Effect of the COVID-19 pandemic on surgery for indeterminate thyroid nodules (THYCOVID): a retrospective, international, multicentre, cross-sectional study

Background Since its outbreak in early 2020, the COVID-19 pandemic has diverted resources from non-urgent and elective procedures, leading to diagnosis and treatment delays, with an increased number of neoplasms at advanced stages worldwide. The aims of this study were to quantify the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic; and to evaluate whether delays in surgery led to an increased occurrence of aggressive tumours.Methods In this retrospective, international, cross-sectional study, centres were invited to participate in June 22, 2022; each centre joining the study was asked to provide data from medical records on all surgical thyroidectomies consecutively performed from Jan 1, 2019, to Dec 31, 2021. Patients with indeterminate thyroid nodules were divided into three groups according to when they underwent surgery: from Jan 1, 2019, to Feb 29, 2020 (global prepandemic phase), from March 1, 2020, to May 31, 2021 (pandemic escalation phase), and from June 1 to Dec 31, 2021 (pandemic decrease phase). The main outcomes were, for each phase, the number of surgeries for indeterminate thyroid nodules, and in patients with a postoperative diagnosis of thyroid cancers, the occurrence of tumours larger than 10 mm, extrathyroidal extension, lymph node metastases, vascular invasion, distant metastases, and tumours at high risk of structural disease recurrence. Univariate analysis was used to compare the probability of aggressive thyroid features between the first and third study phases. The study was registered on ClinicalTrials.gov, NCT05178186.Findings Data from 157 centres (n=49 countries) on 87 467 patients who underwent surgery for benign and malignant thyroid disease were collected, of whom 22 974 patients (18 052 [78 center dot 6%] female patients and 4922 [21 center dot 4%] male patients) received surgery for indeterminate thyroid nodules. We observed a significant reduction in surgery for indeterminate thyroid nodules during the pandemic escalation phase (median monthly surgeries per centre, 1 center dot 4 [IQR 0 center dot 6-3 center dot 4]) compared with the prepandemic phase (2 center dot 0 [0 center dot 9-3 center dot 7]; p<0 center dot 0001) and pandemic decrease phase (2 center dot 3 [1 center dot 0-5 center dot 0]; p<0 center dot 0001). Compared with the prepandemic phase, in the pandemic decrease phase we observed an increased occurrence of thyroid tumours larger than 10 mm (2554 [69 center dot 0%] of 3704 vs 1515 [71 center dot 5%] of 2119; OR 1 center dot 1 [95% CI 1 center dot 0-1 center dot 3]; p=0 center dot 042), lymph node metastases (343 [9 center dot 3%] vs 264 [12 center dot 5%]; OR 1 center dot 4 [1 center dot 2-1 center dot 7]; p=0 center dot 0001), and tumours at high risk of structural disease recurrence (203 [5 center dot 7%] of 3584 vs 155 [7 center dot 7%] of 2006; OR 1 center dot 4 [1 center dot 1-1 center dot 7]; p=0 center dot 0039).Interpretation Our study suggests that the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic period could have led to an increased occurrence of aggressive thyroid tumours. However, other compelling hypotheses, including increased selection of patients with aggressive malignancies during this period, should be considered. We suggest that surgery for indeterminate thyroid nodules should no longer be postponed even in future instances of pandemic escalation.Funding None.Copyright (c) 2023 Published by Elsevier Ltd. All rights reserved

Metachronous appearance of second malignancies in medullary thyroid carcinoma (MTC) patients: a diagnostic challenge and brief review of the literature

Medullary thyroid carcinoma (MTC) is a rare tumour which frequently occurs in the context of the multiple endocrine neoplasia syndromes, where it coexists with other usually benign tumours. The clinical picture varies and distant metastases are frequently present at diagnosis. Calcitonin levels are elevated in the presence of metastatic disease. Two MTC cases are presented, which had elevated postoperative calcitonin levels. Imaging revealed lung lesions which were originally attributed to metastatic disease from the MTC. However, at follow-up, these cases presented unusual features. The rapid increase in the lung lesions and the development of hypercalcaemia in the first patient suggested a second unrelated tumour. Biopsy of the lung lesion was compatible with lung adenocarcinoma. In the second patient, the appearance of a liver mass, although calcitonin levels remained stable, led to biopsy of the lesion: this was negative for calcitonin and compatible with metastatic lung adenocarcinoma. These MTC cases show that further malignancies may coexist with MTC and may obscure the clinical picture and influence the therapeutic decisions, especially in the case of metastatic disease. Features such as unusual imaging characteristics and the development of hypercalcemia, never encountered in MTC outside the MEN2 syndromes, as well as ‘disproportionately’ low calcitonin levels, incompatible with extensive metastatic disease, were the factors that led to further work-up. Both the cases subsequently proved to carry an unsuspected second malignancy. It is crucial to discriminate the metastatic lesion attributed to MTC from another coexisting primary malignancy, because different therapeutic strategies are needed for each setting

Metachronous appearance of second malignancies in medullary thyroid carcinoma (MTC) patients: a diagnostic challenge and brief review of the literature

Medullary thyroid carcinoma (MTC) is a rare tumour which frequently occurs in the context of the multiple endocrine neoplasia syndromes, where it coexists with other usually benign tumours. The clinical picture varies and distant metastases are frequently present at diagnosis. Calcitonin levels are elevated in the presence of metastatic disease. Two MTC cases are presented, which had elevated postoperative calcitonin levels. Imaging revealed lung lesions which were originally attributed to metastatic disease from the MTC. However, at follow-up, these cases presented unusual features. The rapid increase in the lung lesions and the development of hypercalcaemia in the first patient suggested a second unrelated tumour. Biopsy of the lung lesion was compatible with lung adenocarcinoma. In the second patient, the appearance of a liver mass, although calcitonin levels remained stable, led to biopsy of the lesion: this was negative for calcitonin and compatible with metastatic lung adenocarcinoma. These MTC cases show that further malignancies may coexist with MTC and may obscure the clinical picture and influence the therapeutic decisions, especially in the case of metastatic disease. Features such as unusual imaging characteristics and the development of hypercalcemia, never encountered in MTC outside the MEN2 syndromes, as well as ‘disproportionately’ low calcitonin levels, incompatible with extensive metastatic disease, were the factors that led to further work-up. Both the cases subsequently proved to carry an unsuspected second malignancy. It is crucial to discriminate the metastatic lesion attributed to MTC from another coexisting primary malignancy, because different therapeutic strategies are needed for each setting

Lower early morning plasma cortisol levels are associated with thyroid autoimmunity in the elderly

Objectives: Thyroid autoimmunity decreases in the very old. We investigated whether glucocorticoid (GC) activity, which increases in old age, is involved in this process. Subjects and methods: A total of 321 ambulatory subjects (age 51-95 years, median 71, 207 female) were studied. Thyroid function tests, cortisol, glucose, insulin and biochemical parameters were measured. A modified overnight dexamethasone suppression test (0.25 mg) was performed as an index of GC sensitivity. Results: Forty subjects had positive anti-thyroid peroxidase antibodies and 36 had positive anti-thyroglobulin antibodies, while 57 had either one or the other or both thyroid autoantibodies (ThAbs) positive. Mean basal cortisol levels were significantly lower in the ThAbs (+) groups (320 +/- 125 vs 378 +/- 128 nmol/l, P=0.002). Triiodothyronine, free thyroxine, post-dexamethasone cortisol levels, C-reactive protein, homeostasis model assessment-insulin-resistance-index and body mass index did not differ between these two groups. Mean age of ThAbs (C) subjects was lower compared to the ThAbs (-) group (67.38 +/- 7.38 vs 71.64 +/- 8.57 years, P=0.001). Conclusions: Reduced GC activity is associated with an increased prevalence of ThAbs positivity in older ambulatory subjects. Subjects without ThAbs in this population sample are relatively older. It is not known whether this is related to increasing GC activity with age

Familial MTC with RET exon 8 Gly533Cys mutation: Origin and prevalence of second malignancy

Introduction: High prevalence of RET p.Gly533Cys (c.1597G > T) has been found in familial MTC in Greece (exon 8 fMTC). We studied their origin and compared clinical characteristics with non-exon 8 fMTC. Methods: 102 fMTC (FMTC and MEN2A) patients (31.4% males) were followed for 2.9-37 years (median 6 years). Fifty-one carried the RET exon 8 mutation; the remaining were non-exon 8 fMTC (exons 10, 11, 13, 14). Pre-, post-operative calcitonin, disease extent at diagnosis and follow-up and families’ place of origin were recorded. Results: Exon 8 fMTC were older (42.3 ± 13.3 vs 30.8 ± 17.8 years, P < 0.001), including index cases (P = 0.016). In index cases, the stage at diagnosis was more favorable in exon 8 fMTC compared to non-exon 8 fMTC (stage I and II: 65% vs 23.8%, stage III: 25% vs 57.1%, stage IV: 10% vs 19%, P = 0.025). More favorable outcome was noted in exon 8 fMTCs (remission: 72.5% vs 45.8%, stable disease: 27.5% vs 41.7%, progression: 0.0% vs 12.5%, P = 0.001). Exon 8 fMTC patients carried more frequently a second malignancy (25.5% vs 6.3%, P = 0.009); 69% of these were PTCs. Exon 8 fMTC patients were significantly older at diagnosis compared to non-exon 8 moderate-risk RET carriers and presented more favorable clinical outcome (remission: 72.5% vs 50%, stable disease: 27.5% vs 41.7%, progression: 0.0% vs 8.3%, P = 0.021). This difference remained when only index cases were analyzed. ‘Hot spots’ in the origin of exon 8 fMTCs families were recognized. No phenotype or outcome differences were found between the exon 8 families from the various regions. Conclusions: In exon 8 fMTCs’ older age, favorable disease stage at diagnosis and favorable outcome suggest slow disease progression compared to non-exon 8 fMTC. Compared with moderate-risk RET mutation carriers, exon 8 fMTC patients have a more favorable clinical outcome. The higher prevalence of second malignancies, especially PTC, not previously reported, merits further investigation. Increased awareness for inherited disease is required for patients with apparently sporadic MTC originating from recognized ‘hot spots’, as the age at presentation is usually delayed. © 2017 The authors

Increasing prevalence of papillary thyroid carcinoma in recent years in greece: The majority are incidental

Background: New cases of well-differentiated thyroid cancer (DTC) are diagnosed more frequently worldwide. We investigated trends and differences in clinical and histological characteristics of new DTC cases presenting in one large center. Methods: During the last 34 years 852 follicular cell-derived DTC cases (83% papillary [PTC], 17% follicular [FTC] carcinoma) presented in the Endocrine Unit of the Department of Clinical Therapeutics in Alexandra Hospital (18.8% men, mean age 42.4±14.5 years). Patients were classified in three period groups according to year of diagnosis: period 1, 1963-1982; period 2, 1983-1992; and period 3, 1993-2007. We recorded the histological type, age at diagnosis, and, in period 3, the type of pre-existing thyroid disease, the stage, and tumor size. Results: During periods 1, 2, and 3, the mean age at diagnosis was 37.7±12.3, 42.4±14.53, and 44.1±14.9 years (p=0.001), respectively, and the male to female ratio was similar. The prevalence of FTC was 22.7%, 28.1%, and 6.5%, respectively. In period 3, 51.6% of the PTCs were microcarcinomas (microPTC) ≤10mm; these patients tended to be older (p=0.09). Microcarcinomas were more frequent among patients operated for pre-existing multinodular goiter (MNG) or prominent hot nodule compared to pre-existing single cold nodule (p<0.001, Pearson χ2). In period 3, 88% of the microPTC diagnoses were incidental. Of the incidental microPTCs detected in MNG, 25% had capsular invasion, 4.5% had lymph node involvement, and 3.6% had soft tissue involvement. Conclusions: We hypothesize that the prevalence of FTC during the last decade in our center in Greece was very low due to correction of iodine deficiency and a relative increase in the prevalence of microPTC. More than 50% of PTC diagnosed during the last decade were microPTCs that were detected incidentally in older persons with preexisting MNG or a prominent hot nodule. This is one of the highest, if not the highest percentage of microPTCs that were incidentally detected. Despite many of these having features of invasiveness, most appear to remain clinically silent. Research is needed to identify factors predisposing microPTCs to evolve from a subclinical to a clinically apparent form. © 2009 Mary Ann Liebert, Inc

Cortisol levels and metabolic parameters in middle- and advanced- age subjects: Associations with age

Background: It has been reported that morning cortisol levels increase with age, although there is some controversy in the literature. Aim: The aim of this study was to examine associations of cortisol levels with advancing age in an elderly population and investigate possible interactions with metabolic and hormonal parameters. Subjects and methods: From 372 subjects initially evaluated, we studied 251 ambulatory subjects aged 51-90 yr, median 71 yr (169 women), all permanent residents of a small town in southern Greece. Anthropometric parameters, glucose, insulin, cortisol, and biochemical parameters were recorded. Results: Fasting cortisol levels (08:00-09:00 h) varied between 150.9-854 nmol/l (mean 362.4 nmol/l). A significant association was found between age and cortisol levels (Spearman’s rho =0.170, p=0.01). There was a positive correlation between cortisol levels and creatinine (Spearman’s rho =0.144, p=0.023), homocysteine (Spearman’s rho =0.283, p<0.001) and a negative correlation with body mass index (Spearman’s rho =-0.128, p=0.047). Multivariate analysis showed that when creatinine was taken into account, the association of cortisol with age and with homocysteine was no longer significant. When, however, diabetic subjects were included in the analysis, the adjusted for creatinine association of cortisol with age was significant (beta=0.168, p<0.05). Conclusions: It is concluded that, in elderly ambulatory subjects, the reported associations between cortisol levels, age, and homocysteine may be affected by coexisting co-morbidities or possibly by a decline in renal function. In subsequent studies it is important that fasting glycemia is taken into account. (J. Endocrinol. Invest. 34: e398-e402, 2011) (C)2011, Editrice Kurti

Genetic screening of patients with medullary thyroid cancer in a referral center in Greece during the past two decades

Objective: Mutations in the RET gene are responsible for hereditary medullary thyroid cancer (MTC) and may vary between ethnic groups. We report the spectrum of mutations detected in patients with MTC in a referral center in Greece. Patients and methods: Screening for RET mutations was performed in 313 subjects from 188 unrelated families: 51 patients had clinical suspicion for familial disease, 133 were apparently sporadic, four patients had only C cell hyperplasia, and 125 were family members. Exons 8, 10, 11, and 13-16 were screened. Results: A total of 58 individuals (30.85%) were RET mutations carriers, 120 (63.8%) were finally classified as sporadic, 13 apparently sporadic cases (9.8%) were identified with RET mutation: ten carried the exon 8 at codon 533 mutation (previously reported), two the exon 14 at codon 804 mutation, and one the exon 13 at codon 768 mutation. Six patients (3.19%) with clinical features of multiple endocrine neoplasia type 2A and negative for RET mutations were classified as 'unknown cause'. The mutations of hereditary cases were as follows: 21 cases (36.2%) in exon 8 codon 533, 19 (32.8%) in exon 11 codon 634, nine (15.5%) in exon 10, five (8.6%) in exon 16, three (5.2%) in exon 14 codon 804, and one in exon 13 codon 768 (1.7%). Conclusion: The spectrum of RET mutations in Greece differs from that in other populations and the prevalence of familial cases is higher. The exon 8 (Gly533Cys) mutation was the most prevalent in familial cases unlike other series, followed by exon 11 (codon 634) mutations which are the most frequent elsewhere. The wide application of genetic screening in MTC reveals new molecular defects and helps to characterize the spectrum of mutations in each ethnic group. © 2015 European Society of Endocrinology

Increasing prevalence of papillary thyroid carcinoma in recent years in Greece: the majority are incidental

Background: New cases of well-differentiated thyroid cancer (DTC) are diagnosed more frequently worldwide. We investigated trends and differences in clinical and histological characteristics of new DTC cases presenting in one large center. Methods: During the last 34 years 852 follicular cell-derived DTC cases (83% papillary [PTC], 17% follicular [FTC] carcinoma) presented in the Endocrine Unit of the Department of Clinical Therapeutics in Alexandra Hospital (18.8% men, mean age 42.4±14.5 years). Patients were classified in three period groups according to year of diagnosis: period 1, 1963-1982; period 2, 1983-1992; and period 3, 1993-2007. We recorded the histological type, age at diagnosis, and, in period 3, the type of pre-existing thyroid disease, the stage, and tumor size. Results: During periods 1, 2, and 3, the mean age at diagnosis was 37.7±12.3, 42.4±14.53, and 44.1±14.9 years (p=0.001), respectively, and the male to female ratio was similar. The prevalence of FTC was 22.7%, 28.1%, and 6.5%, respectively. In period 3, 51.6% of the PTCs were microcarcinomas (microPTC) ≤10mm; these patients tended to be older (p=0.09). Microcarcinomas were more frequent among patients operated for pre-existing multinodular goiter (MNG) or prominent hot nodule compared to pre-existing single cold nodule (p<0.001, Pearson χ2). In period 3, 88% of the microPTC diagnoses were incidental. Of the incidental microPTCs detected in MNG, 25% had capsular invasion, 4.5% had lymph node involvement, and 3.6% had soft tissue involvement. Conclusions: We hypothesize that the prevalence of FTC during the last decade in our center in Greece was very low due to correction of iodine deficiency and a relative increase in the prevalence of microPTC. More than 50% of PTC diagnosed during the last decade were microPTCs that were detected incidentally in older persons with preexisting MNG or a prominent hot nodule. This is one of the highest, if not the highest percentage of microPTCs that were incidentally detected. Despite many of these having features of invasiveness, most appear to remain clinically silent. Research is needed to identify factors predisposing microPTCs to evolve from a subclinical to a clinically apparent form. © 2009 Mary Ann Liebert, Inc