Prognostic factors and long-term outcome of pancreatic neuroendocrine neoplasms: Ki-67 index shows a greater impact on survival than disease stage. The large experience of the Spanish National Tumor Registry (RGETNE).

INTRODUCTION: Pancreatic neuroendocrine neoplasms (PNENs) are uncommon neoplasms with a wide spectrum of clinical behavior. The objective of this study was to assess in a large cohort of patients the relative impact of prognostic factors on survival. METHODS: From June 2001 through October 2010, 1,271 patients were prospectively registered online (www.getne.org) at the Spanish National Cancer Registry for Gastroenteropancreatic Neuroendocrine Tumors (RGETNE) by participating centers. Clinical and histopathological features were assessed as potential prognostic factors by uni- and multivariate analyses. RESULTS: Of 483 PNENs, 171 (35%) were functional (F) and 312 (65%) non-functional (NF). NF-PNENs were associated with a higher incidence of histological features denoting more aggressive disease, such as poor tumor differentiation, Ki-67 >20%, or vascular invasion (NF- vs. F-PNENs, respectively, p < 0.05). Nevertheless, functionality was not a significant predictor of survival (p = 0.19). Stage at diagnosis, Ki-67 index, tumor differentiation and surgical resection of the primary tumor were all significant prognostic factors in univariate analysis. However, Ki-67 (>20 vs. ≤2%) (hazard ratio (HR) 2.21, p = 0.01) and surgical resection (yes vs. no) (HR 0.92, p = 0.001) were the only independent predictors of survival in multivariate analysis. Among patients who underwent surgery, high Ki-67 index (HR 10.37, p = 0.02) and poor differentiation (HR 8.16, p = 0.03) were the only independent predictors of clinical outcome. CONCLUSION: Ki-67 index and tumor differentiation are key prognostic factors influencing survival of patients with PNENs and, in contrast to what it is observed for other solid malignancies, they seem to have a greater impact on survival than the extent of disease. This should be borne in mind by physicians in order to appropriately tailor therapeutic strategies and surveillance of these patients.

Clinical practice guideline for hypotalamic-pituitary disturbances in pregnancy and the postpartum period.

During pregnancy, the body undergoes a major adaptation process as a result of the interaction between mother, placenta and fetus. Major anatomical and histological changes are produced in the pituitary, with an increase of up to 40% in the size of the gland. There are wide variations in the function of the hypothalamus-pituitary-thyroid axis that effect iodine balance, the overall activity of the gland, as well as transport of thyroid hormones in plasma and peripheral metabolism of thyroid hormones. The incidence of goiter and thyroid nodules increases throughout pregnancy. The management of differentiated thyroid carcinoma should be individually tailored according to tumoral type and pregnancy stage. Given the effects of hypothyroidism on fetal development, both the diagnosis and appropriate therapeutic management of thyroid hypofunction are essential. The most important modification to the hypothalamus-pituitary-adrenal axis during pregnancy is the rise in serum cortisol levels due to an increase in cortisol-binding proteins. Although Cushing's syndrome during pregnancy is infrequent, both diagnosis and treatment of this disorder are especially difficult. Adrenal insufficiency during pregnancy does not substantially differ from that occurring outside pregnancy. However, postpartum pituitary necrosis (Sheehan's syndrome) is a well-known complication that occurs after delivery and, together with lymphocytic hypophysitis, constitutes the most frequent cause of adrenal insufficiency. The management of prolactinoma during pregnancy requires suppression of dopaminergic agonists and their reintroduction if there is tumoral growth. Notable among the neuropituitary disorders that can occur throughout pregnancy is diabetes insipidus, which occurs as a consequence of increased vasopressinase activity.

Clinical practice guideline for the diagnosis and treatment of hypophysitis.

Hypophysitis are a group of inflammatory lesions affecting the pituitary gland and pituitary stalk. These lesions should be included in the differential diagnosis of sellar masses. There are three types of primary hypophysitis: lymphocytic, granulomatous and xanthomatous. Lymphocytic hypophysitis is the most frequent form of chronic pituitary inflammation and is believed to have an autoimmune origin. This form characteristically affects women during the peripartum, with diverse types of pituitary deficiency, especially ACTH deficiency, and frequently there are other associated autoimmune processes. Lymphocytic hypophysitis can affect the anterior pituitary only, the infundibular stalk and posterior lobe of the pituitary (infundibuloneurohypophysitis), or the entire pituitary (panhypophysitis). Clinically, lymphocytic hypophysitis can manifest with compression symptoms, hypopituitarism, diabetes insipidus or hyperprolactinemia. The imaging technique of choice is magnetic resonance imaging, which helps to characterize the sellar lesion. Treatment includes replacement of the functional pituitary deficiency and the use of corticosteroids, generally at high doses. Surgical treatment is reserved for patients unresponsive to conservative therapy. Granulomatous hypophysitis can be of known etiology, whether infectious (currently highly infrequent) or non-infectious (ruptured Rathke's cyst, etc.). Granulomatous hypophysitis of unknown etiology is manifested by the presence of idiopathic granulomas. Xanthomatous hypophysitis is characterized by a histiocytic infiltrate with cystic characteristics on imaging. Secondary hypophysitis is due to pituitary inflammation caused by surrounding lesions or can form part of systemic diseases.

Kennedy's disease and partial androgen insensitivity syndrome. Report of 4 cases and literature review.

Kennedy's disease, also known as bulbospinal muscular atrophy, is a rare, X-linked recessive neurodegenerative disorder affecting adult males. It is caused by expansion of an unstable cytosine-adenine-guanine tandem-repeat in exon 1 of the androgen-receptor gene on chromosome Xq11-12, and is characterized by spinal motor neuron progressive degeneration. Endocrinologically, these patients often have the features of hypogonadism associated to the androgen insensitivity syndrome, particularly its partial forms. We report 4 cases with the typical neurological presentation, consisting of slowly progressing generalized muscle weakness with atrophy and bulbar muscle involvement; these patients also had several endocrine manifestations; the most common non-neurological manifestation was gynecomastia. In all cases reported, molecular analysis showed an abnormal cytosine-adenine-guanine triplet repeat expansion in the androgen receptor gene.

Endocrine changes in histiocytosis of the hypothalamic-pituitary axis.

Histiocytosis is characterized by proliferation of cells from the mononuclear phagocyte system, and may be divided into Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (including Erdheim-Chester disease [ECD]). While diabetes insipidus (DI) is the most common hypothalamic-pituitary consequence, anterior pituitary deficiencies are less known. This study analyzed the frequency and progression of pituitary hormone deficiencies and the radiographic findings in 9 patients (7 with LCH and 2 with ECD) with hypothalamic-pituitary (HP) axis. Eighty-nine percent of patients had DI (62% at diagnosis), and 78% had one or more anterior pituitary deficiencies (71% at diagnosis). HP involvement is relatively common in patients diagnosed with histiocytosis and hormone deficiencies may be present at diagnosis or appear gradually during the course of disease. Regular monitoring of these patients is recommended.