Persistent Structural Disease Research Articles

Recurrent Middle Eastern Differentiated Thyroid Carcinoma Has Worse Outcomes Than Persistent Disease.

Background: Despite the excellent prognosis of differentiated thyroid carcinoma (DTC), recurrent and persistent disease remain major challenges. Emerging studies to differentiate between recurrent and persistent disease are controversial, with studies from the Middle East lacking. Methods: We retrospectively analyzed 1691 patients who underwent surgery ± I131 treatment for DTC, with a median age of 38.7 years and median follow-up of 95.3 months. Results: We found a similar prevalence rate for persistent and recurrent disease (17.7% vs. 17.9%) in Middle Eastern DTC patients. Relative to patients with persistent disease, patients with recurrent disease were significantly older (median age: 36.1 vs. 45.8 years; p < 0.0001) and were more likely to have ATA high-risk tumors (61.5% vs. 75.2%; p = 0.0003). On multivariate logistic regression analysis, both T and N status were independent predictors for recurrent as well as structural persistent disease. However, older age, bilaterality and extrathyroidal extension were independent predictors of recurrent disease alone. In addition, patients with recurrent disease had significantly worse cancer-specific survival (p < 0.0001), which remained significant in multivariate analysis. Conclusions: Although persistent and recurrent disease in Middle Eastern DTC have similar frequencies, recurrent disease has worse outcomes compared to persistent disease. Hence, differentiating recurrence from persistence has great potential clinical relevance for therapeutic and follow-up approaches, contributing to improving the outcomes of DTC patients of Middle Eastern ethnicity.

Prognostic Factors Improving ATA Risk System and Dynamic Risk Stratification in Low- and Intermediate-Risk DTC Patients.

American Thyroid Association (ATA) guidelines do not consider age at diagnosis as a prognostic factor on the estimation of the risk of persistent/recurrent disease in differentiated thyroid carcinoma (DTC) patients. While age at diagnosis has already been assessed in high-risk patients, it remains to be established in low- and intermediate-risk patients. The aim of our study was to investigate the role of age as a prognostic factor in the short- and long-term outcome of DTC patients classified at low and intermediate risk according to the ATA stratification risk system. We retrospectively evaluated 863 DTC patients (mean follow-up: 10 ± 6.2 years) 52% classified as low (449/863) and 48% as intermediate risk (414/863). For each ATA-risk class patients were divided into subgroups based on age at diagnosis (<55 or ≥55 years). In the intermediate-risk group, patients aged 55 years or older had a higher rate of structural disease (11.6% vs 8.9%), recurrent disease (4.1% vs 0.7%), and death (4.1% vs 1%) when compared with younger patients (<55 years) (P = .007). Multivariate analysis confirmed that older age at diagnosis (odds ratio [OR] = 3.9; 95% CI, 1.9-8.6; P < .001) was an independent risk factor for worse long-term outcome together with response to initial therapy (OR = 13.0; 95% CI, 6.3-27.9; P < .001), and T (OR = 32; 95% CI, 1.4-7.1; P = .005) and N category (OR = 2.3; 95% CI, 1.1-5.0; P = .03). Nevertheless, a negative effect of older age was documented only in the subgroup of intermediate DTC patients with persistent structural disease after initial therapy. Indeed, the rate of worse long-term outcome rose from 13.3% in the whole population of intermediate DTC patients to 47.8% in patients with persistent structural disease after initial therapy (P < .001) and to 80% in patients older than 55 years and persistent structural disease after initial therapy (P = .02). Our results suggest that age at diagnosis further predict individual outcomes in Intermediate-Risk DTC allowing ongoing management to be tailored accordingly.

Comparison of the initial presentation and long-term outcome of differentiated thyroid carcinoma (DTC) between children and adults: A single institution experience in Taiwan.

163 Background: Differentiated thyroid carcinoma (DTC) in children is known to be more aggressive than in adults. However, there are no cohort studies in Asia that have compared the presentation and long-term outcomes of pediatric DTC with adult DTC. In this study, we aimed to compare the clinical characteristics and outcomes of pediatric DTC with a comparison cohort of adult DTC patients. Methods: We reviewed the data of 46 pediatric DTC patients who underwent total thyroidectomy from January 1991 to December 2021, along with a comparison cohort of 350 adult DTC patients at our hospital. All patients received postoperative radioiodine therapy. Clinicopathologic features and surgical outcomes were analyzed retrospectively, and patients were stratified according to the American Thyroid Association (ATA) risk stratification system. Clinical outcomes were classified according to Dynamic Risk Stratification (DRS) at the end of follow-up. Results: Children with DTC had less common papillary thyroid carcinoma (80 vs. 93%) but had larger primary tumors, more multifocal disease, and more lymph node and distant metastasis at presentation compared to adults. Thus, at initial risk stratification, more children had intermediate-to-high risk (62 vs. 49%) than adults. At the end of follow-up, fewer children were classified as having excellent response (no evidence of disease) than adults (48 vs. 79%). Based on the ATA risk stratification system, a higher percentage of high-risk children had structural-persistent disease (60%) compared to high-risk adults (29%), and a lower percentage of low-risk children became no evidence of disease (76%) compared to low-risk adults (93%). Conclusions: Children with DTC present with more extensive disease and have worse outcomes compared to adults. The ATA initial risk stratification system can predict long-term outcomes in both children and adult DTC patients and guide personalized management and follow-up strategies.

Case Report: Heart failure in the puerperium

BACKGROUND: Cardiomyopathies that occur de novo in relation to pregnancy or childbirth have diverse etiologies, although they are uncommon, they contribute substantially to maternal morbidity and mortality. In addition, during gestation there are hemodynamic changes that could make hidden heart disease manifest and produce ventricular remodeling with the consequent appearance of persistent or transient structural heart disease. Currently, there is little data on the prevalence of heart disease that occurs during or after pregnancy; for this reason it is of utmost importance to know the cardiovascular diseases related to this period. CASE REPORT: A 26-year-old female patient, who during her late puerperium, after her first pregnancy, terminated by cesarean section due to preeclampsia with severity criteria, presented signs and symptoms of heart failure. After evaluation, ischemic causes were ruled out, maintaining a high diagnostic suspicion of peripartum cardiomyopathy, based on the absence of a history of heart disease prior to pregnancy, the presence of preeclampsia during gestation and the clinical presentation associated with the puerperium; however, after searching for the etiology by cardiac imaging studies, suggestive data of left ventricular non-compaction cardiomyopathy was reported. EVOLUTION: After definitive diagnosis was made, optimal medical therapy for heart failure with reduced ejection fraction was established. The patient presented a favorable evolution, with symptomatic improvement and decrease of clinical and radiological signs of pulmonary congestion and was discharged with the same pharmacotherapy and indications for outpatient monitoring. CONCLUSION: In this case we are dealing with a patient with no cardiac pathology prior to pregnancy, who debuted with symptoms of heart failure in the late puerperium. Although imaging studies confirmed the diagnosis of left ventricular non-compaction cardiomyopathy, the case should be closely followed up due to the probability of reversible ventricular trabeculations associated with pregnancy and not a noncompacted left ventricular cardiomyopathy per se. Given the difficulty for diagnosis and identification of the etiology, the pathology should be studied exhaustively, especially in patients with a high probability of presenting trabeculations as part of adaptive remodeling.

Papillary Thyroid Microcarcinoma: Insights from a Cohort of 257 Thyroidectomized Patients.

Papillary thyroid microcarcinoma management evolved, and less aggressive strategies are now considered. Questions, however, remain on these tumors' behavior, particularly on developing countries' real ground healthcare scenarios. Our aim is to gather insights on the natural history of papillary thyroid microcarcinoma on patients treated with thyroidectomy in Brazil. Consecutive patients diagnosed with papillary thyroid microcarcinoma had their clinical characteristics, interventions, and outcomes described. Patients were classified as incidental or nonincidental based on the diagnosis after or before surgery, respectively. A sum of 257 patients were included, 84.0% of which were women, and the mean age was of 48.3±13.5 years. The mean tumor size was of 0.68±0.26 cm, 30.4% were multifocal, 24.5% had cervical metastasis, and 0.4% distant metastasis. The nonincidental and incidental tumors differed in tumor size (0.72±0.24 and 0.60±0.28 cm, respectively, p=0.003) and in presence of cervical metastasis (31.3% and 11.9%, respectively, p<0.001). Male sex, nonincidental diagnosis, and younger age were independent predictors of cervical metastasis. After 5.5 years (P25-75 2.5-9.7) of follow-up, only 3.8% of patients had persistent structural disease (3.4% cervical). Predictors of persistent disease at multivariate analysis included cervical metastasis and multicentricity. In conclusion, incidental and nonincidental papillary thyroid microcarcinoma patients of the population studied displayed excellent outcomes. Cervical metastasis and multicentricity were frequent findings and prognostic factors for persistent disease.

An Undetectable Postoperative Calcitonin Level Is Associated with Long-Term Disease-Free Survival in Medullary Thyroid Carcinoma: Results of a Retrospective Cohort Study.

Background: Calcitonin measurement is widely used in the diagnosis, prognosis, and follow-up of patients with medullary thyroid carcinoma (MTC). The prognostic value of undetectable postoperative calcitonin (POCal) in long-term disease outcomes remains uncertain. Objective: The aim of this study is to evaluate POCal as a prognostic marker for long-term MTC disease status. Methods: A retrospective cohort study was carried out. We collected data from the medical records of patients with MTC attending two tertiary teaching hospitals. Patients were divided according to POCal into two groups: undetectable (below the detection limit) or detectable. The outcome was determined at the last medical visit and defined as disease free (undetectable calcitonin and no evidence of disease on imaging), persistent disease (detectable calcitonin with or without structural disease), or disease-related death. Results: Three hundred thirty-four MTC patients were included in the study. The mean age at diagnosis was 41.1 ± 18.6 years; 202 patients (60.5%) were women; and 167 patients (50.0%) had sporadic MTC. The median tumor size was 2.0 cm (1.1-3.5 cm); 164 patients (49.1%) had lymph node metastasis and 63 patients (18.9%) had distant metastasis. At the first postoperative evaluation (3-6 months after surgery), 141 patients had undetectable POCal (mean age = 37.9 years, 70.9% women, median tumor size 1.5 cm [0.7-2.5 cm]; 28 [19.9%] had lymph node metastasis and none had distant metastasis). After a median follow-up of 7.7 years (2.1-13.2 years), 127 (90.1%) of these patients were free of disease, whereas 14 (9.9%) had persistent biochemical disease with stable calcitonin levels. No patient with undetectable POCal died of the disease. In the detectable POCal group (mean age = 42.9 years, 52.8% women, median tumor size 3.0 cm [1.8-4.2 cm]; 136 [70.5%] had lymph node metastasis and 63 [32.6%] had distant metastasis), 18 (9.2%) patients achieved disease-free status, 51 (26.6%) had biochemical disease, and 61 (31.6%) had persistent structural disease. Sixty-three (32.6%) patients died of disease-related events. Further analysis using a multivariate model identified undetectable POCal as an independent prognostic variable for disease-free status (HR = 5.33, CI = 2.86-9.94; p < 0.001). Conclusions: POCal is a strong prognostic marker for long-term disease-free survival and might help define follow-up strategies for MTC patients.

ODP532 Fractionated Radioactive Iodine Therapy in Management of Differentiated Thyroid Cancer

Abstract Introduction Management of differentiated thyroid cancer (DTC) requires individualized treatment plans that are tailored to the risk of disease recurrence. Radioactive iodine treatment (RIT) remains a treatment modality that is valuable in certain patients with DTC. The lack of institutional availability and travel bans imposed by the COVID-19 pandemic did not allow a subset of our patients to get intermediate or high-dose RIT. As an alternative, fractionated low-dose RITs given over a short time interval have been used. We aim to study the response to therapy in this patient population. Materials and methods This retrospective study was performed at a tertiary care hospital in Qatar. Between 2015-2020, patients who completed at least 2 doses of low-dose RIT within 6-12 months with at least one staging visit 3-6 months after their last treatment were included in the study. Results 69 patients met our inclusion criteria, 30 (43.5%) of whom were males and 39 (56.5%) females. The mean age at diagnosis was 40.7 +/- 9.35 years. Classic papillary thyroid cancer was the predominant histological variant (76.6%). Based on surgical pathology, the initial risk of disease recurrence was high in 24 (34.8%) patients, intermediate in 21 (30.4%) patients, and low in 21 (30.4%) patients. 3 (4.3%) patients did not have complete data for classification. Lymphatic invasion was noted in 16 (23.2%), vascular invasion in 15 (21.7%), positive margins in 30 (43.5%) and extra-nodal invasion in 10 (14.5%) patients. Patients underwent between 2-6 fractionated RITs, with the majority having undergone 2. In the low-risk group, 9 (42.9%) patients had an excellent response to therapy at last follow-up, 3 (14.3%) had the persistent structural disease, and 9 (42.8%) patients had an indeterminate response. In the intermediate-risk group, 7 (33.4%) patients had excellent response, 2 (9.5%) had the biochemically persistent disease, 8 (38.1%) had the structurally persistent disease, and 4 (19%) had an indeterminate response. In the high-risk group, 5 (20.8%) patients had excellent response, 13 (54.2%) had a structurally persistent disease, and 6 (25%) patients had an indeterminate response to therapy. Conclusion A similar response to therapy has been reported in the literature in the low and high-risk recurrence groups, suggesting that additional RIT may not be beneficial. In the intermediate risk of recurrence group, there is a higher percentage of patients with structural evidence of disease compared to what is reported in the literature, suggesting that perhaps a single intermediate or high dose RIT may be more beneficial. Either way, the c urrent management of DTC should be based on dynamic risk assessment to guide the need for further therapies. Presentation: No date and time listed

Puberty and sex in pediatric thyroid cancer: could expression of estrogen and progesterone receptors affect prognosis?

ObjectiveA sharp increase in pediatric thyroid cancer incidence is observed during adolescence, driven mainly by girls. Differences in disease presentation across sexual maturity stages raise the question of whether sex steroids have a role in the heterogeneity. The aims of this study were to analyze the influence of puberty and sex on clinical presentation and prognosis and to evaluate the correlation between the expression of sex hormone receptors.Design and methodsClinical records and immunohistochemical of specimens from 79 patients were analyzed. Puberty was analyzed by two criteria: end of puberty and beginning, in which the age of 10 was the cutoff.ResultsPostpubertal were more frequently classified as having low-risk disease and a lower frequency of persistent disease, especially when the completion of puberty was used as the criteria. Male sex was associated with a higher risk of persistent disease at the end of the observation period. Estrogen receptor α positivity was low in the entire sample, while progesterone receptor positivity was positive in 30% of the cases. Female hormone receptor expression was not associated with sex, American Thyroid Association risk score, persistent structural disease, or pubertal status.ConclusionOur study showed that the completion of puberty correlated best with the clinical behaviour of pediatric thyroid cancer. It was also shown that postpubertal patients have a less aggressive initial presentation and better outcomes. However, this observation could not be explained by the expression of estrogen and progesterone receptors in the primary tumors.

Is eNAMPT/visfatin a potential serum marker of papillary thyroid cancer?

Purpose:The role of nicotinamide phosphoribosyltransferase (NAMPT)/visfatin in a more aggressive course of many malignancies has been proven. Previous studies have noticed the importance of visfatin in thyroid neoplastic tissue, but the diagnostic and prognostic value of its serum concentration has not been investigated so far. Our study aimed to consider whether extracellular NAMPT (eNAMPT) could be a potential serum marker in recurrent papillary thyroid cancer (PTC).Methods:It was a prospective observational study with consecutive enrolment. We recruited 100 patients with PTC after thyroidectomy with postoperative 131I ablation and 100 healthy controls. Also, 50 randomly selected patients underwent laboratory assessment (including eNAMPT serum concentration by ELISA Assay Kit, TSH, free thyroid hormones, TSH-stimulated thyroglobulin Tg, antibodies – TgAbs, TPOAb) and body composition analysis twice: at admission and 6 months after being on suppressive levothyroxine doses. TSH-stimulated Tg of 1 ng/ml was defined as the cutoff value for predicting disease status as complete remission (n = 55) and recurrent or persistent structural disease (n = 45).Results:The visfatin serum concentrations in patients diagnosed with PTC and in healthy subjects were not statistically significantly different (p = 0.9425). The eNAMPT levels were also similar in disease-free patients and the ones with tumour relapse. Besides, ROC curve analysis did not detect eNAMPT as a biomarker of PTC.Conclusion:We have not found visfatin as a potential serum marker of papillary thyroid cancer. Also, eNAMPT has no prognostic value in assessing the risk of disease recurrence or metastasis in PTC management.

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

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

Tailoring the approach to radioactive iodine treatment in thyroid cancer.

The treatment of differentiated thyroid cancer continues to move away from a 'one size fits all' approach to a process of tailored therapeutic decision-making that incorporates disease-specific factors and individual patient preferences. Management options range from active surveillance to thyroid lobectomy to total thyroidectomy with or without the use of postoperative radioactive iodine (RAI). RAI may be administered for one or more reasons: Thyroid remnant ablation, adjuvant therapy, or therapy for persistent structural disease. It is important to be cognizant of the therapeutic intent of RAI and weigh the risks and benefits of treatment for each individual patient. Risk stratification should be used to identify those patients who are most likely to benefit from RAI and guide therapeutic choices. Available data suggest that RAI can be safely deferred for most patients considered at low risk for structural recurrence, while adjuvant RAI is associated with improved disease-free survival in patients with higher-risk disease. Although progress has been made, many areas of uncertainty related to the use of RAI remain. These include: (1) The appropriate selection of intermediate-risk patients to receive adjuvant RAI, (2) the superiority or inferiority of different RAI dosing activities, (3) the optimal approach to the use of RAI in special populations, including patients with end-stage renal disease and children, and (4) the management of patients with RAI-refractory disease.

Can Age at Diagnosis and Sex Improve the Performance of the American Thyroid Association Risk Stratification System for Prediction of Structural Persistent and Recurrent Disease in Patients With Differentiated Thyroid Carcinoma? A Multicenter Study

ObjectiveAlthough the age at diagnosis has been suggested as a major determinant of disease-specific survival in the recent TNM staging system, it is not included in the recent American Thyroid Association (ATA) guidelines to estimate the risk of recurrence. Nevertheless, the effect of sex on differentiated thyroid carcinoma (DTC) recurrence is controversial. Therefore, this multicenter study was conducted to assess whether age at diagnosis and sex can improve the performance of the ATA 3-tiered risk stratification system in patients with DTC with at least 5 years of follow-up. MethodsIn this study, the computer-recorded data of the patients diagnosed with DTC between January 1985 and January 2016 were analyzed. Only patients with proven structural persistent/recurrent disease were selected for comparisons. ResultsThis study consisted of 1691 patients (female, 1367) with DTC. In Kaplan-Meier analysis, disease-free survival (DFS) was markedly longer in females only in the ATA low-risk category (P = .045). Nevertheless, a markedly longer DFS was observed in patients aged <45 years in the ATA low- and intermediate-risk categories (P = .004 and P = .009, respectively), whereas in patients aged <55 years, DFS was markedly longer only in the ATA low-risk category (P < .001). In the Cox proportional hazards model, ages of ≥45 and ≥55 years at diagnosis and the ATA risk stratification system were all independent predictors of persistent/recurrent disease. ConclusionApplying the age cutoff of 45 years in the ATA intermediate- and low-risk categories may identify patients at a higher risk of persistence/recurrence and may improve the performance of the ATA risk stratification system, whereas sex may improve the performance of only the ATA low-risk category.

Difference in clinical characteristics of patients with common variable immunodeficiency (CVID) according to pulmonary alterations - A cohort of 182 patients from a Brazilian tertiary hospital

One of the main clinical manifestations in CVID patients is predisposition to recurrent sinopulmonary infections that can lead to persistent structural lung disease. We evaluated the difference in clinical characteristics between CVID patients with and without bronchiectasis.

Early preablation rhTSH-stimulated thyroglobulin predicts outcome of differentiated thyroid cancer (DTC) patients.

Total thyroidectomy and risk-adapted 131-radioiodine therapy (RaIT) are the treatments of choice in differentiated thyroid cancer (DTC) patients. The response to treatments is assessed 6-12months after RaIT. However, thyroglobulin (Tg) values obtained just before RaIT also provide reliable informations on patients'outcome. As available data were mostly obtained in hypothyroid status, we evaluated the predictive role of preablation-Tg in patients underwent RaIT after rhTSH stimulation. We enrolled 299 low-to-intermediate risk DTC patients underwent rhTSH-stimulated RaIT (standard protocol). Serum Tg levels were measured before rhTSH administration (basal Tg), before RaIT (early-stimulated Tg), and 2days after RaIT (late-stimulated Tg). The early response assessment was done 12months after RaIT according to 2015 American Thyroid Association (2015 ATA) criteria. Most patients (277/299, 92.6%) had an excellent response (ER) to RaIT, while 15/299 (5.1%) and 7/299 (2.3%) patients showed biochemical incomplete/indeterminate response or persistent structural disease, respectively. At receiver operating characteristic analysis, the optimal cutoff to predict ER was set at 1.55 (AUC = 0.792), 2.6 (AUC = 0.931), and 4.9 (AUC = 0.874)ng/mL, for basal, early-, and late-stimulated Tg, respectively. The overall sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) for basal, early-, and late-stimulated Tg were 50%, 96.7%, 93.3%, 55%, and 96.1%; 90.9%, 84.5%, 84.9%, 31.7%, and 99.1%; and 90.9%, 71.8%, 73.2%, 20.4%, and 99%, respectively. In univariate and multivariate logistic regression analysis, early-stimulated Tg cutoff resulted as an independent prognostic marker for predicting ER regardless of gender, age, histotype, histological variant, tumor size, risk classification, and stage of disease. Early-stimulated Tg is a reliable diagnostic tool for predicting the response to primary treatment of DTC.

Reoperations for structurally persistent or recurrent disease after thyroidectomy: analysis via preoperative CT

The incidence rates of structural persistent disease (PD) and recurrent disease (RD) after thyroidectomy, and their clinicoradiological (CT) characteristics, remain poorly understood. Therefore, we characterized differentiated thyroid cancer (DTC) patients who underwent re-operations, with a focus on preoperative CT scans. We examined neck CT scans obtained prior to initial surgery and reoperation, and classified the disease into four categories according to the persistence/recurrence and neck dissection/non-dissection status. In total, 121 of 9,173 DTC patients underwent reoperations to treat PD or RD; the mean time to reoperation was 25.5 and 54.1 months, respectively. Of all reoperations, 19% (23/121) were performed to treat RD; 81% (98/121) were performed to treat PD. Compared to RD, PD was commonly detected in the non-dissected neck. Tumor multiplicity and the number of pathologically positive lymph nodes were greater in the non-dissected than dissected neck. A review of the CT data revealed more false-negative findings on the 60-s- versus 30–40-s-delay scans of PD patients with non-dissected necks. In conclusion, most of the reoperations performed on DTC patients were for management of PD. Improved preoperative CT assessments and initial surgery, based on the information of clinico-radiological characteristics, are required in the care of DTC patients.

High Ratio of Early Postoperative Calcitonin to Preoperative Calcitonin Could be a Novel Indicator of Poor Prognosis in Patients with Biochemical Incomplete Responses in Sporadic Medullary Thyroid Cancer

In a cohort of medullary thyroid cancer (MTC) patients with biochemical incomplete responses, 37 to 48% developed structural persistent disease; however, few indictors were available to distinguish those patients who were more likely to develop structural disease. We hypothesized that the relationship between preoperative calcitonin (Ctn) and postoperative Ctn (within 3 days after surgery) could be used to predict early prognosis of these patients. A total of 92 sporadic MTC patients were enrolled in this study. Our team proposed a novel indicator of structural persistent MTC called the calcitonin ratio (CR; CR = postoperative Ctn/preoperative Ctn). Cox regression models and the Kaplan-Meier method were used to evaluate the prognostic capability of CR. The area under the time-dependent receiver-operating characteristic curves (AUC) and the Harrell concordance index (C-index) were used for analysis. The cutoff CR value used to determine MTC prognosis was 0.15. Multivariate Cox analysis revealed that CR (hazard ratio &lsqb;HR]: 22.974, 95% confidence interval &lsqb;CI]: 3.259 to 161.959, P = .002), tumor-node-metastasis (HR: 3.968, 95% CI: 1.360 to 21.857; P = .031), and multifocality (HR: 8.466, 95% CI: 1.286 to 55.716; P = .026) independently correlated with MTC prognosis. Kaplan-Meier survival curves demonstrated a lower proportion with structural persistent disease in patients with CR <0.15 (P<.001). The 3, 5, and 10-year AUC values were 0.798, 0.752, and 0.743, respectively. The C-index of CR was 0.788 (95% CI: 0.763 to 0.813). In this study, CR was identified as a sensitive and specific risk stratification marker for patients with biochemical incomplete responses in sporadic MTC. ATA = American Thyroid Association; AUC = area under curve; CEA = carcinoembryonic antigen; CR = calcitonin ratio; Ctn = calcitonin; HR = hazard ratio; MTC = medullary thyroid cancer; ROC = receiver operating characteristic; TNM = tumor-node-metastasis.

Real-World Performance of the American Thyroid Association Risk Estimates in Predicting 1-Year Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study of 2000 Patients.

Background: One of the most widely used risk stratification systems for estimating individual patients' risk of persistent or recurrent differentiated thyroid cancer (DTC) is the American Thyroid Association (ATA) guidelines. The 2015 ATA version, which has increased the number of patients considered at low or intermediate risk, has been validated in several retrospective, single-center studies. The aims of this study were to evaluate the real-world performance of the 2015 ATA risk stratification system in predicting the response to treatment 12 months after the initial treatment and to determine the extent to which this performance is affected by the treatment center in which it is used. Methods: A prospective cohort of DTC patients collected by the Italian Thyroid Cancer Observatory web-based database was analyzed. We reviewed all records present in the database and selected consecutive cases that satisfied inclusion criteria: (i) histological diagnosis of DTC, with the exclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features; (ii) complete data of the initial treatment and pathological features; and (iii) results of 1-year follow-up visit (6-18 months after the initial treatment), including all data needed to classify the estimated response to treatment. Results: The final cohort was composed of 2071 patients from 40 centers. The ATA risk of persistent/recurrent disease was classified as low in 1109 patients (53.6%), intermediate in 796 (38.4%), and high in 166 (8.0%). Structural incomplete responses were documented in only 86 (4.2%) patients: 1.5% in the low-risk, 5.7% in the intermediate-risk, and 14.5% in the high-risk group. The baseline ATA risk class proved to be a significant predictor of structural persistent disease, both for intermediate-risk (odds ratio [OR] 4.67; 95% confidence interval [CI] 2.59-8.43) and high-risk groups (OR 16.48; CI 7.87-34.5). Individual center did not significantly influence the prediction of the 1-year disease status. Conclusions: The ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC in real-world clinical settings characterized by center heterogeneity in terms of size, location, level of care, local management strategies, and resource availability.

Risk of structural persistent disease in pediatric patients with low or intermediate risk differentiated thyroid cancer.

In pediatric patients with differentiated thyroid cancer (DTC), the risk of recurrence is high and the indication for postoperative 131I administration is still debated. The aim of this study was to assess the outcome in low and intermediate risk pediatric DTC patients. We retrospectively evaluated 45 pediatric patients with low or intermediate risk DTC, treated with surgery and 131I between 1992 and 2002 and with no detectable antithyroglobulin (Tg) antibodies. Follow-up was performed every 6-12 months with Tg blood level determination and imaging procedures. During follow-up (64 ± 53 months), 15 events occurred (33% cumulative event rate, with an annual event rate of 5% person years). Five of these patients were submitted to additional surgery and all these 15 patients underwent a second 131I treatment course. All patients were alive at the end of the follow-up. Structural persistent disease occurred more frequently in patients at intermediate risk (p < 0.01) and in those with Tg values after thyroid hormone withdrawal >10 ng/ml before 131I therapy (p < 0.01). At multivariate analysis, only a postoperative thyroid stimulating hormone-stimulated Tg level >10 ng/ml was an independent predictor of persistent disease. In pediatric patients with DTC, postoperative high stimulated Tg values (>10 ng/ml) should be taken into account for deciding the extent of both initial treatment and follow-up.

MON-LB015 Sporadic MTC in Children: Characterization of a Rare Disease

INTRODUCTION: Medullary thyroid carcinoma (MTC) is rare in children and is hereditary (hMTC), caused by germline mutations in the RET proto-oncogene, in about 95% of cases. Very little is known about sporadic MTC (sMTC) when diagnosed in children/young adults. Our aim was to study the clinical presentation and long-term outcomes of a large cohort of sMTC seen at a tertiary cancer center and to compare sMTC with hMTC in young patients (pts). METHODS: Through a review of institutional databases, we identified pts diagnosed with MTC ≤ age 21 years (y.). Charts were retrospectively reviewed and data abstracted. The diagnosis of sMTC vs hMTC was determined based on germline RET testing and family history. RESULTS: We identified 146 pts (53% female), of whom 20 (14%) had sMTC and 126 (86%) had hMTC (80 MEN2a and 46 MEN2b), with a median follow-up of 10 y. (range: 0.08-58, IQR 4.8-18). In pts with sMTC, the stage at diagnosis was I-II in 3/15 (20%) and stage III-IV in 12/15 (80%). Somatic mutations were identified in 11/12 tumors tested (6 RET p.M918T, 1 RET p.G691S, 2 RET deletions p.L629_L633del and p.E632_L633del, 1 RET c.2698_2710delinsC, and 1 CCDC6-ALK fusion). In contrast to hMTC, pts with sMTC were diagnosed at an older age [mean 18.0 y. ± 3.4 (range: 10-21) vs 12.9 y. ± 5.4 (range: 1.5-21), p<0.001], had higher calcitonin [median 889 (IQR 528-2634) vs 16 (IQR 3-117) x Upper Limit of Normal, p<0.001] and CEA levels [median 186 (IQR 46-468) vs 11 (IQR 4-16) x Upper Limit of Normal, p<0.001], larger tumors [median 2.5 cm (IQR 2-3.7) vs. 0.8 cm (IQR 0.4-1.9), p<0.001], and were more likely to be stage IV at diagnosis [73% vs 28%, p<0.001]. sMTC pts were less likely to have bilateral tumors [27% vs 81%, p<0.001] and, at last follow-up, had more persistent structural disease [79% vs 46%, p=0.007] and distant metastases [74% vs 37%, p=0.005]. Death from MTC occurred in 15% of pts with sMTC vs 6% pts with hMTC; median overall survival was not significantly different [30.6 y. in sMTC vs 39.3 y. in hMTC]. CONCLUSION: In this largest reported series of MTC in children/young adults, and the only study to look at sMTC in this population, we identified sMTC in 14% of MTC cases, a higher prevalence than is traditionally recognized but one that is possibly confounded by a referral bias. Somatic mutations were identified in 92% of samples tested, allowing for targeted therapy in those with distant metastases if needed. Compared with hMTC, patients with sMTC presented at an older age with higher tumor markers, larger tumors, and more unilateral disease. At last follow-up, persistent structural disease and distant metastases were more common in sMTC. The differences in clinical presentation and long-term outcomes likely reflect a variable path to MTC diagnosis. In conclusion, sMTC in pts ≤ age 21 y. presents at an older age with more advanced disease, frequently has an actionable driver mutation, and may be more common than previously thought.

OR21-07 The 2015 American Thyroid Association Risk Stratification System Is a Predictor of Persistent Disease in Real-World Clinical Practice

Background. Management and follow-up of differentiated thyroid cancer (DTC) are guided by the likelihood of disease persistence or recurrence. The American Thyroid Association (ATA) practice guidelines provide a risk-estimation system based on data mainly derived by retrospective, single-center, and small cohorts. Aim. To validate the ATA risk-stratification system in predicting persistent structural disease. Methods. We analyzed data from the Italian Thyroid Cancer Observatory’s observational, web-based database, which prospectively enrolls newly diagnosed DTC patients in 40 Italian centers. For the present study we selected consecutive cases satisfying the inclusion criteria: 1) histological diagnosis of DTC, including papillary, follicular, and poorly differentiated tumors; 2) registration in the ITCO database between January 1, 2013 and April 23, 2019; 3) clinical evaluation between 6 and 18 month after primary treatment, including enough data to estimate the response to the initial treatment. Exclusion criteria were: histological diagnosis of NIFTP, medullary, or anaplastic thyroid cancer. The response to the initial treatment was categorized as excellent, biochemical incomplete, structural incomplete, or indeterminate based on imaging findings (neck ultrasound and other imaging studies, if performed), basal or stimulated serum thyroglobulin levels, and anti-Tg antibody levels. To model the response to treatment, we used a cumulative link model; given the hierarchical structure of the data, with patients nested within centers, we used a mixed-effect model, with a center-specific intercept summarizing unobserved center-specific characteristics. Results. Complete data about initial treatment and response to treatment after 6-18 months since initial treatment was available for 2071 patients. According to the ATA system, 1109 patients (53.6%) were classified as low-risk, 796 (38.4%) as intermediate, and 166 (8.0%) as high-risk. Excellent response was recorded in 1576 (76.1%) patients, indeterminate in 376 (18.2%), biochemical incomplete in 33 (1.6%), and structural incomplete in 86 (4.2%).The ATA risk stratification system is a significant predictor of response to treatment after 6-18 months: classification as intermediate- and high-risk increased the likelihood of a response worse than excellent (OR 1.68 [95% confidence intervals, CI 1.34-2.10] and 3.23 [95% CI 2.23-4.67], respectively), and a persistent structural disease (OR 4.67 [95% CI 2.59-8.43] and 16.48 [95% CI 7.87-34.5], respectively. In both analyses, the effect of the center (taking into account center-specific features) was negligible and not statistically significant. Conclusion. The 2015 ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC, also if applied in a real-world setting consisting of several different clinical sites.