RESUMEN
Current WHO terminology and recent publications have classified tumoral (grossly visible) intraductal pre-invasive neoplasms of bile duct (TIDN) into three categories: intraductal papillary neoplasm of bile duct (IPNB), intraductal papillary oncocytic neoplasm (IOPN), and intraductal tubulopapillary neoplasm (ITPN). A total of 227 cases of TIDN and related lesions ≥3 mm in height were examined by 10 biliary pathologists referring to these 3 categories and two pathologic gradings: two-tiered system (low- and high-grade dysplasia) and modified types 1 and 2 subclassification. Among them, IPNB was the most frequent (183 cases), followed by IOPN (28 cases), while ITPN was rare (2 cases), and interobserver agreement in this classification was "substantial" (κ-value, 0.657). The interobserver agreement of two-tiered grading system of TIDN was "slight" (κ-value, 0.201), while that of modified types 1 and 2 subclassification was "moderate" (κ-value, 0.515), and 42 % were of type 1, and 58 % were of type 2. Type 1 TIDN showed occasional stromal invasion (6.7 %), whereas type 2 TIDN was frequently associated with stromal invasion (49.6 %) (p < 0.01). In conclusion, the classification of TIDN into three categories and modified types 1 and 2 subclassification are a practically applicable classification and grading system for TIDN.
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Neoplasias de los Conductos Biliares , Neoplasias Pancreáticas , Humanos , Neoplasias de los Conductos Biliares/patología , Variaciones Dependientes del Observador , Conductos Biliares Intrahepáticos/patología , Conductos Biliares/patología , Neoplasias Pancreáticas/patologíaRESUMEN
AIMS: Given that bile duct adenoma was significantly more prevalent in the liver with small duct type intrahepatic cholangiocarcinoma (small duct iCCA), compared to other primary liver carcinomas, we examined the possibility of bile duct adenoma as a precursor of small duct iCCA by analysing genetic alterations and other features in bile duct adenomas. METHODS AND RESULTS: Subjects included 33 bile duct adenomas and 17 small-sized (up to 2 cm in diameter) small duct iCCAs. Genetic alterations were examined by direct sequencing for hot-spot regions and immunohistochemical staining. The expression of p16INK4a , EZH2 and IMP3 and stromal and inflammatory components were also examined. Genetic alterations examined including BRAF were not detected in bile duct adenomas, whereas genetic alterations of p53 (47%), ARID1A (41%), PBRM1 (12%), MTAP (12%), IDH1 (6%), KRAS (6%) and TERT promoter (6%) were detected in 16 small-sized small duct iCCA (94%) (P < 0.01). The expression of IMP3 and EZH2 was not detected in bile duct adenomas, whereas it was detected in most small duct iCCA (94%) (P < 0.01). Immature stroma and neutrophilic infiltration were significantly more prevalent in small duct iCCA, compared to bile duct adenoma (P < 0.01). CONCLUSION: Bile duct adenomas and small-sized small duct iCCAs show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components. There was no evidence suggesting that bile duct adenoma is a precursor of small duct iCCA. Immunohistochemical staining for IMP3, EZH2, p53, ARID1A and MTAP may be useful for differential diagnosis between bile duct adenomas and small duct iCCAs.
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Adenoma de los Conductos Biliares , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Adenoma de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/metabolismo , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/patología , Proteína p53 Supresora de TumorRESUMEN
BACKGROUND AND AIMS: Pyloric gland adenoma (PGA) of the gallbladder is a polypoid, preinvasive epithelial neoplasm composed of uniform back-to-back, pyloric glands in a tubular configuration. Intracholecystic papillary neoplasm (ICPN), another preinvasive grossly visible neoplasm of the gallbladder, is subdividable into four subtypes, including gastric subtype. In this study, PGA was reappraised referring to gastric subtype of ICPN (gICPN). MATERIALS AND METHODS: PGA and gICPN pathologically defined by WHO 2019 classification were surveyed in a total of 104 cases of gallbladder epithelial neoplasms of our Hospital (2002 January to 2021 May) and were pathologically and immunohistochemically compared. RESULTS: PGA (7 cases) was characterized by i) a well-demarcated, polypoid lesion and ii) packed tubular components resembling pyloric glands. gICPNs (14 cases) were subdivided into i) pyloric gland predominant (2 cases), ii) foveola predominant (6 cases) and iii) mixed foveola and pyloric gland type (6 cases). gICPNs were also divided into a solitary, polypoid lesion with well demarcation from the surrounding mucosa (5 cases) and a conglomerated polypoid and granular lesions with poor demarcation (9 cases). PGA shared gross and histologic features with solitary, polypoid gICPNs, and PGA could be regarded as solitary gICPN predominantly composed of pyloric glands. Nuclear expression of ß-catenin was found in 6 of 7 PGA, but absent in gICPN, including solitary, polypoid gICPN. CONCLUSION: PGA could correspond to a solitary gICPN mainly composed of pyloric glands, but may undergo a different molecular pathway from gICPN.
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Adenoma/patología , Neoplasias de la Vesícula Biliar/patología , Vesícula Biliar/patología , Mucosa Gástrica/patología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estómago/patologíaRESUMEN
BACKGROUND: The current WHO classification proposed high-grade biliary intraepithelial neoplasm (BilIN) and intracholecystic papillary neoplasm (ICPN) as precursors of the gallbladder carcinoma (GBC). Herein, conventional GBCs (cGBCs) were pathologically examined with respect to these two precursors. METHODS: Forty-seven cases of GBC with grossly visible invasions were collected from Fukui Saiseikai Hospital. The association of two precursors was analyzed referring to pathologic features of cGBCs and post-operative survival. RESULTS: 20 cGBCa (42.6%) were associated with either of two precursors in the surrounding mucosa: high-grade BilIN in 15 cases (31.9%) or ICPN in 5 cases (10.6%). Association of precursors was not related to gross types of and histological differentiation of cGBC. cGBCs without precursors showed frequent vascular/perineural invasion and lymph node metastasis, though cGBCs with and without precursors presented a similar post-operative survival. High-grade BilIN and ICPN associated with cGBCs showed more complicated cytoarchitectural features compared with those with no or focal invasion. CONCLUSION: More than 40% of cGBCs were associated with high-grade BilIN or ICPN, and the former was a frequent precursor. cGBCs without precursors showed aggressive pathologic features. Clinical detection of these precursors may make early treatment of cGBCs possible.
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Adenocarcinoma , Carcinoma in Situ , Neoplasias de la Vesícula Biliar , Adenocarcinoma/patología , Pigmentos Biliares , Carcinoma in Situ/patología , Neoplasias de la Vesícula Biliar/patología , HumanosRESUMEN
The pathologic features of invasive carcinoma associated with IPNB remain to be clarified. By using 82 cases of IPNB, the pathologic spectrum of associated invasive carcinoma and its correlation with their post-operative overall survival (OS) were examined. Invasive carcinoma was found in 52 cases (63 %) of IPNB and was classifiable into three patterns (patterns A, B and C). Pattern A was characterized by microscopic foci of invasive carcinoma in the fibrovascular stalks or confined to the bile duct mucosa and wall beneath the intraluminal pre-invasive neoplastic components of IPNB (23 cases) and pattern B by invasive carcinoma in the periductal connective tissue and in the adjacent organ(s) mainly near or beneath the intraluminal component(s) of IPNB (15 cases). Pattern C showed nodular invasive carcinoma considerably involving the intraluminal pre-invasive components and the bile duct mucosa and wall adjacent to the intraluminal pre-invasive components of IPNB (14 cases). Recognition of these three patterns of invasive carcinoma associated with IPNB may expand the pathologic spectrum of IPNB. IPNBs without invasive carcinoma showed a favorable post-operative-OS compared with those with invasion as a whole and those of pattern B and C, respectively, but showed a similar post-operative-OS to that of pattern A. IPNB of pattern B and C showed an unfavorable post-operative outcome, though there was no difference between pattern B and C. Understanding of the pathologic spectrum of associated invasive carcinoma may facilitate further pathological analysis of IPNB.
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Adenocarcinoma Mucinoso , Neoplasias de los Conductos Biliares , Carcinoma Papilar , Humanos , Conductos Biliares Intrahepáticos/patología , Neoplasias de los Conductos Biliares/patología , Conductos Biliares/patología , Adenocarcinoma Mucinoso/patología , Carcinoma Papilar/patologíaRESUMEN
BACKGROUND/AIMS: Precursor lesions of small duct type intrahepatic cholangiocarcinoma (small duct iCCA) have not been clarified so far. We hypothesised that precursor lesions may be frequently distributed in the background liver of small duct iCCA. METHODS AND RESULTS: We determined by histology the presence of bile duct adenomas and von Meyenburg complexes as candidate precursor lesions in the background liver of small duct iCCA, with other primary liver carcinomas as control. Subjects included 28 patients with small duct iCCA, 29 with large duct iCCAs, 60 with combined hepatocellular-cholangiocarcinoma (Comb) and 40 with hepatocellular carcinoma (HCC). The prevalence of bile duct adenomas in the background liver was significantly higher in small duct iCCA (35.7%) compared to other primary liver carcinomas (Comb, 4.9%; 10%, HCC) (P < 0.01). The prevalence of bile duct adenomas was significantly associated with the presence of von Meyenburg complexes and ductal plate malformation-like patterns in small duct iCCAs and Combs. Von Meyenburg complexes were detected in 11 small duct iCCA (39.3%), five large duct iCCAs (17.2%), 10 Comb (16.4%) and 13 HCC (33.3%), respectively (P > 0.05). Small duct iCCAs showed altered expression of ARID1A (46.4%), p53 (39.3%), PBRM1 (14.3%), IMP3 (85.7%) and EZH2 (82.1%), whereas these markers were negative in bile duct adenomas. CONCLUSION: Bile duct adenomas may be precursor lesions of small duct iCCAs. Alteration of ARID1A, p53 or PBRM1 may be involved in the carcinogenesis of small duct iCCAs.
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Adenoma de los Conductos Biliares/complicaciones , Colangiocarcinoma/etiología , Adenoma de los Conductos Biliares/diagnóstico , Adenoma de los Conductos Biliares/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Biomarcadores de Tumor , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/patología , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/patología , Diagnóstico Diferencial , Femenino , Humanos , Hígado/patología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana EdadRESUMEN
AIMS: Mass-forming intrahepatic cholangiocarcinomas (MF-iCCAs), involving small bile ducts, bile ductules or canals of Hering, remain treated as a single entity. We aimed to examine the diversity in histology, phenotype and tumour vasculature of MF-iCCAs. METHODS AND RESULTS: Based on morphology and immunophenotype, we classified MF-iCCAs into small bile duct (SBD), cholangiolocarcinoma (CLC), ductal plate malformation (DPM) and hepatocellular carcinoma (HCC)-like subtypes. Genetic correlations among the histological subtypes were examined by multi-region tumour sequencing. Vasculatures and other clinicopathological features were compared among tumour groups with various proportions of the histological subtypes in 62 MF-iCCAs. Cases of pure SBD, CLC, DPM and HCC-like subtypes numbered 18 (29%), seven (11.3%), none (0%) and two (3%), respectively; the remaining 35 (56.4%) cases comprised several components. Genetic alterations, isocitrate dehydrogenase (IDH)1/2, KRAS, TP53, polybromo-1 (PBRM1) and BRCA1-associated protein 1 (BAP1), were shared among SBD, CLC, DPM and hepatoid components within a tumour. We uncovered distinct vascularisation mechanisms among SBD, CLC and DPM subtypes with a prominent vessel co-option in CLC tumours. iCCA with a DPM pattern had the highest vascular densities (mean microvascular density,140/mm2 ; arterial vessel density, 18.3/mm2 ). Increased CLC component was correlated with longer overall survival time (r = 0.44, P = 0.006). Pure SBD tumours had a lower 5-year overall survival rate compared with MF-iCCA with CLC pattern (30.5 versus 72.4%, P = 0.011). CONCLUSIONS: MF-iCCAs comprise four histological subtypes. Given their sharing some driver gene alterations, indicating they can have a common cell origin, SBD, CLC and DPM subtypes, however, differ in cell differentiation, histology, phenotype or tumour vasculature.
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Colangiocarcinoma , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Diferenciación Celular , Colangiocarcinoma/clasificación , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patología , Femenino , Histocitoquímica , Humanos , Isocitrato Deshidrogenasa/genética , Hígado/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Vasos Retinianos/patología , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
Intracholecystic papillary neoplasm (ICPN) is a recently proposed gallbladder neoplasm. Its prevalence and pathologies remain to be clarified. A total of 38 ICPN cases (28 ICPNs identified among 1904 cholecystectomies (1.5%) and in 100 surgically resected primary gallbladder neoplasms (28%) in Fukui Prefecture Saiseikai Hospital, Japan, and other 10 ICPNs) were examined pathologically and immunohistochemically. They were composed of 21 males and 17 females with a mean age of 75 years old, and presented intraluminal growth of papillary lesions with fine fibrovascular stalks. ICPNs were relatively frequent in the fundus (n = 11) and body (n = 9). Grossly, the conglomerated sessile type (n = 30) was more frequent than the isolated polypoid type (n = 8). All cases were classified as high-grade dysplasia, and they were further divided into 22 cases presenting irregular structures and 16 cases presenting regular structures. The former showed frequent complicated lesions and stromal invasion (54.5%) compared to the latter (12.5%). Twenty-four cases showed predominantly either of four subtypes (11 gastric, 7 intestinal, 4 biliary and 2 oncocytic subtype), while the remaining14 cases showed mixture of more than two subtypes. In conclusion, ICPN presented unique preinvasive neoplasm with characteristic histopathologies. Irregular histologies and complicated lesions of ICPN were related to stromal invasion.
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Adenocarcinoma Papilar/diagnóstico , Conductos Biliares/patología , Carcinoma in Situ/patología , Neoplasias de la Vesícula Biliar/patología , Adenocarcinoma Papilar/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Conductos Biliares/cirugía , Carcinoma in Situ/diagnóstico , Carcinoma in Situ/epidemiología , Colecistectomía/métodos , Colecistectomía/estadística & datos numéricos , Femenino , Neoplasias de la Vesícula Biliar/cirugía , Humanos , Inmunohistoquímica/métodos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , PrevalenciaRESUMEN
BACKGROUND & AIMS: Senescent biliary epithelial cells (BECs) may be involved in the pathophysiology of primary biliary cholangitis (PBC) by secreting senescence-associated secretory phenotypes. We examined an association of the extent of cellular senescence in BECs with clinicopathological features including response to ursodeoxycholic acid (UDCA) and a possibility of senolytic therapy in PBC. METHODS: The expression of senescent markers (p21WAF1/Cip1, p16INK4a) and B-cell lymphoma-extra large (Bcl-xL), a key regulator of senescent cell anti-apoptotic pathway, was immunohistochemically examined in livers from patients with PBC (n = 145) and 103 control livers. Senolytic effect of Bcl-xL inhibitors (A-1331852 and Navitoclax) was examined in senescent murine BECs. RESULTS: Senescent BECs were increased in small bile ducts in PBC, compared with control livers (p < 0.01). Senescent BECs were increased in ductular reactions in PBC, stage 3-4, compared with PBC, stage 1-2 and control livers (p < 0.01). The extent of senescent BECs in bile ductules was significantly correlated with stage and hepatitis activity (p < 0.01) and the expression of p16INK4a in bile ductules was significantly correlated to inadequate response to UDCA in PBC (p < 0.01). Double immunofluorescence revealed an increased expression of Bcl-xL in p16INK4a-positive senescent BECs in PBC. Bcl-xL inhibitors selectively induced apoptosis in senescent murine BECs (p < 0.01). CONCLUSION: The extent of senescent BECs in small bile ducts and bile ductules was closely related to stage and activity of PBC and the increased expression of p16 INK4a in bile ductules was correlated with inadequate response to UDCA.
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Senescencia Celular/efectos de los fármacos , Senescencia Celular/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Cirrosis Hepática Biliar/etiología , Ácido Ursodesoxicólico/farmacología , Animales , Conductos Biliares/inmunología , Conductos Biliares/metabolismo , Conductos Biliares/patología , Biomarcadores , Estudios de Casos y Controles , Senescencia Celular/inmunología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Células Epiteliales/inmunología , Expresión Génica , Humanos , Cirrosis Hepática Biliar/tratamiento farmacológico , Cirrosis Hepática Biliar/metabolismo , Cirrosis Hepática Biliar/patología , Ratones , Ácido Ursodesoxicólico/uso terapéutico , Proteína bcl-X/antagonistas & inhibidores , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMEN
Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as "combined (or mixed) hepatocellular-cholangiocarcinoma." These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, because of a lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This article represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation. CONCLUSION: It is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin (H&E); immunostains are supportive, but not essential for diagnosis. (Hepatology 2018;68:113-126).
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Carcinoma Hepatocelular/diagnóstico , Colangiocarcinoma/diagnóstico , Neoplasias Hepáticas/clasificación , Anciano , Carcinoma Hepatocelular/patología , Colangiocarcinoma/patología , Femenino , Humanos , Hígado/patología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Radiografía , Terminología como AsuntoRESUMEN
Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare vascular liver disease that has attracted new interest in recent years. It is characterised by clinical signs of portal hypertension in the absence of cirrhosis or severe fibrosis and any known cause of portal hypertension. As much uncertainty exists about INCPH pathophysiology, and no definite diagnostic tests are available, liver biopsy is an essential tool for achieving a definite diagnosis. Unfortunately, the histological diagnosis of INCPH is not always straightforward, as the characteristic lesions are unevenly distributed, vary greatly in their severity, are often very subtle, and are not all necessarily present in a single case. Furthermore, specifically for the characteristic portal vessel changes observed in INCPH, the terminology and definition are ambiguous, which adds complexity to the already complex clinicopathological scenario. An international study group of liver pathologists and hepatologists pursued a consensus on nomenclature for the portal vascular lesions of INCPH. Such standardisation may assist pathologists in the recognition of such lesions, and will possibly facilitate further advancement in this field.
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Hipertensión Portal/patología , Hígado/patología , HumanosRESUMEN
Dysregulated autophagy may be a central player in trehe pathogenesis of primary biliary cholangitis (PBC) by inducing autoimmune processes via abnormal expression of mitochondrial antigens such as pyruvate dehydrogenase complex, E2 component (PDC-E2) and also by inducing cellular senescence in biliary epithelial cells (BECs) in bile duct lesions in PBC. We examined the association of an impaired "biliary bicarbonate umbrella" due to dysfunction of anion exchanger 2 (AE2) with dysregulated autophagy and cellular senescence in PBC. The expression of AE2 was examined in cultured BECs treated with bile acids such as glycochenodeoxycholic acid (GCDC) and tauro-ursodeoxycholic acid (TUDCA), various cytokines (IL-4, IL-13, IFNγ, TNFα, TGFß), and serum deprivation. The effect of AE2 knockdown using siRNA on autophagy, cell surface expression of PDC-E2, and cellular senescence was also examined. The expression of AE2 and its association with autophagy-related markers and senescent markers p16INK4a and p21WAF1/Cip1 were immunohistochemically determined in livers taken from the patients with PBC (n = 50) and 69 control diseased and normal livers. The expression of AE2 was significantly induced in the cultured BECs shortly treated with GCDC and other stresses, whereas it was significantly decreased in senescent BECs induced by GCDC and other stresses (p < 0.05). Dysregulated autophagy, cell surface expression of PDC-E2, and cellular senescence were significantly increased by knockdown of AE2 (p < 0.05). The expression of AE2 was significantly decreased in cholangitis in PBC, compared to control livers (p < 0.05). The decreased expression of AE2 was correlated with dysregulated autophagy, abnormal expression of PDC-E2, and cellular senescence in bile duct lesions in PBC. In conclusion, an impaired biliary bicarbonate umbrella may be involved in the pathogenesis of PBC by inducing dysregulated autophagy.
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Autofagia , Bicarbonatos/metabolismo , Conductos Biliares/metabolismo , Antiportadores de Cloruro-Bicarbonato/fisiología , Colangitis/etiología , Animales , Células Cultivadas , Senescencia Celular , Antiportadores de Cloruro-Bicarbonato/genética , Colangitis/metabolismo , Colangitis/patología , Femenino , Humanos , Ratones , Ratones Endogámicos BALB CRESUMEN
AIM: As primary biliary cholangitis (PBC) is a heterogeneous disease, we hypothesized that there is a population of patients with early PBC who do not require prompt treatment with ursodeoxycholic acid (UDCA). In this study, we analyzed data from a large-scale PBC cohort in Japan, and retrospectively investigated whether outcomes of early PBC patients were affected with prompt or deferred/no UDCA treatment. METHODS: We defined early PBC as asymptomatic, serum alkaline phosphatase <1.67-fold the upper limit of normal, normal bilirubin, and histological stages I-II at presentation. We compared the outcomes of early PBC patients between the treatment regimens; prompt treatment group (UDCA was initiated within 1 year after diagnosis) and deferred/no treatment group (UDCA initiated >1 year after diagnosis or never initiated). Furthermore, we examined the outcomes of early PBC patients alternatively defined only with symptomatology and biochemistry. RESULTS: We identified 562 early PBC patients (prompt: n = 509; deferred/no treatment: n = 53). Incidence rates (per 1000 patient-years) for liver-related mortality or liver transplantation and decompensating events were 0.5 and 5.4, respectively, in the prompt treatment group, and 0 and 8.7, respectively, in the deferred/no treatment group. Multivariate analyses showed that age and bilirubin were significantly associated with developing decompensating events, whereas the prompt and deferred/no treatments were not. We obtained similar results in early PBC patients defined without histological examination. CONCLUSIONS: We showed that deferred/no treatment for early PBC patients did not affect the outcomes. This study provides a rationale for a future prospective, randomized study.
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AIM: The aim of this study is to clarify the correlation of the co-activation of ß-catenin and hepatocyte nuclear factor (HNF)4α with the findings of gadoxetic acid-enhanced magnetic resonance imaging (MRI), organic anion transporting polypeptide (OATP)1B3 expression, and histological findings in hepatocellular carcinoma (HCC). METHODS: One hundred and ninety-six HCCs surgically resected from 174 patients were enrolled in this study. The HCCs were classified into four groups by immunohistochemical expression of ß-catenin, glutamine synthetase (GS), and HNF4α: (i) ß-catenin/GS (positive [+]) HNF4α (+); (ii) ß-catenin/GS (+) HNF4α (negative [-]); (iii) ß-catenin/GS (-) HNF4α (+); and (iv) ß-catenin/GS (-) HNF4α (-). We compared the four groups in terms of the enhancement ratio on the hepatobiliary phase of gadoxetic acid-enhanced MRI, immunohistochemical organic anion transporter polypeptide (OATP)1B3 (a main uptake transporter of gadoxetic acid) expression and histological features, overall survival, and no recurrence survival. The Kruskal-Wallis test, Steel-Dwass multiple comparisons test, Fisher's exact test, and log-rank (Mantel-Cox) test were used for statistical analyses. RESULTS: Enhancement ratio on gadoxetic acid-enhanced MRI in HCC with ß-catenin/GS (+) HNF4α (+) was significantly higher than those of the other three groups (P < 0.001). The OATP1B3 grade was also significantly higher in HCC with ß-catenin/GS (+) HNF4α (+) (P < 0.001). Hepatocellular carcinoma with ß-catenin/GS (+) HNF4α (+) showed the highest differentiation grade as compared to the other groups (P < 0.004). There were no significant differences in portal vein invasion, macroscopic growth pattern, or prognosis analyses between the four groups. CONCLUSION: Co-activation of ß-catenin and HNF4α would promote OATP1B3 expression, and consequently higher enhancement ratio on gadoxetic acid-enhanced MRI and higher differentiation grade in HCC.
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BACKGROUND: The indication of surgery in intrahepatic cholangiocarcinoma (ICC) patients with lymph node metastasis (LNM), macroscopic periductal infiltration (PI), and intrahepatic metastasis (IM) remains unclear. METHODS: Patients who underwent resection for mass-forming (MF) dominant ICC and unresected patients caused by LNM, IM, or locally advanced tumors (UR group) were enrolled. The significance of CA19-9 was investigated in advanced ICC. RESULTS: Seventy-three patients who underwent resection and 20 UR patients were analyzed. Using the minimum p value approach based on the overall survival, the optimal CA19-9 cutoff value was 300 U/mL. The OS of the patients with CA19-9 < 37 U/mL (n = 26; MST, 49.6 months) and 37-300 U/mL (n = 28; MST, 45.1 months) was comparable (P = 0.842); however, the OS of the patients with CA19-9 = 37-300 U/mL was significantly better than that with CA19-9 ≥ 300 U/mL (n = 19; MST, 15.3 months; P < 0.001). CA19-9 > 300 U/mL, MF + PI, and IM were independently associated with OS. The OS of the patients with CA19-9 < 300 U/mL who developed LNM (MST, 34.0 months), MF + PI (MST, 32.9 months), or IM (MST, 35.2 months), or who required major vascular resection (MST, 45.1 months) was better than those with CA19-9 ≥ 300 U/mL who developed LNM (MST, 8.7 months; P = 0.005), MF + PI (MST, 7.5 months; P = 0.040), or IM (MST, 8.7 months; P = 0.001), or who required major vascular resection (MST, 14.8 months; P = 0.015); their prognosis was similar with the UR group. CONCLUSIONS: Even if patients had ICC developing LNM, PI, or IM, or require major vascular resection, surgical resection can be indicated for patients with CA19-9 < 300 U/mL. However, the indications for either adjuvant therapy or resection should be carefully determined in patients with CA19-9 ≥ 300 U/mL.
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Neoplasias de los Conductos Biliares/cirugía , Antígeno CA-19-9/sangre , Colangiocarcinoma/cirugía , Anciano , Neoplasias de los Conductos Biliares/sangre , Conductos Biliares Intrahepáticos/cirugía , Colangiocarcinoma/sangre , Terapia Combinada , Femenino , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática/patología , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Valores de Referencia , Adulto JovenRESUMEN
AIMS: Combined hepatocellular carcinoma and cholangiocarcinoma (cHC-CC), which generally has a poor prognosis, comprises hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and diverse components with intermediate features between HCC and CC. Histological subtypes with stem cell (SC) features (the SC subtype) have different clinicopathological significance in cHC-CC. The mutational status may reflect the clinicopathological subgroup of cHC-CC together with the histological subtype. METHODS AND RESULTS: We examined the mutational statuses of KRAS, IDH1 or IDH2 (IDH1/2), ARID1A, the TERT promoter, and TP53, and their relationships with clinicopathological features in 53 patients with cHC-CC. Background liver diseases were hepatitis B (n = 9), hepatitis C (n = 22), alcoholic liver disease (n = 5), non-alcoholic fatty liver disease (NAFLD) (n = 8), and unknown (n = 9). Mutations in KRAS, IDH1/2, ARID1A, the TERT promoter and TP53 were detected in four (7.5%), six (11.8%) seven (13.2%), 16 (31.3%), and 24 patients (45.3%), respectively. KRAS mutations correlated with higher histological diversity scores and a higher M-factor (P < 0.05). ARID1A mutations correlated with alcoholic liver disease, smaller tumour size, a lower grade of coexistent HCC, and α-fetoprotein (AFP) positivity, and were associated with cholangiolocellular carcinoma subtype predominance (P < 0.05). TERT promoter mutations correlated with hepatitis B, an intermediate subtype-predominant histology, higher clinical stage, and a higher N-factor (P < 0.05), and were associated with gender (female-predominant) and previous therapy. TP53 mutations correlated with AFP positivity (P < 0.05). CONCLUSIONS: The results of the mutational analysis revealed that cHC-CC has diverse types of mutations, and also that mutations in the TERT promoter and ARID1A may reflect aetiological impact, different histological subtypes, histogenesis, and tumour aggressiveness. These results suggest the potential efficacy of molecular-based subclassification of cHC-CC.
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Neoplasias de los Conductos Biliares/genética , Carcinoma Hepatocelular/genética , Colangiocarcinoma/genética , Neoplasias Hepáticas/genética , Neoplasias Primarias Múltiples/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/patología , Carcinoma Hepatocelular/patología , Colangiocarcinoma/patología , Análisis Mutacional de ADN , Femenino , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/patologíaRESUMEN
BACKGROUND: Primary biliary cholangitis (PBC) is characterized by a high prevalence of serum anti-mitochondrial antibodies against the E2 subunit of the pyruvate dehydrogenase complex and bile duct lesions called chronic non-suppurative destructive cholangitis (CNSDC) in small bile ducts, eventually followed by extensive bile duct loss and biliary cirrhosis. Macroautophagy (a major type of autophagy) is a process of cellular self-digestion that plays a critical role in energy homeostasis and in the cytoprotection to various stresses. Deregulated autophagy is thought to be associated with various human diseases. Key Messages: Accumulating evidences suggest that deregulated autophagy may be a central player in the pathogenesis of PBC. Damaged cholangiocytes involved in CNSDC show vesicular expression of autophagy marker LC3 and accumulation of p62/sequestosome-1, suggesting deregulated autophagy. Deregulated autophagy may be involved in the autoimmune process via the abnormal expression of mitochondrial antigens and also in cholangiocyte senescence in bile duct lesions in PBC. In vitro study showed that hydrophobic bile acids, such as glycochenodeoxycholic acid (GCDC), as well as serum deprivation and oxidative stress, cause autophagy, deregulated autophagy and abnormal expression of mitochondrial antigens followed by cellular senescence in cholangiocytes. Although exact mechanisms of deregulated autophagy remain to be clarified, endoplasmic reticulum (ER) stress may be a plausible cause of deregulated autophagy induced by GCDC in cholangiocytes. Impaired 'biliary bicarbonate umbrella' may further exacerbate the toxicity of GCDC to cholangiocytes. Interestingly, pretreatment with ursodeoxycholic acid (UDCA) and tauro-UDCA, which is a chemical chaperone enhancing the adaptive capacity of the ER, significantly suppressed ER stress, deregulated autophagy and cellular senescence induced by GCDC and other stresses in cholangiocytes. CONCLUSIONS: GCDC may play a role in the occurrence of deregulated autophagy and cellular senescence at least partly through the induction of ER stress in PBC. Deregulated autophagy and cellular senescence can be a promising therapeutic target in PBC.
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Autofagia , Ácidos y Sales Biliares/metabolismo , Conductos Biliares/patología , Colangitis/patología , Animales , Senescencia Celular , Estrés del Retículo Endoplásmico , HumanosRESUMEN
An outbreak of cholangiocarcinoma in a printing company was reported in Japan, and these cases were regarded as an occupational disease (occupational cholangiocarcinoma). This study examined the expression status of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in occupational cholangiocarcinoma. Immunostaining of PD-1, PD-L1, CD3, CD8, and CD163 was performed using tissue sections of occupational cholangiocarcinoma (n = 10), and the results were compared with those of control cases consisting of intrahepatic (n = 23) and extrahepatic (n = 45) cholangiocarcinoma. Carcinoma cells expressed PD-L1 in all cases of occupational cholangiocarcinoma, whereas the detection of PD-L1 expression in cholangiocarcinoma cells was limited to a low number of cases (less than 10%) in the control subjects. In cases of occupational cholangiocarcinoma, occasional PD-L1 expression was also noted in precancerous/preinvasive lesions such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. Additionally, tumor-associated macrophages and tumor-infiltrating T cells expressed PD-L1 and PD-1, respectively. The number of PD-L1-positive mononuclear cells, PD-1-positive lymphocytes, and CD8-positive lymphocytes infiltrating within the tumor was significantly higher in occupational cholangiocarcinoma compared with that in control cases. These results indicate that immune escape via the PD-1/PD-L1 axis may be occurring in occupational cholangiocarcinoma.
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Antígeno B7-H1/biosíntesis , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Enfermedades Profesionales/patología , Receptor de Muerte Celular Programada 1/biosíntesis , Adulto , Anciano , Apoptosis/fisiología , Antígeno B7-H1/análisis , Neoplasias de los Conductos Biliares/inducido químicamente , Neoplasias de los Conductos Biliares/inmunología , Colangiocarcinoma/inducido químicamente , Colangiocarcinoma/inmunología , Femenino , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Japón , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Persona de Mediana Edad , Enfermedades Profesionales/etiología , Enfermedades Profesionales/inmunología , Exposición Profesional/efectos adversos , Lesiones Precancerosas/patología , Impresión , Receptor de Muerte Celular Programada 1/análisis , Solventes/efectos adversosRESUMEN
Some biliary diseases mimic pancreatic diseases pathologically as well as pathogenetically. Such diseases can be called "biliary diseases with pancreatic counterparts". Biliary intraepithelial neoplasm (BilIN), intraductal papillary neoplasm of bile ducts (IPNB), hepatobiliary mucinous cystic neoplasm (hMCN), and IgG4-inflammatory pseudotumor represent the biliary counterparts of pancreatic intraepithelial neoplasm (PanIN), intraductal papillary mucinous neoplasm of pancreas (IPMN), pancreatic MCN, and mass forming type 1 autoimmune pancreatitis (AIP), respectively. BilIN and PanIN represent pre-invasive intraepithelial stages of nodular sclerosing cholangiocarcinoma and pancreatic ductal adenocarcinoma, respectively. IPNB and IPMN are grossly visible, predominant papillary, intraductal neoplasms that may progress to invasive carcinoma. Morphologically similar MCNs with subepithelial ovarian-like stroma occur in both the hepatobiliary system as well as the pancreas. IgG4-inflammatory pseudotumor, usually of the lymphoplasmacytic type, and mass forming type 1 AIP represent IgG4-related disease in the biliary tree and pancreas respectively. The biliary tract, which is associated with the peribiliary glands, including the pancreatic acini, can be regarded as an incomplete pancreas, so several diseases mimicking pancreatic diseases may be expected to occur in the biliary tract (biliary diseases with pancreatic counterparts).
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Adenocarcinoma Papilar/patología , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Cistadenocarcinoma Mucinoso/patología , Neoplasias Pancreáticas/patología , Anciano , Femenino , Granuloma de Células Plasmáticas , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana EdadRESUMEN
Immunoglobulin G4-related disease (IgG4-RD) is a systemic disease involving many organs; it includes IgG4-related sclerosing cholangitis and inflammatory pseudotumor in the hepatobiliary system. Two types of hepatic parenchymal involvement have been reported in IgG4-RD: IgG4-related autoimmune hepatitis (AIH) and IgG4-hepatopathy. Moreover, only three cases of IgG4-related AIH have been reported. Immunoglobulin G4-related AIH is clinicopathologically similar to AIH, except for an elevated serum IgG4 level and heavy infiltration of IgG4-positive plasma cells in the liver tissue. Interestingly, IgG4-related AIH can be complicated by well-known IgG4-RD(s). Immunoglobulin G4-hepatopathy, which includes various histopathological lesions encountered in the liver of patients with type I autoimmune pancreatitis, is classified into five histological categories: portal inflammation, large bile duct damage, portal sclerosis, lobular hepatitis, and cholestasis. Immunoglobulin G4-hepatopathy is currently a collective term covering hepatic lesions primarily or secondarily related to IgG4-related sclerosing cholangitis and type 1 autoimmune pancreatitis. In conclusion, the liver is not immune to IgG4-RD, and at least two types of hepatic involvement in IgG4-RD have been reported: IgG4-related AIH and IgG4-hepatopathy. Additional studies are required to clarify their precise clinical significance with respect to IgG4-RD and inherent liver diseases.