Krystallenia Alexandraki

The ectopic ACTH syndrome

Ectopic Cushing’s syndrome usually relates to the ectopic ACTH syndrome (EAS) and represents ∼20% of ACTH-dependent and ∼10% of all types of Cushing’s syndrome (CS). Nearly any neuroendocrine or non-endocrine tumours may be associated with EAS, but the more prevalent tumours are bronchial carcinoids, small cell lung carcinomas, pancreatic carcinoids, thymic carcinoids, medullary carcinomas of the thyroid, and phaeochromocytomas. Occult tumours are highly represented in all the series (12–38%) and constitute the more challenging cases of EAS, requiring long term follow-up. The lack of any completely reliable diagnostic test procedure and imaging to clearly reveal the source of EAS suggests that we should adopt a step-by-step multidisciplinary approach for their diagnosis and therapeutic management. Clinical features are often similar in ACTH-dependent CS, but the rapid onset and progress may suggest an ectopic source. A combination of biochemical tests and imaging studies seems the most appropriate approach for the prompt identification of EAS, even if there are several pitfalls to be avoided along the way. The most appropriate management for cure of EAS, when its source is identified, is surgical excision after controlling the hypercortisolaemia by inhibitors of cortisol secretion and other newer modalities alone or in combination; bilateral adrenalectomy remains an alternative option. Tumour histology, the presence of metastases and the effective control of hypercortisolaemia affect mortality and morbidity. If a source repeatedly fails to be found, the prognosis is often favourable but the identification of a malignant tumour should still be sought during life-long follow-up to avoid the calamity of misdiagnosis.

Endocrine manifestations in Langerhans cell histiocytosis

Langerhans cell histiocytosis is a rare, multisystem disease that shows a particular predilection for hypothalamo-pituitary axis involvement. Diabetes insipidus is the most frequent permanent consequence of Langerhans cell histiocytosis, developing in around a quarter of patients. Although the exact prevalence of anterior pituitary hormone deficiencies is not known, it is probably high and is almost always associated with diabetes insipidus. Established pituitary hormone deficiencies are mostly permanent and require prompt diagnosis and treatment, whereas continuous follow-up is needed to detect deficiencies that might evolve later during the course of the disease. Involvement of endocrine tissues other than the pituitary has also been described but is relatively rare. Further studies are needed to evaluate the effect that endocrine deficiencies exert on the overall prognosis of patients with Langerhans cell histiocytosis.

LONG ACTING SOMATOSTATIN ANALOGUES ARE AN EFFECTIVE TREATMENT FOR TYPE 1 GASTRIC CARCINOID TUMOURS

BACKGROUND Gastric carcinoid tumours type 1 (GCA1) originate from hyperplastic enterochromaffin-like (ECL) cells secondary to hypergastrinaemia. Treatment with somatostatin analogues (SSA) might impede ECL-cell hyperplasia by suppressing gastrin secretion and/or by a direct anti-proliferative effect on ECL cells. We conducted a multicentre prospective study to assess the effects of long-acting SSA on hypergastrinaemia and ECL-cell proliferation in patients with GCA1. METHODS We studied 15 patients with GCA1 treated with monthly long-acting release octreotide (LAR) (20-30 mg; n=14) or Lanreotide 90 mg (n=1) for at least 6 months. Patients had serum gastrin and chromogranin A measurements performed and biopsies taken from both tumours and surrounding mucosa before, and every 6-12 months following treatment. Sections were immunostained for neuroendocrine markers. The cell proliferation index Ki-67, intensity of staining before and after treatment and the degree of gastric wall invasion were also assessed. RESULTS All patients tolerated treatment well (mean follow-up of 18 months). In 11 patients (73%), a complete disappearance of the tumours at 1 year of treatment was observed on endoscopy, while in three patients (20%), the tumours decreased significantly in number and size. Gastrin levels normalized in 25% of patients, and were reduced by more than 80% in the remaining 75%. CONCLUSIONS Treatment with SSAs in GCA1 leads to a substantial tumour load reduction, with a concomitant decrease of serum gastrin levels. Our data indicate an important anti-proliferative effect of SSA on ECL cells, providing clinical benefit and obviating, at least temporarily, the need for invasive therapies for GCA1.

Is urinary free cortisol of value in the diagnosis of Cushing's syndrome?

Purpose of review Cushings syndrome results from prolonged and inappropriately high exposure of tissues to glucocorticoids. Biochemical tests are always needed to confirm the clinical suspicion: these include measurement of excess total endogenous cortisol secretion assessed by 24-h urinary free cortisol (UFC), loss of the normal feedback of the hypothalamo-pituitary-adrenal axis assessed by suppressibility after dexamethasone testing, and disturbance of the normal circadian rhythm of cortisol secretion assessed by midnight serum or salivary cortisol. This review focuses on recent data emerging on the value of UFC as a screening test for Cushings syndrome. Recent findings Considerable evidence has emerged regarding the utility of UFC in the diagnosis of Cushings syndrome because of its long-term use in clinical practice. Despite the fact that UFC assesses the active (free) component of cortisol, the methodological difficulties in 24-h urine collection and in assay precision have rendered this screening technique increasingly unpopular. Furthermore, the increased prevalence of mild, preclinical or cyclic Cushings syndrome along with the fact that cortisol is not uniformly secreted during the day do not support its use as a screening test, although strikingly high levels can be useful. Summary Since the sensitivity and specificity of UFC are less than ideal when compared with other diagnostic modalities, we suggest the use of other more novel tests as first-step diagnostic tests to screen for hypercortisolaemia.

Novel insights in the diagnosis of Cushing's syndrome.

Cushing’s syndrome (CS) results from sustained pathologic hypercortisolism. Increased identification of cyclical CS and the similarities between the metabolic syndrome and mild CS has resulted in an increased prevalence of CS, necessitating more accurate diagnostic tests to screen and diagnose CS in its earliest stages. Many studies have examined the utility of resistance to steroid feedback by the dexamethasone suppression tests and increases in secretion assessing 24-hour urinary free cortisol; however, the most sensitive indicator is the loss of circadian rhythmicity. Therefore, midnight sleeping cortisol is undoubtedly an extremely sensitive indicator of CS but impractical for screening purposes. In this situation assessment late-night salivary cortisol (NSC) is being increasingly investigated as a simple and convenient outpatient procedure. Salivary cortisol has also been used in stimulation or suppression tests because of the detection of rapid changes in cortisol concentration. This paper discusses the effectiveness of SC as a putative accurate, stress-free, and non-invasive sampling procedure. Some studies have shown no difference between tests while others demonstrated a higher sensitivity of SC, while the combination of tests seems to increase their diagnostic value. However, the different assays used for SC estimation and the variable types of control groups in the published studies render a comparison of studies difficult. In conclusion, NSC measurement is increasingly being used as a first-line test for CS, but we recommend that local centres establish their own normative ranges, and there is still a place for the more traditional tests to confirm the diagnosis.

Assessment of serum-free cortisol levels in patients with adrenocortical carcinoma treated with mitotane: a pilot study

Objective  Mitotane treatment in adrenocortical carcinoma (ACC) results in unreliable measurement of serum total cortisol (TC) levels because of an elevation in corticosteroid‐binding globulin (CBG).

Oncogene-induced senescence in pituitary adenomas and carcinomas.

OBJECTIVEThe model of ‘oncogene-induced senescence’ (OIS), resulting in cell-proliferation arrest, has recently been suggested as a possible explanation for the non-progression of pituitary tumours to malignancy. The aim of the study was to compare the expression of β-galactosidase as a molecular marker of OIS, and p21/p16 as additional markers involved in mediating OIS, in pituitary adenomas, carcinomas and normal pituitary tissue.DESIGNWe performed: a) semi-quantitative immunohistochemistry (β-galactosidase, p16, p21) in 41 pituitary adenomas [(11 GH-secreting, 9 PRL-secreting, 10 ACTH-secreting, 11 non-functioning (NFPAs)], 6 carcinomas (3 multihormonal: PRL/ACTH/GH, PRL/ACTH, PRL/GH/FSH; 1 non-functioning; 2 ACTH-secreting) and 7 normal pituitary tissues; b) quantitative PCR of mRNA (p16 and p21) in 6 GH-secreting, 6 NFPAs and 6 normal pituitary tissues.RESULTSβ-galactosidase was significantly increased in GH-secreting tumours (P=0.002), NFPAs (P=0.04), macroadenomas (P=0.03) and carcinomas (P=0.02), as compared to normal pituitary tissue. We found that p16 expression was significantly lower in all tumours (both adenomas and carcinomas) probably secondary to reduced transcription, at least for NFPAs; p21 showed a different biological behaviour, implying that p21 and p16 may play different roles in the senescence of each individual type of adenoma.CONCLUSIONSβ-galactosidase was significantly over-expressed in GH-secreting and NFPAs, and unexpectedly also in carcinomas. We speculate that the senescence pathway, which may explain the rarity of malignant progression to carcinomas in GH-secreting and NFPAs, might not be universal but cell-type specific.

Current size criteria for the management of neuroendocrine tumors of the appendix: are they valid? Clinical experience and review of the literature.

We evaluated the latest pathological criteria for completion right hemicolectomy (RHC) in patients with appendiceal neuroendocrine tumors (ANETs) with emphasis on the size of the primary tumor. Data of 28 consecutive patients who underwent RHC for ANETs in three tertiary hospitals were reviewed retrospectively to assess the indications for completion RHC. 10/28 patients were found to have residual disease (36%). In 8/28 patients (29%), the tumor diameter was <1 cm (mean 0.7 ± 0.2 cm, range 0.5-0.9 cm); the indications for RHC included: tumor presence in surgical margins (1 patient), extensive mesoappendiceal invasion (EMI) (1 patient), vascular invasion (VI) (3 patients), Ki-67 ≥2% (3 patients); residual disease was present in 1 patient (3.5%). In 13/28 patients (46%), the tumor diameter was ≥1 and <2 cm (mean 1.30 ± 0.2 cm, range 1.0-1.8 cm); the indications for RHC were: EMI (2 patients), VI (2 patients), Ki-67 ≥2% (2 patients); residual disease was present in 5 patients (18%). In 7/28 patients (25%), the tumor diameter was ≥2 cm (mean 2.5 ± 0.7 cm, range 2.0-4.0 cm). In this final subgroup, RHC was an accepted practice irrespective of other pathologic findings: the tumor was present in surgical margins in 2 patients, in 5 patients VI was demonstrated, and Ki-67 ≥2% was found in 5 patients; residual disease was present in 4 patients (14%). Using the latest European Neuroendocrine Tumor Society criteria for RHC, residual disease may be missed in 18% of ANET patients.

Pituitary-targeted medical therapy of Cushing's disease

Background: The goals of ideal medical therapy for Cushings disease should be to target the aetiology of the disorder, as is the case for surgery, which is the current ‘gold standard’ treatment. However, no effective drug that directly and reliably targets the adrenocorticotropin-secreting pituitary adenoma has yet been found. Objective: To summarise pituitary-targeted medical treatment of Cushings disease. Methods: Compounds with neuromodulatory properties and ligands of different nuclear hormone receptors involved in hypothalamo–pituitary regulation have been investigated. Results: The somatostatin analogue pasireotide and the dopamine agonist cabergoline, as well as their combination, show some therapeutic promise in the medical therapy of Cushings disease. Other treatments such as retinoic acid analogues look promising and may be a possible option for further investigation. No other medical therapies seem to be reliably effective currently. Conclusion: Since a percentage of patients treated with surgery are not cured, or improve and subsequently relapse, there is an urgent need for effective medical therapies for this disorder. At present, only cabergoline and pasireotide are under active investigation.

Specific electrocardiographic features associated with Cushing's disease

Objective  Hypercortisolaemia is associated with an increased risk of cardiovascular disease (CVD), either through a direct action on the myocardium or by increased traditional cardiovascular risk factors. The aim of this study was to investigate whether the alterations in the ECG in Cushing’s disease (CD) are predictable from risk factor analysis alone.