Marco Mendola

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.

Multiple Cerebral Hemorrhagic Foci From Metastases During Temozolomide Treatment in a Patient With Corticotroph Pituitary Carcinoma

Pituitary carcinoma is a rare disorder accounting for 0.1–0.5% of pituitary neoplasia (1, 2), with a poor prognosis despite maximal multimodal standard therapies. Temozolomide has been suggested as effective in treating pituitary carcinomas (3–5). Here, we describe the case of a 58-year-old man with active Cushing’s disease due to a huge pituitary tumor. Repeated adenomectomy failed to control the disease. Histology examination revealed a pituitary adenoma, with positive immunostaining for ACTH and a Ki-67 proliferation index of 10%, whereas Crooke’s cells were absent. Ketoconazole and cabergoline treatment being ineffective, conventional radiotherapy (48.6 Gy) was administered. Five years later, magnetic resonance imaging showed a residual pituitary lesion of 28 16 mm with suprasellar extension. The hormonal evaluation indicated persistent severe hypercortisolism. Bilateral adrenalectomy was then performed. Twelve months later, plasma ACTH levels dramatically increased (up to 1250 pg/mL), and the pituitary neoplasm extended to the clivus and the C2 body (Figure 1A). Liver, vertebral, and meningeal lesions were detected (Figure 1B); biopsies of hepatic lesions confirmed ACTH-positive neuroendocrine metastases. Temozolomide (160 mg/m daily for 5 d) was started. Plasma ACTH levels were unaffected; 27 days later, the patient complained of severe headache, blindness, and rigor nucalis. He was admitted to the intensive care unit where severe thrombocytopenia (18 000/mm), a previously reported adverse event of temozolomide (3), and multiple cerebral hemorrhagic foci from metastases were diagnosed (Figure 1, C and D). He died a few months after discharge. This case report emphasizes the risk of hemorrhages associated with temozolomide and the need for careful management in patients with aggressive pituitary tumors.

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

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.

Asymptomatic myotonia congenita unmasked by severe hypothyroidism

Myotonia congenita is an inherited muscle disorder sustained by mutations in the skeletal muscle chloride channel gene CLCN1. Symptoms vary from mild to severe and generalized myotonia and worsen with cold, stressful events and hormonal fluctuations. Here we report the case of a young woman who sought medical attention because of subacute onset of diffuse and severe limb myotonia. CLCN1 gene sequencing showed a heterozygous transversion (T550M), two polymorphisms and one silent mutation. Thyroid function screening revealed severe hypothyroidism. She was placed on l-thyroxine replacement therapy which dramatically improved myotonia. We conclude that hypothyroidism unmasked a genetically determined, clinically asymptomatic chloride channelopathy. Diagnostic work-up in patients with clinically isolated myotonia should not be limited to genetic screening of non-dystrophic or dystrophic myotonias. Considering the high prevalence of hypothyroidism in females, systematic thyroid function screening by looking for additional hypothyroid symptoms and serum TSH levels measurement is mandatory in these patients.

1360 Differences between peritoneal and pleural mesothelioma in lombardy, italy

Introduction Asbestos is the main risk factor for development of both peritoneal (PEM) and pleural (PLM) mesothelioma, but characteristics of this two diseases and their association with asbestos show some differences. We examined characteristics of PEM and PLM in Lombardy, Italy, the most populated (currently, 10 million residents) and industrialised Italian region. Methods The RML, established in 2000, is a population-based registry which records all cases of mesothelioma among Lombardy residents. It is part of a national network of mesothelioma registries (ReNaM). Notification of mesothelioma cases is compulsory by law. Additional sources of mesothelioma cases include hospital admission, mortality, occupational diseases, and pathology databases. Verified mesothelioma cases are interviewed about past asbestos exposure using a standardised questionnaire. For this study, from the RML database we selected PEM and PLM cases diagnosed in 2000–2014. We investigated asbestos exposure, presence of asbestosis or pleural plaques, and past employment in economical sectors. Results We identified 300 PEM and 5,011 PLM cases. Incidence rates (per 1.000.000 person-years, world standardised) of PEM were 2.4 (men) and 1.7 (women), compared with 52.4 and 19.9 for PLM. Asbestosis (both genders) and pleural plaques (men) were more frequent among PEM cases. Occupational asbestos exposure was similar in PEM and PLM cases. We found higher proportions of PEM employed in the asbestos cement production. Conclusion The higher frequency of pleural plaques in PEM cases and the similar frequency of past occupational asbestos exposure confirm the association between asbestos exposure and peritoneal mesothelioma. The higher proportions of asbestosis and of past employment in the asbestos-cement sector among PEM cases suggest a possible role of high exposures to asbestos in the peritoneal mesothelioma genesis.

Differences between peritoneal and pleural mesothelioma in Lombardy, Italy

BACKGROUND We examined characteristics of peritoneal (PEM) and pleural (PLM) mesothelioma in Lombardy, Italy. METHODS From the Lombardy Mesothelioma Registry we selected PEM (N=300) and PLM (N=5011) cases diagnosed in 2000-2014. We investigated asbestos exposure and presence of asbestosis or pleural plaques. RESULTS Incidence rates (per 1,000,000 person-years, world standardized) of PEM were 1.2 (men) and 0.9 (women), compared with 22.6 and 8.4 for PLM. Asbestosis (both genders) and pleural plaques (men) were more frequent among PEM cases. Occupational asbestos exposure was similar in PEM and PLM cases. We found higher proportions of PEMs employed in the asbestos cement production. CONCLUSION The higher frequency of pleural plaques in PEM cases confirm the association between asbestos and peritoneal mesothelioma. The higher proportions of asbestosis and of past employment in the asbestos-cement sector among PEM cases suggest a possible role of high exposures to asbestos in the peritoneal mesothelioma genesis.

Autoimmune Polyendocrine Syndrome 3 Onset with Severe Ketoacidosis in a 74-Year-Old Woman

Type 1 diabetes mellitus (T1D), autoimmune thyroid disease, and autoimmune gastritis often occur together forming the so-called autoimmune polyendocrine syndrome type 3 (APS3). We here report a clinical case of a 74-year-old woman who presented for the first time with severe hyperglycemia and ketoacidosis diagnosed as T1D. Further clinical investigations revealed concomitant severe hypothyroidism with autoimmune thyroid disease and severe cobalamin deficiency due to chronic atrophic gastritis. The diagnosis of type 1 diabetes mellitus was confirmed by the detection of autoantibodies against glutamic acid decarboxylase 65, islet cell antibodies, and anti-insulin autoantibodies. Anti-thyroperoxidase, anti-thyroglobulin, and anti-gastric parietal cell antibodies were also clearly positive. The case emphasized that new onset diabetic ketoacidosis, hypothyroidism, and cobalamin deficiency may simultaneously occur, and one disease can mask the features of the other, thereby making diagnosis difficult. It is noteworthy that an APS3 acute episode occurred in an asymptomatic elder woman for any autoimmune diseases.

Diagnosi di malattia di Cushing in una giovane donna africana

Una donna camerunense di 37 anni veniva ricoverata per ipopotassiemia refrattaria, associata a grave astenia, anoressia e importante calo ponderale. La paziente presentava da 3 anni ipertensione arteriosa, diabete mellito scarsamente controllato con antidiabetici orali e sindrome depressiva. La paziente aveva di recente portato a termine due gravidanze, entrambe complicate da gestosi. Obiettivamente non si evidenziavano pletora, strie rubre, irsutismo e gibbo, mentre erano apprezzabili facies lunare e acne al volto (Figura 1). Lo studio ormonale mostrava un marcato ipercortisolismo ACTH-dipendente, con perdita del ritmo circadiano, associato a ipotiroidismo e ipogonadismo centrali. Non si osservava soppressione dell’asse ipotalamo-ipofisi-surrene dopo desametasone 1 mg e 8 mg alle h 24. Una risonanza magnetica nucleare della regione ipofisaria evidenziava, a destra, una lesione ipointensa, di 12×7 mm, con focolaio necrotico centrale, estesa alle cisterne sovrasellari, indicativa di macroadenoma. La donna veniva perrtanto sottoposta ad adenomectomia ipofisaria per via transfenoidale. Dopo un decorso post-operatorio privo di complicanze, si osservava netto miglioramento dell’aspetto clinico (Figura 2), associato a normalizzazione della potassiemia, a un miglior controllo glicemico e a una progressiva riduzione dei livelli di cortisolo e ACTH basali. La pecualiarita del caso sta nel fatto che le caratteristiche razziali avevano reso difficoltoso l’approccio diagnostico iniziale, mascherando in qualche modo i segni clinici della malattia, che pur si presentava in