今日の臨床サポート

肝内胆管癌、その他の原発性肝癌

著者: 千代永卓1) 熊本労災病院 消化器内科

著者: 佐々木裕2) 長崎国際大学健康栄養学科/熊本大学消化器内科

監修: 金子周一 金沢大学大学院

著者校正/監修レビュー済:2021/03/31
参考ガイドライン:
  1. 日本肝癌研究会:肝内胆管癌診療ガイドライン2021年版
患者向け説明資料

概要・推奨   

  1. 切除不能肝内胆管癌に推奨される薬物療法は、ゲムシタビン+シスプラチン+S-1併用療法、ゲムシタビン+シスプラチン併用療法、またはゲムシタビン+S-1併用療法である(推奨度2)。
  1. HBV、HCVの感染はICC発生の独立危険因子であり、HCCのみならずICCの合併も念頭に置く必要がある(推奨度2)
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
千代永卓 : 未申告[2021年]
佐々木裕 : 特に申告事項無し[2021年]
監修:金子周一 : 研究費・助成金など(バイエル薬品株式会社,株式会社キュービクス,アボットジャパン合同会社,日東電工株式会社,株式会社スギ薬局,株式会社サイトパスファインダー),奨学(奨励)寄付など(小野薬品工業株式会社,エーザイ株式会社,株式会社ツムラ,アッヴィ合同会社,大日本住友製薬株式会社,ゼリア新薬工業株式会社,塩野義製薬株式会社,大塚製薬株式会社,アステラス製薬株式会社,田辺三菱製薬株式会社,マイランEPD合同会社,EAファーマ株式会社,大鵬薬品工業株式会社,中外製薬株式会社,協和キリン株式会社,持田製薬株式会社,日本ケミファ株式会社,LifeScan Japan株式会社)[2021年]

改訂のポイント:
  1. 肝内胆管癌診療ガイドライン2021年版が刊行され、改訂を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 肝内胆管癌とは、肝内に発生した胆管上皮に似る、あるいはそれに由来する細胞からなる上皮性悪性腫瘍であり、肝内胆管癌と混合型肝癌(肝細胞癌と肝内胆管癌の混合型)を合わせると、原発性肝癌全体の約5%を占める。
  1. その他の原発性肝癌として細胆管細胞癌、粘液嚢胞腺癌、肝芽腫、未分化癌、類上皮性血管内皮腫、血管肉腫、未分化肉腫、横紋筋肉腫などがあるが、いずれもまれである。
  1. 肝内胆管癌、混合型肝癌のいずれも男性に多い[1]
  1. 肝内胆管癌の危険因子として、肝硬変、ウイルス感染(HCV[2]、HBV[3]など)、飲酒、糖尿病、肥満、喫煙、非アルコール性脂肪肝炎、肝吸虫や胆管病変である原発性硬化性胆管炎、肝内結石症、先天性胆道拡張症(総胆管嚢腫)、カロリー病と炎症性腸疾患が報告されている。化学物質ではトリウム-232(トロトラストの主剤)、1.2-ジクロロプロパンとジクロロメタン、ニトロソアミンが危険因子である。
  1. 肝内胆管癌は、肉眼分類により腫瘤形成型、胆管浸潤型、胆管内発育型に分類され、それぞれの画像所見が異なる。
  1. 転移性肝癌との鑑別が問題になるため、他臓器癌の除外が重要である。
問診・診察のポイント  
問診:
  1. 肝内胆管癌は早期には明らかな症状に乏しい。そのため進行した状態で診断される場合が多い。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
常時アップデートされており、最新のエビデンスを各分野のエキスパートが豊富な図表や処方・検査例を交えて分かりやすく解説。日常臨床で遭遇するほぼ全ての症状・疾患から薬剤・検査情報まで瞬時に検索可能です。

まずは15日間無料トライアル
本サイトの知的財産権は全てエルゼビアまたはコンテンツのライセンサーに帰属します。私的利用及び別途規定されている場合を除き、本サイトの利用はいかなる許諾を与えるものでもありません。 本サイト、そのコンテンツ、製品およびサービスのご利用は、お客様ご自身の責任において行ってください。本サイトの利用に基づくいかなる損害についても、エルゼビアは一切の責任及び賠償義務を負いません。 また、本サイトの利用を以て、本サイト利用者は、本サイトの利用に基づき第三者に生じるいかなる損害についても、エルゼビアを免責することに合意したことになります。  本サイトを利用される医学・医療提供者は、独自の臨床的判断を行使するべきです。本サイト利用者の判断においてリスクを正当なものとして受け入れる用意がない限り、コンテンツにおいて提案されている検査または処置がなされるべきではありません。 医学の急速な進歩に鑑み、エルゼビアは、本サイト利用者が診断方法および投与量について、独自に検証を行うことを推奨いたします。

文献 

著者: M Kobayashi, K Ikeda, S Saitoh, F Suzuki, A Tsubota, Y Suzuki, Y Arase, N Murashima, K Chayama, H Kumada
雑誌名: Cancer. 2000 Jun 1;88(11):2471-7.
Abstract/Text BACKGROUND: Hepatitis C virus (HCV) infection is a major risk factor for the development of hepatocellular carcinoma. However, the risk factors for primary cholangiocellular carcinoma of the liver (PCC-L) have not been fully investigated. The authors determined the incidence of PCC-L in patients with HCV-related cirrhosis.
METHODS: Between 1980 and 1997, the authors prospectively studied 600 consecutive patients for the appearance of PCC-L; these patients were positive for HCV and later developed cirrhosis. The follow-up period ranged from 0 to 18.5 years (median, 7.2 years).
RESULTS: During the observation period, PCC-L developed in 14 patients (2.3%). Among these, 11 (1.8%) had cholangiocellular carcinomas and the other 3 (0.5%) had a combined type of hepatocellular and cholangiocellular carcinoma. Within the same period, hepatocellular carcinoma (HCC) developed in 206 patients (34.3%). The cumulative rates of newly diagnosed PCC-L were 1.6% at 5 years and 3.5% at 10 years, which was about 1000 times higher than the estimated incidence of PCC-L in the general population of Japan. PCC-L was treated by surgical resection in 3 patients who survived for > 3 years. However, the other 11 patients received palliative therapy or chemotherapy. The survival rates among PCC-L patients were 39.3%, 23. 6%, and 16.5% at the end of 1, 3, and 5 years, respectively, and were significantly lower than those of HCC (P = 0.0001).
CONCLUSIONS: The results of this study show a relatively high incidence of PCC-L in patients with HCV-related cirrhosis, and also show that this type of liver cancer is associated with a relatively poor prognosis. These results indicate that HCV-related cirrhosis is a major risk factor for PCC-L in Japanese patients.

Copyright 2000 American Cancer Society.
PMID 10861422  Cancer. 2000 Jun 1;88(11):2471-7.
著者: Yanming Zhou, Yanfang Zhao, Bin Li, Jiyi Huang, Lupeng Wu, Donghui Xu, Jiamei Yang, Jia He
雑誌名: BMC Cancer. 2012 Jul 16;12:289. doi: 10.1186/1471-2407-12-289. Epub 2012 Jul 16.
Abstract/Text BACKGROUND: Studies investigating the association between Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and intrahepatic cholangiocarcinoma (ICC) have reported inconsistent findings. We conducted a meta-analysis of epidemiological studies to explore this relationship.
METHODS: A comprehensive search was conducted to identify the eligible studies of hepatitis infections and ICC risk up to September 2011. Summary odds ratios (OR) with their 95% confidence intervals (95% CI) were calculated with random-effects models using Review Manager version 5.0.
RESULTS: Thirteen case-control studies and 3 cohort studies were included in the final analysis. The combined risk estimate of all studies showed statistically significant increased risk of ICC incidence with HBV and HCV infection (OR = 3.17, 95% CI, 1.88-5.34, and OR = 3.42, 95% CI, 1.96-5.99, respectively). For case-control studies alone, the combined OR of infection with HBV and HCV were 2.86 (95% CI, 1.60-5.11) and 3.63 (95% CI, 1.86-7.05), respectively, and for cohort studies alone, the OR of HBV and HCV infection were 5.39 (95% CI, 2.34-12.44) and 2.60 (95% CI, 1.36-4.97), respectively.
CONCLUSIONS: This study suggests that both HBV and HCV infection are associated with an increased risk of ICC.

PMID 22799744  BMC Cancer. 2012 Jul 16;12:289. doi: 10.1186/1471-2407-・・・
著者: J W Valle, H Wasan, P Johnson, E Jones, L Dixon, R Swindell, S Baka, A Maraveyas, P Corrie, S Falk, S Gollins, F Lofts, L Evans, T Meyer, A Anthoney, T Iveson, M Highley, R Osborne, J Bridgewater
雑誌名: Br J Cancer. 2009 Aug 18;101(4):621-7. doi: 10.1038/sj.bjc.6605211.
Abstract/Text BACKGROUND: We assessed the activity of gemcitabine (G) and cisplatin/gemcitabine (C/G) in patients with locally advanced (LA) or metastatic (M) (advanced) biliary cancers (ABC) for whom there is no standard chemotherapy.
METHODS: Patients, aged > or =18 years, with pathologically confirmed ABC, Karnofsky performance (KP) > or =60, and adequate haematological, hepatic and renal function were randomised to G 1000 mg m(-2) on D1, 8, 15 q28d (Arm A) or C 25 mg m(-2) followed by G 1000 mg m(-2) D1, 8 q21d (Arm B) for up to 6 months or disease progression.
RESULTS: In total, 86 patients (A/B, n=44/42) were randomised between February 2002 and May 2004. Median age (64/62.5 years), KP, primary tumour site, earlier surgery, indwelling biliary stent and disease stage (LA: 25/38%) are comparable between treatment arms. Grade 3-4 toxicity included (A/B, % patients) anaemia (4.5/2.4), leukopenia (6.8/4.8), neutropenia (13.6/14.3), thrombocytopenia (9.1/11.9), lethargy (9.1/28.6), nausea/vomiting (0/7.1) and anorexia (2.3/4.8). Responses (WHO criteria, % of evaluable patients: A n=31 vs B n=36): no CRs; PR 22.6 vs 27.8%; SD 35.5 vs 47.1% for a tumour control rate (CR+PR+SD) of 58.0 vs 75.0%. The median TTP and 6-month progression-free survival (PFS) (the primary end point) were greater in the C/G arm (4.0 vs 8.0 months and 45.5 vs 57.1% in arms A and B, respectively).
CONCLUSION: Both regimens seem active in ABC. C/G is associated with an improved tumour control rate, TTP and 6-month PFS. The study has been extended (ABC-02 study) and powered to determine the effect on overall survival and the quality of life.

PMID 19672264  Br J Cancer. 2009 Aug 18;101(4):621-7. doi: 10.1038/sj.・・・
著者: Juan Valle, Harpreet Wasan, Daniel H Palmer, David Cunningham, Alan Anthoney, Anthony Maraveyas, Srinivasan Madhusudan, Tim Iveson, Sharon Hughes, Stephen P Pereira, Michael Roughton, John Bridgewater, ABC-02 Trial Investigators
雑誌名: N Engl J Med. 2010 Apr 8;362(14):1273-81. doi: 10.1056/NEJMoa0908721.
Abstract/Text BACKGROUND: There is no established standard chemotherapy for patients with locally advanced or metastatic biliary tract cancer. We initially conducted a randomized, phase 2 study involving 86 patients to compare cisplatin plus gemcitabine with gemcitabine alone. After we found an improvement in progression-free survival, the trial was extended to the phase 3 trial reported here.
METHODS: We randomly assigned 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer to receive either cisplatin (25 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter on days 1 and 8, every 3 weeks for eight cycles) or gemcitabine alone (1000 mg per square meter on days 1, 8, and 15, every 4 weeks for six cycles) for up to 24 weeks. The primary end point was overall survival.
RESULTS: After a median follow-up of 8.2 months and 327 deaths, the median overall survival was 11.7 months among the 204 patients in the cisplatin-gemcitabine group and 8.1 months among the 206 patients in the gemcitabine group (hazard ratio, 0.64; 95% confidence interval, 0.52 to 0.80; P<0.001). The median progression-free survival was 8.0 months in the cisplatin-gemcitabine group and 5.0 months in the gemcitabine-only group (P<0.001). In addition, the rate of tumor control among patients in the cisplatin-gemcitabine group was significantly increased (81.4% vs. 71.8%, P=0.049). Adverse events were similar in the two groups, with the exception of more neutropenia in the cisplatin-gemcitabine group; the number of neutropenia-associated infections was similar in the two groups.
CONCLUSIONS: As compared with gemcitabine alone, cisplatin plus gemcitabine was associated with a significant survival advantage without the addition of substantial toxicity. Cisplatin plus gemcitabine is an appropriate option for the treatment of patients with advanced biliary cancer. (ClinicalTrials.gov number, NCT00262769.)

2010 Massachusetts Medical Society
PMID 20375404  N Engl J Med. 2010 Apr 8;362(14):1273-81. doi: 10.1056/・・・
著者: T Okusaka, K Nakachi, A Fukutomi, N Mizuno, S Ohkawa, A Funakoshi, M Nagino, S Kondo, S Nagaoka, J Funai, M Koshiji, Y Nambu, J Furuse, M Miyazaki, Y Nimura
雑誌名: Br J Cancer. 2010 Aug 10;103(4):469-74. doi: 10.1038/sj.bjc.6605779. Epub 2010 Jul 13.
Abstract/Text BACKGROUND: A British randomised study of gemcitabine plus cisplatin (GC) combination showed promising results in biliary tract cancer (BTC) patients. In our study, we evaluated the efficacy and safety of this combination compared with gemcitabine alone (G) in Japanese BTC patients.
METHODS: Overall, 84 advanced BTC patients were randomised to either cisplatin 25 mg m(-2) plus gemcitabine 1000 mg m(-2) on days 1, 8 of a 21-day cycle (GC-arm), or single-agent gemcitabine 1000 mg m(-2) on days 1, 8 and 15 of a 28-day cycle (G-arm). Treatments were repeated for at least 12 weeks until disease progression or unacceptable toxicity occurred, up to a maximum of 48 weeks.
RESULTS: A total of 83 patients were included in the analysis. For the GC and G-arms, respectively, the 1-year survival rate was 39.0 vs 31.0%, median survival time 11.2 vs 7.7 months, median progression-free survival time 5.8 vs 3.7 months and overall response rate 19.5 vs 11.9%. The most common grade 3 or 4 toxicities (GC-arm/G-arm) were neutropenia (56.1%/38.1%), thrombocytopenia (39.0%/7.1%), leukopenia (29.3%/19.0%), haemoglobin decrease (36.6%/16.7%) and gamma-GTP increase (29.3%/35.7%).
CONCLUSIONS: Gemcitabine plus cisplatin combination therapy was found to be effective and well tolerated, suggesting that it could also be a standard regimen for Japanese patients.

PMID 20628385  Br J Cancer. 2010 Aug 10;103(4):469-74. doi: 10.1038/sj・・・
著者: P E STEINER, J HIGGINSON
雑誌名: Cancer. 1959 Jul-Aug;12(4):753-9.
Abstract/Text
PMID 13663020  Cancer. 1959 Jul-Aug;12(4):753-9.
著者: N D Theise, R Saxena, B C Portmann, S N Thung, H Yee, L Chiriboga, A Kumar, J M Crawford
雑誌名: Hepatology. 1999 Dec;30(6):1425-33. doi: 10.1002/hep.510300614.
Abstract/Text Small, extraportal, hepatic parenchymal cells, positive for biliary-type cytokeratins, may represent hepatic stem cells, canals of Hering (CoH), and/or ductal plate remnants. We evaluated these cells 3 dimensionally in normal human liver and massive necrosis. Tissues from normal human livers and from 1 liver with acetaminophen-induced massive necrosis were serially sectioned, immunostained for cytokeratin 19 (CK19), and sequentially photographed. Images were examined to determine 3-dimensional relationships among CK19-positive cells. Immunostains for other hepatocyte and progenitor cell markers were examined. In normal livers, intraparenchymal CK19-positive cells lined up as linear arrays in sequential levels. One hundred of 106 (94.3%) defined, complete arrays within levels examined, most having 1 terminus at a bile duct, the other in the lobule, beyond the limiting plate. In massive necrosis, there were 767 individual CK19-positive cells or clusters around a single portal tract, 747 (97.4%) of which were spatially related forming arborizing networks connected to the interlobular bile duct by single tributaries. C-kit was positive in normal CoH. CK19 co-expressed with HepPar1, c-kit, and alpha-fetoprotein (AFP) in parenchymal cells in massive necrosis. Small, extraportal, biliary-type parenchymal cells represent cross-sections of the CoH that radiate from the portal tract, usually extending past the limiting plate into the proximate third of the hepatic lobule. The 3-dimensional structure of ductular reactions in massive necrosis suggests that these reactions are proliferations of the cells lining the CoH. Therefore, the CoH consist of, or harbor, facultative hepatic stem cells in humans.

PMID 10573521  Hepatology. 1999 Dec;30(6):1425-33. doi: 10.1002/hep.51・・・
著者: Louis Libbrecht, Tania Roskams
雑誌名: Semin Cell Dev Biol. 2002 Dec;13(6):389-96.
Abstract/Text The canals of Hering and bile ductules in human liver contain hepatic progenitor cells that can differentiate towards the biliary and hepatocytic lineage. Proliferation and differentiation of hepatic progenitor cells is referred to as 'activation' and this process occurs to a variable degree in almost all human liver diseases. Several studies indicate that hepatic progenitor cell activation in diseased liver is regulated by neural and neuroendocrine factors such as the vagal innervation. Analogous to oval cells in animal liver, there is evidence that human hepatic progenitor cells may be able to give rise to hepatocellular carcinoma and other liver tumors.

PMID 12468238  Semin Cell Dev Biol. 2002 Dec;13(6):389-96.
著者: C J Vessey, P M de la Hall
雑誌名: Pathology. 2001 May;33(2):130-41.
Abstract/Text The existence of a liver stem cell population has only gained credence recently, following the results of animal experiments. These cells are thought to reside in the terminal bile ductules (canals of Hering). Hepatocyte division is responsible for liver regeneration after most causes of injury. However, stem cells may contribute to hepatocyte regeneration, or even take over this role if the liver injury is severe and associated with an impairment of hepatocyte proliferation as in cirrhosis or submassive/massive necrosis, due to drugs, toxins or viruses. "Oval" cells are the descendants of the stem cells and are found in the portal and periportal regions in experimental animals within days of the liver injury. These cells proliferate to form narrow ductules, which may stain positively for biliary cytokeratins CK 19, and radiate out into the damaged parenchyma. Both in vitro and in vivo animal studies now suggest that oval cells can differentiate into bile ductular cells or hepatocytes to allow repopulation of the injured liver. As the oval cells differentiate into hepatocytes they may show positive staining for pyruvate kinase isoenzyme L-PK, albumin and alpha-fetoprotein. There is also growing evidence that bone marrow stem cells may contribute to liver regeneration. The possible involvement of hepatic stem cells in the development of dysplastic nodules, hepatocellular carcinoma and cholangiocarcinoma has been suggested but remains highly controversial. Oval cell isolation and culture techniques, together with stem cell transplantation strategies, may in the future provide novel treatments for individuals with inherited and acquired hepatic disorders.

PMID 11358043  Pathology. 2001 May;33(2):130-41.

ページ上部に戻る

戻る

さらなるご利用にはご登録が必要です。

こちらよりご契約または優待日間無料トライアルお申込みをお願いします。

(※トライアルご登録は1名様につき、一度となります)


ご契約の場合はご招待された方だけのご優待特典があります。

以下の優待コードを入力いただくと、

契約期間が通常12ヵ月のところ、14ヵ月ご利用いただけます。

優待コード: (利用期限:まで)

ご契約はこちらから