Active surveillance of nodal metastasis in differentiated thyroid carcinoma: a systematic review and meta-analysis.

PURPOSE: Cervical lymph nodes (LN) represent the most common site of recurrence in differentiated thyroid cancer (DTC), frequently requiring repeated interventions that contribute to increase morbidity to a usually indolent disease. Data on active surveillance (AS) of nodal metastasis are limited. Therefore, we performed a systematic review and meta-analysis to evaluate AS in nodal metastasis of DTC patients. METHODS: MEDLINE, EMBASE, and Cochrane databases were searched up to July 2023 for studies including DTC patients with metastatic LN who were followed up with AS. The primary outcome was disease progression, according to the study's definition. Additional outcomes were LN enlargement ≥3 mm, occurrence of new cervical metastasis, and conversion from AS to surgical treatment. RESULTS: The search identified 375 studies and seven were included, comprising 486 patients with metastatic nodal DTC. Most were female (69.5%) and had papillary thyroid cancer (99.8%). The mean AS follow-up ranged from 28-86 months. Following each study's definition of progression, the pooled incidence was 28% [95% confidence interval (CI), 20-37%]. The pooled incidence of LN growth ≥ 3 mm was 21% [95% CI, 17-25%] and the emergence of new LN sites was 19% [95% CI, 14-25%]. Combining growth of 3 mm and the emergence of new LN criteria, we found an incidence of 26% [95% CI, 20-33%]. The incidence of neck dissection during AS was 18% [95% CI, 12-26%]. CONCLUSIONS: AS seems to be a suitable strategy for selected DTC patients with small nodal disease, avoiding or postponing surgical reintervention. PROSPERO REGISTRATION: CRD42023438293.

Age-related variation in malignant cytology rates of thyroid nodules: insights from a retrospective observational study assessing the ACR TI-RADS.

OBJECTIVE: The influence of age on the malignant cytology rate of thyroid nodules remains uncertain. The American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) is currently used to guide subsequent investigations of thyroid nodules, regardless of clinical variables. This study aimed to investigate the impact of age on the malignant cytology rates of thyroid nodules and the diagnostic performance of ACR TI-RADS across different age groups. DESIGN: A retrospective, single-center, observational study. METHODS: Patients aged ≥ 20 years with thyroid nodules, who underwent fine-needle aspiration biopsy between 2012 and 2019 were evaluated. Ultrasound images were used to obtain the TI-RADS data. Malignancy was determined based on suspicious for malignancy (Bethesda V) and malignant (Bethesda VI) cytology results or malignancy in cell block analysis. RESULTS: A total of 1023 nodules from 921 patients (88.2% female) were analyzed. The median age was 58.5 (interquartile range [IQR], 41.1-66.6) years, and the median nodule size was 2.4 (IQR, 1.7-3.6) cm. Stratification by age revealed a decreasing prevalence of malignant cytology across subgroups of 20-39, 40-59, and ≥60 years (10.7%, 8.5%, and 3.7%, respectively; P = .002). After adjusting for sex, multinodularity, nodule size, and ACR TI-RADS category, we observed that each year of age reduced the OR for malignant cytology by 3.0% (95% CI: 0.7%-5.3%; P = .011). When comparing the subgroups of 20-39 and ≥60 years, the malignant cytology rate decreased by half in TI-RADS 4 (from 21.4% to 10.4%) and two-thirds in TI-RADS 5 (from 64.7% to 22.6%). CONCLUSIONS: Our study demonstrated that as patient age increased, the rate of malignant cytology in thyroid nodules decreased. Moreover, age significantly influences the malignancy rates of thyroid nodules classified according to the ACR TI-RADS.

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.

Active Surveillance of Differentiated Thyroid Cancer Metastatic Cervical Lymph Nodes: A Retrospective Single-Center Cohort Study.

Background: The most frequent site of recurrence of differentiated thyroid cancer (DTC) is cervical lymph nodes (LNs), which often necessitates repeated surgical interventions and morbidity in a generally indolent disease. Data on active surveillance (AS) of small cervical nodal metastasis are still scarce, particularly in real-world clinical settings. In this study, we evaluated the DTC outcomes of AS of metastatic cervical LNs and explored factors associated with disease progression. Methods: We conducted a retrospective cohort study, including DTC patients with biopsy-proven metastatic cervical LNs, who were followed on AS in a tertiary care, university-based institution in Brazil. The inclusion criteria were cervical metastasis ≤2.0 cm and an AS duration of at least 6 months. We excluded lesions with aggressive histology, those in close proximity to or invading local structures. The primary outcome was disease progression (enlargement ≥3 mm in any diameter or a new cervical metastasis). Results: Data from 40 patients were analyzed. Most were female (77.5%) and had papillary thyroid cancer (97.5%). The mean age was 47.0 (± standard deviation 15.8) years. The 8th edition of the tumor, node, metastasis stage (TNM8) staging for DTC was as follows: 29 in stage I (74.4%), 8 in stage II (20.5%), and 2 in stage IV (5.0%). The median maximum LN diameter was 0.9 (interquartile range [IQR], 0.8-1.3) cm, and the median AS follow-up duration was 27.5 (IQR, 16.5-47.3) months. Disease progression occurred in 14 (35%) patients: 7 (17.5%) due to enlargement ≥3 mm, and 7 (17.5%) had new cervical metastasis. The cervical progression-free survival was 51.0 (confidence interval, 47.0-55.0) months. No demographic, oncological, or biochemical factors were associated with disease progression. Of the 14 patients with disease progression, 8 were referred for surgery. No permanent surgical complications were reported. Of the six patients who remained on AS despite disease progression, five showed no further progression during subsequent follow-up (range 6-40 months). Conclusions: We observed that most small metastatic cervical LNs remained stable and were safely managed with AS. Nevertheless, these observations are limited by the retrospective design, small sample size, and short follow-up. Further prospective and long-term studies are warranted.

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.

Effect of Suppressive Levothyroxine Therapy on Bone Mineral Density in Young Patients with Differentiated Thyroid Carcinoma.

Suppressive levothyroxine therapy (sT4) is a cornerstone in the management of differentiated thyroid cancer (DTC). Long-term sT4 may affect bone mineral density (BMD). We evaluated the effect of sT4 on the bone mass of young DTC patients. In this cross-sectional study, BMD was evaluated via dual-energy X-ray absorptiometry in DTC patients younger than 25 years at diagnosis and undergoing sT4 for ≥1 year. The two control groups comprised patients matched for sex, age, and body-mass-index who were thyroidectomized for indications other than DTC and undergoing L-T4-replacement therapy, and healthy individuals with no prior known thyroid disease. Ninety-three participants were included (thirty-one in each group). There were no differences in the mean age, female sex (77.4% in all groups), or BMI between the sT4 group and each control group. The median TSH level was lower (0.4 [0.04-6.5] vs. 2.7 [0.8-8.5] mIU/mL, p = 0.01) and the mean L-T4 mcg/Kg levels were higher (2.4 ± 0.6 vs. 1.6 ± 0.3, p = 0.01) in the sT4 group compared to the L-T4-replacement therapy group. Lumbar spine, femoral neck, and total femur BMD were all similar among the groups. sT4 does not impact BMD in young DTC patients after a median time of suppression of 8 years. These findings may help in the decision-making and risk/benefit evaluation of sT4 for this population.

Reappraising the Diagnostic Accuracy of Post-Treatment Whole-Body Scans for Differentiated Thyroid Carcinoma.

Initial treatment for differentiated thyroid carcinoma (DTC) often consists of surgery and the administration of radioiodine. In this context, post-treatment Whole-Body Scans (ptWBS) are currently recommended, but data on its diagnostic accuracy are rare. The aim of the study was to evaluate the performance of ptWBS for distant metastasis in DTC patients. We included DTC patients who received radioiodine and underwent ptWBS between 2009-2015. The medical data were independently reviewed by two specialists to evaluate the concordance of positive distant ptWBS uptake and distant metastasis documented by imaging exams (gold standard). We studied 268 DTC patients. The mean age was 46±16 years (82% women), and papillary thyroid carcinoma was diagnosed in 87% of the patients. The median tumor size was 2.7 cm, 40% had lymph node involvement, and 11% had distant metastasis. Twenty-eight patients (10%) had distant ptWBS uptake, and nine of them (32%) were false-positives. In addition, nine false-negative ptWBS uptakes were identified. The overall performance of ptWBS showed 68% sensitivity and 96% specificity with significantly different performance according to the American Thyroid Association (ATA) risk groups. While the ptWBS performance for ATA low-intermediate-risk showed 29% sensitivity, 97% specificity, and Kappa of 0.19, the ATA high-risk group ptWBS displayed high sensitivity (82%), specificity (100%), and good agreement (Kappa 0.74). ptWBS is useful for a subgroup of ATA high-risk DTC patients. The overall poor performance of ptWBS suggests that it should be reconsidered for routine use in ATA at low to intermediate risk: the exam has little value to this subgroup.

Neoadjuvant Multikinase Inhibitor in Patients With Locally Advanced Unresectable Thyroid Carcinoma.

Background: Papillary thyroid carcinoma (PTC) is the most common and less aggressive thyroid cancer, but some patients may display locally advanced disease. Therapeutic options are limited in these cases, particularly for those patients with unresectable tumors. Neoadjuvant therapy is not part of the recommended work up. Methods: Report a case of an unresectable grossly locally invasive PTC successfully managed with neoadjuvant therapy and provide a systematic review (SR) using the terms "Neoadjuvant therapy" AND "Thyroid carcinoma." Results: A 32-year-old man with a 7.8 cm (in the largest dimension) PTC was referred to total thyroidectomy, but tumor resection was not feasible due to extensive local invasion (trachea, esophagus, and adjacent structures). Sorafenib, a multikinase inhibitor (MKI), was initiated; a 70% tumor reduction was observed after 6 months, allowing new surgical intervention and complete resection. Radioactive iodine (RAI) was administered as adjuvant therapy, and whole body scan (WBS) shows uptake on thyroid bed. One-year post-surgery the patient is asymptomatic with a status of disease defined as an incomplete biochemical response. The SR retrieved 123 studies on neoadjuvant therapy use in thyroid carcinoma; of them, 6 were extracted: 4 case reports and 2 observational studies. MKIs were used as neoadjuvant therapy in three clinical cases with 70-84% of tumor reduction allowing surgery. Conclusion: Our findings, along with other reports, suggest that MKIs is an effective neoadjuvant therapy and should be considered as a therapeutic strategy for unresectable grossly locally invasive thyroid carcinomas.

Dynamic Risk Stratification in the Follow-Up of Children and Adolescents with Differentiated Thyroid Cancer.

BACKGROUND: Risk stratification for persistent disease is an important step in pediatric differentiated thyroid cancer (DTC) management. The dynamic risk stratification (DRS) is a well validated system for adults, but not yet for children and adolescents. This study evaluated the DRS as well as other prognostic factors in pediatric DTC. METHODS: Patients aged ≤18 years from four DTC tertiary teaching hospitals in Southern Brazil were included. Clinical characteristics were systematically retrieved, and all patients were classified according to the risk-stratification system of the 2015 American Thyroid Association pediatric DTC guidelines (ATA risk) and according to DRS (excellent, indeterminate, biochemical, or structural incomplete responses). Disease status was evaluated after initial therapy and at last follow-up visit. RESULTS: Sixty-six patients aged 14.5 ± 3.0 years were studied of whom 54 (81.8%) were girls and 62 (93.9%) had papillary thyroid carcinomas. Tumor size was 2.3 cm (P25-75 1.6-3.5); 41 (63.1%) had cervical and 18 (27.7%) distant metastasis at diagnosis. All patients underwent total thyroidectomy, and 63 (95.5%) received radioiodine. Patients were classified according to DRS after initial therapy (n = 63) as follows: 21 (33%) excellent, 13 (21%) indeterminate, 6 (9%) biochemical, and 23 (37%) structural incomplete responses. Notably, after six years (P25-75 2.7-10.0), most patients remained in the same category. Interestingly, the cutoff analysis of stimulated postoperative thyroglobulin (sPOTg) through receiver operating characteristic curve showed that the value of 37.8 ng/mL showed 81% sensitivity and 100% specificity to predict an excellent response. Prognostic factors associated with persistent disease in the univariate analysis were TNM, ATA risk, DRS, and sPOTg. CONCLUSION: DRS after initial therapy and sPOTg are strong predictors of disease outcome and might be helpful for defining follow-up strategies in pediatric DTC.

Impact of Serum TSH and Anti-Thyroglobulin Antibody Levels on Lymph Node Fine-Needle Aspiration Thyroglobulin Measurements in Differentiated Thyroid Cancer Patients.

BACKGROUND: Thyroglobulin measurements in the washout of fine needle aspiration (FNA-Tg) are an excellent tool to detect lymph node (LN) metastases of differentiated thyroid carcinoma (DTC). Nevertheless, how to define the best cutoffs and the influence of potential confounders are still being discussed. OBJECTIVE: To evaluate the accuracy of FNA-Tg measurement to detect DTC metastases and the influence of thyroid status and anti-thyroglobulin antibodies (TgAb). METHODS: One hundred thirty-eight patients with DTC and suspicious cervical LN were included. Patients underwent ultrasound (US)-guided FNA for cytological examination and FNA-Tg measurements. Final diagnoses were confirmed by histological examination or clinical and US follow-up for at least 1 year. RESULTS: Data from 119 subjects with suspicious LN were evaluated. The median value of FNA-Tg in patients with metastatic LN (n = 65) was 3,263.0 ng/mL (838.55-12,507.5), while patients without LN metastasis (n = 54) showed levels of 0.2 ng/mL (0.2-0.2). According to the ROC curve analysis, the best cutoff value to predict metastasis was 4.41 ng/mL for FNA-Tg, with a sensitivity of 98% and specificity of 96%. There were no differences in the median of FNA-Tg measurements between those on (TSH 0.16 mUI/mL) and those off levothyroxine (TSH 99.41 mUI/mL) therapy (47.94 vs. 581.15 ng/mL, respectively; p = 0.79). Interestingly, the values of FNA-Tg in patients with LN metastasis (n = 65) did not differ between patients with positive and those with negative TgAb (88.8 vs. 3,263.0 ng/mL, respectively; p = 0.57). CONCLUSION: US-guided FNA-Tg proved to be a useful examination in the follow-up of patients with DTC, independently of TSH status and the presence of TgAb.

Insuficiência adrenal primária como primeira manifestação de câncer pulmonar metastático / Primary adrenal insufficiency as first manifestation of metastatic lung cancer

A insuficiência adrenal primária é, na maioria das vezes, causada por infecções e adrenalite auto-imune. Metástases adrenais são relativamente comuns em neoplasias de pulmão, mas usualmente são assintomáticas, mesmo quando bilaterais. Há poucos relatos de metástases adrenais levando à insuficiência adrenal. Descrevemos aqui um caso de insuficiência adrenal primária como primeira manifestação clínica de neoplasia pulmonar metastática. Paciente de 59 anos, feminina, branca, tabagista, queixava-se de dor em flanco direito associada a náuseas e emagrecimento. Exames laboratoriais confirmaram o diagnóstico de insuficiência adrenal primária. Iniciou tratamento com prednisona e fludrocortisona, com melhora progressiva dos sintomas. Na investigação da etiologia, tomografia computadorizada (TC) de abdômen mostrou aumento bilateral das adrenais. Foi submetida à biopsia de adrenal, com citopatológico positivo para células malignas. Linfonodo supraclavicular esquerdo foi biopsiado, com anátomo-patológico (AP) confirmando adenocarcinoma metastático, com imunohistoquímica sugerindo pulmão como sítio primário. Atentar para o diagnóstico de insuficiência adrenal nesse contexto é importante, porque os sintomas iniciais são inespecíficos, podendo ser atribuídos à neoplasia

Primary adrenal insufficiency is, in most cases, caused by infections and autoimmune adrenalitis. Adrenal metastasis are relatively common in lung cancer, but they are usually asymptomatic, even when bilateral. There are few reports of adrenal metastasis as a cause of adrenal insufficiency. We describe a case of primary adrenal insufficiency presenting as the first clinical manifestation of metastatic lung cancer. A 59 year-old, white, smoker woman, complaining of right flank pain associated with nausea and weight loss. Laboratory exams confirmed the diagnosis of primary adrenal insufficiency. It was started treatment with prednisone and fludrocortisones with progressive improvement. At the etiologic investigation, abdominal computadorized tomography (CT) showed bilateral increase of the adrenal glands. It was performed an adrenal biopsy and the cytologic study was positive for malignant cells. It was made another biopsy, of a supraclavicular lymph node, and the histopathologic study revealed a metastatic adenocarcinoma, immunohistochemistry study suggested lung as the primary site. Awareness of this diagnosis is important because initial symptoms of adrenal insufficiency are unspecific and may misguidedly be attributed to the neoplasm