RESUMO
As a result of the high approval dynamics and the growing number of immuno-oncological therapy concepts, the complexity of therapy decisions and control in the area of carcinomas of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.
Assuntos
Carcinoma , Neoplasias Gástricas , Humanos , Antígeno B7-H1/metabolismo , Neoplasias Gástricas/diagnóstico , Biomarcadores , Esôfago/metabolismoRESUMO
As a result of the high approval dynamics and the growing number of immuno-oncological concepts, the complexity of treatment decisions and control in the area of cancers of the esophagus, gastroesophageal junction and stomach is constantly increasing. Since the treatment indication for PD-1 inhibitors that are currently approved in the European Union is often linked to the expression of PD-L1 (programmed cell death-ligand 1), the evaluation of tissue-based predictive markers by the pathologist is of crucial importance for treatment stratification. Even though the immunohistochemical analysis of the PD-L1 expression status is one of the best studied, therapy-relevant biomarkers for an immuno-oncological treatment, due to the high heterogeneity of carcinomas of the upper gastrointestinal tract, there are challenges in daily clinical diagnostic work with regard to implementation, standardization and interpretation of testing. An interdisciplinary group of experts from Germany has taken a position on relevant questions from daily pathological and clinical practice, which concern the starting material, quality-assured testing and the interpretation of pathological findings, and has developed recommendations for structured reporting.
Assuntos
Antígeno B7-H1 , Carcinoma , Humanos , Antígeno B7-H1/metabolismo , Biomarcadores , Esôfago , Junção Esofagogástrica/patologia , Carcinoma/patologia , Biomarcadores Tumorais/metabolismoRESUMO
Predictive biomarkers are the mainstay of precision medicine. This review summarizes the advancements in tissue-based diagnostic biomarkers for gastric cancer, which is considered the leading cause of cancer-related deaths worldwide. A disease seen in the elderly, it is often diagnosed at an advanced stage, thereby limiting therapeutic options. In Western countries, neoadjuvant/perioperative (radio-)chemotherapy is administered, and adjuvant chemotherapy is administered in the East. The morpho-molecular classification of gastric cancer has opened novel avenues identifying Epstein-Barr-Virus (EBV)-positive, microsatellite instable, genomically stable and chromosomal instable gastric cancers. In chromosomal instable tumors, receptor tyrosine kinases (RKTs) (e.g., EGFR, FGFR2, HER2, and MET) are frequently overexpressed. Gastric cancers such as microsatellite instable and EBV-positive types often express immune checkpoint molecules, such as PD-L1 and VISTA. Genomically stable tumors show alterations in claudin 18.2. Next-generation sequencing is increasingly being used to search for druggable targets in advanced palliative settings. However, most tissue-based biomarkers of gastric cancer carry the risk of a sampling error due to intratumoral heterogeneity, and adequate tissue sampling is of paramount importance.
Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Humanos , Idoso , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamento farmacológico , Biomarcadores , Instabilidade de Microssatélites , Receptores Proteína Tirosina Quinases , Biomarcadores Tumorais/genéticaRESUMO
Amyloid is a pathologic fibrillar aggregation of polypeptides in a cross-ß-sheet conformation. Amyloidoses are caused by the deposition of amyloid and may occur as cerebal and extracerebral diseases. A total of 35 different amyloid proteins have been identified. The Amyloid Registry Kiel was founded in 2009â¯at the Department of Pathology of the Christian-Albrechts-University Kiel. It currently houses more than 6700 cases of diverse anatomical origin with histologically confirmed amyloid and amyloidosis. This large series of cases provides unique insights into an otherwise rare disease. This includes the validation of novel dyes for the histological recognition and diagnosis of amyloid (luminescent conjugated polythiophenes), the in-depth analysis of amyloid associated with carpal tunnel syndrome, the distribution pattern of diverse amyloids in biopsies of the gastrointestinal tract and the prognostic significance of immunoglobulin light chain-derived AL amyloid load in cardiac biopsies. Finally, the application of MALDI (matrix-assisted laser desorption/ionization) mass spectrometry imaging provided valuable insights into the complexity of amyloid deposits, which consist of a diagnostic disease-specific and amyloid-specific protein/peptide mixture.
Assuntos
Amiloidose , Amiloide , Proteínas Amiloidogênicas , Humanos , Sistema de Registros , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Malignant tumors, such as colorectal cancer (CRC), are heterogeneous diseases characterized by distinct metabolic phenotypes. These include Warburg- and reverse Warburg phenotypes depending on differential distribution of the lactate carrier proteins monocarboxylate transporter-4 and -1 (MCT4 and MCT1). Here, we elucidated the role of the antioxidant transcription factor nuclear factor E2-related factor-2 (Nrf2) as the key regulator of cellular adaptation to inflammatory/environmental stress in shaping the metabolism toward a reverse Warburg phenotype in malignant and premalignant colonic epithelial cells. Immunohistochemistry of human CRC tissues revealed reciprocal expression of MCT1 and MCT4 in carcinoma and stroma cells, respectively, accompanied by strong epithelial Nrf2 activation. In colorectal tissue from inflammatory bowel disease patients, MCT1 and Nrf2 were coexpressed as well, relating to CD68+inflammatory infiltrates. Indirect coculture of human NCM460 colonocytes with M1- but not M2 macrophages induces MCT1 as well as G6PD, LDHB and TALDO expression, whereas MCT4 expression was decreased. Nrf2 knockdown or reactive oxygen species (ROS) scavenging blocked these coculture effects in NCM460 cells. Likewise, Nrf2 knockdown inhibited similar effects of tBHQ-mediated Nrf2 activation on NCM460 and HCT15 CRC cells. M1 coculture or Nrf2 activation/overexpression greatly altered the lactate uptake but not glucose uptake and mitochondrial activities in these cells, reflecting the reverse Warburg phenotype. Depending on MCT1-mediated lactate uptake, Nrf2 conferred protection from TRAIL-induced apoptosis in NCM460 and HCT15 cells. Moreover, metabolism-dependent clonal growth of HCT15 cells was induced by Nrf2-dependent activation of MCT1-driven lactate exchange. These findings indicate that Nrf2 has an impact on the metabolism already in premalignant colonic epithelial cells exposed to inflammatory M1 macrophages, an effect accompanied by growth and survival alterations. Favoring the reverse Warburg effect, these Nrf2-dependent alterations add to malignant transformation of the colonic epithelium.
Assuntos
Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Transportadores de Ácidos Monocarboxílicos/genética , Proteínas Musculares/genética , Fator 2 Relacionado a NF-E2/metabolismo , Simportadores/genética , Apoptose/genética , Biópsia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Técnicas de Cocultura , Colo/citologia , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibroblastos , Técnicas de Silenciamento de Genes , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Ácido Láctico/metabolismo , Macrófagos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Estromais/metabolismo , Células Estromais/patologia , Simportadores/metabolismo , Microambiente Tumoral/genéticaRESUMO
OBJECTIVES: To analyze clinical predictors of mortality in wild-type transthyretin amyloidosis (wt-ATTR). METHODS: In total, 191 patients (73.8 ± 0.5 years; 176 males, 15 females) with histologically proven wt-ATTR amyloidosis and genetic exclusion of a transthyretin gene variant were included. Comprehensive clinical characteristics, ECG, biomarkers, and echocardiography were analyzed retrospectively. Strain analyses were performed offline using TomTec Imaging Systems, Germany. Univariable and multivariable analyses predicting all-cause mortality were carried out. RESULTS: Patients presented with significant heart failure (NYHA 2.5 ± 0.8; NT-proBNP 3644 (4981) pg/ml; LV ejection fraction 45.8 ± 15.0%). LogNT-proBNP correlated with indicators of disease severity. Similar results were obtained for basal and midventricular, but not apical longitudinal strain. During median follow-up of 26.2 ± 1.7 months 46 (25.5%) patients died (40 males, 23%; six females, 40%). In female patients 1-/2-year survival was lower [92.9/67.7%; median survival 30.6 (21.1-40.1) months] when compared to male patients [96.5%/86.6%; median survival 63.9 (45.8-82.0) months]. Parameters associated with survival were NT-proBNP, NYHA class, heart rate, midventricular longitudinal strain, mitral annular plane systolic excursion (MAPSE), Karnofsky Index, systolic blood pressure, estimated glomerular filtration rate. Multivariable analysis revealed MAPSE and NT-proBNP as independent predictors of mortality in the whole cohort and midventricular strain in the subgroup of patients in sinus rhythm. CONCLUSIONS: No sex-specific bias was observed between male and female patients with wt-ATTR regarding age at onset and morphological characteristics. Multivariable analysis revealed MAPSE and NT-proBNP as independent predictors of survival in the whole cohort, whereas midventricular longitudinal strain was the only independent predictor in patients in sinus rhythm.
Assuntos
Neuropatias Amiloides Familiares/mortalidade , Cardiomiopatias/mortalidade , Idoso , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/fisiopatologia , Biomarcadores/sangue , Pressão Sanguínea , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/fisiopatologia , Ecocardiografia , Eletrocardiografia , Feminino , Alemanha/epidemiologia , Frequência Cardíaca , Humanos , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Masculino , Valva Mitral/fisiopatologia , Análise Multivariada , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Volume Sistólico , Fatores de Tempo , Função Ventricular EsquerdaRESUMO
Background: Recent whole-genome sequencing identified four molecular subtypes of gastric cancer (GC), of which the subgroup of Epstein-Barr virus-associated GC (EBVaGC) showed a significant enrichment of PIK3CA mutations. We here aimed to validate independently the enrichment of PIK3CA mutations in EBVaGC of a Central European GC cohort, to correlate EBV status with clinico-pathological patient characteristics and to test for a major issue of GC, intratumoral heterogeneity. Patients and methods: In a first step, 484 GCs were screened for EBV and PIK3CA hot spot mutations of exon 9/20 using EBER in situ hybridization and pyrosequencing, respectively. Secondly, an extended sequencing of PIK3CA also utilizing next generation sequencing was carried out in all EBVaGCs and 96 corresponding lymph node metastases. Results: Twenty-two GCs were EBER-positive, all being of latency type I. Intratumoral heterogeneity of EBER-positivity was found in 18% of EBVaGCs. Twenty-three GCs held PIK3CA mutations in hot spot regions of exon 9 or 20, being significantly more common in EBVaGCs (P < 0.001). Subsequent extended sequencing of PIK3CA of EBVaGCs showed that 14% harvested three to five different PIK3CA genotypes (including wildtype) in the same primary tumor, albeit in histologically and spatially distinct tumor areas, and that intratumoral heterogeneity of PIK3CA was also present in the corresponding lymph node metastases. Conclusions: Our findings unravel issues of tumor heterogeneity and illustrate that the assessment of the EBV status in tissue biopsies might carry the risk of sampling errors, which may significantly hamper adequate molecular tumor classification in a more clinical setting. Moreover, this is the first report of intratumoral heterogeneity of PIK3CA mutations in GC, and our findings lead to the conclusion that PIK3CA mutant and -wildtype tumor subclones are skilled to metastasize independently to different regional lymph nodes.
Assuntos
Adenocarcinoma/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Infecções por Vírus Epstein-Barr/genética , Neoplasias Gástricas/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adenocarcinoma/virologia , Idoso , Infecções por Vírus Epstein-Barr/mortalidade , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Heterogeneidade Genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Técnicas de Diagnóstico Molecular , Mutação , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologiaRESUMO
Gastric cancer is the fifth (men) and sixth (women) most common cause of cancer-related death in Germany. Despite a declining incidence of distal gastric cancer, the prognosis remains dismal: the 5year survival rate ranges between 35% for women and 31% for men. The majority are adenocarcinomas, which occur sporadically, familial or hereditary. Adenomas and intraepithelial neoplasms are considered as precursor lesions. Recently, whole genome sequencing and comprehensive molecular profiling described four molecular subtypes of gastric cancer: Epstein-Barr virus (EBV) positive, microsatellite unstable, chromosomal unstable and genomically stable gastric cancer. Currently, only the TNM classification has stood the test of time for the assessment of patient prognosis. Neuroendocrine tumor types 1-3 and soft tissue tumors occur significantly less often in the stomach. Gastrointestinal stromal tumors and inflammatory fibroid polyps are among the more common soft tissue tumors of the stomach and show distinct phenotypes. This review gives an overview of the current World Health Organization (WHO) classification of gastric tumors.
Assuntos
Neoplasias Gástricas/classificação , Adenocarcinoma/genética , Adenocarcinoma/patologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Instabilidade Genômica , Alemanha , Herpesvirus Humano 4 , Humanos , Instabilidade de Microssatélites , Neoplasias Gástricas/patologia , Organização Mundial da SaúdeRESUMO
Valid HER2 testing is essential for optimal therapy of patients with HER2 positive gastric cancer and the correct use of first-line treatment. While each breast cancer is routinely being tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is often only done upon request by the therapist. An interdisciplinary German expert group took the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions for the practical use of HER2 testing in this indication from the perspective of pathologists and therapists. The recommendations made in this manuscript reflect the consensus of all participants and correspond to their opinions and long-term experience.
Assuntos
Biomarcadores Tumorais/metabolismo , Técnicas de Diagnóstico do Sistema Digestório/normas , Oncologia/normas , Guias de Prática Clínica como Assunto , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Medicina Baseada em Evidências , Alemanha , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Valid HER2 testing is essential for the optimal care of patients with HER2-positive gastric cancer and the correct use of first-line treatment. Although all cases of breast cancer are routinely tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is usually only done upon request by the therapist. An interdisciplinary group of German experts has taken on the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions on the practical use of HER2 testing in this indication from the perspective of pathologists and therapists. The recommendations made in this article reflect the consensus of all participants and correspond to their opinions and long-term experience.
Assuntos
Adenocarcinoma/genética , Receptor ErbB-2/genética , Neoplasias Gástricas/genética , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Algoritmos , Biópsia , Regulação Neoplásica da Expressão Gênica/genética , Fidelidade a Diretrizes , Humanos , Comunicação Interdisciplinar , Colaboração Intersetorial , Prognóstico , Reprodutibilidade dos Testes , Estômago/patologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapiaRESUMO
Amyloidosis is a multisystem disease, which is characterized by the extracellular deposition of insoluble abnormal fibrils. Histological and subsequent immunohistochemical examinations are necessary for the determination of the diagnosis and the classification of the amyloid type. The most common systemic variant is immunoglobulin-derived light chain (AL) amyloidosis. However, local or organ-limited AL amyloidosis can occur. Isolated pulmonary amyloidosis is a rare condition and frequently an incidental finding at chest scans or during autopsy. Generally, it is associated with a benign prognosis. Here, we present two fatal cases, in which the cause of death was asphyxiation due to severe blood aspiration. During autopsy, several nodules were found in the lungs. Based on histological and immunohistochemical analysis, the diagnosis of an isolated nodular pulmonary AL amyloidosis lambda light chain was made. Amyloid was also present in pulmonary blood vessels, which lead to fragility and finally fatal hemorrhage.
Assuntos
Amiloidose/patologia , Hemorragia/patologia , Pneumopatias/patologia , Aspiração Respiratória/etiologia , Idoso , Idoso de 80 Anos ou mais , Amiloidose/complicações , Feminino , Hemorragia/etiologia , Humanos , Pneumopatias/complicações , Masculino , Aspiração Respiratória/patologiaRESUMO
Urachal carcinoma is a rare form of cancer. It often is diagnosed incidentally, like in our case report, because its cardinal symptom also occurs in a number of other urological diseases. We report the case of a 26-year-old man with a mucinous adenocarcinoma of the urachus. The carcinoma was removed via partial cystectomy with umbilical tumour excision.