The Tumor Microenvironment and the Estrogen Loop in Thyroid Cancer.

Thyroid cancer (TC) cells employ multiple signaling pathways, such as PI3K/AKT/mTOR and RAS/Raf/MAPK, fostering cell proliferation, survival and metastasis. Through a complex interplay with immune cells, inflammatory mediators and stroma, TC cells support an immunosuppressive, inflamed, pro-carcinogenic TME. Moreover, the participation of estrogens in TC pathogenesis has previously been hypothesized, in view of the higher TC incidence observed among females. In this respect, the interactions between estrogens and the TME in TC could represent a relevant, unexplored area of research. We thereby collectively reviewed the available evidence concerning the potential carcinogenic role of estrogens in TC, specifically focusing on their crosstalk with the TME.

Thyroid findings in pediatric and adult patients with PTEN hamartoma tumor syndrome: A retrospective analysis, and literature review.

PURPOSE: PTEN hamartoma tumor syndrome (PHTS) comprises a group of rare genetic conditions caused by germline mutations in PTEN gene and characterized by development of both benign and malignant lesions in many body tissues. In this study, we aimed to evaluate the incidence of thyroid findings in both adult and pediatric PHTS patients. METHODS: A retrospectively analysis conducted in 19 (13 adult and 6 pediatric) patients with PHTS, all confirmed with genetic testing, observed from 2015 to 2021 at the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. RESULTS: We found a thyroid involvement in 12 adult patients (92%): 11 patients had benign lesions (85%) and the remaining developed a follicular thyroid carcinoma (8.3%). The median age at time of the first available record was 30 years. Among benign lesions, multinodular goiter was the most observed finding (10/11, 91%). Only 1 out of 6 (16%) pediatric patients was diagnosed with a thyroid lesion (unifocal lesion in mild lymphocytic thyroiditis) at the age of 8 years. CONCLUSIONS: Thyroid disorders affected nearly all adult PHTS patients, but a much lower proportion of pediatric patients. We discuss about the natural history of thyroid involvement, age of PHTS clinical onset, and optimized surveillance.

Is Encapsulated Medullary Thyroid Carcinoma Associated With a Better Prognosis? A Case Series and a Review of the Literature.

Context: Medullary thyroid carcinoma (MTC) is a malignant neuroendocrine neoplasm that may spread to lymph nodes before the primary tumor is diagnosed; moreover, distant metastases are already present in about 10% of patients at diagnosis. Serum calcitonin (Ctn) usually reflects the spread of disease, thus orienting the extent of surgery and predicting the possibility of biochemical remission. Tumor size and vascular invasion are important prognostic factors, but little is known on the relationship between other histopathological features, such as the presence of a tumor capsule, and long term outcome of MTC. Purpose: To evaluate the prevalence of encapsulated tumors among MTCs and the association of tumor capsule with a favorable outcome after surgery. Methods: A retrospective observational single-center study was conducted together with a narrative review of the available literature. Results: Among 44 patients (27 female, 17 male; median age: 56 years) with MTC (6 hereditary, 37 sporadic) followed up at our center in the last four years (median follow-up: 29.2 months), seven (15.9%) showed an encapsulated tumor at histology and a clinical remission after surgery. None of them had nodal metastases and median preoperative Ctn (398 pg/mL, IQR 126.5-7336) did not differ significantly from that of the 14 patients (31.8%) with persistent disease after surgery (787 pg/mL, IQR 340.5-2905.5; p=0.633), although their tumor size was significantly higher (median 33 mm versus 16 mm respectively, p=0.036). Among patients with preoperative Ctn levels above 500 pg/mL (n=11), only two (18.2%) showed undetectable Ctn levels during follow-up, both having an encapsulated MTC (OR 0.000, p=0.02). Notably, they were two similar cases of large MTC (> 3 cm) with extensive hyalinization and calcification, associated with very high Ctn levels (> 13'500 and 1'100 pg/mL, respectively) but no nodal nor distant metastases, in complete remission after surgery although one of them carried the aggressive M918T somatic RET mutation. Conclusion: MTC rarely shows a tumor capsule, which seems to correlate with a better prognosis and absence of nodal metastases, regardless of RET or RAS mutational status. Among encapsulated MTCs (E-MTC), Ctn levels and tumor size are not predictive of persistence of disease after surgery.

Adrenal Insufficiency at the Time of COVID-19: A Retrospective Study in Patients Referring to a Tertiary Center.

CONTEXT: Coronavirus disease 2019 (COVID-19) represents a global health emergency, and infected patients with chronic diseases often present with a severe impairment. Adrenal insufficiency (AI) is supposed to be associated with an increased infection risk, which could trigger an adrenal crisis. OBJECTIVE: Our primary aim was to evaluate the incidence of COVID-19 symptoms and complications in AI patients. DESIGN AND SETTING: We conducted a retrospective case-control study. All patients were on active follow-up and lived in Lombardy, Italy, one of the most affected areas. PATIENTS: We enrolled 279 patients with primary and secondary AI and 112 controls (patients with benign pituitary lesions without hormonal alterations). All AI patients had been previously trained to modify their replacement therapy on stress doses. INTERVENTION: By administering a standardized questionnaire by phone, we collected data on COVID-19 suggestive symptoms and consequences. RESULTS: In February through April 2020, the prevalence of symptomatic patients (complaining at least 1 symptom of viral infection) was similar between the 2 groups (24% in AI and 22.3% in controls, P = 0.79). Highly suggestive COVID-19 symptoms (at least 2 including fever and/or cough) also occurred equally in AI and controls (12.5% in both groups). No patient required hospitalization and no adrenal crisis was reported. Few nasopharyngeal swabs were performed (n = 12), as indicated by sanitary regulations, limiting conclusions on the exact infection rate (2 positive results in AI and none in controls, P = 0.52). CONCLUSIONS: AI patients who are adequately treated and trained seem to display the same incidence of COVID-19-suggestive symptoms and disease severity as controls.

Adrenal Insufficiency at the Time of COVID-19: A Retrospective Study in Patients Referring to a Tertiary Center.

CONTEXT: Coronavirus disease 2019 (COVID-19) represents a global health emergency, and infected patients with chronic diseases often present with a severe impairment. Adrenal insufficiency (AI) is supposed to be associated with an increased infection risk, which could trigger an adrenal crisis. OBJECTIVE: Our primary aim was to evaluate the incidence of COVID-19 symptoms and complications in AI patients. DESIGN AND SETTING: We conducted a retrospective case-control study. All patients were on active follow-up and lived in Lombardy, Italy, one of the most affected areas. PATIENTS: We enrolled 279 patients with primary and secondary AI and 112 controls (patients with benign pituitary lesions without hormonal alterations). All AI patients had been previously trained to modify their replacement therapy on stress doses. INTERVENTION: By administering a standardized questionnaire by phone, we collected data on COVID-19 suggestive symptoms and consequences. RESULTS: In February through April 2020, the prevalence of symptomatic patients (complaining at least 1 symptom of viral infection) was similar between the 2 groups (24% in AI and 22.3% in controls, P = 0.79). Highly suggestive COVID-19 symptoms (at least 2 including fever and/or cough) also occurred equally in AI and controls (12.5% in both groups). No patient required hospitalization and no adrenal crisis was reported. Few nasopharyngeal swabs were performed (n = 12), as indicated by sanitary regulations, limiting conclusions on the exact infection rate (2 positive results in AI and none in controls, P = 0.52). CONCLUSIONS: AI patients who are adequately treated and trained seem to display the same incidence of COVID-19-suggestive symptoms and disease severity as controls.

TNM 8th edition in thyroid cancer staging: is there an improvement in predicting recurrence?

TNM 8th edition introduces changes in the staging of patients with differentiated thyroid carcinoma (DTC). This study aims at assessing the value of TNM 8th edition in predicting response to therapy and structural recurrence of DTC. Four hundred and eighty DTC patients were retrospectively evaluated by 7th and 8th editions of TNM staging system in relationship with risk stratification, response to therapy and recurrence of disease as defined by 2015 ATA guidelines. As compared to the 7th edition, TNM 8th led to downstage 136 patients (28.3%), with 97.5% of patients falling into lower stages (I-II) and only 2.5% remaining in higher stages (III-IV) (P < 0.001). Patients who were downstaged in stages I-II by TNM 8th were classified more frequently at intermediate-high risk (P < 0.001), had more frequently structural incomplete response to therapy (P = 0.009) and had higher risk of structural recurrence (P = 0.002) as compared to patients who were in the same TNM stages but were not downstaged. Specifically, the risk of structural recurrence was significantly higher in patients in whom the downstaging was induced by changes in tumour classification (hazard ratio (HR) 6.18, 95% CI 2.20-17.40; P = 0.001) but not in those who were downstaged for the increase in age cut-off (HR 2.80, 95% CI 0.86-9.19; P = 0.09). In conclusion, TNM 8th edition did not show reliability in predicting aggressiveness of DTC. In fact, the downstaging of DTC patients especially when performed due to changes in tumour classification may overlook patients predisposed to structural recurrence, potentially causing uncertainty in the therapeutic decision-making at the time of disease's diagnosis.

Post-surgical Thyroid Bed Pyoderma Gangrenosum Mimicking Recurrent Papillary Thyroid Carcinoma.

Background: Pyoderma gangrenosum (PG) is a rare inflammatory disease presenting with chronic-recurrent cutaneous ulcers histopathologically hallmarked by neutrophilic infiltrates, which may occur more frequently at sites of surgical traumas. The disease is habitually limited to the skin, but it can virtually involve any organ. Nevertheless, no prior cases of PG involving the thyroid bed have ever been reported. Case Report: A bilateral PG of the breast was diagnosed in a 51-year-old woman and treated with intravenous methylprednisolone pulse-therapy and cyclosporine, with partial improvement. During the hospitalization, cytological examination of two hypoechoic thyroid nodules by fine-needle aspiration (FNA) was consistent with thyroid carcinoma. After total thyroidectomy, histopathology confirmed a papillary thyroid cancer (PTC), and radioactive iodine ablation was performed. At 12-month ultrasonographic follow-up, two hypoechoic avascular areas localized in the empty thyroid bed raised the suspect of PTC recurrence. However, (i) undetectable levels of thyroglobulin without anti-thyroglobulin antibodies, (ii) neutrophilia and increased inflammatory marker levels, and (iii) cytological examination of FNA showing numerous neutrophils induced to suspect thyroid bed PG infiltration. An ex juvantibus approach with high-dose methylprednisolone led to dimensional reduction of the hypoechoic areas on ultrasonography, thus confirming the hypothesis of thyroid bed PG. Conclusion: This case of thyroid bed PG supports the idea that PG reflects a cutaneous phenotype encompassed in the spectrum of systemic neutrophilic diseases. Endocrinologists should be aware that thyroid bed PG involvement is an albeit rare differential diagnosis to consider in patients who had undergone thyroid surgery, especially with a history of PG.

Rare case of Cushing's disease due to double ACTH-producing adenomas, one located in the pituitary gland and one into the stalk.

UNLABELLED: We describe a patient affected by Cushing's disease due to the presence of double pituitary adenomas, one located within the anterior pituitary and the other in the infundibulum associated with a remnant of Rakthe's pouch. Cure was achieved only after the infundibulum lesion was surgically removed. CASE REPORT: A 38-year-old female presented with unexplained weight gain, hirsutism, amenorrhea, asthenia, recurrent cutaneous micotic infections and alopecia. Hormonal studies indicated Cushing's disease and MRI showed an enlarged pituitary gland with a marked and homogeneous enhancement after injection of gadolinium and an enlarged infundibulum with a maximum diameter of 8 mm. As a venous sampling of the inferior petrosal sinus after 10 µg iv desmopressin stimulation revealed a central to peripheral ACTH ratio consistent with a pituitary ACTH-secreting tumor, transphenoidal explorative surgery was performed and a 4-mm pituitary adenoma immunopositive for ACTH was disclosed and removed. Since postoperative hormonal evaluation showed persistent hypercortisolism, confirmed by dynamic tests, the patient again underwent surgery by transcranial access and the infundibulum mass was removed. Histology and immunochemistry were consistent with an ACTH-secreting adenoma. A few months after the second operation, cushingoid features were significantly reverted and symptoms improved. CONCLUSION: Although Cushing's patients bearing multiple adenomas have already been documented, the presence of two adenomas both immunohistochemically positive for ACTH is a very rare cause of Cushing's disease and this is the first report of a case of double ACTH-producing adenomas, one located in the pituitary gland and one attached to the stalk.

Long-term follow-up in adrenal incidentalomas: an Italian multicenter study.

CONTEXT: The long-term consequences of subclinical hypercortisolism (SH) in patients with adrenal incidentalomas (AIs) are unknown. SETTING AND PATIENTS: In this retrospective multicentric study, 206 AI patients with a ≥5-year follow-up (median, 72.3 mo; range, 60-186 mo) were enrolled. INTERVENTION AND MAIN OUTCOME MEASURES: Adrenocortical function, adenoma size, metabolic changes, and incident cardiovascular events (CVEs) were assessed. We diagnosed SH in 11.6% of patients in the presence of cortisol after a 1 mg-dexamethasone suppression test >5 µg/dL (138 nmol/L) or at least two of the following: low ACTH, increased urinary free cortisol, and 1 mg-dexamethasone suppression test >3 µg/dL (83 nmol/L). RESULTS: At baseline, age and the prevalence of CVEs and type 2 diabetes mellitus were higher in patients with SH than in patients without SH (62.2 ± 11 y vs 58.5 ± 10 y; 20.5 vs 6%; and 33.3 vs 16.8%, respectively; P < .05). SH and type 2 diabetes mellitus were associated with prevalent CVEs (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1-9.0; and OR, 2.0; 95% CI, 1.2-3.3, respectively), regardless of age. At the end of the follow-up, SH was diagnosed in 15 patients who were without SH at baseline. An adenoma size >2.4 cm was associated with the risk of developing SH (sensitivity, 73.3%; specificity, 60.5%; P = .014). Weight, glycemic, lipidic, and blood pressure control worsened in 26, 25, 13, and 34% of patients, respectively. A new CVE occurred in 22 patients. SH was associated with the worsening of at least two metabolic parameters (OR, 3.32; 95% CI, 1.6-6.9) and with incident CVEs (OR, 2.7; 95% CI, 1.0-7.1), regardless of age and follow-up. CONCLUSION: SH is associated with the risk of incident CVEs. Besides the clinical follow-up, in patients with an AI >2.4 cm, a long-term biochemical follow-up is also required because of the risk of SH development.