Two Main Subtypes of Aldosterone-Producing Adrenocortical Adenomas by Morphological and Expression Phenotype

Background: Aldosteronism is still a considerable diagnostic challenge generally diagnosed in a 3-tiered system (initial screening, a confirmation of the diagnosis, and a determination of the specific subtype). Since the recognition that ¾ of cases are due to bilateral hyperplasia, the spectrum of adenomas needs further characterization to determine the origin of aldosterone secretion. Design: We selected unilateral aldosterone-producing adrenocortical adenomas (AP-ACA, 33) responsible of primary aldosteronism defined by WHO criteria from a consecutive series of 98 ACA. We analyzed the histological features (growth pattern, nuclear characteristics, cytoplasmic staining qualities) of the tumor and the expression profile by quantitative RT-PCR of key molecular players of glomerulosa differentiation (SFRP2, β-catenin, AT1R, CYP21 CYP11B2, NURR1 and NUR77) in both the tumor and the surrounding parenchyma. RNA was extracted, cleaned from normal and neoplastic tissues (RNeasy columns), first-strand cDNA synthesized using T7-(dT24)-oligomer and used as template for cRNA synthesis.. The peritumoral parenchyma was also evaluated for the cytohistological features of the glomurulosa and its extension into deep cortex/medulla and periadrenal soft tissues. Quantitative results were cross-validated (expression factor>2, significance<0.01). Variables were studied regarding morphological appearances of the tumor and the status of the peritumoral glomerulosa. Results: Two main groups of AP-ACA were identified morphologically with a corresponding molecular profile. AP-ACA composed predominantly of clear foamy cells (10) that revealed minimal expression of AT1R, CYP21 and CYP11B2 and AP-ACA composed predominantly of eosinophilic cells (23) expressing significantly high AT1R, CYP21 and CYP11B2. The peritumoral parenchyma revealed functional hyperplastic glomerulosa in 31 cases, more prominent and with extra-adrenal extension in clear cell AP-ACA. Conclusions: The common presence of peritumoral hyperplasia suggests a proliferative response of cells to unidentified paracrine/autocrine factor as main mechanism in AP-ACA, which are not involved in glomerulosa differentiation in the clear cell subtype. Clear cell AP-ACA causes a syndrome of aldosteronism characterized by histologic features intermediate between adrenal adenoma and adrenal hyperplasia. Category: Endocrine PathologyUniversidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Histological Risk Classification Predicts Malignancy and Recurrence in Paragangliomas

Background: Mid-term outcome information in risk stratified patient cohort is needed to inform prognosis in individual patients with paragangliomas (PGL), adjuvant therapy choice and future research. The objective is to define the outcome relevance of a novel risk stratification scheme for PGLs. Design: A classification scheme for PGLs was devised and specimen were assessed for invasion capacity (infiltrative edges with broad fibrous bands, extra-adrenal extension [recording capsular, microscopic periadrenal and gross periadrenal], capsular and peritumoral vascular invasion [recording thin- and thick-walled blood vessels]), tumorigenic expansion (expansile nodules with diffuse areas, hypercellular homogenous areas, necrosis [recording multifocal and confluent subtypes]) and mitogenic activity (MFC/10HPF, presence of atypical mitotic figures). Patients were prospectively stratified as low risk or high risk (presence of at least one feature of invasive capacity and two features of tumorigenic expansion). Patients underwent systematic treatment and follow up for their PGLs in a tertiary referral center. Results: The multilevel analysis based on 78 patients identified statistically significant differences in clinical and biochemical presentation between low risk and high risk patients for gender (p<0.05), noradrenalin (4.6±8.5 vs 11.6±16.9), dopamine (0.6±0.3 vs 1.7±2.4), size of lesion (49.8±19.5 vs 89.2±45.8) and malignancy, 0% vs 21.6% (p<0.01), treatment modalities for MIBG therapy, 0% vs 40.5% (p<.0001), MVR, 0% vs 23.3% (p<.001) and lymph node dissection, 13.5% vs 40.5% (p<0.01) and distant metastases, 0% vs 21.6% (p<0.01). Disease free survival was significantly lower in HR patients 0% vs 78.4% (p=0.004). Histological risk stratification predicts DFS with AUC of 0.8 (95% CI: 0.69-0.90; p<0.01). 7/37 patients with HR had a synchronous diagnosis of malignancy based on other criteria and 4 patients suffered local recurrence. Conclusions: Stratification as low risk excluded a synchronous diagnosis of malignancy and disease recurrence of a follow-up interval of 1-75 months (median 12 months). A high-risk status is associated with high risk of malignancy and disease recurrence.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

CSR and branding in emerging economies: The effect of incomes and education

Sustainable development is a fundamental objective for guaranteeing the future of the planet. Taking into account the impact of emerging economies on the global economy and the scarcity of papers that have considered the effect of CSR initiatives on consumer behavior on those economies, it seems that further research on this issue is necessary. In particular, we analyze the extent to which CSR affects the connection and links of the consumer to the brand (i.e., self–brand connection, brand engagement). The main contribution of the paper to the field is the analysis of the interaction between CSR and branding in the context of an emerging economy. To that aim, and also in a novel way, we use the Stimuli–Organism–Response (SOR) model for a sample of more than 400 food and beverage consumers in Metropolitan Lima, Peru. Our results show that CSR effectively acts as a stimulus for consumers to identify and link to brands and that, in addition, these links generate buy-back (i.e., loyalty) and recommendation behaviors (i.e., WOM) which, in turn, create a great commercial value for companies. This research also analyses how incomes and educational levels moderate the intensity of such links. For practical implications, global trends in managing CSR and branding may be useful, although some cross-cultural and context-specific adaptations are necessary

Urinary Steroid Profiling for the Preoperative Identification of Adrenocortical Adenomas with Regression and Myelolipomatous Changes

Background: Adrenocortical neoplasms are classically divided into adenomas (ACA) and carcinomas (ACC). Heterogeneous appearance and greater size are criteria to suggest malignancy, along with the urinary steroid profile (USP). The presence of regression and myelolipomatous changes in adenomas (ACA-RML) can contribute to confusion with ACC and its USP remains unknown. Objective: To evaluate the features of ACA-RML in comparison with other adrenocortical neoplasms. Design: We selected consecutive ACA (11), ACA-RML (7) and ACC (13) cases for which USP analysis was performed before surgery and tissue was available for histological evaluation (King's College Hospital, 2005-2012). Cases were classified according to WHO and Armed Forces Institute of Pathology criteria. USPs were obtained by gas chromatography/mass spectrometry. Total excretion of individual steroids and indices (sums and ratios chosen to reflect steroid metabolic activity) were compared between ACA-RML, ACA, and ACC. Steroids that have proved to be useful markers of ACC were also compared empirically between groups, including tetrahydro-11-deoxycortisol, pregnene3,16,20-triols, 16a- and 21-hydroxypregnenolone and tetrahydro-11-deoxycorticosterone. Results: In comparison with ACA, tumors in ACA-RML were significantly larger (8.5±2.4 vs. 3.5±1.0, P=0.002), presented in older patients and showed relatively higher incidence in males. Mitotic figure counts were significantly lower (0.39±0.04 vs. 0.93±0.11 in ACA, p=0.001) and revealed higher frequency of apoptotic cells (100% vs. 9% in ACA, p= 0.001). The USP of ACA-RML showed no diagnostic features of ACC, along with lower levels of DHA and DHA metabolites. Conclusions: ACA-RML reveals distinctive histological features, and lack of USP markers of malignancy. It is important to recognize ACA-RML because its size and heterogeneous appearance raise the possibility of ACC; in this context, USP is an important tool for a correct preoperative diagnosis. Category: Endocrine PathologyUniversidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Contribution of the microvessel network to the clonal and kinetic profiles of adrenal cortical proliferative lesions

Monoclonal adrenocortical lesions have been characterized by an inverse correlation between proliferation and apoptosis, and polyclonal lesions show a direct correlation. Their relationship with the vascular pattern remains unknown in adrenocortical nodular hyperplasias (ACNHs), adenomas (ACAs), and carcinomas (ACCs). We studied 20 ACNHs, 25 ACAs, and 10 ACCs (World Health Organization classification criteria) from 55 women. The analysis included X-chromosome inactivation assay (on microdissected samples), slide and flow cytometry, and in situ end labeling. Endothelial cells were stained with anti-CD31, and the blood vessel area and density were quantified by image analysis in the same areas. Appropriate tissue controls were run in every case. Regression analyses between kinetic and vascular features were performed in both polyclonal and monoclonal lesions. Polyclonal patterns were observed in 14 of 18 informative ACNHs and 3 of 22 informative ACAs, and monoclonal patterns were seen in 4 of 18 ACNHs, 19 of 22 ACAs, and 9 of 9 ACCs. A progressive increase in microvessel area was observed in the ACNH–ACA–ACC transition but was statistically significant between benign and malignant lesions only (191.36 ± 168.32 v 958.07 ± 1279.86 μm2; P 186 μm2 (P =.0000008). Monoclonal lesions showed parallel trends (but with opposite signs) for microvessel area and density in comparison with proliferation and apoptosis, whereas polyclonal lesions showed inverse trends. In conclusion, the kinetic advantage of monoclonal adrenal cortical lesions (increased proliferation, decreased apoptosis) is maintained by parallel increases in microvessel area and density. HUM PATHOL 32:1232-1239. Copyright © 2001 by W.B. Saunders Compan

Clonal patterns in phaeochromocytomas and MEN-2A adrenal medullary hyperplasias: histological and kinetic correlates

The relationship among histological features, cell kinetics, and clonality has not been studied in adrenal medullary hyperplasias (AMHs) and phaeochromocytomas (PCCs). Thirty-four PCCs (23 sporadic and 11 MEN-2A (multiple endocrine neoplasia type 2A)-related tumours, the latter associated with AMH) from females were included in this study. Representative samples were histologically evaluated and microdissected to extract DNA and evaluate the methylation pattern of the androgen receptor alleles. At least two tissue samples (from the peripheral and internal zones in each tumour) were analysed with appropriate tissue controls run in every case. The same areas were selected for MIB-1 staining and in situ end labelling (ISEL). Malignant PCCs were defined by histologically confirmed distant metastases. All monoclonal AMH nodules from the same patient showed the same X-chromosome inactivated. Six sporadic PCCs revealed liver metastases (malignant PCC) and eight additional sporadic PCCs showed periadrenal infiltration (locally invasive PCC). All informative PCCs were monoclonal, except for five locally invasive PCCs and one benign PCC that revealed polyclonal patterns. Those cases also showed a fibroblastic stromal reaction with prominent blood vessels, focal smooth muscle differentiation, and significantly higher MIB-1 (126.8±29.9) and ISEL (50.9±12.8) indices. Concordant X-chromosome inactivation in nodules from a given patient suggests that MEN-2A AMH is a multifocal monoclonal condition. A subgroup of PCCs characterized by balanced methylation of androgen receptor alleles, high cellular turnover, and stromal proliferation also shows locally invasive features. Copyright © 2000 John Wiley & Sons, Ltd

Lesion-based indicators predict long-term outcomes of pheochromocytoma and paraganglioma– SIZEPASS

AimWe seek a simple and reliable tool to predict malignant behavior of pheochromocytoma and paraganglioma (PPGL).MethodsThis single-center prospective cohort study assessed size of primary PPGLs on preoperative cross-sectional imaging and prospectively scored specimens using the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS). Multiplication of PASS points with maximum lesion diameter (in mm) yielded the SIZEPASS criterion. Local recurrence, metastasis or death from disease were surrogates defining malignancy.Results76 consecutive PPGL patients, whereof 58 with pheochromocytoma and 51 female, were diagnosed at a mean age of 52.0 ± 15.2 years. 11 lesions (14.5%) exhibited malignant features at a median follow-up (FU) of 49 months (range 4-172 mo). Median FU of the remaining cohort was 139 months (range 120-226 mo). SIZEPASS classified malignancy with an area under the curve (AUC) of 0.97 (95%CI 0.93-1.01; p&lt;0.0001). Across PPGL, SIZEPASS &gt;1000 outperformed all known predictors of malignancy, with sensitivity 91%, specificity 94%, and accuracy 93%, and an odds ratio of 72 fold (95%CI 9-571; P&lt;0.001). It retained an accuracy &gt;90% in cohorts defined by location (adrenal, extra-adrenal) or mutation status.ConclusionsThe SIZEPASS&gt;1000 criterion is a lesion-based, clinically available, simple and effective tool to predict malignant behavior of PPGLs independently of age, sex, location or mutation status

Clinico‐biological features and outcome of patients with splenic marginal zone lymphoma with histological transformation

We describe 36 patients with splenic marginal zone lymphoma (SMZL) with transformation (SMZL-T), including 15 from a series of 84 patients with SMZL diagnosed at the Hospital Clinic of Barcelona (HCB) and 21 diagnosed with SMZL-T in other centres. In the HCB cohort, the cumulative incidence of transformation at 5 years was 15%. Predictors for transformation were cytopenias, hypoalbuminaemia, complex karyotype (CK) and both the Intergruppo Italiano Linfomi (ILL) and simplified Haemoglobin, Platelet count, lactate dehydrogenase (LDH) and extrahilar Lymphadenopathy (HPLL)/ABC scores (P < 0·05). The only independent predictor for transformation in multivariate analysis was CK [hazard ratio (HR) 4·025, P = 0·05]. Patients with SMZL-T had a significantly higher risk of death than the remainder (HR 3·89, P < 0·001). Of the 36 patients with SMZL-T, one developed Hodgkin lymphoma and 35 a diffuse large B-cell lymphoma, 71% with a non-germinal centre phenotype. The main features were B symptoms, lymphadenopathy, and high serum LDH. CK was observed in 12/22 (55%) SMZL-T and fluorescence in situ hybridisation detected abnormalities of MYC proto-oncogene, basic helix-loop-helix transcription factor (MYC), B-cell leukaemia/lymphoma 2 (BCL2) and/or BCL6 in six of 14 (43%). In all, 21 patients received immunochemotherapy, six chemotherapy, one radiotherapy and three splenectomy. The complete response (CR) rate was 61% and the median survival from transformation was 4·92 years. Predictors for a worse survival in multivariate analysis were high-risk International Prognostic Index (HR 5·294, P = 0·016) and lack of CR (HR 2·67, P < 0·001)

All-cause mortality in the cohorts of the Spanish AIDS Research Network (RIS) compared with the general population: 1997Ł2010

Abstract Background: Combination antiretroviral therapy (cART) has produced significant changes in mortality of HIVinfected persons. Our objective was to estimate mortality rates, standardized mortality ratios and excess mortality rates of cohorts of the AIDS Research Network (RIS) (CoRIS-MD and CoRIS) compared to the general population. Methods: We analysed data of CoRIS-MD and CoRIS cohorts from 1997 to 2010. We calculated: (i) all-cause mortality rates, (ii) standardized mortality ratio (SMR) and (iii) excess mortality rates for both cohort for 100 personyears (py) of follow-up, comparing all-cause mortality with that of the general population of similar age and gender. Results: Between 1997 and 2010, 8,214 HIV positive subjects were included, 2,453 (29.9%) in CoRIS-MD and 5,761 (70.1%) in CoRIS and 294 deaths were registered. All-cause mortality rate was 1.02 (95% CI 0.91-1.15) per 100 py, SMR was 6.8 (95% CI 5.9-7.9) and excess mortality rate was 0.8 (95% CI 0.7-0.9) per 100 py. Mortality was higher in patients with AIDS, hepatitis C virus (HCV) co-infection, and those from CoRIS-MD cohort (1997. Conclusion: Mortality among HIV-positive persons remains higher than that of the general population of similar age and sex, with significant differences depending on the history of AIDS or HCV coinfection