OBJECTIVE: Owing to their increasing rate of discovery as incidental findings, the characterization of adrenal masses is an important diagnostic problem which frequently challenges the clinician's skill. DESIGN: The results of dehydroepiandrosterone sulfate (DHEAS) measurement were evaluated in a consecutive series of 107 patients with an adrenal mass (39 men, 68 women aged 15-81 years, median 56 years). DHEAS levels observed in the patients were categorized as reduced, normal or elevated according to sex- and age-adjusted reference ranges obtained by measuring DHEAS in 214 healthy women and 142 healthy men aged 17-93 years. The working hypothesis was that a low DHEAS level is a marker of benignity. METHODS: In 84 patients, the adrenal mass was discovered serendipitously, while in the remainder the mass was clinically symptomatic. Patients with known extra-adrenal malignancies were excluded. The adrenal masses were categorized as benign or malignant by computerized tomography (CT) criteria. All patients with suspected malignant tumors or with overtly hypersecreting tumors underwent adrenalectomy. The patients with a presumptive benign tumor were followed-up for at least 12 months. RESULTS: In the overall series, the sensitivity and specificity of a low DHEAS level in the identification of a benign lesion were 41% and 100% respectively. Superimposable figures were obtained when considering only adrenal incidentalomas. DHEAS levels in adrenal cancers displayed some overlap with adrenal adenomas, but in only 2/11 adrenal cancers were DHEAS levels normal, while they were elevated in the remainder. CONCLUSIONS: The present data suggest that DHEAS measurement may help to differentiate benign from malignant adrenal masses as a complementary test of CT in a clinical research setting. The value of DHEAS measurement in general practice is limited because it may be difficult to differentiate between low and low-normal values, particularly in the elderly.
M Terzolo, A Ali, G Osella, G Reimondo, A Pia, P Peretti, P Paccotti and A Angeli
A Calabrese, V Basile, S Puglisi, P Perotti, A Pia, L Saba, P Berchialla, F Porpiglia, A Veltri, M Volante, G Reimondo, A Berruti and M Terzolo
Many patients with adrenocortical carcinoma (ACC) suffer from tumor recurrence despite radical surgery. Evidence on the post-operative use of mitotane is controversial and no predictors of response are available. We aimed to assess whether adjuvant mitotane treatment may prolong survival in patients with non-metastatic ACC following complete resection and whether ACC patients at high risk of recurrence may benefit from treatment.
Design and methods
We retrospectively reviewed data from 152 non-metastatic ACC patients followed at the San Luigi Gonzaga Hospital: 100 patients were treated with adjuvant mitotane and 52 patients were left untreated following surgery. We assessed a number of potential predictive factors of recurrence and death. Mitotane effect was explored stratifying patients by staging (stage I–II vs stage III), hormone secretion (yes vs no) and Ki67 index.
The non-treated group had a higher risk of recurrence (HR: 2.79, 95%CI: 1.58–4.91; P < 0.001) than mitotane-treated group, while overall survival was not significantly different between groups. Hormone secretion, elevated Weiss score and elevated Ki67 index confer a higher risk of both recurrence and death and stage III ACC of death. Adjuvant mitotane treatment reduced significantly the risk of death in patients with elevated Ki67 index (P = 0.005) and in patients with stage III ACC (P = 0.02).
Adjuvant mitotane may prolong recurrence-free survival in radically resected ACC patients with acceptable toxicity and may also prolong overall survival in a subgroup of ACC patients at high risk of recurrence.
M Terzolo, B Allasino, A Pia, G Peraga, F Daffara, F Laino, A Ardito, A Termine, P Paccotti, P Berchialla, G Migliaretti and G Reimondo
Recent studies have questioned the reversibility of complications of Cushing's syndrome (CS) after successful surgical treatment. The aim of this study was to assess the outcome of patients with CS who achieved disease remission compared with those patients with persistent hypercortisolism and matched controls.
A retrospective study of 75 patients with CS followed at an academic center.
Cardiovascular risk profile was evaluated in 51 patients with CS in remission (group 1) and 24 patients with persistent disease (group 2) and compared with 60 controls. Mortality of patients with CS was compared with the background population.
In group 1, the frequency of cardiovascular risk factors dropped after disease remission even if it remained higher at the last follow-up than in the control group. In group 2, the frequency of cardiovascular risk factors remained unchanged during follow-up. The rate of cardiovascular and thromboembolic events was higher in group 2 than in group 1, as was the mortality rate (two deaths in group 1 and nine in group 2; ratio of two SMRs, 0.11; 95% CI, 0.011–0.512). Survival was significantly longer in group 1 than in group 2 (87 months, 80–98 vs 48 months, 38–62; P<0.0001).
Successful surgical treatment of hypercortisolism significantly improves cardiovascular risk and may reduce the mortality rate. Patients with persistent disease have increased morbidity and mortality when compared with patients in remission.
Annamaria Colao, Rosario Pivonello, Renata S Auriemma, Maria Cristina De Martino, Martin Bidlingmaier, Francesco Briganti, Fabio Tortora, Pia Burman, Ione A Kourides, Christian J Strasburger and Gaetano Lombardi
Objective: We aimed to investigate the efficacy of pegvisomant in patients with acromegaly resistant to long-term (≧ 24-month), high-dose treatment with octreotide-LAR (40 mg/month) or lanreotide (120 mg/month).
Design: This was an open, prospective study.
Subjects and Methods: We studied 16 patients with acromegaly (nine women; aged 28–61 years). The main outcome measures were IGF-I levels, blood pressure, glucose tolerance and safety (liver function and tumor size). Pegvisomant was given at doses of 10–40 mg s.c. daily. Dose titration was performed every month by IGF-I assay.
Results: Three patients spontaneously stopped pegvisomant treatment after 6–9 months because of poor compliance; from the measurement of serum pegvisomant, another patient was found not to inject herself properly. After 6 months, IGF-I levels decreased by 63 ± 19% (767.8 ± 152.9 vs 299.8 ± 162.9 μg/l, P < 0.0001, t-test); serum IGF-I levels normalized in 57%. After 12 months, IGF-I levels normalized in nine (75%) patients and were reduced by over 50% in another three (25%). The mean tumor volume remained stable during the study (1198 ± 1234 vs 1196 ± 1351 mm3, P = 0.37): it did not change ( ± 25% vs basal) in nine patients, increased by 39.4% and 40.8% in two and decreased by 30.8–46.5% in four. The total/high-density lipoprotein (HDL):cholesterol ratio (from 4.4 ± 1.0 to 3.7 ± 0.6, P= 0.0012), glucose levels (from 5.6 ± 1.2 to 4.4 ± 1.4 mmol/l, P = 0.026), insulin levels (from 12.4 ± 6.7 to 8.1 ± 3.0 mUl/l, P = 0.0023) and homeostasis model assessment (HOMA) index (from 3.4 ± 2.1 to 1.9 ± 1.0, P = 0.0017) decreased.
Conclusions: Treatment for 12 months with pegvisomant normalized IGF-I levels, and improved cardiovascular risk parameters and insulin sensitivity in patients with acromegaly resistant to long-term, high-dose treatment with somatostatin analogs. The tolerance of treatment was good.
M Terzolo, A Stigliano, I Chiodini, P Loli, L Furlani, G Arnaldi, G Reimondo, A Pia, V Toscano, M Zini, G Borretta, E Papini, P Garofalo, B Allolio, B Dupas, F Mantero and A Tabarin
To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice.
A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus.
Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma).
Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l.
Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.
A Veltroni, E Cosaro, F Spada, N Fazio, A Faggiano, A Colao, S Pusceddu, M C Zatelli, D Campana, A Piovesan, A Pia, E M Grossrubatscher, A Filice, A Bianchi, P Razzore, M Toaiari, S Cingarlini, L Landoni, R Micciolo and M V Davì
Management of malignant insulinomas is challenging due to the need to control both hypoglycaemic syndrome and tumor growth. Literature data is limited to small series.
Aim of the study
To analyze clinico-pathological characteristics, treatments and prognosis of patients with malignant insulinoma.
Materials and methods
Multicenter retrospective study on 31 patients (male: 61.3%) diagnosed between 1988 and 2017.
The mean age at diagnosis was 48 years. The mean NET diameter was 41 ± 31 mm, and 70.8% of NETs were G2. Metastases were widespread in 38.7%, hepatic in 41.9% and only lymph nodal in 19.4%. In 16.1% of the cases, the hypoglycaemic syndrome occurred after 46 ± 35 months from the diagnosis of originally non-functioning NET, whereas in 83.9% of the cases it led to the diagnosis of NET, of which 42.3% with a mean diagnostic delay of 32.7 ± 39.8 months. Surgical treatment was performed in 67.7% of the cases. The 5-year survival rate was 62%. Overall survival was significantly higher in patients with Ki-67 ≤10% (P = 0.03), insulin level <60 µU/mL (P = 0.015) and in patients who underwent surgery (P = 0.006). Peptide Receptor Radionuclide Therapy (PRRT) was performed in 45.1%, with syndrome control in 93% of patients.
Our study includes the largest series of patients with malignant insulinoma reported to date. The hypoglycaemic syndrome may occur after years in initially non-functioning NETs or be misunderstood with delayed diagnosis of NETs. Surgical treatment and Ki67 ≤10% are prognostic factors associated with better survival. PPRT proved to be effective in the control of hypoglycaemia in majority of cases.
Marco Medici, Wendy M van der Deure, Michael Verbiest, Sita H Vermeulen, Pia S Hansen, Lambertus A Kiemeney, Ad R M M Hermus, Monique M Breteler, Albert Hofman, Laszlo Hegedüs, Kirsten Ohm Kyvik, Martin den Heijer, André G Uitterlinden, Theo J Visser and Robin P Peeters
Minor variation in serum thyroid hormone (TH) levels can have important effects on various clinical endpoints. Although 45–65% of the inter-individual variation in serum TH levels is due to genetic factors, the causative genes are not well established. We therefore studied the effects of genetic variation in 68 TH pathway genes on serum TSH and free thyroxine (FT4) levels.
Design and methods
Sixty-eight genes (1512 polymorphisms) were studied in relation to serum TSH and FT4 levels in 1121 Caucasian subjects. Promising hits (P<0.01) were studied in three independent Caucasian populations (2656 subjects) for confirmation. A meta-analysis of all four studies was performed.
For TSH, eight PDE8B polymorphisms (P=4×10−17) remained significant in the meta-analysis. For FT4, two DIO1 (P=8×10−12) and one FOXE1 (P=0.0003) polymorphisms remained significant in the meta-analysis. Suggestive associations were detected for one FOXE1 (P=0.0028) and three THRB (P=0.0045) polymorphisms with TSH, and one SLC16A10 polymorphism (P=0.0110) with FT4, but failed to reach the significant multiple-testing corrected P value (P<0.0022 and P<0.0033 respectively).
Using a large-scale association analysis, we replicated previously reported associations with genetic variation in PDE8B, THRB, and DIO1. We demonstrate effects of genetic variation in FOXE1 on serum FT4 levels, and borderline significant effects on serum TSH levels. A suggestive association of genetic variation in SLC16A10 with serum FT4 levels was found. These data provide insight into the molecular basis of inter-individual variation in TH serum levels.
Marco Bonomi, Valeria Vezzoli, Csilla Krausz, Fabiana Guizzardi, Silvia Vezzani, Manuela Simoni, Ivan Bassi, Paolo Duminuco, Natascia Di Iorgi, Claudia Giavoli, Alessandro Pizzocaro, Gianni Russo, Mirella Moro, Letizia Fatti, Alberto Ferlin, Laura Mazzanti, Maria Chiara Zatelli, Salvo Cannavò, Andrea M Isidori, Angela Ida Pincelli, Flavia Prodam, Antonio Mancini, Paolo Limone, Maria Laura Tanda, Rossella Gaudino, Mariacarolina Salerno, Pregnolato Francesca, Mohamad Maghnie, Mario Maggi, Luca Persani and Italian Network on Central Hypogonadism
Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation.
Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals.
We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8).
90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann’s syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH.
Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.