Intrahepatic cholangiocarcinoma

Japanese: 肝内胆管癌

Definition, Concept, and ClassificationThis is an epithelial malignant tumor that originates in the intrahepatic bile duct and usually develops in normal liver. It forms a grayish-white hard mass or a nodular, eight-headed mass. The macroscopic classification by the Japan Liver Cancer Study Group has three basic types: 1) mass-forming type, 2) bile duct infiltration type, and 3) intrabile duct growth type (Figure 9-12-6). The mass-forming type forms a clearly similar, localized mass in the liver parenchyma, with a clear boundary between cancerous and non-cancerous areas. The bile duct infiltration type shows branching growth along the longitudinal axis of the bile duct, involving the blood vessels and connective tissue surrounding the bile duct, and often shows dilation of the peripheral bile duct. The intrabile duct growth type shows papillary and granular growth into the bile duct lumen, but sometimes shows superficial expansion or shows the form of an intrabile duct tumor thrombus.
Clinically, tumors are classified as hilar type, which originates from the large bile duct in the hilum of the liver, and peripheral type, which originates from the peripheral intrahepatic bile duct. The hilar type often causes jaundice, but peripheral type does not show symptoms until the terminal stage, so it is often discovered late. In patients with no history of liver disease, the tumor is often detected as a mass on diagnostic imaging.
Histopathologically , adenocarcinoma predominates and often has a tubular glandular structure, but occasionally shows a papillary adenocarcinoma type. Another characteristic is the well-developed fibrous stroma. There have been occasional recent reports that hepatitis C virus infection is a risk factor for intrahepatic cholangiocarcinoma.
Macroscopically similar to intrahepatic cholangiocarcinoma, cancer originating from the bile ductules or Hering's duct is called cholangiolocellular carcinoma. Small, round tumor cells with little atypia are accompanied by abundant fibrous stroma and show a small luminal structure similar to hyperplastic bile ductules, which proliferate in an irregular anastomosing fashion. Unlike intrahepatic cholangiocarcinoma, mucus production is not observed. Some cases often have histological findings similar to hepatocellular carcinoma or intrahepatic cholangiocarcinoma.
Clinical manifestations
1) Symptoms:
Small intrahepatic bile duct cancer does not cause any symptoms. Larger cancers cause abdominal distension and fatigue.
2) Objective symptoms:
When the tumor becomes large, the liver becomes enlarged and a hard mass can sometimes be palpated.
Regarding serum biochemistry test results , about half of the cases show signs of cholestasis accompanied by high values of ALP and γ-GTP. In the hilar type, various degrees of jaundice appear depending on the degree of hilar bile duct obstruction. Regarding tumor markers, CEA and CA19-9 tend to be elevated.
Diagnostic ultrasound diagnosis of mass-forming type shows irregular borders that are octagonal or lobulated, and intrahepatic bile duct dilation on the peripheral side of the tumor is frequently seen (Figure 9-12-7). In bile duct infiltration type, it is difficult to visualize the tumor itself, but dilation of the peripheral bile duct is quite frequent. Therefore, cholangiocarcinoma is often discovered as a result of intrahepatic bile duct dilation. Sonazoid contrast ultrasound often shows hypervascularity.
CT scans of the hilar type do not show a circular shape, and often show only the dilation of the surrounding bile duct. On the other hand, peripheral type tumors are octagonal, lack a capsule, and often show irregular bumps or an octagonal shape. Traditionally, these tumors were thought to be hypovascular, but recently, dynamic CT scans have shown many of them to be hypervascular, with early darkening of the periphery and delayed enhancement of the fibrotic areas after 120 seconds (Figure 9-12-8). This is because contrast medium leaked out of the blood vessels and accumulates in the fibrotic areas. This finding is similar to the image findings of metastatic liver cancer, making differentiation difficult. The key to differentiation is that in cholangiocarcinoma, bile duct dilation is more common on the peripheral side than on the tumor mass.
On MRI, the tumor shows low signal intensity on _T1 weighted images and high signal intensity on _T2 weighted images (Figure 9-12-9), and often shows MRI findings similar to those of general tumors such as hepatocellular carcinoma and metastatic liver cancer. However, this disease is often accompanied by bile duct dilation on the peripheral side of the tumor, which can lead to the diagnosis (Figure 9-12-9). MRCP is also useful for diagnosis (Figure 9-12-10). As with dynamic CT, dynamic MRI shows mild to moderate staining of the tumor margins early on, and over time the staining spreads to the fibrotic area in the center of the tumor.
Differential diagnosis: Differentiation from metastatic liver cancer is the most important factor. Differentiation from hepatocellular carcinoma can sometimes be problematic.
Course and prognosis: The prognosis for intrahepatic cholangiocarcinoma is extremely poor. The prognosis for intrahepatic cholangiocarcinoma discovered at an unresectable stage is extremely poor. According to a follow-up study report by the Liver Cancer Study Group of Japan, the five-year survival rate is 21.0%.
Hepatic resection is the only curative treatment for peripheral bile duct cancer with limited treatment scope. Surgery is often difficult in cases of bile duct invasion or hilar cancer, but surgery is attempted whenever possible. When surgery is impossible, jaundice reduction is performed as a palliative treatment. For jaundice reduction, a stent is placed endoscopically. When internal fistula creation is difficult, percutaneous biliary drainage (PTCD) is performed.
Chemotherapy is primarily based on Gemzar (gemcitabine). Gemzar and TS-1 (TS-1) have been approved for insurance coverage for biliary tract cancer, but in Japan's biliary tract cancer regulations, intrahepatic cholangiocarcinoma is treated separately from biliary tract cancer, and strictly speaking, it is not covered by health insurance. However, overseas, in unresectable biliary tract cancer, including intrahepatic cholangiocarcinoma, it has been reported that response rates for Gemzar alone are 13-36%, and for the combination of Gemzar and cisplatin, 28-38%. [Kudo Masatoshi]
■ References
Kojiro M, Wanless IR, et al: The International Consensus Group for Hepatocellular Neoplasia: Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology, 49: 658-664, 2009.
Makuuchi M, Kokudo N, et al: Development of evidence-based clinical guidelines for the diagnosis and treatment of hepatocellular carcinoma in Japan. Hepatol Res, 38: 37-51, 2008.
Kudo M, Izumi N, et al: Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Digest Dis, 29: 339-364, 2011.

Figure 9-12-6
Macroscopic morphology of intrahepatic cholangiocarcinoma ">

Figure 9-12-6

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

定義・概念・分類
　肝内胆管から発生する上皮性の悪性腫瘍で通常正常肝から発生する．灰白色で硬い塊状ないし，結節状で八ツ頭状の腫瘤を形成する．日本肝癌研究会の肉眼分類では①腫瘤形成型，②胆管浸潤型，③胆管内発育型の3基本型がある（図9-12-6）．腫瘤形成型は肝実質に明瞭な類縁形の限局性腫瘤を形成しているもので癌部，非癌部の境界が明瞭である．胆管浸潤型は胆管周囲の血管，結合組織を巻き込みつつ，胆管の長軸方向への樹枝状進展を示しているものであり，しばしば，末梢胆管の拡張がみられる．胆管内発育型は胆管内腔へ乳頭状，顆粒状の発育を示すが，ときに表層拡大進展を示したり，胆管内腫瘍栓の形態を示す．
　臨床的には腫瘍が肝門部の太い胆管に由来した肝門部型，肝内末梢胆管に由来した末梢型に分類される．肝門部型はしばしば黄疸をきたしやすいが，末梢型は末期に至るまで症状が出現しないため，発見が遅れることが多い．肝疾患の既往がなく，画像診断で腫瘤として検出されることが多い．
病理
　組織学的には腺癌が主体を占め，管状の腺管構造をとることが多いが，ときに乳頭状腺癌の型を示す．線維性間質がよく発達していることも特徴である．C型肝炎ウイルス感染が肝内胆管癌のリスク因子であるとの報告も最近散見される．
　肉眼的に肝内胆管癌に類似するが，細胆管もしくはHering管由来の癌を細胆管細胞癌（cholangiolocellular carcinoma）と呼称する．異型に乏しい小型，類円型の腫瘍細胞が豊富な線維性間質を伴い，増生細胆管に類似する小管腔構造を示し，これらが互いに不規則に吻合するように増殖する．肝内胆管癌と異なり，粘液産生を認めない．一部には肝細胞癌，あるいは肝内胆管癌類似の組織像を伴うことが多い．
臨床症状
1）自覚症状：
小型の肝内胆管癌は全く症状がない．巨大になると腹部膨満や倦怠感を示す．
2）他覚症状：
巨大になると肝腫大，ときに硬い腫瘤を触知する．
検査成績
　血清生化学検査値としては約半数の例でALPやγ-GTPの高値を伴う胆汁うっ帯所見を示す．肝門部型では肝門部胆管閉塞の程度により種々の程度の黄疸が出現する．腫瘍マーカーではCEAとCA19-9が高値をきたしやすい．
診断
　超音波診断で腫瘤形成型では八ツ頭状，もしくは分葉状の辺縁不正な境界を示し，腫瘍末梢側の肝内胆管拡張も高率に見られる（図9-12-7）．胆管浸潤型では腫瘤そのものの描出は困難であるが，末梢胆管の拡張はかなり高率である．したがって肝内胆管拡張を契機に胆管細胞癌が発見されることが多い．ソナゾイド造影エコーでは多血性を示すことが多い．
　CTでは肝門部型では類円形を呈さず，周囲の胆管拡張所見のみを示すことが多い．一方，末梢型では八ツ頭状を呈し，被膜を有さず，不整な凹凸，あるいは八ツ頭状を示すことが多い．従来は乏血性の腫瘍と考えられていたが，最近ではダイナミックCTでは多くが多血性に描出され，早期に辺縁が濃染し，120秒以降の遅延相で線維化の部分が濃染を呈するいわゆるdelayed enhancementの所見を示す（図9-12-8）．これは血管外に漏出した造影剤が線維化の部分に貯留するためである．この所見は，転移性肝癌の画像所見と類似するために鑑別がしばしば問題となる．鑑別のポイントは腫瘤よりも末梢側の胆管拡張が胆管細胞癌の場合には多いということである．
　MRIでは腫瘍はT₁強調像では低信号，T₂強調像では高信号を示し（図9-12-9），肝細胞癌や転移性肝癌などの一般の腫瘍と同様のMRI所見を示すことが多い．しかしながら本症で腫瘍の末梢側に胆管拡張を伴うことが多いためにこれが診断のきっかけとなる（図9-12-9）．MRCPも診断に有用である（図9-12-10）．ダイナミックMRIではダイナミックCTと同様に早期に軽度から中等度に腫瘍辺縁が濃染し，時間経過とともに腫瘍中心部の線維化の部分に染まりが広がってくる．
鑑別診断
　転移性肝癌との鑑別が最も重要である．ときに肝細胞癌との鑑別が問題となることもある．
経過・予後
　肝内胆管癌の予後はきわめて不良である．生存は切除不能の段階で見つかった肝内胆管癌の予後はきわめて悪い．５年生存率は日本肝癌研究会の追跡調査報告によると21.0％である．
治療
　限局した末梢胆管癌では肝切除が唯一の根治的治療法である．胆管浸潤型，あるいは肝門部型では手術が困難な場合が多いが，可能な限り手術を試みる．手術が不可能な場合には姑息的治療として減黄術を行う．減黄術は内視鏡的にステントを留置する．内瘻化が困難な場合には経皮的に胆道ドレナージ術（PTCD）を行う．
　化学療法ではジェムザール（ゲムシタビン）を主軸とした化学療法が行われている．ジェムザール，およびティーエスワン（TS-1）が胆道癌で保険適用が認可されたが，わが国の胆道癌取扱い規約では，肝内胆管癌を胆道癌とは別に扱っており厳密な意味では保健適用となっていない．しかし，海外では，肝内胆管癌を含めた切除不能胆道癌において，ジェムザール単独で13～36％の奏効率が，ジェムザールとシスプラチンの併用で28～38％の奏効率が報告されている．［工藤正俊］
■文献
Kojiro M, Wanless IR, et al: The International Consensus Group for Hepatocellular Neoplasia:Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology, 49: 658-664, 2009.
Makuuchi M, Kokudo N, et al: Development of evidence-based clinical guidelines for the diagnosis and treatment of hepatocellular carcinoma in Japan. Hepatol Res, 38: 37-51, 2008.
Kudo M, Izumi N, et al: Management of hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version. Digest Dis, 29: 339-364, 2011.

図9-12-6
肝内胆管癌の肉眼形態">

図9-12-6

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