Differences in intraoperative and surgical outcomes between normotensive pheochromocytomas and sympathetic paragangliomas (PPGLs) and hypertensive PPGLs: results from the PHEO-RISK STUDY.

PURPOSE: To compare the intraoperative and surgical outcomes of normotensive pheochromocytomas and sympathetic paragangliomas (PPGLs), hypertensive PPGLs and non-PPGL adrenal lesions. METHODS: This a retrospective multicenter cohort study of patients with PPGLs from 18 tertiary hospitals. A control group of histologically confirmed adrenocortical adenomas (non-PPGL group) was selected to compare intraoperative and surgical outcomes with of the normotensive PPGLs. RESULTS: Two hundred and ninety-six surgeries performed in 289 patients with PPGLs were included. Before surgery, 209 patients were classified as hypertensive PPGLs (70.6%) and 87 as normotensive PPGLs. A higher proportion of normotensive PPGLs than hypertensive PPGLs did not receive alpha presurgical blockade (P = 0.009). When we only considered those patients who received presurgical alpha blockers (200 hypertensive PPGLs and 76 normotensive PPGLs), hypertensive PPGLs had a threefold higher risk of intraoperative hypertensive crisis (OR 3.0 [95% 1.3-7.0]) and of hypotensive episodes (OR 2.9 [95% CI 1.2-6.7]) than normotensive PPGLs. When we compared normotensive PPGLs (n = 76) and non-PPGLs (n = 58), normotensive PPGLs had a fivefold higher risk of intraoperative complications (OR 5.3 [95% CI 1.9-14.9]) and a six times higher risk of postoperative complications (OR 6.1 [95% CI 1.7-21.6]) than non-PPGLs. CONCLUSION: Although the risk of intraoperative hypertensive and hypotensive episodes in normotensive PPGLs is significantly lower than in hypertensive PPGLs, normotensive PPGLs have a greater risk of intraoperative and postoperative complications than non-PPGL adrenal lesions. Therefore, it is recommended to follow the standard of care for presurgical and anesthetic management of PPGLs also in normotensive PPGLs.

Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic/parasympathetic neural ganglia, respectively. The heterogeneity in its etiology makes PPGL diagnosis and treatment very complex. The aim of this article was to provide practical clinical guidelines for the diagnosis and treatment of PPGLs from a multidisciplinary perspective, with the involvement of the Spanish Societies of Endocrinology and Nutrition (SEEN), Medical Oncology (SEOM), Medical Radiology (SERAM), Nuclear Medicine and Molecular Imaging (SEMNIM), Otorhinolaryngology (SEORL), Pathology (SEAP), Radiation Oncology (SEOR), Surgery (AEC) and the Spanish National Cancer Research Center (CNIO). We will review the following topics: epidemiology; anatomy, pathology and molecular pathways; clinical presentation; hereditary predisposition syndromes and genetic counseling and testing; diagnostic procedures, including biochemical testing and imaging studies; treatment including catecholamine blockade, surgery, radiotherapy and radiometabolic therapy, systemic therapy, local ablative therapy and supportive care. Finally, we will provide follow-up recommendations.

Role of pituitary stalk and gland radiological status on endocrine function and outcome after endoscopic transsphenoidal surgery for non-functioning pituitary adenomas.

PURPOSE: To investigate endocrine function changes after non-functioning pituitary adenomas (NFPA) transsphenoidal surgery and to search for predictors of hypopituitarism resolution and development. METHODS: We included 117 patients with NFPA who underwent endoscopic transsphenoidal surgery from 2005 to 2019 by two neurosurgeons. Twenty-one patients were excluded because of previous pituitary surgery or radiotherapy. We assessed symptoms at diagnosis, tumour volume, tumour removal, hormonal status at diagnosis, hormonal outcomes at 2- and 12-month follow-up, and complications. Pituitary stalk and gland MRI status (visible or not) were included, and it theirs association to hormonal function was studied for the first time, to our knowledge. RESULTS: Pituitary gland visualization was more frequent in those patients who showed a smaller number of axes affected at 12 months (p = 0.011). Pituitary stalk status showed no association to hormonal function. The hormonal normalization rate at 12 months was 13%. The endocrine improvement rate at 12 months was 16.7%. Worsening of hormonal function occurred in 19.8% of patients. Younger age was associated to hormonal improvement (p = 0.004). Higher preoperative tumour volume (p = 0.015) and absence of gross total resection (GTR) (p = 0.049) were associated with worsening in at least one hormonal axis after surgery. CONCLUSIONS: Pituitary gland visibility was higher in those patients who showed better hormonal outcomes. Assessment of initial hormonal function and outcome after surgery regarding pituitary stalk status showed no significant association. Higher preoperative tumour volumes and absence of GTR were associated to postoperative endocrine function worsening, while younger age was associated to its improvement.

[Non-functioning pituitary adenomas: epidemiology, clinical and postoperative outcome]. / Adenomas hipofisarios no funcionantes: epidemiología, clínica y evolución posquirúrgica.

INTRODUCTION: Non-functioning pituitary adenomas are the most frequent tumor group in the sellar region. They are usually benign neoplasms diagnosed after visual or hormonal symptoms, although it is not uncommon to detect them as a casual finding. AIM: To analyze the clinical aspects found in this disease and its response after surgical treatment. PATIENTS AND METHODS: In a series of 100 cases, epidemiological, clinical, endocrinological, visual and radiological data were analyzed before and after surgical treatment, as well as the complications related to surgery and long-term follow-up. RESULTS: The most frequent symptom at the time of diagnosis was visual field involvement (62%), and only the 7% of adenomas were a casual finding. The most common hormonal deficit was hypogonadotropic hypogonadism (48%). After surgery, complete recovery of the visual field defect was observed in 54.8% of the patients, only 1% worsening after surgery, and the incidence of diabetes insipidus was 4%. The resection was superior to 95% in 63% of cases, although the percentage of adenomas with invasion of the cavernous sinus in Knosp grades 3 and 4 it was high (45%). CONCLUSIONS: Although the most frequent symptom of non-functioning pituitary adenomas is campimetric involvement, it has an excellent response to surgery if it is performed within the appropriate time. The grade of invasion of the cavernous sinus is the most limiting factor for a complete surgical resection.

TITLE: Adenomas hipofisarios no funcionantes: epidemiología, clínica y evolución posquirúrgica.Introducción. Los adenomas hipofisarios no funcionantes son el grupo tumoral más frecuente en la región selar. Suelen ser neoplasias benignas diagnosticadas por síntomas visuales u hormonales, aunque no es infrecuente detectarlos como un hallazgo casual. Objetivo. Analizar los aspectos clínicos hallados en esta enfermedad y su respuesta tras el tratamiento quirúrgico. Pacientes y métodos. En una serie de 100 casos, se analizaron datos epidemiológicos, clínicos, endocrinológicos, visuales y radiológicos antes y después del tratamiento quirúrgico, y se recogen las complicaciones relacionadas con la cirugía y el seguimiento a largo plazo. Resultados. El síntoma más frecuente en el momento del diagnóstico fue la afectación del campo visual (62%), y sólo el 7% de los adenomas se trataba de un hallazgo casual. El déficit hormonal más frecuente era el hipogonadismo hipogonadótropo (48%). Tras la cirugía se observó recuperación completa del defecto campimétrico en el 54,8% de los pacientes, con sólo un 1% de empeoramiento tras la cirugía, y la incidencia de diabetes insípida fue del 4%. La resección fue superior al 95% en el 63% de los casos, a pesar de que el porcentaje de adenomas con invasión del seno cavernoso en grados altos fue elevado (45%). Conclusiones. Aunque el síntoma más frecuente de los adenomas hipofisarios no funcionantes es la afectación campimétrica, ésta tiene una excelente respuesta a la cirugía si se realiza dentro del tiempo adecuado. El grado de invasión del seno cavernoso parece el factor más limitante para una resección quirúrgica completa.

Safety of long-term treatment with Pegvisomant: analysis of Spanish patients included in global ACROSTUDY.

PURPOSE: To evaluate the long-term safety of Pegvisomant (PEG) in the Spanish cohort of ACROSTUDY. METHODS: As of July 2013, 199 Spanish patients were included in ACROSTUDY, a global non interventional safety PEG surveillance study. Patients were observed for safety, biochemical outcome and magnetic resonance imaging evaluations. RESULTS: PEG was administered during an average period of 6.7 ± 2.1 years and a mean daily dose of 15.5 ± 7.5 mg. 48.2% of patients received PEG monotherapy. 90.9% of patients had received other medical treatment before PEG start. 195 adverse events (AEs) were reported in 88 patients (44.2%), and serious AEs were described in 31 patients (15.6%). There were no cases of liver tests >10 ULN, or permanent liver damage. Tumor size changes were locally reported in 61 cases (33.5%), with increases observed in 11 patients (6%). In acromegalic patients with diabetes mellitus a decrease in fasting serum glucose value was reported, reaching statistical significance after 1 and 4 years of treatment (-24.6 and -25.9 mg/dl, p = 0.04). After 60 months, normal or lower limit of normal (LLN) IGF-I levels were found in 67.9% of patients. 85.5% of patients showed an IGF-I normal or

Kaposi sarcoma secondary to endogenous adrenocorticotropic hormone-dependent Cushing syndrome.

Kaposi sarcoma (KS) is an angioproliferative tumour that develops as a result of an infection by human herpesvirus 8, which is considered a necessary cause but not sufficient. Other factors - genetic, immunological and environmental - might play a role in the development of the disease. We report a case of KS secondary to endogenous Cushing syndrome (ECS) due to a pituitary adenoma, an association that has been reported only once. We also conducted a search through the Medline and PubMed databases for cases involving KS and ECS, finding only three additional cases that shared common clinical and prognostic features with ours. ECS might favour the development of KS due to immunosuppression. Dermatologists and other clinicians should be aware of this association, as it might be an underdiagnosed condition. It also has an important impact on the management of KS, and based on this review it relies on a good prognosis when ECS is well controlled.

Pegvisomant and cabergoline combination therapy in acromegaly.

Combination with cabergoline may offer additional benefits to acromegalic patients on pegvisomant monotherapy. We evaluated the safety and efficacy profile of this combination and investigated the determinants of response. An observational, retrospective, cross-sectional study. Fourteen acromegalic patients (9 females), who were partially resistant to somatostatin analogs and on pegvisomant monotherapy. Cabergoline was added because of the presence of persistent mildly increased IGF-I. The mean follow-up time was 18.3 ± 10.4 months. The efficacy and safety profile was assessed. The influence of clinical and biochemical characteristics on treatment efficacy was studied. IGF-I levels returned to normal in 4 patients (28%) at the end of the study. In addition, some decline in IGF-I levels was observed in a further 5 patients. The % IGF-I decreased from 158 ± 64% to 124 ± 44% (p = 0.001). The average change in IGF-I was -18 ± 27% (range -67 to +24%). Lower baseline IGF-I (p = 0.007), female gender (p = 0.013), lower body weight (p = 0.031), and higher prolactin (PRL) levels (p = 0.007) were associated with a better response to combination therapy. There were no significant severe adverse events. Significant tumour shrinkage was observed in 1 patient. Combination therapy with pegvisomant and cabergoline could provide better control of IGF-I in some patients with acromegaly. Baseline IGF-I levels, female gender, body weight, and PRL levels affect the response to this combination therapy.

Somatotroph tumor progression during pegvisomant therapy: a clinical and molecular study.

CONTEXT: There is concern that pegvisomant could be associated with a higher risk of tumor growth. The rate and possible determinants of this tumor growth are unknown. OBJECTIVE: The objective of the study was to investigate the clinical, immunohistological, and molecular factors conditioning tumor growth in patients taking pegvisomant. DESIGN AND SETTING: This was a cross-sectional study performed from 2004 to 2010 in four university hospitals in Spain. PATIENTS: Seventy-five acromegalic patients with active disease resistant to somatostatin analogs treated with pegvisomant were followed up for a mean of 29 ± 20 months. MAIN OUTCOME MEASURES: Magnetic resonance images before initiation of pegvisomant, at 6 months, and then yearly were examined in all patients. Immunohistological and molecular studies were performed in tumors that grew. RESULTS: A significant increase in tumor size was observed in five patients (6.7%). Absence of previous irradiation (P = 0.014) and shorter duration of prepegvisomant somatostatin analog therapy (P < 0.001) were associated with an increased risk of tumor growth. A stepwise multivariate linear regression analysis (R(2) = 0.334, P < 0.001) identified the duration of somatostatin analog therapy prior to pegvisomant (beta = -4.509, P = 0.014) as the only significant predictor of tumor growth. In those tumors that grew, GH expression and insulin receptor expression were higher (P = 0.033 in both cases) than in the control group. CONCLUSIONS: No previous radiotherapy, shorter duration of prepegvisomant somatostatin analog therapy, and higher tumor expression of GH and insulin receptor could be risk factors for tumor growth during pegvisomant therapy.

[Laparoscopic adrenalectomy. Five-year experience]. / Suprarrenalectomía laparoscópica. Experiencia de 5 años.

OBJECTIVE: Adrenal conditions requiring surgery are uncommon and are usually seen in several surgical departments. Our experience in laparoscopic management of adrenal pathology after almost five years of use of laparoscopy for retroperitoneal conditions at our center is reported. MATERIALS AND METHODS: A total of 37 laparoscopic adrenalectomies were performed over 53 months for benign and malignant conditions. The transperitoneal approach was used in most cases (97%) because of the greater surgeon experience with this route. Pregnancy and suspected periadrenal infiltration were considered as absolute contraindications. RESULTS: Mean operating time was 90 minutes, mean intraoperative bleeding 80 ml, and mean hospital stay was 2 days. The main complication was one death. A malignancy was found in 4 patients (10%), while all other patients (90%) had a benign condition, including 8 pheochromocytomas. CONCLUSIONS: Laparoscopy is considered to be the gold standard for benign adrenal conditions. When the malignant mass is a single metastasis from a primary tumor, the laparoscopic approach appears to be reliable. When the malignant lesion is a primary adrenal tumor, laparoscopic management is more controversial, although the results reported by experienced surgeons in their series appear to be adequate.

Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE).

BACKGROUND: Neuroendocrine tumors (NETs) are an unusual family of neoplasms with a wide and complex spectrum of clinical behavior. Here, we present the first report of a National Cancer Registry of gastroenteropancreatic neuroendocrine tumors from a Southern European country. PATIENTS AND METHODS: Data was provided online at www.retegep.net by participating centers and assessed for internal consistency by external independent reviewers. RESULTS: The study cohort comprised 907 tumors. The most common tumor types were carcinoids (55%), pancreatic nonfunctional tumors (20%), metastatic NETs of unknown primary (9%), insulinomas (8%) and gastrinomas (4%). Forty-four percent presented with distant disease at diagnosis, most often those from small intestine (65%), colon (48%), rectum (40%) and pancreas (38%), being most unusual in appendix primaries (1.3%). Stage at diagnosis varied significantly according to sex, localization of primary tumor, tumor type and grade. Overall 5-year survival was 75.4% (95% confidence interval 71.3% to 79.5%) and was significantly greater in women, younger patients and patients with hormonal syndrome and early stage or lower grade tumors. Prognosis also differed according to tumor type and primary tumor site. However, stage and Ki-67 index were the only independent predictors for survival. CONCLUSION: This national database reveals relevant information regarding epidemiology, current clinical practices and prognosis of NETs in Spain, providing valuable insights that may contribute to understand regional disparities in the incidence, patterns of care and survival of this heterogeneous disease across different continents and countries.

Pheochromocytoma in Eisenmenger's syndrome: a therapeutic challenge.

Surgical treatment of pheochromocytoma is associated with high hemodynamic risk, which is even higher in patients with complex congenital heart disease. Nowadays, patients with cyanotic congenital heart disease are living longer and an increased incidence of pheochromocytoma has been reported in this population. We demonstrate the feasibility and importance of minimally invasive surgery in the management of pheochromocytoma in a 45-year-old woman with complex congenital heart disease and Eisenmenger's syndrome. A successful laparoscopic resection of the tumor was performed in association with multidisciplinary management during hospitalization.

Rationalization of genetic testing in patients with apparently sporadic pheochromocytoma/paraganglioma.

Hereditary susceptibility to pheochromocytoma (PCC) and paraganglioma (PGL) represents a very complex genetic scenario. It has been reported that the absence of familial antecedents of the disease does not preclude the existence of a mutation affecting any of the five major susceptibility genes. In fact, 11-24% of apparently sporadic cases (without familial or syndromic antecedents) harbor an unexpected germline mutation, but we do not know what is happening in "truly apparently" sporadic patients (i.e., apparently sporadic cases diagnosed with only one tumor). In the present study, we have analyzed 135 apparently sporadic patients developing a single tumor for the five major susceptibility genes: VHL, RET, SDHB, SDHC, and SDHD. Fourteen percent of cases were found to harbor a germline mutation, and only 2.2% of patients were older than 45 years at onset. By taking into account the tumor location and a threshold age at onset of 45 years, we propose a rational scheme for genetic testing. Analyzing VHL and RET genes would be recommended only in young patients developing a single PCC. On the other hand, genetic testing of SDHD should be done in all patients developing an extra-adrenal tumor before the age of 45, and SDHC could be the responsible gene in cases developing a single head and neck tumor, independently of age. Finally, the analysis of SDHB should always be performed because of its association to malignancy and the low penetrance of mutations affecting this gene.

Abnormal functional behavior of peripheral blood mononuclear cells from Hashimoto's disease patients. Immunomodulatory effects of cyclosporin A.

In vitro studies of activation and proliferation induced by mitogens in the presence of Cyclosporin A (CsA) and or cytokines were carried out to determine the effects of CsA and cytokines on mitogen activated peripheral blood mononuclear cells (PBMC) from thirteen Hashimoto's disease patients (HP) and ten healthy controls. The proliferative response (PR) of PBMC from HP to mitogens at 7 days of culture was higher than in controls. Interleukin 2 (IL-2) addition significantly increased the PR in phytohemagglutinin-stimulated PBMC from HP, but not in controls. CsA inhibited in a dose dependent manner the PR, as well as the expression of activation antigens induced by mitogens in both groups of subjects, but PBMC from HP were sensitive to CsA at lower doses than those that were effective on PBMC from controls. Both IL-2 or IL-4 overcame the inhibitory effect of CsA on PBMC from HP and controls. Conversely, IL-10 or IFN-alpha addition increases the inhibitory effect of CsA on the PR of PBMC from both HP and controls. We conclude that PBMC from Hashimoto's disease patients shown an abnormal pattern of PR that is associated to increased PR to mitogens and higher sensitivity to immunomodulatory effects of IL-2 and CsA.