병사용 진단서 발급을 위해 복강경검사에서 간조직검사를 시행한 젊은 성인 남자의 간침생검 소견 : 새로운 만성간염병리분류를 기준으로 Histologic Grading and Staging of Chronic Hepatitis

전재윤,문영명,박영년,백용한,박찬일,한광협 대한소화기학회 2000 대한소화기학회지 Vol.36 No.2

Background/Aims: This study was designed to assess the etiology and characteristics of chronic liver disease among the young male adults. It was also investigated whether grades of activity and status of fibrosis defined by the new histopathologic classification system of chronic hepatitis are related with alanine aminotransferase (ALT) level and HBeAg status in HBsAg-positive case. Methods: Peritoneoscopic findings, clinical features and histopathologic features of liver were investigated for 140 young men who received liver biopsy for military medical certificate from January 1994 to December 1997. These features were evaluated according to the grade and stage of chronic hepatitis. Results: In Korea, hepatitis B virus was the main cause of chronic hepatitis (87.7%) in young male adults and the infection of hepatitis C virus was rare (1.4%). Among HBsAg-positive cases with normal ALT level, 82.2% of them revealed chronic liver disease, and 48.3% of them showed chronic active hepatitis/cirrhosis in biopsy specimens. The grade of chronic hepatitis showed weak correlation with ALT level and the stage did not. There was no significant difference in the grade and stage of chronic hepatitis according to the serum HBeAg status. Conclusions: The most common cause of chronic liver disease in Korean young male adults was hepatitis B virus, and most (92.6%) of HBsAg-positive cases were proved to have chronic liver diseases histologically, regardless of the serum ALT level. According to new histopathologic classification system of chronic hepatitis, serum ALT level correlated with necroinflammatory activity of chronic hepatitis B, but not with fibrosis in HBsAg-positive cases.

Pathologic Biomarkers that Indicate the Aggressiveness and Prognosis of Hepatocellular Carcinoma

( Young Nyun Park ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Pathological features related to prognosis of hepatocellular carcinoma (HCC) include tumor differentiation grade, tumor size, vascular invasion and intrahepatic metastasis. HCCs are classified into early HCCs and progressed HCCs. Early HCCs are suggested to be the earliest lesion of HCC, corresponding to carcinoma in situ of the other organs. Early HCCs are well differentiated without vascular invasion and its prognosis is very good. In contrast, progressed HCCs are usually moderate to poor differentiated, even in the small sized (< 2cm) HCCs, and vascular invasion and intrahepatic metastasis are found in 27 % and 10%, respectively. The changes in transcriptomes of early HCCs are modest and homogenous, whereas extensive genetic alterations and subsequent activation of prognostic adverse signaling pathways occur only late during hepatocarcinogenesis, and are centered on TGF-ß, WNT, NOTCH, and epithelial-mesenchymal transition (EMT)-related genes highlighting the molecular diversity of progressed HCCs. Recently, new HCC subtypes have been reported based on pathological-molecular classification, and some of them have been reported to be related to poor prognosis. HCCs expressing stemness markers including K19 have been reported to have an aggressive behavior. HCCs with high expression of stemness markers (K19, EpCAM) show activation of YAP pathway, TP53 mutation, FGF19 amplification, and they correlate with aggressive gene expression signatures including S2 (Hoshida et al.) and G1 (Boyault et al.) subclasses. There are some characteristic clinicopathological features that have been more frequently seen in HCCs expressing stemness-related markers compared to those without these markers. HCCs with K19 expression, approximately 10-28% of HCCs show high serum alpha-fetoprotein (AFP) levels, chronic hepatitis B, and decreased overall and recurrence-free survival. HCCs with K19 expression are less frequently encapsulated compared to those without, imparting a more infiltrative growth pattern. Vascular invasion is more frequent in HCCs with K19 expression compared to those without. A fibrous stromal component is more frequently identified in HCCs with K19 expression compared to those without. There is a crosstalk between tumor epithelial cells and stromal cells, and K19 expression is regulated by fibroblast-derived HGF via a MET-ERK1/2-AP1 and SP1 Axis. HCCs with K19 expression are associated with increased expression of EMT-related genes and their proteins, and they are also associated with longer telomeres, increased hTERT expression and increased chromosomal instability, suggesting that HCCs with K19 expression have a survival advantage over those without by maintaining telomeres despite the increased chromosomal instability. Hypoxic microenvironment is known to be important in the generation and maintenance of stemness, and we found that HCCs with stemness (K19, EpCAM) and hypoxia (CAIX)-related markers showed more resistance to transarterial chemoembolization (TACE) and poorer outcome compared those without, and their tumor microenvironment was found to be altered under TACE-induced hypoxia, which might promote the aggressive biology of HCC. The expression of stemness and hypoxia-related markers were correlated each other, and evaluation for both markers of stemness and hypoxia may have an additional value in predicting HCC outcome, especially for TACE-treated HCCs. Scirrhous HCC subtype, which frequency is 4% of HCCs shows dense intratumoral fibrosis > 50% of tumor, and correlates with aggressive gene expression signature of G2 subclass (Boyault et al.). Its key molecular features are TSC1/2 mutations, and TGF-ß signaling activation. The fibrous stroma of scirrhous HCC contains abundant cancer-associated fibroblasts and tumor-infiltrating macrophages, suggesting a possible role for this complex tumor microenvironment in the aggressive behavior of scirrhous HCC. In fact, the majority of scirrhous HCCs have been demonstrated to express K19 or other “stemness”-related markers, and therefore, K19-positive HCCs and scirrhous HCCs may lie on the same spectrum of HCCs, with the latter being defined as containing more intratumoral fibrous stroma. Mactrotrabecular massive (MTM) HCC subtype is defined as trabecular pattern with more than 6-10 cells thickness in 50% of tumor. Its frequency is 5% of HCCs and reported to have a poor prognosis. It correlates with aggressive gene expression signature of G3 subclass (Boyault et al.). Its key molecular features are TP53 mutations and FGF19 amplication. Vessels that encapsulate tumor clusters (VETC), which is defined as ≥ 55% tumor area by CD34 immunostaining is a new HCC subtype related to poor prognosis. VETC was significantly associated to high serum AFP level, tumor size >5 cm, poor differentiation, macrotrabecular pattern, and frequent microvascular invasion. Therefore, the identification of pathologic biomarkers related to aggressiveness and poor prognosis on HCC tissues obtained by biopsy, resection or transplantation could provide useful information for treatment of HCC patient. Moreover, the recent accumulation of molecular-pathological data will hopefully lead to the development of targeted therapy for this aggressive subset of HCCs.

골수 이식후 HBsAg이 소실된 급성 골수성 백혈병 환자 1예

박인서,정정일,한광협,민유홍,최원,문영명,배종엽,박영년,박찬일 대한내과학회 1997 대한내과학회지 Vol.53 No.3S

저자들은 만성 HBV 보유자 상태인 급성 골수성 백혈병 환자에서 HBV에 대한 예방 접종으로 면역능을 갖고있는 공여자로부터 동종 골수 이식을 받은 후 혈청 HBsAg이 소실된 환자 1예를 경험하였기에 문헌 고찰과 함께 보고하였다. Chronic hepatitis B virus infection is still a major cause of liver disease for which no definite therapy is available as yet. We report a case of HBsAg carrier who was treated for acute myelocytic leukemia by bone marrow transplantation from a hepatitis B virus immune donor. Following bone marrow transplantation, immune reconstitution of the recipient's bone marrow resulted in clearance of the circulating HBsAg. Therefore, this report provides an evidence that adoptive transfer of specific immunity against hepatitis B virus through allogenic bone marrow transplantation may lead to the clearance of the persistent hepatitis B virus infection. Allogenic bone marrow transplantation is associated with high morbidity and mortality and hence has not been suggested as a therapeutic mean for the clearance of the hepatitis B virus. However, although not practical at this time, selective transfer of specific cell-mediated immunity to hepatitis B virus and possibly also to other life threatening infectious agents can be used as a new therapeutic modality.

자기 면역성 담관염 2예

박용범,문영명,박영년,최병현,박찬일,이수곤,이천균,한광협,황영웅 대한소화기학회 1998 대한소화기학회지 Vol.31 No.6

We describe two patients showing features of primary biliary cirrhosis but negative antimitochondrial antibody. Botn were females. Serum biochemical study showed increase in alkaline phosphatase and gamma glutamyl transpeptidase levels. Markers of hepatitis B and C virus were absent. In both patients, serum anti-mitochondrial antibodies were not detected on immunofluorescence study. Both had high titers of serum antinuclear antibodies. Liver biopsy specimen showed histological features of primary biliary cirrhosis with marked cellular infiiltration of the portal areas and bile duct damage. Intralabular intlammation and piecemeal necrosis were mild. These patients were treated with prednisolone or UDCA and then, showed decrease in serum alkaline phosphatase level. We thought these patients were cornpatible with autoimmune cholangiopathy.

The effect of deferoxamine on the preneoplastic lesions in the chemically induced hepatocarcinogenesis

Park, Young Nyun,Jung, Woo Hee,Park, Chanil Yonsei University, College of Medicine 1994 Yonsei medical journal Vol.35 No.4

SALL4 Expression in Hepatocellular Carcinomas Is Associated with EpCAM-Positivity and a Poor Prognosis

Park, Hyunjin,Lee, Hyejung,Seo, An Na,Cho, Jai Young,Choi, Young Rok,Yoon, Yoo-Seok,Han, Ho-Seong,Park, Young Nyun,Kim, Haeryoung The Korean Society of Pathologists and the Korean 2015 Journal of Pathology and Translational Medicine Vol.49 No.5

<P><B>Background:</B></P><P>There is increasing interest in hepatocellular carcinomas (HCC) expressing “stemness”-related markers, as they have been associated with aggressive behavior and poor prognosis. In this study, we investigated the usefulness of Sal-like protein 4 (SALL4), a recently proposed candidate marker of “stemness.”</P><P><B>Methods:</B></P><P>Immunohistochemical stains were performed for SALL4, K19, and epithelial cellular adhesion molecule (EpCAM) on tissue microarrays constructed from 190 surgically resected HCCs, and the results were correlated with the clinicopathological features and patient survival data.</P><P><B>Results:</B></P><P>Nuclear SALL4 expression was observed in 39/190 HCCs (20.5%), while K19 and EpCAM were expressed in 30 (15.9%) and 92 (48.7%) HCCs, respectively. The nuclear expression was generally weak, punctate or clumped. SALL4 expression was significantly associated with a poor overall survival compared to SALL4-negative HCCs (p = .014) compared to SALL4-negative HCCs. On multivariate analysis adjusted for tumor size, multiplicity, vascular invasion, and pathological tumor stage, SALL4 remained as a significant independent predictor of decreased overall survival (p= .004). SALL4 expression was positively correlated with EpCAM expression (p = .013) but not with K19 expression. HCCs that expressed both SALL4 and EpCAM were associated with significantly decreased overall survival, compared to those cases which were negative for both of these markers (p = .031).</P><P><B>Conclusions:</B></P><P>Although SALL4 expression was not significantly correlated with other clinicopathological parameters suggestive of tumor aggressiveness, SALL4 expression was an independent predictor of poor overall survival in human HCCs, and was also positively correlated with EpCAM expression.</P>

Histopathological and immunohistochemical studies of polymorphic reticulosis

Park, Young Nyun,Yang, Woo Ick,Lee, Kwang Gil,Choi, In Joon Yonsei University, College of Medicine 1990 Yonsei medical journal Vol.31 No.3

Aberrant breast tissue of the perineum : A report on two cases

Park, Young Nyun,Jeong, Hyeon Joo,Lee, Kook Yonsei University, College of Medicine 1990 Yonsei medical journal Vol.31 No.2

Hepatocarcinogenesis: imaging-pathologic correlation

Park, Young Nyun,Kim, Myeong-Jin Springer-Verlag 2011 Abdominal imaging Vol.36 No.3

만성 간염의 새로운 등급체계에 따른 만성 B 형 간염의 장기간 추적결과

박병규,이관식,안상훈,전재윤,한광협,문영명,박영년,박찬일 대한간학회 2000 Clinical and Molecular Hepatology(대한간학회지) Vol.6 No.3

$quot;목적: 만성 간염은 과거에는 만성 지속성 간염, 만성 소엽성 간염, 만성 활동성 간염으로 분류하였으나 이 분류법의 문제점과 한계점이 제기되어 왔다. 이를 보완하기 위하여 새로운 병리등급이 제시되어 왔고 국내에서는 대한병리학회 소화기병리연구회에서 만성 간염을 간염활성 정도(grade)와 섬유화 진행정도(stage)로 나누고, 간염활성의 등급은 소엽내 활성도와 문맥역/문맥주변부 활성도로 구분하는 새로운 만성 간염의 등급체계를 제시하였다. 본 연구에서는 간조직 검사를 시행받은 만성 B형 간염환자들을 새로운 만성 간염의 등급체계에 따라 재분류하여 장기간 추적결과와 예후인자를 알아보고자 하였다. 대상과 방법: 본 연구는 1984년부터 1996년까지 연세대학교 의과대학 세브란스병원에 내원하여 간조직 검사로 만성 B형 간염으로 확진된 환자들 중 적어도 6개월 이내의 간격으로 2년 이상 추적 관찰이 가능하였던 188명을 대상으로 하였다. 조직검사시의 연령, 성별, 간기능 검사를 알아보고, 추적 관찰 기간동안의 생화학적 간염활성도를 구분하기 위해 혈청 ALT치의 변화에 따라 생화학적 간염활성군과 생화학적 간염비활성군으로 분류하였다. 대상 환자들에서 임상적 또는 조직학적포암종 발생률이 통계적으로 유의하게 높았다(p$lt; 0.01). 대상성 간경변증과 비대상성 간경변증 발생의 독립적인 위험인자는 고령과 추적 관찰 기간동안의 생화학적 간염활성도였고, 간세포암종에서는 고령, 남성 그리고 추적 관찰 기간동안의 생화학적 간염활성도였다(p$lt;0.05). 결론: 새로운 만성 간염의 등급체계는 만성 B형 간염 환자에서 간염의 활성정도를 나타내고, 간경변증으로의 진행을 예측가능하게 한다. 만성 B형 간염 환자에서 추적 관찰 기간동안의 생화학적 간염활성도는 간경변증과 간세포암종 발생의 독립적인 예후인자였다. 그러므로 간염활성을 줄이기 위한 효과적인 치료가 만성 B형 간염 환자에서 간경변증과 간세포암종의 발생을 줄일 수 있을 것으로 기대된다. $quot;Background/Aims: Chronic hepatitis has been divided into chronic persistent hepatitis, chronic lobular hepatitis and chronic active hepatitis. These terms should be discontinued in favor of etiologic terminology. The activity of necro-inflammation and the degree of fibrosis should be evaluated for grading the severity and the stage of the disease. In this study, we sought to evaluate the long-term outcome and prognostic factors of chronic hepatitis B according to the new histological classification of chronic hepatitis proposed by the Korean Study Group for the Pathology of Digestive Diseases. Method: One hundred and eighty-eight patients (mean age, 35.0 years; male/female 3.9:1) with biopsy-proven chronic hepatitis B were retrospectively assessed with a mean follow-up of 80.6 months. The patients were divided into a biochemically-active group and a biochemically-inactive group according to serum alanine aminotransferase (ALT) changes during follow-up periods. The development of compensated cirrhosis and hepatocellular carcinoma were investigated during follow-up periods. As well, the liver biopsy specimens of the patients were reviewed according to the new histological classification of chronic hepatitis (grade of lobular activity and porto-periportal activity, stage of fibrosis). Results: Lobular activity and porto-periportal activity correlated with the serum ALT level at the time of biopsy (p$lt;0.05). The development of compensated cirrhosis correlated with porto-periportal activity and stage of fibrosis (p$lt;0.05). The probability of the development of compensated cirrhosis, decompensated cirrhosis and hepatocellular carcinoma increased significantly in the older age group (≥40 years) and the biochemically-active hepatitis group (p$lt;0.01). The risk factors for the development of compensated cirrhosis and decompensated cirrhosis were old age (≥40 years) and biochemically-active hepatitis during follow-up periods. For hepatocellular carcinoma they were old age (≥40 years), male gender and biochemically-active htitis during follow up periods by multivariate analysis. Conclusions: The present study suggests that the new histological classification of chronic hepatitis indicates hepatitis activity and the prospect for progression to cirrhosis in chronic hepatitis B. The biochemical hepatitis activity during follow-up periods is the independent prognostic factor for the development of cirrhosis and hepatocellular carcinoma in chronic hepatitis B. Therefore, effective treatment to decrease hepatitis activity may reduce the develoment of cirrhosis and hepatocellular carcinoma$quot;.