Mild autonomous cortisol secretion (MACS) is a frequent finding in adrenal incidentalomas (AI), yet its diagnosis remains challenging. We aimed to compare clinical and biochemical profiles between MACS and non-functioning AIs (NFAI) and to identify reliable biomarkers, alternative to the 1-mg dexamethasone suppression test (DST), that can support the diagnosis of MACS. We retrospectively analyzed 171 patients with AIs (70 MACS, 101 NFAI) evaluated between 2005 and 2025. MACS was defined by DST cortisol >1.8 μg/dL without overt Cushing's syndrome. Patients with MACS showed a higher prevalence of dyslipidemia (68.1% vs. 52.0%; p=0.037) and anxiety-depressive disorders (25.0% vs. 11.0%; p=0.018). Biochemically, they showed lower adrenocorticotropic hormone (ACTH) (11.1 pg/mL vs. 16.8 pg/mL; p=0.014), dehydroepiandrosterone-sulfate (DHEA-S) (0.3 μg/mL vs. 0.9 μg/mL; p<0.001), and testosterone levels in male (3.56 ng/ml vs. 5.41 ng/ml, p=0.04), with higher post-DST cortisol (2.8 μg/dL vs. 1.2 μg/dL; p<0.001), 24-hour urinary-free cortisol (67.2 μg/24h vs. 44.8 μg/24h; p<0.001), and late-night serum cortisol (8.2 μg/dL vs. 3.6 μg/dL, p<0.001). ACTH <15 pg/mL (p=0.029) and DHEA-S <0.5 μg/mL (p=0.009) independently predicted MACS (AUC: 0.78) and were combined into a 2-point diagnostic score with 89.5% sensitivity and 97.5% negative predictive value. Late-night cortisol ≥5.1 μg/dL showed good accuracy (AUC: 0.83) for identifying patients with MACS and correlated with the number of MACS-related comorbidities (p=0.0178). MACS is associated with neuropsychiatric and gonadal dysfunction. A simple and easily applicable biochemical score, together with late-night cortisol, may support diagnosis, particularly when the DST is inconclusive or in hospitalized patients.

Background: Hypothyroidism (hT) presents heterogeneous symptoms and findings. Evidence on this topic comes mainly from heterogeneous populations in terms of disease duration, residual thyroid function, and comorbidities. Therefore, it would be useful to assess systemic inflammation in a homogeneous hT population. The aim of this study was to investigate inflammation in a population that underwent standardized controlled hT. Methods: We recruited thyroidectomized patients diagnosed with thyroid cancer who were otherwise fit and healthy, showing hypothyroidism before I131 treatment using a standard protocol of LT4 withdrawal. The blood inflammatory indexes (BIIXs) (i.e., NLR, PLR, MLR, SII, SIRI, and AISI) were calculated using the blood tests collected just before I131 administration. Patients were divided according to sex, BMI, and thyroglobulin. The relationships between the BIIXs, age, and thyroid hormones were also investigated. Results: We included 143 patients. The median age of the sample was 43 years. The BIIX median values showed significant differences based on sex, BMI, and thyroglobulin levels (p < 0.05). No significant correlations were found between the BIIXs and age, TSH, FT4, and FT3. Conclusions: This study shows the BIIX median values of a population which underwent standardized hT. It suggests a role for some BIIXs in the evaluation of hypothyroidism in obese people and as hypothetical prognostic markers for thyroid cancer.

Background: Brain metastases (BM) are the most common intracranial neoplasms in adults and are a significant cause of morbidity and mortality. The brain is an unusual site for distant metastases of thyroid cancer; indeed, the most common sites are lungs and bones. In this narrative review, we discuss about the clinical characteristics, diagnosis, and treatment options for patients with BM from differentiated thyroid cancer (DTC). Summary: BM can be discovered before initial therapy due to symptoms, but in most patients, BM is diagnosed during follow-up because of imaging performed before starting tyrosine kinase inhibitors (TKI) or due to the onset of neurological symptoms. Older male patients with follicular thyroid cancer (FTC), poorly differentiated thyroid cancer (PDTC), and distant metastases may have an increased risk of developing BM. The gold standard for detection of BM is magnetic resonance imaging with contrast agent administration, which is superior to contrast-enhanced computed tomography. The treatment strategies for patients with BM from DTC remain controversial. Patients with poor performance status are candidates for palliative and supportive care. Neurosurgery is usually reserved for cases where symptoms persist despite medical treatment, especially in patients with favorable prognostic factors and larger lesions. It should also be considered for patients with a single BM in a surgically accessible location, particularly if the primary disease is controlled without other systemic metastases. Additionally, stereotactic radiosurgery (SRS) may be the preferred option for treating small lesions, especially those in inaccessible areas of the brain or when surgery is not advisable. Whole brain radiotherapy is less frequently used in treating these patients due to its potential side effects and the debated effectiveness. Therefore, it is typically reserved for cases involving multiple BM that are too large for SRS. TKIs are effective in patients with progressive radioiodine-refractory thyroid cancer and multiple metastases. Conclusions: Although routine screening for BM is not recommended, older male patients with FTC or PDTC and distant metastases may be at higher risk and should be carefully evaluated for BM. According to current data, patients who are suitable for neurosurgery seem to have the highest survival benefit, while SRS may be appropriate for selected patient.

Oncocytic adrenocortical carcinoma (OAC) is a rare variant of conventional adrenocortical carcinoma (ACC), characterized by oncocytic tumor cells comprising more than 90% of the tumor. Due to its rarity, there is a lack of reliable data on the clinicopathological features and outcomes of OAC. The aim of this study was to assess the clinical presentation, treatment modalities, and outcomes of patients with OAC, comparing these results with a cohort of patients with conventional ACC. Data from 9 referral centers in Italy on 44 patients with OAC were retrospectively analyzed and compared with data from 145 patients with conventional ACC. Patients with OAC had a smaller median tumor size, more favorable resection margin status, and lower incidences of venous invasion and persistent/recurrent disease during follow-up. Additionally, patients with OAC exhibited longer times to progression (TTP) and overall survival (OS) compared to patients with conventional ACC. Multivariable analyses identified Ki67 and tumor size as features independently associated with disease progression during post-surgical follow-up, while Ki67 and distant metastases at diagnosis were independently associated with OS in OAC patients. After complete tumor removal, the risk of recurrent disease was higher in patients with either Ki67 ≥ 20% or ENSAT stage III/IV. OAC appears to have a more indolent clinical course and better prognosis than conventional ACC. Similar to conventional ACC, Ki67 remains a significant prognostic marker for OAC and, along with ENSAT stage, serves as a reliable biomarker for identifying patients who may benefit from adjuvant mitotane therapy.

Background: In medullary thyroid cancer (MTC), lymph node metastases are often present at diagnosis and the extent of surgery is usually based upon pre-operative calcitonin and CEA levels as well as ultrasound findings. The aim of this study was to evaluate the role of pre-operative calcitonin and CEA levels as predictive markers of the burden of lymph node metastases at diagnosis. Methods: we conducted a retrospective study analyzing 87 MTC patients. Results: The median levels of calcitonin and CEA were 88.4 pg/mL and 7.0 ng/mL, respectively, in patients with no lymph nodes metastases; 108.0 pg/mL and 9.6 ng/mL, respectively, in patients with metastases to 1–5 lymph nodes; 520.5 pg/mL and 43.2 ng/mL, respectively, in patients with metastases to >5 lymph nodes. There were no significant differences in pre-operative calcitonin and CEA values between N0 and N1a patients, whereas they were significantly higher in N1b patients. Pre-operative cut-off levels distinguishing N0/N1a from N1b patients were 90 pg/mL for calcitonin (sensitivity 100%, specificity 59.3%, AUC = 0.82) and 17 ng/mL for CEA (sensitivity 100%, specificity 75%, AUC = 0.89). Conclusions: in patients with MTC, pre-operative serum calcitonin and CEA levels may drive the decision-making process to better define the extent of surgery.

Thyroidectomy with neck lymph node dissection is curative for most patients with medullary thyroid cancer (MTC). Lymph node ratio (LNR, i.e., the ratio between the metastatic and the removed lymph nodes) is a reliable parameter with which to estimate both disease extent and quality of neck dissection. The aim of this study was to investigate the prognostic role of LNR to predict persistent/recurrent disease in patients with MTC. A single-centre, retrospective study of a consecutive cohort of 95 patients with MTC treated with total thyroidectomy and neck dissection. Receiver operating characteristics (ROC) curve analysis was performed to identify the LNR cut-off. LNR was positively associated with tumour size, pre- and post-operative calcitonin values, post-surgery CEA values, persistent/recurrent disease and the occurrence of distant metastases during follow-up. At multivariate analysis, persistent/recurrent disease was independently associated with the LNR value and was accurately predicted by a cut-off value of 0.12 (AUC=0.85). Indeed, patients with LNR ≥0.12 had a higher probability of developing persistent/recurrent disease (79.3% vs 10.6%, OR=32.3, 95%CI=9.8-106.4; p<0.001) and distant metastasis (34.5% vs 3.0%, OR=16.8, 95%CI=3.4-83.6; p<0.001) than patients with LNR <0.12. The median time to progression was 15 months in patients with LNR ≥0.12 whereas it was not reached in patients with LNR <0.12 (HR: 7.18, 95%CI=3.01-17.11, p<0.001). LNR is a reliable prognostic factor to predict the risk of recurrence, persistence and distant metastases in patients with MTC.