Clinical significance of papillary thyroid carcinoma with solid/trabecular growth.

OBJECTIVE: The clinical relevance of solid/trabecular (ST) growth in papillary thyroid carcinoma (PTC) is unclear. In this study, we investigated the impact of any amount of ST growth on tumour characteristics and patient outcomes. Furthermore, we evaluated whether ST growth per se affected patients' prognosis in the absence of aggressive features, namely vascular invasion. DESIGN: We analysed 222 PTC patients followed up for more than 5 years in the Department of Endocrinology of the Instituto Português de Oncologia de Lisboa Francisco Gentil from 2002 to 2020. All PTC cases with any percentage of ST growth were included and compared with PTC without ST growth (1:2). Carcinomas with high-grade features were excluded. RESULTS: There were 74 PTC cases with ST growth and 148 without ST growth (median follow-up of 9.3 years). PTC-ST was associated with larger tumour size (p = 0.001) and increased frequency of vascular invasion (p < 0.001) compared with PTC. However, PTC-ST did not exhibit a higher incidence of extrathyroidal extension (p = 1.000) or lymph node metastasis (p = 0.433). Despite the significantly higher prevalence of distant metastasis in PTC-ST compared with PTC (p = 0.043), the significance is lost when the cases with vascular invasion were excluded (p = 0.347). The total radioiodine activity was higher in PTC-ST than in PTC (p = 0.008). Recurrence rates were similar between groups (p = 0.755). The 10-year overall survival and disease-free survival rates for PTC-ST were 94.6% and 98.6%, respectively, similar to the PCT without ST growth (p = 0.097 and p = 0.333, respectively). There was no evidence of an association between the presence of an ST component (p = 0.201) with the risk of death or recurrence, whereas the presence of distant metastasis significantly increased the risk of these events (hazard ratio 10.14, p < 0.001). CONCLUSIONS: The presence of ST growth was associated with several aggressive clinicopathological features. However, the risk of cancer recurrence and death for PTC-ST were similar to PTC. In the absence of vascular invasion, the clinical impact of ST growth alone is negligible.

Clinical and molecular characterization of parathyroid carcinoma in multiple endocrine neoplasia type 1.

Nineteen cases of parathyroid carcinoma in patients with multiple endocrine neoplasia type 1 have been reported in the literature, of which 11 carry an inactivating germline mutation in the MEN1 gene. Somatic genetic abnormalities in these parathyroid carcinomas have never been detected. In this paper, we aimed to describe the clinical and molecular characterization of a parathyroid carcinoma identified in a patient with MEN1. A 60-year-old man was diagnosed with primary hyperparathyroidism during the postoperative period of lung carcinoid surgery. Serum calcium and parathyroid hormone levels were 15.0 mg/dL (8.4-10.2) and 472 pg/mL (12-65), respectively. The patient underwent parathyroid surgery, and histological findings were consistent with parathyroid carcinoma. Analysis of the MEN1 gene by next-generation sequencing (NGS) identified a novel germline heterozygous nonsense pathogenic variant (c.978C>A; p.(Tyr326*)), predicted to encode a truncated protein. Genetic analysis of the parathyroid carcinoma revealed a c.307del, p.(Leu103Cysfs*16) frameshift truncating somatic MEN1 variant in the MEN1 gene, which is consistent with MEN1 tumor-suppressor role, confirming its involvement in parathyroid carcinoma etiology. Genetic analysis of CDC73, GCM2, TP53, RB1, AKT1, MTOR, PIK3CA and CCND1 genes in the parathyroid carcinoma DNA did not detect any somatic mutations. To our knowledge, this is the first report of a PC case presenting both germline (first-hit) and somatic (second-hit) inactivation of the MEN1 gene.

Chronic caffeine intake decreases circulating catecholamines and prevents diet-induced insulin resistance and hypertension in rats.

We tested the hypothesis that long-term caffeine intake prevents the development of insulin resistance and hypertension in two pathological animal models: the high-fat (HF) and the high-sucrose (HSu) diet rat. We used six groups of animals: control; caffeine-treated (Caff; 1 g/l in drinking water during 15 d); HF; caffeine-treated HF (HFCaff); HSu; caffeine-treated HSu (HSuCaff). Insulin sensitivity was assessed using the insulin tolerance test. Blood pressure, weight gain, visceral fat, hepatic glutathione, plasma caffeine, insulin and NO, and serum NEFA and catecholamines were measured. Caffeine reversed insulin resistance and hypertension induced by both the HF and HSu diets. In the HF-fed animals caffeine treatment restored fasting insulin levels to control values and reversed increased weight gain and visceral fat mass. In the HSu group, caffeine reversed fasting hyperglycaemia and restored NEFA to control values. There were no changes either in plasma NO or in hepatic glutathione levels. In contrast, caffeine totally prevented the increase in serum catecholamines induced by HF and HSu diets. To test the hypothesis that inhibition of the sympathetic nervous system prevents the development of diet-induced insulin resistance we administered carvedilol, an antagonist of ß1, ß2 and also α1 adrenoceptors, to HF and HSu rats. Carvedilol treatment fully prevented diet-induced insulin resistance and hypertension, mimicking the effect of caffeine. We concluded that long-term caffeine intake prevented the development of insulin resistance and hypertension in HF and HSu models and that this effect was related to a decrease in circulating catecholamines.

Mediastinal Thyroid Carcinoma and Graves' Disease: A Rare Presentation.

BACKGROUND: Mediastinal thyroid carcinoma is extremely rare, with few cases reported in the literature. Case Report. A 73-year-old man presented with weight loss for 6 months. Imaging by computed tomography (CT) documented a large mediastinal mass below the thyroid gland and pulmonary metastases. Neck ultrasound found two spongiform nodules in the right thyroid lobe, and fine-needle aspiration citology (FNAC) of these nodules revealed they are benign. Endobronchial ultrasound-guided needle biopsy of the mediastinal mass was compatible with papillary thyroid cancer. A few weeks later, the patient developed overt hyperthyroidism due to Graves' disease, which was treated with antithyroid drugs. 99mPertechnetate scintigraphy showed increased diffuse uptake in the thyroid parenchyma but the absence of uptake in the paratracheal mass and in the lung nodules. The patient was not considered eligible for surgical intervention or therapy with tyrosine kinase inhibitor due to tracheal and mediastinal vessel invasion and was treated with palliative radiotherapy. Two months later, restaging PET-FDG showed an intense uptake in the right lobe of the thyroid gland, lymph nodes, lungs, bone, muscle, myocardial, kidney, and adrenal gland. CONCLUSION: In this case, thyroid carcinoma presented as a mediastinal mass with concurrent hyperthyroidism due to Graves' disease. Although uncommon, the clinicians should be aware of these situations. Obtaining a prompt histological examination of an intrathoracic mass is crucial to ensure an early diagnosis and treatment.

A case report of multiple endocrine neoplasia type 1 and autoimmune disease: Coincidence or correlation?

RATIONALE: Multiple Endocrine Neoplasia type 1 (MEN1) is a familial syndrome that results from the disruption of a tumor suppressor protein called MENIN. Its management is challenging, as MEN1 affects different endocrine tissues and predisposes to both benign and malignant tumors. MENIN-deficient cells have recently been recognized to play a role in triggering autoimmunity. Herein, we present a case of MEN1 with multiple endocrine and autoimmune disorders. PATIENT CONCERNS: A 50 years old female with a 25 years history of complicated nephrolithiasis presented with primary hyperparathyroidism. DIAGNOSES: Over several decades, she was diagnosed with recurrent primary hyperparathyroidism, autoimmune thyroiditis, multinodular goiter, pernicious anemia, metastatic gastric type 1 neuroendocrine tumor, macroprolactinemia, gonadotropin deficiency, mucosa-associated lymphoid tissue lymphoma of the thyroid gland, positive anti-calcium sensor receptor antibodies, and BRCA 1/2-negative invasive breast cancer. The autoimmune regulator gene was sequenced, but no pathogenic variants were found. Next-generation sequencing revealed both a pathogenic MEN1 mutation and a benign CDC73 gene variant. Familial genetic screening revealed a large kindred with multiple carriers of one or both genetic variants (MEN1 = 19; CDC73 = 7). INTERVENTIONS: The patient underwent surgical excision of three parathyroid glands, total thyroidectomy and breast tumorectomy plus tamoxifen, and monthly injections of octreotide. The patient and family members with the MEN1 mutation are under a life-long surveillance program for MEN1 prototypic tumors. OUTCOMES: The patient was stable and alive during a 24-years follow-up period. LESSONS: With the present case, the authors highlight a new interplay between MENIN and the immune system, which may have implications for future targeted life-long surveillance and treatment of MEN1 patients.

Paraganglioma presenting as stress cardiomyopathy: case report and literature review.

Pheochromocytoma/paraganglioma (PPGL) are neuroendocrine tumors that can secrete catecholamines. The authors describe a challenging case who presented as stress cardiomyopathy and myocardial infarction (MI). A 76-year-old man, with a medical history of Parkinson's disease, type 2 diabetes mellitus, hypertension, dyslipidaemia and a previous inferior MI in 2001, presented to the emergency department due to chest pain, headaches and vomiting. He also reported worsening blood glucose levels and increasing constipation over the preceding weeks. BP was 185/89 mmHg (no other relevant findings). EKG had ST segment depression in leads V2-V6, T troponin was 600 ng/L (<14) and the echocardiogram showed left ventricular hypokinesia with mildly compromised systolic function. Nevertheless, he rapidly progressed to severe biventricular dysfunction. Coronary angiogram showed a 90% anterior descendent coronary artery occlusion (already present in 2001), which was treated with angioplasty/stenting. In the following days, a very labile BP profile and unexplained sinus tachycardia episodes were observed. Because of sustained severe constipation, the patient underwent an abdominal CT that revealed a retroperitoneal, heterogeneous, hypervascular mass on the right (62 × 35 mm), most likely a paraganglioma. Urinary metanephrines were increased several fold. 68Ga-DOTANOC PET-CT scan showed increased uptake in the abdominal mass (no evidence of disease elsewhere). He was started on a calcium-channel blocker and alpha blockade and underwent surgery with no major complications. Eight months after surgery, the patient has no evidence of disease. Genetic testing was negative for known germline mutations. This was a challenging diagnosis, but it was essential for adequate cardiovascular stabilization and to reduce further morbidity. Learning points: PPGL frequently produces catecholamines and can manifest with several cardiovascular syndromes, including stress cardiomyopathy and myocardial infarction. Even in the presence of coronary artery disease (CAD), PPGL should be suspected if signs or symptoms attributed to catecholamine excess are present (in this case, high blood pressure, worsening hyperglycaemia and constipation). Establishing the correct diagnosis is important for adequate treatment choice. Inodilators and mechanical support might be preferable options (if available) for cardiovascular stabilization prior to alpha blockade and surgery. Laboratory interference should be suspected irrespective of metanephrine levels, especially in the context of treated Parkinson's disease.

Poorly Differentiated Thyroid Carcinoma Patients with Detectable Thyroglobulin Levels after Initial Treatment Show an Increase in Mortality and Disease Recurrence.

PURPOSE: The role of thyroglobulin (Tg) in predicting death and recurrence risk in patients with poorly differentiated thyroid carcinoma (PDTC) is not well established. We aimed to analyze Tg levels following total thyroidectomy and adjuvant radioiodine treatment (RAI) in PDTC patients and correlate Tg levels with survival and recurrence. METHODS: A retrospective analysis was conducted on 101 patients with PDTC who were treated between 1986 and 2010. Among them, 38 had no distant metastases at presentation, were managed by total thyroidectomy and adjuvant RAI, and had negative anti-Tg antibodies. An unstimulated Tg level < 1 ng/mL was used as a cut-off point for undetectable Tg levels. Association of patient and tumor characteristics with Tg levels was examined by χ2 test. Overall survival, disease-specific survival (DSS), and recurrence-free survival (RFS), stratified by Tg levels, were calculated by the Kaplan-Meier method and compared by the log-rank test. RESULTS: Compared to patients with undetectable Tg, cases with detectable Tg had a lower probability of achieving free surgical margins (21.7 vs. 46.7%; p = 0.04), higher node status (73.3 vs. 21.8%; p = 0.005), decreased 5-year DSS (65 vs. 100%; p = 0.009), and worse 5-year RFS (32 vs. 84%, p = 0.010), with a significant number of patients having a recurrence in the first year (50 vs. 12.5%; p = 0.021). Patients with detectable Tg levels also showed worse locoregional (55.6 vs. 90.9%; p = 0.014) and distant control (5-year distant control of 46.9 vs. 91%; p = 0.017). CONCLUSIONS: Our results suggest that detectable Tg levels after surgery and RAI in a subset of PDTC patients appear to predict a higher rate of death and recurrence.

Hypertension and severe hypokalaemia associated with ectopic ACTH production.

Ectopic adrenocorticotropic hormone (ACTH) secretion represents 5%-10% of cases of Cushing's syndrome (CS), and approximately 50%-60% of these arise from neuroendocrine lung tumours, including small-cell lung cancer (SCLC). We report a 42-year-old man admitted with hypertension, metabolic alkalosis and severe hypokalaemia. On physical examination, centripetal obesity with 'moon face' and 'buffalo's hump' were identified, and wheezing on left lung was heard. A markedly elevated serum cortisol, ACTH and urine free cortisol production supported the diagnosis of CS. Chest CT showed a left hilar mass with metastasis to the liver, adrenal glands and lymph nodes. Bronchoscopy identified bronchial infiltration by SCLC. Treatment with metyrapone and chemotherapy was started. Despite initial improvement, progressive clinical deterioration occurred, culminating in death 1 year after diagnosis. Ectopic ACTH secretion is uncommon but should be suspected in patients with severe hypokalaemia, hypertension and metabolic alkalosis, especially in the context of lung cancer.

A Clinical Roadmap to Investigate the Genetic Basis of Pediatric Pheochromocytoma: Which Genes Should Physicians Think About?

Pheochromocytoma is very rare at a pediatric age, and when it is present, the probability of a causative genetic mutation is high. Due to high costs of genetic surveys and an increasing number of genes associated with pheochromocytoma, a sequential genetic analysis driven by clinical and biochemical phenotypes is advised. The published literature regarding the genetic landscape of pediatric pheochromocytoma is scarce, which may hinder the establishment of genotype-phenotype correlations and the selection of appropriate genetic testing at this population. In the present review, we focus on the clinical phenotypes of pediatric patients with pheochromocytoma in an attempt to contribute to an optimized genetic testing in this clinical context. We describe epidemiological data on the prevalence of pheochromocytoma susceptibility genes, including new genes that are expanding the genetic etiology of this neuroendocrine tumor in pediatric patients. The clinical phenotypes associated with a higher pretest probability for hereditary pheochromocytoma are presented, focusing on differences between pediatric and adult patients. We also describe new syndromes, as well as rates of malignancy and multifocal disease associated with these syndromes and pheochromocytoma susceptibility genes published more recently. Finally, we discuss new tools for genetic screening of patients with pheochromocytoma, with an emphasis on its applicability in a pediatric population.