Catastrophic ACTH-secreting pheochromocytoma: an uncommon and challenging entity with multifaceted presentation.

Summary: Cushing's syndrome due to ectopic adrenocorticotropic hormone (ACTH) secretion (EAS) by a pheochromocytoma is a challenging condition. A woman with hypertension and an anamnestic report of a 'non-secreting' left adrenal mass developed uncontrolled blood pressure (BP), hyperglycaemia and severe hypokalaemia. ACTH-dependent severe hypercortisolism was ascertained in the absence of Cushingoid features, and a psycho-organic syndrome developed. Brain imaging revealed a splenial lesion of the corpus callosum and a pituitary microadenoma. The adrenal mass displayed high uptake on both 18F-FDG PET/CT and 68Ga-DOTATOC PET/CT; urinary metanephrine levels were greatly increased. The combination of antihypertensive drugs, high-dose potassium infusion, insulin and steroidogenesis inhibitor normalized BP, metabolic parameters and cortisol levels; laparoscopic left adrenalectomy under intravenous hydrocortisone infusion was performed. On combined histology and immunohistochemistry, an ACTH-secreting pheochromocytoma was diagnosed. The patient's clinical condition improved and remission of both hypercortisolism and catecholamine hypersecretion ensued. Brain magnetic resonance imaging showed a reduction of the splenial lesion. Off-therapy BP and metabolic parameters remained normal. The patient was discharged on cortisone replacement therapy for post-surgical hypocortisolism. EAS due to pheochromocytoma displays multifaceted clinical features and requires prompt diagnosis and multidisciplinary management in order to overcome the related severe clinical derangements. Learning points: A small but significant number of cases of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome are caused by ectopic ACTH secretion by neuroendocrine tumours, which is usually associated with severe hypercortisolism causing severe clinical and metabolic derangements. Ectopic ACTH secretion by a pheochromocytoma is exceedingly rare but can be life-threatening, owing to the simultaneous excess of both cortisol and catecholamines. The combination of biochemical and hormonal testing and imaging procedures is mandatory for the diagnosis of ectopic ACTH secretion, and in the presence of an adrenal mass, the possibility of an ACTH-secreting pheochromocytoma should be taken into account. Immediate-acting steroidogenesis inhibitors are required for the treatment of hypercortisolism, and catecholamine excess should also be appropriately managed before surgical removal of the tumour. A multidisciplinary approach is required for the treatment of this challenging entity.

Role of 18F-Choline Positron Emission Tomography/Computed Tomography to Detect Structural Relapse in High-Risk Differentiated Thyroid Cancer Patients.

BACKGROUND: This study aimed to evaluate the role of 18F-choline (18F-FCH) positron emission tomography (PET)/computed tomography (CT) in high-risk differentiated thyroid cancer (DTC) patients with suspected relapse. It also compared 18F-FCH-PET/CT results with those of fludeoxyglucose (18F-FDG)-PET/CT and evaluated the additional diagnostic value and clinical impact of the combined use of these two tracers. Finally, it assessed the association between the clinical, biochemical, and histological parameters and 18F-FCH-PET/CT and 18F-FDG-PET/CT results. METHODS: The study prospectively enrolled high-risk DTC patients treated with thyroidectomy and radioactive iodine therapy and presenting high/increasing thyroglobulin levels under thyrotropin suppression, negative/inconclusive neck ultrasound, and negative 131I whole-body scan. All patients underwent 18F-FDG-PET/CT and 18F-FCH-PET/CT within 30 days of each other. Experienced nuclear medicine physicians examined the images of both procedures, and an integrated analysis of the two PET/CT modalities was also conducted. For each modality, a patient-based analysis (PBA) and lesion-based-analysis (LBA) was performed. On PBA, sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were calculated. On LBA, only sensitivity was calculated. The standard of reference was based on clinical, imaging, and histological data. RESULTS: Twenty-five high-risk DTC patients were included; DTC relapse/persistence was confirmed in 23 patients. On PBA, 18F-FDG-PET/CT, 18F-FCH-PET/CT, and the integrated evaluation of the two imaging modalities showed the following rates: sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were 69.6%, 100%, 22.2%, 100%, and 72% versus 56.5%, 100%, 16.7%, 100%, and 60% versus 82.6%, 100%, 33.3%, 100%, and 84%, respectively. When compared with 18F-FDG-PET/CT, the integrated analysis of these two imaging procedures changed the clinical management in 4/23 (17%) patients. On LBA, the sensitivity rates of 18F-FDG-PET/CT, 18F-FCH-PET/CT, and the combined evaluation of the two modalities were 58.7%, 38.1%, and 66.7%, respectively; when only lymph node involvement was considered, the rates were 56.3%, 53.1%, and 68.8%, respectively. Serum thyroglobulin doubling time (Tg-DT) <12 months was significantly associated with positive 18F-FCH-PET/CT. A trend toward a significant association was also found between positive 18F-FDG-PET/CT and both Tg-DT <12 months and DTC aggressive subtypes. CONCLUSION: 18F-FCH-PET/CT may add important information during the follow-up of high-risk DTC patients. 18F-FCH-PET/CT may be considered a useful complementary tool in patients affected by non-aggressive DTC subtypes, with Tg-DT <12 months, high risk of lymph node spreading, and negative or doubtful 18F-FDG-PET/CT.

Differentiated Thyroid Cancer lymph-node relapse. Role of adjuvant radioactive iodine therapy after lymphadenectomy.

PURPOSE: Our purpose as to evaluate the impact of adjuvant radioactive iodine therapy (RAI) on prognosis, as assessed by progression-free survival (PFS) and overall survival (OS), in patients affected by differentiated thyroid carcinoma (DTC) lymph-node relapse and previously treated with lymphadenectomy. METHODS: We retrospectively evaluated DTC patients treated with lymph-node dissection for disease relapse. All patients had previously undergone total thyroidectomy and radioiodine remnant ablation (RRA). We used clinical and histological data obtained during follow-up to assess response and outcome. By means of univariate and multivariate time-to-event analyses, we assessed the impact of RAI on outcome (PFS and OS) and the prognostic role of thyroglobulin (Tg) levels under suppression with levothyroxine (Tg-on) measured 1-3 months after lymphadenectomy and of other risk factors. RESULTS: We evaluated 113 patients (age at diagnosis: median 41 years, interquartile range: 31-59), 64 of whom were treated with RAI. Over a median follow-up time of 5.7 years, 27 patients showed disease progression and 13 died. Kaplan-Meier PFS and OS curves showed that age on diagnosis, tumor histology, tumor size, DTC aggressive variant, and Tg-on were associated with prognosis. Patients with Tg-on ≥1 ng/ml treated with RAI showed a better PFS (Log-rank pp 0.001) and OS (p = 0.005) than untreated patients, while no effect of RAI was observed in patients with Tg-on <1 ng/ml. Multivariate models showed that age, Tg-on (≥1 vs. < 1 ng/ml, HR: 18.2, 95% CI: 5.09-64.8, p = 0.001) and RAI (Yes vs. No, HR: 0.36,95%CI: 0.15-0. 9, p = 0.02) remained the only independent factors associated with PFS, but only age and Tg-on remained significantly associated with OS (HR: 8.31, 95%CI:1.56-44.3, p = 0.01). Nonetheless, patients treated with RAI showed a lower risk of mortality (HR: 0.34, 95%CI: 0.1-1.15 p = 0.08) than untreated patients. CONCLUSIONS: RAI after lymphadenectomy for DTC relapse is significantly associated with better PFS only in patients with Tg-on ≥1 ng/ml.

Iodine-induced hyperthyroidism as combination of different etiologies: an overlooked entity in the elderly.

Iodine-induced thyrotoxicosis, which raises several diagnostic and therapeutical challenges, is often overlooked. Hyperthyroidism can induce atrial fibrillation, a harmful arrhythmia which can precipitate heart failure and cause stroke. We report the case of an elderly man who was diagnosed with tachyfibrillation secondary to hyperthyroidism. Thyroid hyperfunction was subsequently related both to previous amiodarone therapy (probably mixed form) and the recent use of iodinated contrast medium for computed tomography scan. Thyroid ultrasonography showed a plongeant multinodular goitre. After initial worsening, thyroid function improved slowly but progressively on high-dose thyreostatic therapy combined with steroid therapy; tachyfibrillation caused heart failure and a thrombus in the left atrium, and proved initially resistant to combined antiarrhythmic treatments. Progressive reduction in thyroid hormone levels, together with combined cardiologic therapies, controlled the heart rate, though atrial fibrillation persisted; anticoagulant therapy resolved the atrial thrombus. Alterations in thyroid function are common in amiodarone-treated patients, who therefore require regular hormonal checks. The different forms of amiodarone-induced thyrotoxicosis must be investigated, since they require different therapies, though mixed forms often occur. The superimposition of further iodine excess due to other causes may be catastrophic and cause severe cardiac problems in these patients.

CHARGE syndrome as unusual cause of hypogonadism: endocrine and molecular evaluation.

Coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies (CHARGE) syndrome is a genetic syndrome in which hypogonadism is a frequent feature. A causative mutation within the chromodomain helicase DNA-binding protein-7 gene, which plays an important role in the embryonic development, is present in 2/3 of affected patients. We describe the clinical, hormonal and molecular characteristics of a young man from Ecuador who was diagnosed as having CHARGE syndrome at an adult age. The patient showed several phenotypic features of the syndrome, associated with a prepubertal state and cryptorchidism; hypogonadotrophic hypogonadism with undetectable testosterone levels not responsive to hCG testing and severe osteoporosis were ascertained. Molecular evaluation of the CHD7 gene showed the novel frameshift truncating heterozygous mutation p.Tyr1046Glyfs*23 in exon 12. Magnetic resonance imaging revealed mild hypoplasia of the pituitary gland and hypoplasia of the posterior cranial fossa. Parenteral testosterone therapy led to sexual development over time and, in combination with diphophonate therapy and calcium-vitamin D supplementation, significantly improved bone mineralisation. Early proper hormonal treatment of hypogonadism in patients with complex genetic syndromes is important to achieve normal sexual maturation, improve quality of life and avoid significant comorbidities, such as osteoporosis.

Intrathyroidal parathyroid carcinoma as cause of hypercalcemia and pitfall of localization techniques: clinical and biologic features.

OBJECTIVE: To describe an unusual case of intrathyroidal parathyroid carcinoma (PC), which was retrospectively diagnosed in a woman who underwent surgical treatment of a recurrent nodular goiter. METHODS: We report the clinical and biologic features of an intrathyroidal PC, discuss the challenges with distinguishing PC from parathyroid adenoma, and review the related literature. RESULTS: A 67-year-old woman sought medical attention for dysphagia attributable to the recurrence of a normal functioning multinodular goiter. Thyroid ultrasonography disclosed a 3-cm solid inferior nodule. Because she refused surgical treatment and a trial of levothyroxine was unsuccessful, periodic follow-up examinations were scheduled. At 1-year follow-up, hypercalcemia (12.1 to 12.6 mg/dL) and low phosphorus levels (2.0 to 2.3 mg/dL) were found, and parathyroid hormone (PTH) levels were profoundly increased (481 to 721 pg/mL). Neck ultrasonography showed a large hypoechogenic solid nodule, not clearly cleaved from the right thyroid lobe, which was possibly compatible with an enlarged parathyroid gland; however, a sestamibi scan was negative. During total thyroidectomy, intraoperative frozen sections of the intrathyroid nodule were compatible with nodular goiter with cellular pleomorphism. Final histologic examination showed cellular nests with nuclear pleomorphism and invasive behavior into the thyroid tissue and likely into the vessels, in conjunction with immunohistochemical negativity for thyroglobulin and strong positivity for PTH. These findings were highly suggestive of and supported the diagnosis of PC. Postoperatively, calcium levels normalized, and PTH values declined considerably but remained slightly increased. Vitamin D supplementation helped normalize the PTH levels. The patient has undergone follow-up for 5 years and has shown no morphologic or biochemical signs of tumor recurrence. CONCLUSION: PC is a rare entity but should be suspected in patients with hypercalcemia, substantially increased PTH levels, and a neck mass. In such patients, techniques such as sestamibi scanning may fail to localize the neoplasm. Surgical treatment remains the preferred technique for an optimal outcome of the disease. Nevertheless, lifelong follow-up is necessary.

Experimental assessment of chemotherapy-induced early intestinal damage in colon cancer the lactulose-mannitol permeability test.

AIMS AND BACKGROUND: Although chemotherapy plays an important role in the management and cure of cancer, it has undesiderable side effects mostly affecting the bone marrow and gastrointestinal tract, which greatly limit patient compliance and treatment efficacy. METHODS: The lactulose-mannitol test was used to assess intestinal mucosa damage 48 hours after the end of the first adjuvant chemotherapy cycle with 5-fluorouracil (5-FU) and levamisole in 12 patients with colon cancer. Fifteen age- and sex-matched subjects were studied as controls. The excreted amount of lactulose and mannitol was expressed as the percentage of the administered doses recovered in the urine as well as their ratio. RESULTS: The percent urinary recovery of lactulose was significantly (P < 0.001) higher in colon cancer patients (1.1 +/- 0.5%) than in the control group (0.3 +/- 0.03%), whereas the mannitol recovery was only slightly reduced in the former. As a result, the lactulose/mannitol excretion ratio was significantly (P < 0.001) higher in colon cancer patients (0.07 +/- 0.03) than in the control group (0.01 +/- 0.01). CONCLUSIONS: As assessed by the lactulose-mannitol test, the combined chemotherapy regimen with 5-FU and levamisole affects mainly the barrier function of the intestinal mucosa rather than its absorption capacity. The toxic effect seems to be attributable to the 5-FU molecule rather than to levamisole. The lactulose-mannitol test is a simple, safe and reliable tool to evaluate chemotherapy-induced early damage to the intestinal epithelium, in particular when new kinds of substances are being administered. Its use in clinical practice seems appropriate to establish the correct timing of drug administration, thereby enhancing treatment efficacy and improving patient compliance.