Introduction: Although the TSH-receptor antibody (TRAb) plays a central role in the pathogenesis of Graves' disease (GD), the association between TRAb at first diagnosis and clinical and laboratory parameters is not well known. On the other hand, a minority of patients with GD may be TRAb negative, and there is a lack of adequate evidence to demonstrate the clinical and laboratory characteristics of these patients. Therefore, we aimed to investigate the association of TRAb at the initial diagnosis of GD with the clinical and laboratory parameters in a large number of patients with GD and to compare the clinical and laboratory parameters between patients with high TRAb levels and TRAb-negative patients. Material and methods: This study included 440 patients [326 (74%) female, 114 (26%) make]. All patients were classified according to gender, age, smoking habit, and TRAb level. Results: TRAb levels were significantly higher in male compared to female patients and in smokers compared to non-smokers. Smoking male patients had the highest TRAb levels. In regression analysis, goitre size, male gender, cigarette smoking, Graves' orbitopathy, fT3, and anti-TPO antibody levels were independently associated with high TRAb levels, while age at diagnosis and fT4 levels were not independently associated with high TRAb levels. TRAbnegative GD was diagnosed in 80 (18%) patients. TRA-negative patients had markedly less severe clinical and laboratory hyperthyroidism compared to patients with high TRAb levels. Moreover, the smoking habit was significantly lower in patients with TRAb-negative GD. Conclusions: According to our study results, TRAb levels at the initial diagnosis of GD are differently associated with clinical and laboratory parameters. Male patients and smoking patients with GD tended to have markedly higher TRAb levels and more severe clinical hyperthyroidism. Therefore, besides other contributing factors, male gender and smoking may affect TRAb levels and consequently the severity of hyperthyroidism in patients with GD. Furthermore, male gender and smoking may have a synergistic effect on TRAb levels and consequently on the severity of hyperthyroidism in patients with GD.

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Histologically aggressive micropapillary thyroid carcinomas (PTMC) subtypes are thought to be associated with an aggressive clinical course. However, evidence for unfavorable clinical outcomes in patients with aggressive PTMC subtypes is not clear. In this study, we intended to determine the difference in clinical outcomes between patients with aggressive and non-aggressive PTMC subtypes. In this multicenter cohort study, the computer-recorded clinical and histopathological data of patients who underwent thyroid surgery between January 2000 - January 2021 in 9 referral centers and were diagnosed as PTMC were analyzed. A total of 1585 patients [female 1340 (84.5%), male 245 (15.5%), mean age 47.9±11.63 years), with a mean follow-up time of 66.55±37.16 months], were included in the study. Ninety-eight cases were diagnosed as aggressive and 1487 as non-aggressive subtypes. Persistent/recurrent disease was observed in 33 (33.7% )and 41(2.8%) patients with aggressive and non-aggressive subtypes (p <0.001). Diseases-free survival rates were markedly lower in patients with aggressive than in those with non-aggressive PTMC subtypes (66.3% vs 94.8%, Log-rank p <0.001). Moreover, in multivariate analysis, aggressive histology was an independent predictor of persistent/recurrent disease, after controlling for other contributing factors (HR 5.78, 95% CI 3,32-10, p <0,001). Patients with aggressive PTMC subtypes had higher rates of incomplete biochemical and structural response than patients with non-aggressive subtypes as well (p <0.001). Aggressive PTMC subtypes share many characteristics with histologically identical tumors >1 cm in size. Therefore, the histopathological subtype of PTMC should be taken into consideration to tailor a personalized management plan.

Introduction Neurofibromatosis type-1 (NF-1) is an autosomal dominant genetic disorder. It is associated with the development of café-au-lait macules, axillary and/or inguinal frecklings, Lisch nodules, hypertension, osteoporosis, skeletal abnormalities, as well as benign and malignant tumors, such as optic gliomas, peripheral nerve sheet tumors, and rarely, pheochromocytomas. However, primary hyperparathyroidism is rarely documented in patients with bilateral pheochromocytomas associated with NF-1 and is typically linked to MEN-2 A syndrome. Here we present two cases of NF-1-associated bilateral pheochromocytomas who developed primary hyperparathyroidism during follow-up. Clinical case In 2010, diagnostic ultrasonography performed for abdominal pain in a 60-year-old female patient revealed an adrenal mass. Multiple neurofibromas, axillary freckling, café-au-lait macules, and lisch nodules were found on physical examination (Figure 1A, B, C, and D). A diagnosis of pheochromocytoma was confirmed by high urine metanephrines and a hyperintense, 35 x40 mm mass on T2 weighted MRI sequences. The patient underwent right adrenalectomy. One year later, a diagnosis of primary hyperparathyroidism was made based on the high serum levels of calcium and intact PTH, and low serum phosphorus levels (Table-1). Radiotracer uptake was seen on a parathyroid MIBI scan in the thyroid's right inferior area. During follow-up, a 50×51 mm mass, hyperintense on T2 weighted MRI sequences was discovered on the left adrenal gland (figure 1-E). A diagnosis of pheochromocytoma was confirmed by detecting high plasma metanephrine and normetanephrine levels. The patient underwent left adrenalectomy 5 years following the initial diagnosis. Clinical case A 64-year-old female patient was admitted due to recently developed hypercalcemia. She had previously undergone two successive adrenalectomies, 4 years apart in 1999 and 2003, and was confirmed to have bilateral pheochromocytomas by histopathological analysis. Multiple neurofibromas, axillary freckling, café-au-lait macules, and Lisch nodules were found on physical examination. A diagnosis of primary hyperparathyroidism was made by detecting high serum calcium, intact parathormone, and low serum phosphorus levels. The patient underwent a right parathyroidectomy in 2012. In both cases, a panel analysis of pheochromocytoma gene mutations was carried out. In cases 1 and 2, a heterozygous nonsense mutation (17q11.2, C.2023G&gt;T (P.G675*) and a non-frameshift deletion (17q11.2 c.5036) in the NF-1 gene were respectively found. Both instances tested negative for genetic alterations for RET, FH, MAX, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM-127, and VHL. Conclusion The development of primary hyperparathyroidism in these two cases of pheochromocytomas associated with genetically confirmed NF-1 raises the possibility that primary hyperparathyroidism may develop in patients with NF-1-associated pheochromocytoma.

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