a nonparallel pattern and may have a distinct diagnostic meaning with respect to CT levels. In some cases, particularly in advanced disease, CEA may be a more useful marker of poor prognosis.

Metastatic disease is common in medullary thyroid carcinoma (MTC) and it is usually detected by raising calcitonin and carcinoembryonic antigen (CEA) levels. Nuclear medicine imaging has an important role in lesion identification/characterisation. We aim to compare 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT performance and to explore the correlations between tumoral markers and functional imaging. This a retrospective cross-sectional study including 13 patients with MTC and high calcitonin/CEA levels that underwent both 68Ga-DOTANOC PET/CT and 18F-FDG PET/CT. 68Ga-DOTANOC PET/CT identified MTC metastases in 2twopatients that were 18F-FDG-negative (sensitivity of 69.2% vs. 53.9%, respectively). 68Ga-DOTANOC PET/CT also detected a higher number of lesions than 18F-FDG PET/CT in seven patients, with only one patient showing the opposite pattern. Both differences lacked statistical significance (p = 0.50 and p = 0.86, respectively) but 68Ga-DOTANOC PET/CT better performance allowed changes in patients' management. 68Ga-positive/18F-FDG-negative patients were the ones with the lowest calcitonin doubling time and presented a CEA doubling time >24 months, while the patient with more 18F-FDG-positive lesions was the one with the highest CEA/calcitonin ratio. The number of lesions found in 68Ga-DOTANOC PET/CT were correlated with calcitonin levels (r = 0.73; p < 0.01) but not with CEA ones (r = 0.42; p = 0.15). The number of 18F-FDG hypermetabolic focus were correlated with CEA levels (r = 0.60; p < 0.05) but not with calcitonin (r = 0.48; p = 0.09). This is the first study to describe a positive correlation between 68Ga-positive lesions and calcitonin levels and between 18F-FDG-positivity and CEA levels. Tumoral markers pattern in metastatic MTC could help clinicians to decide which exam to perform first.

The present study aimed to explore the clinical value of color Doppler ultrasound combined with serum tumor markers, including calcitonin (CT) and carcinoembryonic antigen (CEA), for the diagnosis of medullary thyroid carcinoma (MTC). A total of 39 patients with MTC (MTC group), 50 patients with papillary thyroid carcinoma (PTC) (PTC group) and 30 patients with thyroid adenoma (benign control group) were enrolled in the present study. The patients were hospitalized at the Affiliated Hospital of Qingdao University from January 2012 to December 2018 and were diagnosed through surgical procedures and pathology laboratory results. The ultrasound results, as well as serum CT and CEA results, were collected and analyzed. A significant difference was observed between the MTC and PTC groups in regards to morphology, margin, aspect ratio, calcification, internal blood flow and lymph node metastasis (all P<0.01). There was also a significant difference between the MTC and benign control group in regards to internal echo, calcification, internal blood flow and lymph node metastasis (all P<0.01). In addition, the levels of serum CT and CEA in the MTC group were significantly higher than those in the PTC and the benign control groups (both P<0.01). For patients with MTC, the levels of serum CT and CEA were significantly associated with maximum tumor diameter, lymph node metastasis and the patient state after treatment (all P<0.01). Furthermore, the sensitivities of ultrasound, serum CT and CEA for the diagnosis of MTC were 76.92, 74.36 and 68.23%, respectively. The value for the combination of the three markers (94.87%) was significantly higher compared with the sensitivity value of each separate marker (all P<0.05). In conclusion, color Doppler ultrasound combined with detecting the levels of serum tumor markers (CT and CEA) significantly improved the diagnostic efficiency for MTC, which could be useful for the clinical diagnosis and treatment of MTC.

Disclosure: K.N. Youssef: None. L. Salej: None. A. Gavrila-Filip: None. Background: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor arising from the parafollicular or C cells of the thyroid gland that secretes different tumor markers, including calcitonin (CT) and carcinoembryonic antigen (CEA). CT is only produced by parafollicular cells, while CEA is a non-specific marker produced in various normal tissues, such as epithelial cells of the gastrointestinal tract, lung, breast, and prostate. Different benign and malignant conditions are associated with elevated serum CEA levels. Clinical case: A 69 years-old active smoker male with a history of nasal squamous cell carcinoma (SCC) status post resection in the remote past and bilateral pulmonary nodules underwent total thyroidectomy for a thyroid nodule with FNA positive for medullary carcinoma. Surgical pathology revealed a unifocal 1.5 cm medullary carcinoma with clean surgical margins and no lymphadenopathy. Pre-operative studies included an elevated serum CT of 388 pg/mL (normal ≤ 10 pg/mL), normal serum calcium and PTH levels and a normal 24-hour urinary test for pheochromocytoma. Family history was irrelevant, and the RET proto-oncogene test was negative. Initial post-operative serum CT levels were undetectable and CEA levels were normal (0-4 ng/mL). CT levels increased slowly over the next five years and then they remained stable in the range of 32 to 45 pg/mL. Serum CEA started to rise progressively 7 years after the thyroid surgery up to 6.5 pg/mL. Follow-up neck ultrasounds showed no local recurrence or lymphadenopathy. An extensive evaluation was performed to search for possible MTC metastases and other etiologies for the elevated CEA levels. Bone scan was negative. Chest CT scans revealed enlarging small bilateral pulmonary nodules; stable calcified mediastinal lymph nodes were noted, consistent with chronic granulomatous disease. PET-CT scan showed pulmonary nodules, too small to characterize. The patient underwent a left lower pulmonary lobe robotic-assisted wedge resection. Surgical pathology revealed keratinizing SCC, though to represent primary lung SCC versus metastases from his prior nasal SCC. Upper endoscopy and colonoscopy with biopsy were negative for malignancy. On further workup, the patient was diagnosed with prostate adenocarcinoma and underwent surgery followed by external beam radiation with hormonal therapy. Serum CEA levels normalized one year after the prostate cancer treatment. Serum CT levels remained stable. Conclusion: In patients with MTC who show increasing serum CEA and stable CT levels during follow-up after the initial treatment, it is important to exclude other etiologies before concluding that this change is related to a progression of the medullary cancer. Reference: Carcinoembryonic Antigen. Kankanala VL, Mukkamalla SKR.2022 Jan 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. Presentation Date: Saturday, June 17, 2023

This study was conducted to compare the diagnostic and prognostic values of calcitonin (CT) and carcinoembryonic antigen (CEA) measurements in patients with medullary carcinoma of the thyroid (MCT). Plasma CEA, basal CT (BCT), and peak CT (PCT) levels after pentagastrin stimulation were determined in 15 patients with occult familial MCT before treatment. CEA was elevated in 11 patients (73%), BCT in 8 patients (53%), and PCT in all patients. The prognostic values of serial CEA and BCT determinations were studied in 24 other MCT patients followed for a period of 1.5-8 yr. These patients were divided into 2 groups; group I consisted of 11 patients with normal serial CEA levels, and group II consisted of 13 patients with persistently elevated CEA levels. In group I, 2 patients (18%) developed metastases compared with 10 patients (77%) in group II (P less than 0.001). Elevated BCT levels were found in all patients with metastases as well as in 63% of patients with no evidence of disease. When CEA time curves were studied, three patterns could be identified: 1) a steep slope with rapidly rising CEA levels in patients with rapidly progressive disease, 2) a flat slope in patients with no metastasis or nonprogressive disease, and 3) an intermediate type of slope in patients with slowly progressive disease. Slope analysis of BCT time curves was not done because of marked fluctuations in BCT levels. PCT after pentagastrin stimulation remains the best diagnostic marker for MCT. However, CEA may be a better prognostic indicator, as it discriminated more efficiently between patients with and without metastasis. Slope analysis of CEA time curve and calculation of the doubling time are recommended, as they correlated well with the course of the disease.

The prognostic value of serum calcitonin (CT) and carcinoembryonic antigen (CEA) doubling time has been recently demonstrated in medullary thyroid carcinoma (MTC) patients. No study has yet validated the surrogate role of these markers for survival during treatment. The aim of this study was to evaluate, in patients with advanced MTC treated with cytotoxic chemotherapy, the relationship between early changes of serum CT or CEA levels and progression-free survival (PFS). The files of 28 consecutive metastatic MTC patients with progressive disease, treated with cytotoxic chemotherapy in a single tertiary referral center between 2000 and 2010, were retrospectively reviewed. Serum CT and CEA measurements and radiological Response Evaluation Criteria in Solid Tumors (RECIST) evaluations were collected every 3 months. The relationship between changes in serum CT and CEA levels at 3 months, defined by an increase or a decrease of at least 20%, and PFS according to RECIST 1.0, was estimated using Kaplan-Meier curves and log-rank test. The median follow-up for the 28 patients was 68 months. According to RECIST, a partial response, a stabilization or a progression was observed in 14, 43, and 43% of cases respectively. Median PFS from the initiation of cytotoxic chemotherapy was 4.5 months. Median PFS among patients with and without significant CT increase at 3 months was 4.6 and 3.3 months respectively (P=0.75). Median PFS among patients with a significant CEA increase at 3 months was 2.7 months, whereas it was 19.1 months in patients in whom CEA did not increase (P=0.02). At 3 months, an increase of serum CEA but not of CT levels appears as a valuable surrogate marker of short PFS in MTC patients treated with cytotoxic chemotherapy. A prospective validation is expected.

Medullary thyroid carcinoma (MTC) is a rare disease. Treatment options for recurrent disease are limited. Although somatostatin analogues might have a role as anticancer agents in MTC, the evidence is inconclusive. A 64-year-old male was diagnosed with MTC in January 2010. Total thyroidectomy with neck dissection (stage IVA, pT2pN1bM0, R1) was performed, followed by adjuvant locoregional radiotherapy. Two years later, in January 2012, the patient developed recurrent metastatic disease, evidenced by elevated carcinoembryonic antigen (CEA) and calcitonin levels, and a positive uptake (Octreoscan®) in the right adrenal gland and pancreatic head. A further computed tomography (CT) scan revealed metastases in the right adrenal gland, the duodenal bulb, and two pancreatic lesions, which were later confirmed as metastases by endoscopic ultrasound and cytology, and therefore salvage surgery was ruled out. Treatment with Somatuline Autogel® (120 mg subcutaneously every 28 days) was initiated in September 2012, and 11 months later, calcitonin and CEA levels had both normalized, and a new CT scan showed that the metastatic lesions had disappeared or shrunk markedly. An Octreoscan performed in January 2014 and a repeat contrast-enhanced CT in February 2014 showed sustained tumor response. The patient remained in remission until February 2016, when a new Octreoscan revealed recurrent disease in the right adrenal gland, a nodule in the right upper pulmonary lobe, and nodal disease in the celiac trunk. CEA and calcitonin levels remained normal, although with a slight increase in calcitonin levels (47 pg/mL). The unusual case is described of a patient with metastatic MTC involving the adrenal gland, duodenum, and pancreas, who achieved a sustained response to somatostatin analogues after 11 months of treatment. The patient remained in remission for nearly 3.5 years from initiation of treatment with somatostatin analogues. The case presented here is one of the few described in the literature in which long-term treatment with somatostatin analogues resulted in a sustained tumor response in a patient with metastatic recurrent MTC following curative-intent surgery. These findings suggest that prolonged treatment with somatostatin analogues may be beneficial in asymptomatic cases with a low tumor burden and a positive Octreoscan following recurrence. More data are needed to confirm these findings.

Medullary thyroid carcinoma (MTC) is a differentiated neuroendocrine tumor, mostly slowly growing with a relative good prognosis, with an overall 10-year survival of 61–76% [1,2]. Surgery is the only curative therapy for MTC [3]. After surgery, patients with MTC should be assessed regarding the presence of residual disease, the localization of metastases and the identification of progressive disease. Postoperative staging is used to separate low-risk from high-risk patients with MTC [4]. The TNM system utilizes tumor size, extrathyroidal invasion, nodal metastasis and distant spread of cancer. The number of lymph node metastases and involved compartments as well as postoperative serum calcitonin (CTN) and carcinoembryonic antigen (CEA) levels should be documented in addition. The normalization of serum CTN levels postoperatively is associated with an excellent prognosis (10-year survival >95%). In patients with elevated basal serum CTN levels less than 150 pg/ml following thyroid ectomy, persistent or recurrent disease is almost always confined to lymph nodes in the neck. Unfortunately, many patients with MTC who have regional lymph node metastases also have systemic disease and are not cured biochemically despite aggressive surgery, including bilateral neck dissection [3,5]. In patients with higher CTN levels distant metastases are suspected, having a poor prognosis, with only 40% surviving 10 years [6]. If the postoperative serum CTN level exceeds 150 pg/ml patients should be evaluated by imaging procedures including neck and chest CT, contrast-enhanced MRI and ultrasound of the liver, bone scintigraphy, MRI of the bone and PET/CT. One can estimate the growth rate of MTC metastases from sequential imaging studies using response evaluation criteria in solid tumors (RECIST) [7] that document increases in tumor size over time and by measuring serum levels of CTN or CEA over multiple time points to determine the tumor marker doubling time [8,9]. The treatment goals differ depending on the postoperative tumor stage and the parameters of progressive disease [4]. A risk-stratified follow-up with stage-dependent diagnostic approach and therapy is necessary. One of the main challenges remains to find effective adjuvant and palliative options for patients with metastatic disease. Patients with persistent or recurrent 1

Plasma levels of carcinoembryonic antigen (CEA) and calcitonin (CT) were measured in 35 normal control subjects and in 37 patients with suspected or established medullary thyroid carcinoma (MTC). None of the normal control subjects had elevated basal plasma levels of either CEA (greater than 5 ng/ml) or CT (greater than 0.25 ng/ml). However, of the 37 patients with suspected or established MTC, 23 (62%) had elevated basal plasma levels of CEA (range 9.8--7,000 ng/ml) and 27 (73%) had elevated basal plasma CT values (range 0.30--500 ng/ml). Generally, patients with clinically apparent MTC, either primary or metastatic, had higher plasma CEA and CT levels than those with occult disease. A positive correlation was found (r = 0.785, p less than 0.01) when comparing basal plasma CEA and stimulated plasma CT levels in 20 patients. A marked increase above the basal plasma level of CT but not CEA was detected in each of six MTC patients following intravenous calcium or pentagastrin. These data demonstrate that basal plasma levels of CEA and CT were increased in a large percentage of patients with MTC. Plasma calcitonin levels unlike plasma CEA levels were more often elevated in patients with occult disease and were increased above basal following the intravenous administration of either calcium gluconate or pentagastrin.

Objective To investigate the clinical application value of serum carcinoembryonic antigen (CEA) level in predicting lymph node metastasis of resectable medullary thyroid carcinoma (MTC) . Methods 140 patients of resectable MTC from Zhejiang Cancer Hospital and Hangzhou First People’s Hospital from Jan. 2009 to Feb. 2019 were included. The relationship of serum CEA and lymphatic metastasis was retrospectively analyzed in 140 patients of resectable MTC, and the clinical significance of serum CEA for predicting total lymph node, central lymph node, lateral lymph node and upper mediastinal lymph node metastasis was also evaluated. Results The positive rate of serum CEA in resectable MTC was 77.14%. The expression level of serum CEA in resectable MTC with lymph node metastasis was significantly higher than those without lymph node metastasis (P<0.001) . Spearman correlation analysis further indicated that the level of serum CEA expression was positively correlated with the number of lymph node metastases of resectable MTC patients (P<0.001) . The area under curve of predicting lymphatic metastasis of total lymph node, central lymph node, lateral lymph node and upper mediastinum was 0.773, 0.768, 0.827 and 0.847. When the cut-off value of serum CEA was 6.58, 11.43, 15.74 and 30.45 ng/ml, respectively, the sensitivity of serum CEA to predict total, central, lateral neck and upper mediastinal lymph node metastasis was 88.46%, 81.43%, 85.00%, 95.00%, and the specificity was 56.45%, 60.00%, 71.25%, and 69.17%, respectively. Conclusion Serum CEA has a high positive expression rate in resectable MTC, and its expression level has important clinical significance in evaluation of lymphatic metastasis. Key words: Medullary thyroid carcinoma; Carcinoembryonic antigen; Serum; Lymph node metastasis

The value of carcinoembryonic antigen (CEA) assay for diagnosis and follow-up in patients suffering from medullary carcinoma of the thyroid (MCT) was investigated in a large sample (106 cases). High levels of CEA were found in 84% of patients suffering from either the sporadic or the familial form of the disease. Levels of CEA and calcitonin (CT) are significantly and positively correlated. Removal of tumoral tissue is followed by a decrease in both CEA and CT levels. High levels of CEA were also observed in the parents of patients suffering from the familial form of MCT. These patients were operated on and MCT was confirmed histologically. The limitations of the use of CEA assay in the diagnosis of MCT are discussed.

Aim: This study investigates if serum calcitonin or carcinoembryonic antigen (CEA) levels can differentiate between locoregional and metastatic medullary thyroid cancer. Methods: A single institution retrospective analysis was performed on 88 patients with medullary thyroid cancer between 2008 and 2014. Results: In M0disease, calcitonin (p &lt; 0.001) and CEA (p = 0.003) significantly decreased postoperatively. Not only was the correlation significant between calcitonin and CEA preoperatively (r = 0.72; p &lt; 0.001) and postoperatively (r = 0.68; p &lt; 0.001), calcitonin could extrapolate CEA levels (p &lt; 0.001). These findings were statistically insignificant in metastatic disease. Conclusion: Independently, calcitonin and CEA fail to differentiate between locoregional and metastatic disease. Both are essential for prognostication: loss of concordance is suspicious for metastatic disease. Hence, discordant CEA and calcitonin levels should be an indication to pursue additional imaging.

The Combined use of Calcitonin Doubling time and 18F-FDG PET/CT Improves Prognostic Values in Medullary Thyroid Carcinoma: the Clinical Utility of 18F-FDG PET/CT