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2.
Nat Commun ; 12(1): 4474, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294714

RESUMO

Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8+ tissue-resident memory CD8+ T (CD8+ Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69+CD103-CD8+ Trm cell enrichment in NASH resolution livers. The reduction of liver CD8+ Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8+ Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69+CD8+ Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8+ Trm in fibrosis resolution.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Estreladas do Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Transferência Adotiva , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/imunologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Células Estreladas do Fígado/imunologia , Humanos , Memória Imunológica , Interleucina-15/imunologia , Cirrose Hepática/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/terapia , Receptores CCR5/imunologia , Adulto Jovem
3.
Brain Tumor Pathol ; 38(3): 263-270, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33783654

RESUMO

Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disease with angiocentric and angiodestructive infiltrates, and by definition, Epstein-Barr virus (EBV)-associated B-cell malignancy. It most frequently involves the lung, and in some cases, the lesions are confined to the central nervous system (isolated CNS-LYG). However, it remains a controversial disease in terms of pathophysiology, especially in those confined to the CNS. We report the case of a 37-year-old man with CNS lesion pathologically characterized by angiocentric, T-cell-rich lymphoid cell infiltrates that resembled CNS-LYG. The lesion was clinically aggressive with subacute onset and irregular ring-like enhancement on MRI. The resected specimen showed no cytological atypia, EBV-infected cells, or monoclonality for IgH and TCR gene rearrangements. Considering the possibility of latent malignancy, the patient was successfully treated with corticosteroid and chemoradiotherapy with high-dose methotrexate. The present case and the literature suggest that EBV-negative CNS lesions with angiocentric lymphoid infiltrates are probably heterogeneous in their pathogenesis, including those that could fit into the so-called CNS-LYG and those with T-cell predominance. The accumulation of similar cases is warranted for the classification and appropriate treatment of these lesions.

4.
World J Gastroenterol ; 26(7): 725-739, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32116420

RESUMO

BACKGROUND: Liver resection is an effective treatment for benign and malignant liver tumors. However, a method for preoperative evaluation of hepatic reserve has not yet been established. Previously reported assessments of preoperative hepatic reserve focused only on liver failure in the early postoperative period and did not consider the long-term recovery of hepatic reserve. When determining eligibility for hepatectomy, the underlying pathophysiology needs to be considered to determine if the functional hepatic reserve can withstand both surgery and any postoperative therapy. AIM: To identify pre-hepatectomy factors associated with both early postoperative liver failure and long-term postoperative liver function recovery. METHODS: This study was a retrospective cohort study. We retrospectively investigated 215 patients who underwent hepatectomy at our hospital between May 2013 and December 2016. Early post-hepatectomy liver failure (PHLF) was defined using the International Study Group of Liver Surgery's definition of PHLF. Long-term postoperative recovery of liver function was defined as the time taken for serum total bilirubin and albumin levels to return to levels of < 2 mg/dL and > 2.8 g/dL, respectively, and the time taken for Child-Pugh score to return to Child-Pugh class A. RESULTS: Preoperative type IV collagen 7S was identified as a significant independent factor associated with both PHLF and postoperative long-term recovery of liver function. Further analysis revealed that the time taken for the recovery of Child-Pugh scores and serum total bilirubin and albumin levels was significantly shorter in patients with type IV collagen 7S ≤ 6 ng/mL than in those with type IV collagen 7S > 6 ng/mL. In additional analyses, similar results were observed in patients without chronic viral hepatitis associated with fibrosis. CONCLUSION: Preoperative type IV collagen 7S is a preoperative predictor of PHLF and long-term postoperative liver function recovery. It can also be used in patients without chronic hepatitis virus.


Assuntos
Colágeno Tipo IV/sangue , Hepatectomia/efeitos adversos , Falência Hepática/etiologia , Testes de Função Hepática/estatística & dados numéricos , Neoplasias Hepáticas/sangue , Complicações Pós-Operatórias/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bilirrubina/sangue , Feminino , Humanos , Fígado/fisiopatologia , Testes de Função Hepática/métodos , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Período Pré-Operatório , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
5.
Pathol Int ; 70(4): 199-209, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31930673

RESUMO

The clinicopathological characteristics of steatosis in hepatocellular carcinoma (HCC) remain unclear. Here, we elucidate the features of macrovesicular steatosis (MaS) and microvesicular steatosis (MiS) in HCC and their relationships with background liver steatosis. A total of 165 HCC lesions were classified as MaS-HCC, MiS-HCC, or conventional HCC (cHCC) according to the cutoff value of 30% MaS or MiS in tumor cells. We analyzed the clinicopathological differences among these groups. MaS-HCC had less portal vein invasion, a higher proportion of HCC with intratumoral fibrosis, and a lower cumulative risk of recurrence than MiS-HCC or cHCC. Moreover, both MaS-HCC and MiS-HCC had lower incidences of hepatitis virus infection and higher levels of HbA1c than cHCC. Background liver steatosis was also higher in MaS-HCC than in cHCC. Immunohistochemical expression of perilipin (Plin1) and adipophilin (ADRP), major proteins expressed on lipid droplet membranes, revealed that almost all lipid droplets in HCC were Plin1 negative, whereas those in background liver were positive. In contrast, ADRP was expressed on lipid droplets in both HCC and background liver. We concluded that MaS-HCC and MiS-HCC were associated with metabolic abnormalities but exhibited different biologic behaviors. Furthermore, lipid droplets in HCC were pathophysiologically different from those in background liver.


Assuntos
Carcinoma Hepatocelular/patologia , Fígado Gorduroso/patologia , Neoplasias Hepáticas/patologia , Perilipina-1/metabolismo , Perilipina-2/metabolismo , Idoso , Carcinoma Hepatocelular/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico
6.
Pathol Int ; 70(3): 140-154, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31908112

RESUMO

Outcomes for patients with hepatocellular carcinoma (HCC) remain poor because the condition is often unresponsive to the available treatments. Consequently, the early and precise diagnosis of HCC is crucial to achieve improvements in prognosis. For patients with chronic liver disease, the assessment of liver fibrosis is also important to ascertain both the staging of fibrosis and the risk of HCC occurrence. Early HCC was first described in 1991 in Japan and was defined internationally in 2009. As the concept of early HCC spread, the multistage hepatocarcinogenesis process became accepted. Consequently, improvements in imaging technology made the early diagnosis of HCC possible. At present, the most appropriate therapeutic strategy for HCC is determined using an integrated staging system that assesses the tumor burden, the degree of liver dysfunction and the patient performance status; however, pathological and molecular features are not taken into account. The recent introduction of several new therapeutic agents will change the treatment strategy for HCC. Against this background, HCC subclassification based on tumor cellular and microenvironmental characteristics will become increasingly important. In this review, we give an overview of how pathological analysis contributes to understanding the development and progression of HCC and establishing a precision diagnosis of HCC.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Cirrose Hepática/diagnóstico , Neoplasias Hepáticas/diagnóstico , Carcinoma Hepatocelular/classificação , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Progressão da Doença , Diagnóstico Precoce , Humanos , Imuno-Histoquímica , Cirrose Hepática/classificação , Cirrose Hepática/genética , Cirrose Hepática/patologia , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Patologia Molecular , Prognóstico , Risco , Microambiente Tumoral
7.
Hepatol Res ; 50(5): 607-619, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31886596

RESUMO

AIM: Emerging evidence suggests a promising role for tumor stromal factors in characterizing patients with various types of malignancies, including hepatocellular carcinoma (HCC). We quantified the amount of collagen and elastin fibers in HCC samples with the aim of clarifying the clinico-patho-radiological significance of fiber deposition in HCC. METHODS: We computed the amount of collagen and elastin fibers using digital image analysis of whole-slide images of Elastica van Gieson-stained tissues from 156 surgically resected HCCs. Furthermore, we assessed the correlations between the fiber content of HCC samples and clinical, pathological, and radiological features, including immunohistochemistry-based molecular subtypes and immunosubtypes. RESULTS: The intratumoral area ratio of collagen in HCC tissues (median 3.4%, range 0.1-22.2%) was more than threefold that of elastin (median 0.9%, range 0.1-9.0%); there was a strong positive correlation between the amounts of collagen and elastin. Higher levels of combined collagen and elastin were significantly associated with the confluent multinodular macroscopic tumor type, the absence of a fibrous capsule, intratumoral steatosis, scirrhous tumor stroma, dense inflammatory-cell infiltrates, and the biliary/stem cell markers-positive HCC subtype. The associations of higher collagen levels with radiological findings, including heterogeneous enhancement and persistent enhancement on dynamic computed tomography, were significant. In contrast, the associations of radiological findings with elastin fibers were not significant. Intratumoral fibrous stroma in HCC comprised septum-like and perisinusoidal fibrosis; these two forms represented distinct distribution patterns of fibers and fibroblasts. CONCLUSION: Quantitative analysis suggested that stromal fiber-rich HCCs likely represent a distinct clinico-patho-radiological entity.

8.
Hepatol Res ; 50(3): 353-364, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31702093

RESUMO

AIM: Sorafenib inhibits multiple kinase signaling pathways, including the rat sarcoma virus (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, and is a promising therapy for hepatocellular carcinoma (HCC). However, the role of ERK activation in HCC remains unclear. This study was designed to investigate the potential link between ERK activation and aggressive HCC phenotypes. METHODS: We evaluated nuclear ERK expression by immunohistochemistry in 154 resected HCC nodules from 136 patients. We then investigated the associations of ERK expression with the clinicopathological characteristics of HCC, c-MET expression, and the molecular subclass biomarkers Ki-67, keratin 19 (KRT19, CK19, or K19), and sal-like protein 4. Multivariate Cox regression analysis was carried out to determine independent prognostic factors for overall survival and recurrence-free survival. The effects of ERK activation by hepatocyte growth factor (HGF) on eight HCC cell lines were further examined. RESULTS: High-level nuclear expression of ERK was observed in 20 (13%) of 154 nodules and was significantly associated with higher serum alpha-fetoprotein levels (P = 0.034), poorer differentiation (P = 0.003), a higher Ki-67 index (P < 0.001), high-level expression of c-MET (P = 0.008), KRT19 (P = 0.002), or sal-like protein 4 (P < 0.001), and shorter overall survival (multivariate hazard ratio 3.448; P = 0.028) and recurrence-free survival (multivariate hazard ratio 2.755; P = 0.004). HCC cells treated with hepatocyte growth factor showed enhanced cell proliferation together with ERK activation and upregulated KRT19 expression, both of which were inhibited by sorafenib. CONCLUSIONS: High-level ERK activation is associated with a KRT19-positive highly proliferative subtype of HCC with a dismal prognosis. These findings support the key role of the hepatocyte growth factor/c-MET/ERK axis in HCC progression.

9.
J Clin Invest ; 129(8): 3201-3213, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31264967

RESUMO

Acute liver failure (ALF) is a life-threatening condition, and liver transplantation is the only therapeutic option. Although immune dysregulation is central to its pathogenesis, the precise mechanism remains unclear. Here, we show that the number of peripheral and hepatic plasmacytoid DCs (pDCs) decrease during acute liver injury in both humans and mice. Selective depletion of pDCs in Siglechdtr/+ mice exacerbated concanavalin A-induced acute liver injury. In contrast, adoptively transferred BM-derived pDCs preferentially accumulated in the inflamed liver and protected against liver injury. This protective effect was independent of TLR7 and TLR9 signaling, since a similar effect occurred following transfer of MyD88-deficient pDCs. Alternatively, we found an unexpected immunosuppressive role of pDCs in an IL-35-dependent manner. Both Il12a and Ebi3, heterodimeric components of IL-35, were highly expressed in transferred pDCs and CD4+CD25+ Tregs. However, the protective effect of pDC transfer was completely lost in mice depleted of Tregs by anti-CD25 antibody. Moreover, pDCs derived from IL-35-deficient mice had less of a protective effect both in vivo and in vitro even in the presence of Tregs. These results highlight a unique aspect of pDCs in association with Tregs, serving as a guide for immunotherapeutic options in ALF.


Assuntos
Células Dendríticas/imunologia , Interleucinas/imunologia , Falência Hepática Aguda/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Idoso , Animais , Células Dendríticas/patologia , Feminino , Humanos , Subunidade p35 da Interleucina-12/genética , Subunidade p35 da Interleucina-12/imunologia , Interleucinas/genética , Falência Hepática Aguda/genética , Falência Hepática Aguda/patologia , Falência Hepática Aguda/prevenção & controle , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , Linfócitos T Reguladores/patologia , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/imunologia
10.
Pathol Int ; 69(3): 125-134, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30729617

RESUMO

Glypican-3 (GPC3) is expressed in most hepatocellular carcinomas (HCCs). To investigate the significance of various GPC3 staining patterns in HCC, we classified 134 HCC patients into three groups: those with diffuse GPC3 staining, canalicular GPC3 staining, and others (including negative staining). HCCs with diffuse staining were correlated with poor differentiation, high Ki-67 indices, high serum α-fetoprotein (AFP) levels, and early recurrence. In contrast, HCCs with canalicular staining were well differentiated with lower AFP levels. Overall survival in this group was better than that of the other two groups. Comparative analysis of GPC3 staining patterns with markers for HCC subclassification showed that diffuse staining was correlated with the expression of biliary/stem cell markers, whereas canalicular staining was correlated with expression of the markers of WNT-activated HCCs. Induction of leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), known as a target of the WNT signaling pathway, in HCC cells resulted in reduced GPC3 expression in vitro. The LGR5-induced cells formed tumors with canaliculus-like structures in mice and showed canalicular GPC3 staining. The current findings showed the significance of recognizing distinct GPC3 staining patterns, i.e., diffuse and canalicular, which may reflect different carcinogenetic mechanisms and indicate the level of malignancy of HCC.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/patologia , Glipicanas/metabolismo , Neoplasias Hepáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Coloração e Rotulagem/métodos
11.
Hum Pathol ; 86: 222-232, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30597153

RESUMO

We investigated the clinicopathological and molecular characteristics of scirrhous hepatocellular carcinoma (HCC) to elucidate its uniqueness. Samples from 120 resected HCC cases underwent immunohistochemical analysis. Tumor area containing fibrous stroma and the percentage of steatotic cells within the tumor were evaluated. In our previous report, tumors were immunohistochemically subclassified as biliary/stem cell markers-positive (B/S) (cytokeratin 19 and/or sal-like protein 4 and/or epithelial cell adhesion molecule positive), Wnt/ß-catenin signaling-related markers-positive (W/B) (ß-catenin and/or glutamine synthetase positive), or all markers-negative (-/-) groups. Thirty-seven cases (31%) with fibrous stroma making up ≥50% of the largest tumor area were defined as scirrhous HCC (sHCC); the other 83 cases (69%) were categorized as common HCC (cHCC). Clinicopathologically, sHCC had fewer poorly differentiated tumors (P = .037) and a higher percentage of cases with steatosis (P = .025) than cHCC. sHCC cases were further divided into two subgroups: those with ≥5% steatotic cells (steatotic sHCC) and those with <5% steatotic cells (nonsteatotic sHCC). Hepatitis B virus infection was more frequent in nonsteatotic sHCC (P = .029), and non-B, non-C cases were more frequent in steatotic sHCC (P = .006). Steatotic sHCC tended to have a longer time to recurrence than nonsteatotic sHCC and cHCC. Most nonsteatotic sHCC cases belonged to B/S group, whereas most steatotic sHCC belonged to -/- group. The same tendency in sHCC was shown in another cohort. Distinct features were seen in steatotic and nonsteatotic sHCC, and both sHCC subgroups exhibited different clinicopathological and molecular features from cHCC. These findings support the hypothesis that sHCC is an independent entity.


Assuntos
Carcinoma Hepatocelular/patologia , Fígado Gorduroso/patologia , Neoplasias Hepáticas/patologia , Idoso , Biomarcadores Tumorais , Carcinoma Hepatocelular/metabolismo , Fígado Gorduroso/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Via de Sinalização Wnt/fisiologia , beta Catenina/metabolismo
12.
Sci Rep ; 8(1): 14987, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30301901

RESUMO

A feasible large animal model to evaluate regenerative medicine techniques is vital for developing clinical applications. One such appropriate model could be to use retrorsine (RS) together with partial hepatectomy (PH). Here, we have developed the first porcine model using RS and PH. RS or saline control was administered intraperitoneally to Göttingen miniature pigs twice, two weeks apart. Four weeks after the second dose, animals underwent PH. Initially, we tested different doses of RS and resection of different amounts of liver, and selected 50 mg/kg RS with 60% hepatectomy as our model for further testing. Treated animals were sacrificed 3, 10, 17 or 28 days after PH. Blood samples and resected liver were collected. Serum and liver RS content was determined by Liquid Chromatograph-tandem Mass Spectrometer. Blood analyses demonstrated liver dysfunction after PH. Liver regeneration was significantly inhibited 10 and 17 days after PH in RS-treated animals, to the extent of 20%. Histological examination indicated hepatic injury and regenerative responses after PH. Immunohistochemical staining demonstrated accumulation of Cyclin D1 and suppression of Ki-67 and PCNA in RS-treated animals. We report the development of the first large animal model of sustained liver injury with suppression of hepatic regeneration.


Assuntos
Regeneração Hepática/efeitos dos fármacos , Fígado/lesões , Alcaloides de Pirrolizidina/administração & dosagem , Medicina Regenerativa , Animais , Ciclina D1/sangue , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hepatectomia , Hepatócitos/efeitos dos fármacos , Antígeno Ki-67/sangue , Fígado/efeitos dos fármacos , Fígado/cirurgia , Alcaloides de Pirrolizidina/sangue , Suínos , Porco Miniatura
13.
Hepatology ; 68(3): 1025-1041, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29603348

RESUMO

Immune cells constitute an important element of tumor tissue. Accumulating evidence indicates their clinicopathological significance in predicting prognosis and therapeutic efficacy. Nonetheless, the combinations of immune cells forming the immune microenvironment and their association with histological findings remain largely unknown. Moreover, it is unclear which immune cells or immune microenvironments are the most prognostically significant. Here, we comprehensively analyzed the immune microenvironment and its intratumor heterogeneity in 919 regions of 158 hepatocellular carcinomas (HCCs), and the results were compared with the corresponding histological and prognostic data. Consequently, we classified the immune microenvironment of HCC into three distinct immunosubtypes: Immune-high, Immune-mid, and Immune-low. The Immune-high subtype was characterized by increased B-/plasma-cell and T cell infiltration, and the Immune-high subtype and B-cell infiltration were identified as independent positive prognostic factors. Varying degrees of intratumor heterogeneity of the immune microenvironment were observed, some of which reflected the multistep nature of HCC carcinogenesis. However, the predominant pattern of immunosubtype and immune cell infiltration of each tumor was prognostically important. Of note, the Immune-high subtype was associated with poorly differentiated HCC, cytokeratin 19 (CK19)+ , and/or Sal-like protein 4 (SALL4)+ high-grade HCC, and Hoshida's S1/Boyault's G2 subclasses. Furthermore, patients with high-grade HCC of the predominant Immune-high subtype had significantly better prognosis. These results provide a rationale for evaluating the immune microenvironment in addition to the usual histological/molecular classification of HCC. CONCLUSION: The immune microenvironment of HCC can be classified into three immunosubtypes (Immune-high, Immune-mid, and Immune-low) with additional prognostic impact on histological and molecular classification of HCC. (Hepatology 2018).


Assuntos
Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Idoso , Antígeno B7-H1/metabolismo , Carcinoma Hepatocelular/classificação , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Fígado/patologia , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Linfócitos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral
14.
Intern Med ; 57(13): 1849-1853, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29491285

RESUMO

We herein report the case of 74-year-old man with gastric follicular lymphoma resected by endoscopic submucosal dissection (ESD). A submucosal tumor 7 mm in diameter was detected at the gastric middle body. Endoscopic ultrasonography showed a homogenous hypoechoic tumor localized in the submucosa. The tumor was removed by ESD immediately, before further tumor growth would preclude endoscopic resection. The pathological findings indicated follicular lymphoma (FL) with negative horizontal and vertical margins. The clinical stage of FL was confirmed to be stage I by extensive work-up procedures, including contrast-enhanced computed tomography, fluorodeoxyglucose-positron emission tomography, esophagogastroduodenoscopy, and colonoscopy. The patient remains in complete remission without any treatment.


Assuntos
Ressecção Endoscópica de Mucosa/métodos , Mucosa Gástrica/fisiopatologia , Mucosa Gástrica/cirurgia , Linfoma Folicular/diagnóstico , Linfoma Folicular/cirurgia , Idoso , Humanos , Linfoma Folicular/diagnóstico por imagem , Linfoma Folicular/fisiopatologia , Masculino , Resultado do Tratamento
15.
Hepatol Commun ; 2(1): 58-68, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29404513

RESUMO

Accurate staging of liver fibrosis is crucial to guide therapeutic decisions for patients with nonalcoholic fatty liver disease (NAFLD). Digital image analysis has emerged as a promising tool for quantitative assessment of fibrosis in chronic liver diseases. We sought to determine the relationship of histologic fibrosis stage with fiber amounts quantified in liver biopsy specimens for the better understanding of NAFLD progression. We measured area ratios of collagen and elastin fibers in Elastica van Gieson-stained biopsy tissues from 289 patients with NAFLD from four hospitals using an automated computational method and examined their correlations with Brunt's fibrosis stage. As a secondary analysis, we performed multivariable logistic regression analysis to assess the associations of the combined area ratios of collagen and elastin with noninvasive fibrosis markers. The combined fiber area ratios correlated strongly with Brunt's stage (Spearman correlation coefficient, 0.78; P < 0.0001), but this relationship was nonlinear (P = 0.007) with striking differences between stage 4 (median area ratios, 12.3%) and stages 0-3 (2.1%, 2.8%, 4.3%, and 4.8%, respectively). Elastin accumulation was common in areas of thick bridging fibrosis and thickened venous walls but not in areas of perisinusoidal fibrosis. The highest tertile of the combined fiber area ratios was associated with the fibrosis-4 index and serum type IV collagen 7s domain (7s collagen) levels, whereas the upper two tertiles of the fiber amounts significantly associated with body mass index, aspartate aminotransferase, and 7s collagen in the multivariable analysis. Conclusion: Quantitative fibrosis assessment reveals a nonlinear relationship between fibrosis stage and fiber amount, with a marked difference between stage 4 and stage 3 and much smaller differences among stages 0-3, suggesting a heterogeneity in disease severity within NAFLD-related cirrhosis. (Hepatology Communications 2018;2:58-68).

16.
Sci Rep ; 7(1): 244, 2017 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-28325920

RESUMO

Histological molecular classification of hepatocellular carcinoma (HCC) is clinically important for predicting the prognosis. However, a reliable serum marker has not been established. The aim of this study was to evaluate the diagnostic value of serum Wisteria Floribunda agglutinin-positive sialylated mucin 1 (WFA-sialylated MUC1), which is a novel biliary marker, as a marker of HCC with hepatic progenitor cell (HPC)/biliary features and of prognosis. A total of 144 consecutive patients who underwent complete radiofrequency ablation of primary HCC were enrolled. A serum WFA-sialylated MUC1 level of 900 µL/mL was determined as the optimal cutoff value for prediction of immunohistochemical staining for HPC/biliary features [sialylated MUC1 and cytokeratin 19 (CK19)]. Positive staining rate of sialylated MUC1 and CK19 was significantly higher in patients with WFA-sialylated MUC1 ≥900 than those with WFA-sialylated MUC1 <900. Furthermore, cumulative incidence of HCC recurrence was significantly higher in patients with WFA-sialylated MUC1 ≥900 and on multivariate analysis, serum WFA-sialylated MUC1 levels was an independent predictor of HCC recurrence. These results revealed that serum WFA-sialylated MUC1 was associated with histological feature of HCC and recurrence after curative therapy and it could be a novel marker of HPC/biliary features in HCC and of prognosis.


Assuntos
Biomarcadores/sangue , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Mucina-1/sangue , Lectinas de Plantas/sangue , Receptores de N-Acetilglucosamina/sangue , Soro/química , Idoso , Carcinoma Hepatocelular/terapia , Feminino , Histocitoquímica , Humanos , Queratina-19/análise , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva
19.
Hum Pathol ; 50: 24-33, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26997435

RESUMO

Histopathologic parameters and molecular markers are widely accepted as useful predictors of tumor aggressiveness in hepatocellular carcinoma (HCC). However, few studies have analyzed immunohistochemical profiles comprehensively in one series, a fact that has resulted in fragmentation of information that could be applied in clinical practice. We conducted immunohistochemical expression analysis of biliary/stem cell markers (cytokeratin 19, sal-like protein 4, epithelial cell adhesion molecule, and CD133), Wnt/ß-catenin signaling-related molecules (ß-catenin and glutamine synthetase), p53, and cell proliferation markers (Ki-67 and mitosis) in 162 HCCs surgically resected from 142 patients and analyzed the results with respect to clinicopathological features. Immunohistochemical analysis broadly identified 3 groups: the biliary/stem cell marker-positive group, the Wnt/ß-catenin signaling-related marker-positive group, and the biliary/stem cell marker-negative and Wnt/ß-catenin signaling-related marker-negative group. p53 was frequently positive in the biliary/stem cell marker-positive group, but it was rarely positive in the Wnt/ß-catenin signaling-related marker-positive group. The biliary/stem cell marker-positive group exhibited poor tumor differentiation, increased frequency of portal vein invasion and/or intrahepatic metastasis, and highly proliferative activity. In contrast, the biliary/stem cell marker-negative and Wnt/ß-catenin signaling-related marker-negative group exhibited better tumor differentiation, a decreased frequency of portal vein invasion and/or intrahepatic metastasis, and less proliferative activity. The Wnt/ß-catenin signaling-related marker-positive group showed neither tendency. The biliary/stem cell marker-positive group had the shortest time to recurrence among the 3 groups. Immunohistochemical profiling of HCC reflects tumor aggressiveness and suggests the potential efficacy of immunohistochemistry-based subclassification of HCC.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/química , Imuno-Histoquímica , Neoplasias Hepáticas/química , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/secundário , Carcinoma Hepatocelular/cirurgia , Diferenciação Celular , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-67/análise , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia , Valor Preditivo dos Testes , Fatores de Risco , Resultado do Tratamento , Proteína Supressora de Tumor p53/análise , Proteínas Wnt/análise , Via de Sinalização Wnt , beta Catenina/análise
20.
Cancer Sci ; 107(4): 543-50, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26797961

RESUMO

Multistep hepatocarcinogenesis progresses from dysplastic nodules to early hepatocellular carcinoma (eHCC) and to advanced HCC. The aim of the present study was to investigate the detailed histopathological features of eHCC. We investigated 66 small vaguely nodular lesions resected from 40 patients. The degree of cellular and structural atypia and stromal invasion were assessed. The immunohistochemical expression of HCC-related markers adenylate cyclase-associated protein 2 (CAP2), heat shock protein 70 (HSP70), Bmi-1, CD34 and h-caldesmon were evaluated. Of the 66 nodules, 10 were diagnosed as low-grade dysplastic nodules (LGDN), 10 as high-grade dysplastic nodules (HGDN) and 46 as eHCC. Among the 46 eHCC, 18 nodules (39.1%) showed marked stromal invasion and/or the presence of the scirrhous component and were subclassified as high-grade eHCC (HGeHCC). The remaining 28 eHCC, which lacked these features, were subclassified as low-grade eHCC (LGeHCC) and were examined further. HGeHCC showed high levels of cellular and structural atypia and large tumor size. The immunohistochemical expression of CAP2 and the area of sinusoidal vascularization showed increases from LGDN to HGeHCC. The density of arterial tumor vessels was high in HGeHCC compared with other nodule types. Cluster analysis of these parameters subclassified 65 nodules into HGeHCC-dominant, LGeHCC and HGDN-dominant, and LGDN-dominant groups. These results indicate the increased malignant potential of HGeHCC and suggest that it is already a transitional stage to advanced HCC. We consider that our grading classification system may be valuable for considering treatment strategies for eHCC around 2 cm in diameter.


Assuntos
Carcinogênese/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Proteínas de Neoplasias/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Antígenos CD34/biossíntese , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Proteínas de Ligação a Calmodulina/biossíntese , Carcinoma Hepatocelular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas de Choque Térmico HSP70/biossíntese , Humanos , Neoplasias Hepáticas/genética , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Proteína Quinase 7 Ativada por Mitógeno/biossíntese , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Estadiamento de Neoplasias
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