Germline CDH1 G212E Missense Variant: Combining Clinical, In Vitro and In Vivo Strategies to Unravel Disease Burden.

E-cadherin, encoded by CDH1, is an essential molecule for epithelial homeostasis, whose loss or aberrant expression results in disturbed cell-cell adhesion, increased cell invasion and metastasis. Carriers of CDH1 germline mutations have a high risk of developing diffuse gastric cancer and lobular breast cancer, associated with the cancer syndrome Hereditary Diffuse Gastric Cancer (HDGC). The ubiquitous availability of cancer panels has led to the identification of an increasing amount of "incidental" CDH1 genetic variants that pose a serious clinical challenge. This has sparked intensive research aiming at an accurate classification of the variants and consequent validation of their clinical relevance. The present study addressed the significance of a novel CDH1 variant, G212E, identified in an unusually large pedigree displaying strong aggregation of diffuse gastric cancer. We undertook a comprehensive pipeline encompassing family data, in silico predictions, in vitro assays and in vivo strategies, which validated the deleterious phenotype induced by this genetic alteration. In particular, we demonstrated that the G212E variant affects the stability and localization, as well as the adhesive and anti-invasive functions of E-cadherin, triggering epithelial disruption and disorganization. Our findings illustrate the clinical implication of a complementary approach for effective variant categorization and patient management.

Guía práctica para el diagnóstico de displasia y de carcinoma colorrectal en la enfermedad inflamatoria intestinal / Practical guidelines for the diagnosis of dysplasia and colorectal carcinoma in idiopathic inflammatory bowel disease

El importante y significativo incremento de la incidencia de la enfermedad inflamatoria intestinal (EII) en la población europea ha supuesto la creación de unidades clínicas multidisciplinarias y guías prácticas de manejo y estandarización de los informes anatomopatológicos. Recientemente hemos publicado una guía interpretativa de biopsias endoscópicas con sospecha de EII. Sin embargo, el apartado de diagnóstico de lesiones preneoplásicas quedó pendiente y lo abordamos en este documento. El riesgo de carcinoma de colon se halla aumentado en la EII, en la que la displasia epitelial (DE) constituye la manifestación histológica inicial del proceso neoplásico. Su diagnóstico, la gradación y el control determinan las pautas de cribado y manejo del paciente. En este artículo procedemos a revisar: las definiciones de DE, las clasificaciones macroscópicas y microscópicas así como su repercusión en el establecimiento del tratamiento, la distinción entre DE secundaria a EII y adenoma esporádico, la utilidad de la inmunohistoquímica en los estudios histopatológicos además de los protocolos de estudio macroscópico de piezas de colectomía y de disección submucosa endoscópica provenientes del tratamiento quirúrgico de la DE o del carcinoma asociado a EII (AU)

The important, significant increase in the incidence of inflammatory bowel disease (IBD) in the European population has led to the creation of multidisciplinary clinical units and guidelines for specific aspects of Pathology reporting. Recently we published guidelines for the interpretation of endoscopy biopsies in which there was a suspicion of IBD. However, pre-neoplastic diagnosis was not included and is explained here. The risk of colon carcinoma increases in IBD and epithelial dysplasia (ED) is the initial histological manifestation of neoplasia. Diagnosis, grading and control determine guidelines for screening and patient management. We have revised the following: definition of ED, macroscopic and microscopic classifications and their significance in the choice of treatment, the distinction between ED secondary to IBD and sporadic adenoma, the usefulness of immunohistochemistry in histological studies and the protocols for macroscopic examination of submucosal dissection specimens from endoscopy and colectomy during the surgical treatment of ED or carcinoma associated with IBD (AU)

Guía para la interpretación de biopsias endoscópicas con sospecha de enfermedad inflamatoria intestinal idiopática / Guidelines for the endoscopic biopsy diagnosis of suspected idiopathic inflammatory bowel disease

El reciente aumento en la incidencia de enfermedad inflamatoria intestinal (EII) entre la población europea ha dado lugar a la creación en hospitales de unidades multidisciplinares específicas con protocolos definidos que comprometen a los anatomopatólogos. El consiguiente aumento en el número de biopsias requiere establecer unas pautas, tanto sobre los criterios estándar como sobre la nomenclatura, para facilitar el diagnóstico y mejorar el informe. Dichas pautas tienen como finalidad la sistematización, paso a paso, de la interpretación de las biopsias con objetivos que evalúan la confianza diagnóstica a cada nivel. Los distintos pasos determinarán si existe enfermedad en la mucosa intestinal, si la enfermedad es crónica y/o activa y, si la presencia de una EII se considera probable, si se puede diagnosticar la enfermedad como un Crohn (EC) o bien como colitis ulcerosa (CU). Se considerarán los cambios en la arquitectura celular que indican la cronicidad de la enfermedad, los cambios inflamatorios que se pueden graduar en un índice de actividad, el diagnóstico diferencial con otros tipos de colitis y las características microscópicas necesarias para clasificar la colitis como EC o CU. Además, se proponen ejemplos de la comunicación del diagnóstico histopatológico y se analizan algunos de los frecuentes errores en la interpretación microscópica (AU)

The lately increasing cases of inflammatory bowel disease (IBD) in the European population have triggered the creation of specific multidisciplinary units in hospitals, and protocols and consensus of specific action that keep pathologist struggling with. Consequently, the increasing demand of endoscopy biopsies reports calls for a set of standard criteria and nomenclatures in guides which help to resolve diagnosis difficulties and improve the precision in communicating the final reports. This guide intends to systematize the interpretation of this kind of biopsies and to reach the diagnosis objectives step by step, assessing the confidence of diagnosis in every level. These steps are summarized in determining if there is disease of ileocolic mucosa, if the disease is chronic and/or active, if the disease can be diagnosed as IBD or if it is necessary to rule out other types of colitis, and, if a IBD is considered likely true, if it could be diagnoses as Crohn's disease (CD) or ulcerative colitis (UC). Among the different assessed issues are the architectural changes which define chronicity of the disease, the inflammatory changes which can be graduated in activity index, the differential diagnosis with other types of colitis and the microscopic features which make possible classify this colitis as CD or UC. In addition, examples in the communication of the histopathology diagnosis are proposed and many frequent errors in microscopic interpretation are commented (AU)

Melatonin treatment protects liver of Zucker rats after ischemia/reperfusion by diminishing oxidative stress and apoptosis.

Fatty livers occur in up to 20% of potential liver donors and increase cellular injury during the ischemia/reperfusion phase, so any intervention that could enable a better outcome of grafts for liver transplantation would be very useful. The effect of melatonin on liver ischemia/reperfusion injury in a rat model of obesity and hepatic steatosis has been investigated. Forty fa/fa Zucker rats were divided in 4 groups. 3 groups were subjected to 35 min of warm hepatic ischemia and 36 h of reperfusion. One experimental group remained untreated and 2 were given 10mg/kg melatonin intraperitoneally or orally. Another group was sham-operated. Plasma ALT, AST and hepatic content of ATP, MDA, hydroxyalkenals, NOx metabolites, antioxidant enzyme activity, caspase-9 and DNA fragmentation were determined in the liver. The expression of iNOS, eNOS, Bcl2, Bax, Bad and AIF were determined by RT-PCR Melatonin was effective at decreasing liver injury by both ways as assessed by liver transaminases, markers of apoptosis, of oxidative stress and improved liver ATP content. Melatonin administration decreased the activities or levels of most of the parameters measured in a beneficial way, and our study identified also some of the mechanisms of protection. We conclude that administration of melatonin improved liver function, as well as markers of pro/antioxidant status and apoptosis following ischemia/reperfusion in obese rats with fatty liver. These data suggest that this substance could improve outcome in patients undergoing liver transplantation who receive a fatty liver implant and suggest the need of clinical trials with it in liver transplantation.

Age-related differences in hepatic ischemia/reperfusion: gene activation, liver injury, and protective effect of melatonin.

BACKGROUND: Ischemia/reperfusion (I/R) causes functional and structural damage to liver cells, this being more pronounced with increasing age of the tissue. Melatonin is a pineal indole that has been shown to play an important role as a free radical scavenger and anti-inflammatory molecule. MATERIAL AND METHODS: The age-dependent responses to I/R were compared in 2-mo-old and 14-mo-old male Wistar rats. After 35 min of hepatic ischemia followed by 36 h of reperfusion, rats were sacrificed. Sham-operated control rats underwent the same protocol without real vascular occlusion. Animals were intraperitoneally injected with 10 mg/kg melatonin 24 h before the operation, at the time of surgery, and 12 and 24 h after it. The tissues were submitted to histopathologic evaluation. The levels of ALT and AST were analyzed in plasma. The expression of TNF-α, IL-1ß, IL-10, MCP-1, IFN-γ, iNOS, eNOS, Bad, Bax, Bcl2, AIF, PCNA, and NFKB1 genes were detected by RT-PCR in hepatic tissue. RESULTS: I/R was associated with significant increases in the expression of pro-inflammatory and pro-apoptotic genes in liver. Older rats submitted to I/R were found to respond with increased liver damage as compared with young rats, with serum ALT and AST levels significantly higher than in young animals. Mature rats also showed more evident increases in expression of pro-inflammatory cytokines (IL-1ß, MCP-1, and IFN-γ) as well as a decrease in the mRNA expression of IL-10 as compared with young animals. Pro-apoptotic genes (Bax, Bad, and AIF) were significantly enhanced in liver after I/R, without differences between young and mature animals. However, the expression of Bcl2 gene did not show any change. Melatonin treatment was able to lower the expression of pro-inflammatory cytokines and pro-apoptotic genes and to improve liver function, as indicated by normalization of plasma AST and ALT levels and by reduction of necrosis and microsteatosis areas. CONCLUSIONS: Melatonin treatment was able to reduce the I/R-stimulated pro-inflammatory and pro-apoptotic genes in the rat liver. Since older animals showed a more marked increase in inflammation and in liver injury, the treatment was more effective in those subjects.

Neuroendocrine tumor of the pancreas in a patient with tuberous sclerosis: a case report and review of the literature.

A rare case of pancreatic neuroendocrine neoplasm in a patient with tuberous sclerosis complex is described. The patient was a 31-year-old man who had multiple congenital subependymal nodules, bilateral cortical tubers, and seizures of difficult control. A 2.3 cm × 2 cm well-delimitated solid tumor in the tail of the pancreas was discovered during a monitoring abdominal computed tomography. A distal pancreatectomy was performed. Histologically, the tumor was formed by uniform cells with moderated cytoplasm arranged in a combined trabecular and nested pattern. The nuclear features were bland, and mitosis was infrequent. There was no vascular invasion. Immunoreactivity for cytokeratine AE1/AE3, chromogranin A, and synaptophysin confirmed the neuroendocrine nature of this neoplasia. Pancreatic hormones were negatives. One of the 5 lymph nodes isolated from the peripancreatic adipose tissue was positive for metastases. Small series and case reports have documented that in tuberous sclerosis many endocrine system alterations might occur, affecting the function of the pituitary, parathyroid, and other neuroendocrine tissue, including islet cells of the pancreas. However, the true association of these pathological conditions remains uncertain. As far as we know, there are 10 cases reported of pancreatic neuroendocrine tumors in a setting of tuberous sclerosis complex, in which 2 cases resulted in malignant, nonfunctioning pancreatic neuroendocrine tumors.

Protocolo y guía para el diagnóstico histopatológico de carcinoma hepatocelular. Subprotocolo de Anatomía Patológica para un protocolo general hospitalario de hepatocarcinoma / Protocol and guidelines for the histopathological diagnosis of hepatocellular carcinoma

Este protocolo-guía para el diagnóstico histopatológico del carcinoma hepatocelular es un documento de trabajo de la Subcomisión de Tumores Digestivos del Hospital 12 de Octubre que pretende consensuar un acuerdo intrahospitalario para la utilización de las nomenclaturas acreditadas en la literatura de forma que sean homogéneas y uniformes para evitar malentendidos que lleven a conductas diferentes en el manejo de pacientes con el mismo tipo de lesión. Asimismo, intenta informar a clínicos y radiólogos de lo que pueden esperar del diagnóstico citohistológico de los posibles especimenes de un paciente con diagnóstico sospechado o confirmado de carcinoma hepatocelular

This protocol for the histopathological diagnosis of hepatocellular carcinoma is an internal use document of the Subcommitte of Digestive Tumours of the Hospital 12 de Octubre that intends a consensus in the use of accredited nomenclatures to obtain uniform and homogeneous interpretations aiming analogous and correct managements in patients with similar types of lesions. The protocol also aims to give useful information to clinicians and radiologists about what can they expect of a cyto-histological diagnosis in the specimens of a patient with suspected or confirmed diagnosis of hepatocellular carcinoma

Protocolo y guía para el diagnóstico histopatológico de carcinoma hepatocelular. Subprotocolo de Anatomía Patológica para un protocolo general hospitalario de hepatocarcinoma / Protocol and guidelines for the histopathological diagnosis of hepatocellular carcinoma

Este protocolo-guía para el diagnóstico histopatológico del carcinoma hepatocelular es un documento de trabajo de la Subcomisión de Tumores Digestivos del Hospital 12 de Octubre que pretende consensuar un acuerdo intrahospitalario para la utilización de las nomenclaturas acreditadas en la literatura de forma que sean homogéneas y uniformes para evitar malentendidos que lleven a conductas diferentes en el manejo de pacientes con el mismo tipo de lesión. Asimismo, intenta informar a clínicos y radiólogos de lo que pueden esperar del diagnóstico citohistológico de los posibles especimenes de un paciente con diagnóstico sospechado o confirmado de carcinoma hepatocelular

This protocol for the histopathological diagnosis of hepatocellular carcinoma is an internal use document of the Subcommitte of Digestive Tumours of the Hospital 12 de Octubre that intends a consensus in the use of accredited nomenclatures to obtain uniform and homogeneous interpretations aiming analogous and correct managements in patients with similar types of lesions. The protocol also aims to give useful information to clinicians and radiologists about what can they expect of a cyto-histological diagnosis in the specimens of a patient with suspected or confirmed diagnosis of hepatocellular carcinoma

Protocolo e información sistematizada para los estudios histopatológicos relacionados con el carcinoma esofágico / Protocol and standardized information in histopathological reporting for esophagic carcinoma and related esophagic conditions

Este protocolo es el resultado de un consenso multidisciplinario entre patólogos, digestólogos, cirujanos y oncólogos de un mismo hospital. Está basado en la revisión de la literatura científica relevante y en la experiencia profesional orientadas a buscar la mayor efectividad en el diagnóstico y la mejor adecuación en la conducta terapéutica de las situaciones preneoplásicas, premalignas y malignas del esófago y de la unión gastroesofágica. Para ello propone unas normas en el uso de la terminología internacional, en el manejo de los distintos especímenes (biopsia endoscópica, resección endoscópica y pieza de resección quirúrgica) y en el esquema diagnóstico a seguir por el patólogo. Su finalidad es que el informe histopatológico ofrezca la información útil, precisa y estandarizada que es necesaria para una comunicación adecuada y clara entre clínicos y patólogos en orden a establecer una uniformidad en los procesos de diagnóstico, de seguimiento (evaluación y control periódico) y de estadificación

This protocol is the result of a multidisciplinary consensus among pathologists, digestive physicians, surgeons and oncologists from the same hospital. It is based on a review of relevant scientific literature and on professional experience in order to achieve the greatest effectiveness in diagnosis and appropriateness in the management of preneoplastic, premalignant and malignant conditions of the esophagus and the gastroesophagic junction. Guidelines are proposed in the use of international terminology, proper handling and dissection of various types of specimens (endoscopic biopsy, endoscopic excision and surgical resection) and the surgical pathology report. The aim of the histopathologic report is to offer useful, accurate and standardized information, necessary for an adequate and clear communication among clinicians and pathologists to achieve a uniformity in methodologic approach to diagnosis, follow-up and staging of esophageal neoplasms

Protocolo e información sistematizada para los estudios histopatológicos relacionados con el carcinoma esofágico / Protocol and standardized information in histopathological reporting for esophagic carcinoma and related esophagic conditions

Este protocolo es el resultado de un consenso multidisciplinario entre patólogos, digestólogos,cirujanos y oncólogos de un mismo hospital. Está basado en la revisión de la literatura científicarelevante y en la experiencia profesional orientadas a buscar la mayor efectividad en eldiagnóstico y la mejor adecuación en la conducta terapéutica de las situaciones preneoplásicas,premalignas y malignas del esófago y de la unión gastroesofágica. Para ello propone unas normasen el uso de la terminología internacional, en el manejo de los distintos especímenes (biopsiaendoscópica, resección endoscópica y pieza de resección quirúrgica) y en el esquema diagnósticoa seguir por el patólogo. Su finalidad es que el informe histopatológico ofrezca la informaciónútil, precisa y estandarizada que es necesaria para una comunicación adecuada y claraentre clínicos y patólogos en orden a establecer una uniformidad en los procesos de diagnóstico,de seguimiento (evaluación y control periódico) y de estadificación

This protocol is the result of a multidisciplinary consensus among pathologists, digestive physicians,surgeons and oncologists from the same hospital. It is based on a review of relevant scientificliterature and on professional experience in order to achieve the greatest effectiveness in diagnosisand appropriateness in the management of preneoplastic, premalignant and malignant conditionsof the esophagus and the gastroesophagic junction. Guidelines are proposed in the use ofinternational terminology, proper handling and dissection of various types of specimens (endoscopicbiopsy, endoscopic excision and surgical resection) and the surgical pathology report. The aimof the histopathologic report is to offer useful, accurate and standardized information, necessary foran adequate and clear communication among clinicians and pathologists to achieve a uniformity inmethodologic approach to diagnosis, follow-up and staging of esophageal neoplasms

Protocolo e información sistematizada para los estudios histopatológicos relacionados con el carcinoma colorrectal / Protocol and systematized information in histopathological reporting for colorectal carcinoma and related conditions

Este protocolo es el resultado de un consenso multidisciplinario entre patólogos, digestólogos, cirujanos y oncólogos de un mismo hospital. Está basado en la revisión de la literatura científica relevante y en la experiencia profesional orientadas a buscar la mayor efectividad en el diagnóstico y la mejor adecuación en la conducta terapéutica de los adenomas y de los adenocarcinomas colorrectales. Para ello propone unas normas en el uso de la terminología internacional, en el manejo de los distintos especímenes (biopsia endoscópica, polipectomía, resección endoanal y pieza de resección segmentaria) y en el esquema diagnóstico a seguir por el patólogo. Su finalidad es que el informe histopatológico ofrezca la información útil, precisa y estandarizada que es necesaria para una comunicación adecuada y clara entre clínicos y patólogos en orden a establecer una uniformidad en los procesos diagnóstico y de estadificación. (AU)

An unusual expression of hyperplastic gastropathy (Menetrier type) in twins.

Menetrier's disease is an uncommon condition of unknown aetiology. We describe two cases of male identical twins with haematemesis aged 29 and 35 years that exhibited a similar and particular form of this hyperplastic gastropathy. Their stomachs showed confluent polypoid mucosal projections affecting mainly the gastric fundus and the antrum. To the best of our knowledge, only four previous cases have been reported in a familial setting, and this is the first documented example of an occurrence in twins. These two cases suggest the possibility of a genetic predisposition for this condition.

Dedifferentiated liposarcoma of the pyriform sinus: report of a case and review of the literature.

Laryngeal and hypopharyngeal liposarcomas are extraordinarily infrequent tumors. To the best of our knowledge there are fewer than 40 well-documented cases reported to date. Almost all of them are well-differentiated liposarcomas, with only 2 laryngeal-hypopharyngeal dedifferentiated liposarcomas. Dedifferentiated liposarcoma is defined as a well-differentiated liposarcoma with areas of high-grade spindle cell nonlipogenic sarcoma. The well-differentiated areas may be of a lipoma-like, sclerosing, or mixed type, and the dedifferentiated areas most frequently are of malignant fibrous hystiocytoma-like type. Despite its commonly pleomorphic histology, dedifferentiated liposarcoma does not behave as aggressively as most pleomorphic sarcomas of adulthood; however, it has the capacity to metastasize, in contrast to its well-differentiated counterpart. We present a case of dedifferentiated liposarcoma arising in the pyriform sinus, an event only twice reported previously in the literature.