Hepatocellular carcinoma

Japanese: 肝細胞癌

Definition, Concept, and Classification Liver cancer is divided into primary and secondary, depending on the site of origin. Primary liver cancer is classified into hepatocellular carcinoma derived from hepatocytes, intrahepatic cholangiocarcinoma derived from bile duct cells, combined hepatocellular and cholangiocarcinoma, hepatoblastoma, undifferentiated carcinoma, bile duct cystadenocarcinoma, and others. Hepatocellular carcinoma is the most common primary liver tumor. According to the most recent survey in Japan (2004-2005), hepatocellular carcinoma and intrahepatic cholangiocarcinoma accounted for 94% and 4% of all primary liver cancers, respectively, while other liver tumors are extremely rare, accounting for less than 1% of all cases. The age-adjusted mortality rate from liver cancer per 100,000 people in men is third after lung cancer and stomach cancer, and fifth after stomach cancer, lung cancer, breast cancer, and colorectal cancer in women (according to the 2005 Ministry of Health, Labor and Welfare vital statistics).
Causes and pathogenesis Hepatocellular carcinoma is a malignant tumor derived from liver cells that develops on the basis of persistent necrosis, inflammation, and fibrosis caused by chronic hepatitis and cirrhosis, mainly due to hepatitis B or C virus. In Japan, hepatocellular carcinoma is often caused by hepatitis C, and 80-90% of patients have cirrhosis. However, the high incidence of hepatocellular carcinoma in hepatitis B and C virus infected individuals means that it is possible to set a high-risk group, and as a result, early detection is possible. This is a feature not found in other organ carcinomas. In addition, with the establishment of screening systems and advances in imaging diagnosis in recent years, many hepatocellular carcinomas tend to be small when detected. In addition, hepatocellular carcinoma was previously considered to be common in Southeast Asia and Africa, but hepatitis C infection has spread to Europe and North America, and as a result, hepatocellular carcinoma is on the rise worldwide, and international interest has been growing. Recently, advances in treatment and the introduction of new procedures such as liver transplants have led to a marked improvement in prognosis, with the 5- and 10-year survival rates also improving considerably.
Recently, there has been an increase in cancer caused by lifestyle-related diseases such as diabetes and lipid deficiency, and non-alcoholic steatohepatitis (NASH), resulting in an increase in non-B, non-C liver cancer.
In hepatitis C, the annual cancer incidence rate is 0.5% in F1 cases with mild fibrosis, 1.5% in F2 cases, 3% in F3 cases, and 7-8% in F4 cases, with the cancer incidence rate increasing with the severity of fibrosis. On the other hand, it has also been found that the cancer incidence rate is higher in cases of persistent inflammation with high ALT, AST, etc.
The pathological macroscopic morphology of hepatocellular carcinoma is divided into five types: ① small nodular unclear type, ② simple nodular type, ③ simple perinodular proliferation type, ④ multinodular fusion type, and ⑤ invasive type. Histological classification is divided into four types: ① well-differentiated type, ② moderately differentiated type, ③ poorly differentiated type, and ④ undifferentiated type. Histological structure is divided into four types: ① trabecular type, ② pseudoductal type, ③ solid type, and ④ sclerosing type.
Early hepatocellular carcinoma is defined as a lesion that is recognized as a nodule that stands out from the surrounding area in a liver showing chronic hepatitis or cirrhosis, where the underlying hepatic architecture has not been significantly destroyed with the naked eye, and in which portal tract components and pseudolobular stroma are found within the nodule, with increased cellular density, and regional structural atypia such as acinar-like or pseudoductal structures, disruption of the cord-like arrangement, or irregularity, and sometimes interstitial infiltration. Such early hepatocellular carcinoma is difficult to diagnose both histologically and by imaging.
Pathophysiology Hepatocellular carcinoma (HCC) is thought to develop in multiple stages, from precancerous lesions to borderline lesions, early hepatocellular carcinoma, and finally to conventional hepatocellular carcinoma. Among these, large regenerative nodules associated with liver cirrhosis, low-grade dysplastic nodules (LGDN), high-grade dysplastic nodules (HGDN), and early hepatocellular carcinoma are considered to be precancerous lesions, borderline lesions, and early lesions, and early hepatocellular carcinoma is understood to be a nodule that precedes typical HCC. Among these, large regenerative nodules have a microscopic histological appearance similar to that of the surrounding liver tissue, LGDN are nodules with a moderate increase in cell density compared to the surrounding liver tissue but no structural atypia, and HGDN are nodules with areas of high cell density. Early HCC is characterized by a cell density approximately twice that of the surrounding liver tissue, and is accompanied by fatty changes and clear cell transformation. This concept of early HCC originated in Japan and is now accepted worldwide. In addition, LGDN corresponds to adenomatous hyperplasia in the WHO classification, and HGDN corresponds to atypical adenomatous hyperplasia.
Screening The "Evidence-Based Guidelines for the Treatment of Liver Cancer," revised in 2009, defines hepatitis B and C hepatitis as "ultra-high risk" for liver cancer, and recommends screening for these patients with ultrasound examinations and tumor marker measurements (AFP, AFP-L3 fraction, PIVKA-II) every 3-4 months, with optional dynamic CT or dynamic MRI every 6-12 months. In addition, patients with cirrhosis due to 1) chronic hepatitis B, 2) chronic hepatitis C, or 3) other causes are defined as "high risk" for liver cancer, and recommends ultrasound examinations and measurements of three types of tumor markers every 6 months. With this screening method, an increasing number of liver cancers are being detected at a high rate at a small stage where they can be cured.
Clinical symptoms and physical findings: Most hepatocellular carcinoma patients do not show symptoms until they progress to advanced stages. Usually, patients show symptoms and clinical findings of coexisting liver cirrhosis.
In terms of physical findings, in addition to those due to cirrhosis, if the tumor grows significantly, liver enlargement, a palpable mass, tenderness, and vascular murmurs due to arterioportal shunts may be observed. If the tumor compresses the inferior vena cava, edema of the lower limbs alone and ascending collateral circulation in the abdominal wall may be observed. In any case, such highly advanced cancers account for approximately 5% of all liver cancers, and it is rare to encounter patients who exhibit typical symptoms of advanced liver cancer.
In advanced cancer, increases in LDH, ALP, γ-GTP, etc. are seen. Also, positive findings for the hepatocellular carcinoma tumor markers AFP, PIVKA-II, and AFP-L3 fraction are often seen.
Diagnosis A definitive diagnosis of liver cancer is made based on 1) the presence of chronic liver damage or cirrhosis caused by hepatitis B virus or hepatitis C virus, 2) abnormal values with a tendency for tumor markers to continually rise, and 3) typical imaging findings. Early liver cancer can sometimes be diagnosed by imaging diagnosis, but in many cases a biopsy is essential.
Early detection of liver cancer has become more common through regular screening with diagnostic imaging. Approximately 50% of liver cancers are found at a stage where curative treatment is possible (less than 3 cm3).
1) Ultrasound examination:
Ultrasound examinations are non-invasive and have excellent time and spatial resolution, making it possible to detect tumors with a diameter of just a few millimeters. Therefore, ultrasound is generally used for initial screening. In that sense, it plays an important role in the early detection of hepatocellular carcinoma. However, because B-mode ultrasound examination alone is insufficient for differential diagnosis, contrast CT or MRI is often required. However, if typical images are observed using ultrasound alone, the diagnosis is hepatocellular carcinoma. The characteristic ultrasound findings are: 1) mosaic pattern: the tumor is composed of various tissue structures, and therefore presents a mosaic-like echo of a mixture of high and low echoes; 2) peripheral hypoechoic zone (halo): a finding reflecting the capsule structure characteristic of hepatocellular carcinoma (Fig. 9-12-1A); 3) lateral acoustic shadow: acoustic shadow seen parallel to the ultrasound beam on the side of the tumor (also believed to be based on the capsule); 4) nodule-in-nodule pattern: a pattern in which a clearly demarcated nodule is seen within a single tumor; 5) septum: a septum-like linear structure seen within the tumor; 6) in the case of advanced cancer: portal vein tumor thrombus or hepatic vein tumor thrombus is seen. Traditionally, ultrasound examinations have often been performed in B mode only during screening, but by using a color Doppler examination in combination, it is possible to detect blood flow within the nodule. Recently, the appearance of intravenous contrast agents (Sonazoid) has improved the differential diagnosis ability based on the hemodynamics of tumors, and it has become possible to obtain definitive diagnostic ability equivalent to CT and MRI (Fig. 9-12-1B, C, D). However, one of the disadvantages of ultrasound is that only one or two nodules can be evaluated with a single intravenous injection. However, since the sensitivity of detecting blood flow within nodules is superior to that of CT and MRI, it is used as a precision examination for detecting blood flow within nodules. The disadvantages of ultrasound include the presence of blind spots, dependence on the skill of the surgeon, poor visualization after surgery and in obese patients, and difficulty in detecting small tumors when coarse liver parenchymal echoes are observed. After intravenous injection, hepatocellular carcinoma is immediately visualized as a defect because arterial blood flow flows into the nodule earlier and more strongly than the surrounding area, and washout occurs in the post-vascular phase as with CT, and in the post-vascular phase, hepatocellular carcinoma is phagocytosed by Kupffer cells, resulting in the image of the defect. Sonazoid is used as an ultrasound contrast agent. Defect re-perfusion imaging, which allows re-injection of Sonazoid into defects detected in the post-vascular phase, is effective in screening, diagnosis, and treatment support.
2) CT:
Plain CT scans have little diagnostic value for hepatocellular carcinoma. A contrast agent is rapidly injected intravenously, and dynamic CT scans are usually performed using a multi-detector raw CT (MDCT) equipped with 8, 16, or 64 detector rows. A characteristic contrast CT finding of hepatocellular carcinoma is that the tumor appears as a high-attenuation area in the artery-dominant phase, and as the contrast agent is washed out and becomes a low-attenuation area in the portal vein-dominant and equilibrium phases (Figure 9-12-2). However, in tumors 2 cm or less in diameter, early hepatocellular carcinoma, precancerous lesions, and borderline lesions may also be mixed in, and so low-attenuation areas may only be seen in the portal vein and equilibrium phases, and in such cases further detailed examination is required.
3) MRI:
There are four types of MRI for diagnosing hepatocellular carcinoma: 1) plain MRI, 2) dynamic MRI using gadolinium contrast agent, 3) SPIO-MRI using supermagnetic iron contrast agent, which is a negative contrast agent, to depict tumors without Kupffer cells as high signal areas, and 4) Gd-EOB-MRI, which is taken up by transporters (OATP8 or OATP1B3) in the hepatocyte membrane. Typical hepatocellular carcinoma shows low signal in _T1 weighted images and high signal in _T2 weighted images (Figure 9-12-3). Dynamic MRI findings show high signal in the arterial dominant phase and low signal in the portal vein equilibrium phase, showing contrast patterns almost similar to those of dynamic CT. In SPIO-MRI, classical hepatocellular carcinoma does not have Kupffer cells, and hepatocellular carcinoma is depicted as a high signal area because SPIO is taken up by the surrounding liver. EOB-MRI is capable of imaging both blood pool images and the hepatocyte phase from 20 minutes onwards, making it an extremely excellent modality that can diagnose both hemodynamics and the function of OATP8. Typical hepatocellular carcinoma shows hypervascularity in the arterial phase, washout in the portal equilibrium phase, and defects in the hepatocellular phase (Figure 9-12-4). Early hepatocellular carcinoma shows hypovascularity, but is characterized by reduced signals (defective images) in the hepatocellular phase.
4) Angiography:
In hepatic arteriography, superselective hepatic arteriography, in which a catheter is selectively inserted into the hepatic artery to the very peripheral side, is widely used. Since hepatocellular carcinoma, except for early-stage liver cancer, is controlled by arterial blood, angiography is useful for differential diagnosis from other tumors and diagnosis of the extent of progression. In addition, arterial portography is used to diagnose the presence or absence of portal vein invasion. Therefore, angiography is an important test for selecting a treatment method and predicting prognosis. However, since angiography alone has limitations in detecting and differentiating small lesions such as those detected in recent years, intra-arterial CT (CT with hepatic arteriography (CTHA) and CT with arterial portography (CTAP)) is often performed for the purpose of preoperative evaluation. Characteristic findings of hepatocellular carcinoma include vascular proliferation, arterial tumor vessels, tumor hyperplasia, AP shunt, and thread and streak sign in portal vein tumor thrombus.
Differential diagnosis: Differentiation from cholangiocarcinoma and metastatic liver cancer is important, but when typical findings are present, differentiation is easy.
As complications progress, they may be accompanied by rupture of esophageal and gastric varices, intraperitoneal bleeding due to rupture of liver cancer, jaundice, ascites, and liver failure.
Course and prognosis: Because hepatocellular carcinoma often metastasizes intrahepatically and develops into multiple centers, the 5-year recurrence rate is high at 80%, even with curative treatment. According to a follow-up survey report by the Liver Cancer Study Group of Japan, the 5-year survival rates are 73.0% for stage I, 59.7% for stage II, 39.5% for stage III, 21.4% for stage IV A, and 16.5% for stage IV B.
Treatment and Prevention Treatment methods for hepatocellular carcinoma are determined based on a comprehensive assessment of two factors: the stage of the tumor and hepatic reserve capacity. Figure 9-12-5 shows the treatment algorithm based on the consensus of the Japan Society of Hepatology (revised in 2010). This treatment plan does not contradict the other evidence-based treatment algorithm (revised in 2009) that exists in Japan, but the difference is that the former is a simple, evidence-based algorithm, while the algorithm in Figure 9-12-5 is a more realistic algorithm. Essentially, both are similar in that the treatment plan is determined based on hepatic reserve capacity, tumor size, number of tumors, vascular invasion, and distant metastasis.
1) Excision:
Hepatic resection is selected when liver function is good and the number of tumors is solitary or three or less and confined to the periphery. Although it is the most reliable treatment method, it is highly invasive, and even if the initial localized lesion can be completely removed, the recurrence rate in other areas is the same as with local treatment, and the final long-term prognosis is not significantly different from local treatment in the case of solitary, small tumors.
2) Radiofrequency ablation (RFA):
This method involves inserting a coagulation needle for radiofrequency ablation into a tumor under ultrasound guidance to ablate the tumor. RFA uses high-frequency waves with a long wavelength of 450 to 480 kHz. Tumors of approximately 3 cm in size can be completely treated with a single ablation, and this is currently the mainstream percutaneous treatment. There are two types of coagulation needles: a single needle with internal cooling water circulation and an expanding needle. RFA can be performed not only percutaneously, but also laparoscopically, thoracoscopically, and during surgery.
3) Percutaneous ethanol injection therapy (PEIT):
This method is suitable for tumors with a diameter of 3 cm and a maximum of 3 foci, in which the tumor is punctured with a fine needle under ultrasound guidance and 99.9% ethanol is directly injected to cause coagulation necrosis of the cancerous area. Complete necrosis is achieved at a high rate, but recent comparative studies with radiofrequency therapy have shown that radiofrequency therapy has a better long-term prognosis than PEIT, and radiofrequency therapy is now being used as the focus of local treatment.
4) Percutaneous microwave coagulation therapy (PMCT):
MCT is a method of cauterizing tumors using radiofrequency waves with a shorter wavelength (2450 MHz) than RFA. The coagulation range is narrower than that of RFA, and there are many complications, so with the advent of RFA, MCT has become less used recently, except in some facilities and during laparotomy.
5) Transcatheter arterial chemoembolization (TACE):
This is a treatment method in which a catheter is selectively inserted into the artery that controls the tumor using the Seldinger technique, and a suspension of a mixture of lipiodol and an anticancer drug is injected, followed by embolization with gelatin sponge or Gelpart, leading to ischemic necrosis of the tumor. This treatment is usually suitable for cases in which there is no tumor thrombus in the main portal vein or primary branches, and no complications such as refractory ascites or jaundice. It is also suitable for cases with multiple lesions. For large liver cancers, the therapeutic effect is improved by adding RFA after TACE.
6) Radiation therapy:
Radiation therapy is often used for bone metastases to relieve pain. For primary lesions, radiation therapy is appropriate when liver damage is mild and a single tumor of approximately 5-10 cm in size is localized within the liver. Linear accelerator irradiation is usually used, but treatments using proton beams and heavy ion beams have recently been attempted, and have produced good results, but there is a drawback in that treatment facilities are limited, and it is still in the experimental stage.
7) Hepatic arterial infusion chemotherapy (HAIC):
Arterial infusion chemotherapy is being performed for advanced liver cancer with portal vein tumor thrombus. The Liver Cancer Treatment Guidelines also recommend this chemotherapy alongside TACE for liver cancer with four or more treatment algorithms. The two main regimens used are low-dose FP therapy, which combines cisplatin (CDDP) and 5FU, and interferon-combined arterial infusion chemotherapy, which combines arterial infusion of 5FU with subcutaneous interferon injection. Lipiodol TAI, which involves frequent intra-arterial infusion, is also being performed.
8) Systemic chemotherapy:
Cytotoxic systemic chemotherapy is not usually performed as standard treatment, and remains in the experimental stage. However, the recently developed molecular targeted drug sorafenib is also being actively used in liver cancer. Sorafenib exerts antitumor effects by selectively inhibiting the receptor tyrosine kinases of VEGF and PDGF, which are involved in angiogenesis, and RAF, a member of the MAP kinase system involved in cell proliferation, thereby prolonging the prognosis of patients. Sorafenib is intended for patients with 1) advanced liver cancer accompanied by distant metastasis or vascular invasion, and 2) Child-Pugh A liver cancer who are refractory to TACE or intra-arterial chemotherapy.
9) Liver transplantation:
In Europe and the United States, liver transplantation is a well-established treatment for liver cancer, but in Japan, deceased donor liver transplants are extremely rare due to a shortage of deceased donors. However, in Japan, living donor liver transplants are actively performed. This is a major difference from Europe and the United States, where deceased donor liver transplants are the standard treatment. In 2005, there were 3,246 living donor liver transplants in Japan, of which 479 (15%) were for liver cancer. Living donor liver transplantation is an excellent treatment method that can cure both liver cancer and cirrhosis, the root cause of liver cancer, in one go, and the five-year survival rate in Japan is extremely good at 80%.
10) Interferon treatment after radical cure for liver cancer:
Currently, interferon therapy is being actively performed on patients with hepatitis C after liver resection or radiofrequency therapy, as it is known that eliminating the virus through interferon therapy markedly improves the prognosis. It has also been reported that relatively long-term administration of interferon improves the prognosis of patients after the cure of liver cancer, even if a remarkable virological response is not achieved, and this is currently being performed as a general medical practice.
Definition/ConceptA rare benign epithelial tumor that is composed of cells similar to normal hepatocytes and occurs in non-cirrhotic livers. It is most common in women aged 20 to 40 years, and is associated with long-term use of oral contraceptives in women and anabolic hormones in men. Pathologically, it occurs in normal liver, is mostly solitary, and is relatively soft. Tumor diameters range from approximately 1 cm to 30 cm. The cut surface is pale reddish brown to grayish white in appearance and is almost uniform, with a clear border with the surrounding liver tissue, and large adenomas have a thin fibrous capsule. There are no portal veins or bile ducts within the tumor, and partial necrosis or hemorrhagic foci are often found.
Cause and pathogenesis: It has been reported that there is a close relationship with the use of oral contraceptives and that it occurs in conjunction with type 1 glycogen storage disease (von Gierke disease).
Epidemiology: It is extremely rare in Japan, but relatively common in Europe and the United States.
Diagnosis: It is often discovered due to intraperitoneal bleeding within the tumor or due to tumor rupture, accompanied by abdominal pain. In cases where there is no intratumoral bleeding, the tumor is visualized as a uniformly hyperechoic lesion on ultrasound, and as a uniformly hypervascular lesion on contrast CT and angiography. The tumor cross-section image is relatively uniform, and no fibrous capsule is observed. However, in cases where there is intratumoral bleeding, a high absorption area is seen on plain CT, and a high signal is seen on _T1- weighted MRI images. The possibility of this disease should be considered in cases where the patient is a young woman, the patient is negative for hepatitis B and C viruses, and the patient has developed in a normal liver.
Differential diagnosis: Differentiation from hepatocellular carcinoma, focal nodular hepatic hyperplasia, or angiomyolipoma may be required. In particular, differentiation from hepatocellular carcinoma is impossible based on diagnostic imaging.
Treatment: If oral contraceptives or anabolic hormones are being taken, they should be discontinued, and if tumor bleeding is observed, emergency surgical resection is indicated. Since there is also thought to be a malignant subtype, if a biopsy reveals a hepatocellular adenoma, there is a risk of spontaneous tumor rupture, so basically the patient is a candidate for resection.
(3) Focal nodular hyperplasia
Definition and Concept: In the WHO classification, focal nodular hyperplasia is classified as a tumor-like lesion, and is seen in women aged 20 to 50 years as a solitary superficial mass measuring 5 cm in diameter or less in the non-cirrhotic liver. Pathological characteristics include a central scar made of collagen fibers, and the lesion is classified as coarse nodular by fibrous septa radiating toward the periphery. Histologically, there is no atypia in the cells, and the central scar shows blood vessels with abnormal wall thickening and proliferation of small bile ducts accompanied by inflammatory cell infiltration. Clinically, the lesion is asymptomatic. Focal nodular hyperplasia is considered to be a hamartoma or vascular malformation and an associated reactive lesion, rather than a hepatic neoplasm. Unlike hepatocellular adenoma, it is now generally believed that oral contraceptive use is not a cause.
Epidemiology: Compared with hepatocellular adenoma, its frequency in Japan is overwhelmingly higher.
Diagnostic imaging findings: Ultrasound examinations show low to iso-echoic areas relatively close to the surrounding liver parenchyma, and may show a low-echoic area in the center that resembles a stellate scar. Plain CT often shows nodular low to iso-density areas, while contrast CT shows high-density areas in the early stage and iso-density areas in the later stage, with a low-density area in the center that corresponds to the stellate scar. MRI often shows almost iso-signal signals in _T1- weighted images and iso-signal to slightly high-signal signals in T2 _- weighted images. Because the tumor contains Kupffer cells, contrast medium is taken up into the tumor in SPIO-MRI or Kupffer phase contrast ultrasound using Sonazoid, resulting in iso-signal signals with the surrounding liver. Angiography shows the tumor as a clearly demarcated, blood-rich mass (hypervascular nodule), and is characterized by the appearance of a spoke wheel appearance with tortuous and expanded nutrient arteries penetrating the tumor and heading toward the periphery. Contrast-enhanced ultrasound examination reveals characteristic findings of blood flow in the center of the tumor in the arterial phase, followed by rapid staining toward the tumor periphery and uptake in the Kupffer phase.
Diagnosis: If a hypervascular tumor with a spindle-shaped structure is detected in various images of a normal liver, and the presence of Kupffer cells is confirmed by Sonazoid contrast ultrasound, the diagnosis of this disease is not difficult.
Prior to treatment , differentiation from hepatocellular carcinoma was problematic, but recently it has often been definitively diagnosed. Once a definitive diagnosis is made, treatment is no longer necessary.
(4) Hepatic angiomyolipoma (angiomyolipoma)
Definition/Concept Hepatic angiomyolipoma is a benign tumor composed of three components: fat, blood vessels, and smooth muscle. If there is a vascular component, it is hypervascular, and if there is a fatty component, it will be low signal on plain CT and high echo on ultrasound. In typical cases, it will show high signal on _T1 weighted images and low signal on opposed phase _T1 weighted images. However, when there is a small amount of fatty component, diagnosis is somewhat difficult. HMB-45 staining of biopsy specimens is specific and can be used as evidence for a definitive diagnosis. [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 9-12-5
Hepatocellular carcinoma treatment algorithm based on the consensus proposed by the Japan Society of Hepatology

Figure 9-12-5

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

Japanese:

定義・概念・分類
　肝癌は発生母地により原発性と続発性に分けられる．原発性肝癌は肝細胞由来の肝細胞癌（hepatocellular）と胆管細胞由来の肝内胆管癌（胆管細胞癌，cholangiocellularcarcinoma），混合型肝癌（combined hepatocellular and cholangiocarcinoma），肝芽腫（hepatoblastoma），未分化癌，胆管囊胞腺癌（bile duct cystadenocarcinoma），その他に分類される．肝細胞癌は原発性肝腫瘍の中では最も頻度が高い．わが国の最新の調査（2004～2005年）では肝細胞癌，肝内胆管癌はそれぞれ原発性肝癌全体の94％，4％を占めるが，ほかの肝腫瘍は全体の1％以下できわめてまれである．肝癌による年齢調整死亡率は男性では人口10万人あたり肺癌・胃癌についで第3位，女性では胃癌・肺癌・乳癌・大腸癌についで第5位である（2005年厚生省人口動態統計による）．
原因・病因
　肝細胞癌は主としてB型あるいはC型肝炎ウイルスに伴う慢性肝炎，肝硬変などの持続性壊死・炎症および線維化をベースに発癌をきたす肝細胞由来の悪性腫瘍である．日本ではC型肝炎に基づく肝細胞癌が多いため，その80～90％に肝硬変を併存している．しかしながら，B型肝炎およびC型肝炎ウイルス感染者から高率に発癌するということは逆にハイリスク群の設定が可能ということであり，結果として早期発見が可能であるというのも特徴の1つである．これはほかの臓器の癌腫にはない特徴の1つである．また，近年のスクリーニングシステムの確立および画像診断の進歩により多くの肝癌は小型で発見される傾向にある．また，従来より肝癌は東南アジアならびにアフリカに多い癌腫とされていたが，C型肝炎感染がヨーロッパや北米にも広がり，その結果，肝細胞癌は世界的にも増加傾向にあり，国際的に大いに関心が高まってきている．最近では治療法の進歩あるいは肝移植などの新しい手技の導入などにより，予後の改善が著しく5年生存率や10年生存率もかなり改善してきた．
　最近，糖尿病や脂渇などの生活習慣病，非アルコール性脂肪性肝炎（NASH）などからの発癌も増加しており，その結果として非B非C肝癌が増加してきている．
　C型肝炎においては，線維化の程度が軽いF1症例では年率発癌率0.5％，F2症例では年率1.5％，F3症例では年率3％，F4症例では年率7～8％の発癌率であり，線維化が強いほど発癌率が高くなる．一方，ALT，ASTなどが高い炎症の持続例ほど発癌率が高いことも判明している．
病理
　肝細胞癌の病理肉眼形態は①小結節不明瞭型，②単純結節型，③単純結節周囲増殖型，④多結節癒合型，⑤浸潤型の5型に分けられる．組織分類は，①高分化型，②中分化型，③低分化型，④未分化型の4型に分けられる．組織構造については①索状型，②偽腺管型，③充実型，④硬化型の４型に分けられる．
　早期肝細胞癌は慢性肝炎，肝硬変を示す肝臓の中に肉眼的に背景の肝構築を大きくは破壊していないが，結節として周囲より際立った病変として認識されるもののうち，結節内に門脈域の成分，および偽小葉間質が認められながら，細胞密度が増大し，腺房様あるいは偽腺管構造，索状配列の断裂，不規則化などの構造異型が領域性をもってみられ，ときに間質の浸潤を有するものを早期肝細胞癌として定義している．このような早期肝細胞癌は組織学的にもあるいは画像的にも診断が困難である．
病態生理
　肝細胞癌は多段階発癌を示し，前癌病変から境界病変，早期肝癌を経て通常型肝癌へと至ると考えられている．そのうち，肝硬変に伴う大再生結節，low-grade dysplastic nodule（LGDN），high-grade dysplastic nodule（HGDN），早期肝癌の4つが前癌病変および境界病変・早期病変として位置づけられ，早期肝癌は典型的肝細胞癌の前段階の結節として理解されている．このうち，大再生結節は顕微鏡的には周囲肝組織と同様の組織像であり，LGDNは周囲肝組織に比して細胞密度の中等度の増大はあるが，構造異型はみられない結節，HGDNは細胞密度の高度な部分を有する結節である．早期肝細胞癌は細胞密度が，周囲肝組織の約2倍以上で，かつ脂肪化，淡明細胞化を伴うものである．早期肝細胞癌のこのような概念は日本から発信され，現在世界的に受け入れられている概念となっている．なお，LGDNはWHO分類の腺腫様過形成に相当し，HGDNは異型腺腫様過形成に相当する．
スクリーニング
　2009年に改訂された「科学的根拠に基づく肝癌診療ガイドライン」ではB型肝硬変，C型肝硬変を肝癌の「超高危険群」と定義し，これらに対しては3～4カ月ごとの超音波検査と腫瘍マーカー（AFP，AFP-L3分画，PIVKA-Ⅱ）測定にてスクリーニングを行い，さらに6～12カ月ごとのダイナミック CTもしはダイナミックMRIをoptionalに行うことが推奨されている．また，①B型慢性肝炎，②C型慢性肝炎，③その他の原因による肝硬変を「肝癌の高危険群」と定義し，これらに対しては6カ月ごとの超音波検査と3種の腫瘍マーカー測定を推奨している．このスクリーニング法により肝癌は高率に小型で根治的治療可能な段階で検出する例が増加してきている．
臨床症状・身体所見
　肝細胞癌は多くは進行癌になるまではほとんどは症状を有さない．通常は併存する肝硬変の症状や臨床所見を示す．
　身体的所見としては肝硬変に基づく所見以外に腫瘍が著しく増大すると肝腫大，腫瘤触知，圧痛，動門脈シャントに伴う血管雑音が認められることがある．腫瘍による下大静脈の圧迫がもたらされると下肢のみの浮腫や腹壁の上行性の側副血行路がみられる．いずれにしてもこのような高度進行癌は肝癌全体の5％程度であり，典型的な進行肝癌の症状を呈する患者に遭遇することの方が少ない．
検査成績
　進行癌では，LDH，ALP，γ-GTPなどの上昇がみられる．また肝細胞癌の腫瘍マーカーAFP，PIVKA-Ⅱ，AFP-L3分画のいずれかの陽性所見を認めることが多い．
診断
　肝癌の確定診断は①B型肝炎ウイルス，C型肝炎ウイルス由来の慢性肝障害もしくは肝硬変の存在，②腫瘍マーカーの持続上昇傾向を伴う異常値，③典型的な画像所見，により確定診断される．早期肝癌の診断については画像診断にて可能な場合もあるが，多くの場合は生検診断が必須である．
　画像診断による定期的スクリーニングにより肝癌は早期に発見されることが多くなってきている．約50％の肝癌が根治的治療の可能な段階（3 cm3個以下）で見つかることが多い．
1）超音波検査：
超音波検査は非侵襲的でかつ時間分解能，空間分解能にすぐれるため，直径数mm程度の腫瘤の検出も可能である．したがって，一般的に最初のスクリーニングには超音波が行われることが多い．その意味で肝細胞癌の早期発見には重要な役割を果たしている．ただし，Bモードの超音波検査のみでは鑑別診断が十分ではないため，造影CTやMRIなどを必要とする場合が多い．しかしながら，超音波のみにて典型的な像を呈せば肝細胞癌と診断される．その特徴的な超音波所見とは①モザイクパターン：腫瘍がさまざまな組織構造から構築されるために高エコー，低エコーなどの混合したモザイク状のエコーを呈する，②辺縁低エコー帯（ハロー，halo）：肝細胞癌に特徴的な被膜構造を反映する所見（図9-12-1A），③側方音響陰影：腫瘍の側方に超音波ビームと平行してみられる音響陰影（これも被膜に基づくものとされている），④nodule-in-noduleパターン：1つの腫瘤内にさらに境界明瞭な結節がみられるパターン，⑤隔壁：腫瘤内にみられる隔壁様の線状構造，⑥進行癌の場合：門脈腫瘍栓や肝静脈腫瘍栓などがみられる，などである．従来，超音波検査はスクリーニングの時にBモードのみが行われることが多いが，カラードプラ検査を併用することにより結節内の血流も検出することが可能である．さらに最近では経静脈性造影剤（ソナゾイド）の登場により腫瘍の血行動態からみた鑑別診断能が向上し，CTやMRIと同等の確定診断能を有するまでになってきた（図9-12-1B，C，D）．しかしながら，一回の静注検査により一，二結節のみの評価しかできないのが超音波の欠点である．ただし，結節内の血流検出感度はCTやMRIにすぐれるため，むしろ結節内血流の検出の点においては精密検査としての使われ方がなされている．超音波の欠点としては死角の存在，術者の技量に依存すること，手術後や肥満例では描出が不良となること，粗糙な肝実質エコーを示す場合には，小腫瘤を検出しにくい，などの問題点がある．　肝細胞癌は静注後速やかに結節内に動脈血流が周囲よりも早期にまた強く流入し，後血管相ではCTと同様にwash-outが起こり，post-vascular phase（後血管相）ではKupffer細胞に貪食されるため，肝細胞癌は欠損像として描出される．超音波造影剤としてはソナゾイドが使われる．ソナゾイドのpost-vascular phaseで欠損を示したものに対して再静注を行って診断するdefect re-perfusion imageによりスクリーニング，診断，治療支援などに威力を発揮する．
2）CT：
CTは単純CTでは肝細胞癌の診断意義はほとんどない．造影剤を急速静注し，8列，16列，あるいは64列の検出器を備えたmulti-detector raw CT（MDCT）によるダイナミックCTが通常行われる．ダイナミックCTでは動脈優位相で腫瘍は高吸収域，門脈優位相および平衡相では造影剤がwash-outされて低吸収域になることが特徴的な肝細胞癌の造影CT所見である（図9-12-2）．しかしながら，腫瘍径2 cm以下においては早期肝細胞癌や前癌病変，境界病変も混じってくるため，門脈相や平衡相でのみで低吸収域として見られることがあり，このような場合にはさらに精密検査が必要である．
3）MRI：
肝細胞癌のMRI診断としては①単純MRI，②ガドリニウム造影剤によるダイナミックMRI，③陰性造影剤である超磁性体鉄造影剤を使ってKupffer細胞を有さない腫瘍を高信号域として描出するSPIO-MRI，④肝細胞膜のトランスポーター（OATP8またはOATP1B3）に取り込まれるGd-EOB-MRI，の4種類がある．典型的肝細胞癌はT₁強調像で低信号，T₂強調像で高信号を示し（図9-12-3），ダイナミックMRI所見では動脈優位相で高信号，門脈平衡相で低信号を示すことであり，ダイナミックCTとほぼ同様の造影パターンを示す．SPIO-MRIでは古典的肝細胞癌はKupffer細胞を有さず，周囲肝にSPIOが取り込まれるために肝癌は高信号領域として描出される．EOB-MRIはblood pool imageと20分以降の肝細胞相を両方撮像することが可能で血流動態とOATP8の機能の両方を診断できるきわめてすぐれたモダリティである．典型的肝細胞癌は動脈相で多血性，門脈平衡相でwash-outを示し，肝細胞相で欠損を示す（図9-12-4）．早期肝細胞癌では乏血性を示すが，肝細胞相では信号低下（欠損像）を示すのが特徴である．
4）血管造影：
肝動脈造影では肝動脈のかなり末梢側まで選択的にカテーテルを挿入する超選択的肝動脈造影が広く行われている．肝細胞癌は早期肝癌を除き，動脈血支配であるため，ほかの腫瘍との鑑別診断・進展度診断に血管造影は有用である．また経動脈性門脈造影により門脈浸潤の有無の診断が行われる．したがって血管造影は治療法の選択，予後の予測に重要な検査である．ただし，近年検出されるような小病変の検出や鑑別には血管造影のみでは限界があるため，術前評価の目的では動注CT（肝動脈造影下CT（CTHA），および経動脈性門脈造影下CT（CTAP））が行われることが多い．肝細胞癌の特徴的所見としては血管増生，動脈性腫瘍血管，腫瘍濃染，APシャント，門脈腫瘍栓内のthread and streak signなどがあげられる．
鑑別診断
　胆管細胞癌，転移性肝癌との鑑別が重要であるが典型所見を呈した場合は，その鑑別は容易である．
合併症
　進行すれば食道胃静脈瘤破裂，肝癌破裂による腹腔内出血，黄疸，腹水，肝不全などを伴うことがある．
経過・予後
　肝細胞癌は肝内転移および多中心発癌が多いため５年での再発率は根治的に治療しても80％と高い．5年生存率は日本肝癌研究会追跡調査報告によるとステージⅠ 73.0％，ステージⅡ 59.7％，ステージⅢ 39.5％，ステージⅣA 21.4％，ステージⅣB 16.5％である．
治療・予防
　肝細胞癌の治療法は腫瘍の進行度，肝予備能の2点を総合的に判断して決定される．図9-12-5に日本肝臓学会のコンセンサスに基づく治療アルゴリズム（2010年改訂版）を示す．日本にもう1つ存在する科学的根拠に基づく治療アルゴリズム（2009年改訂版）とは互いに矛盾しない治療方針であるが，前者はシンプルでエビデンスに基づくアルゴリズムであり，図9-12-5の方はより現実に則したアルゴリズムという違いがある．基本的には肝予備能，腫瘍径，腫瘍数，血管浸潤，遠隔転移によって治療方針が決定されることは同様である．
1）切除：
肝切除は肝機能が良好で腫瘍個数が単発，もしくは3個以内程度で辺縁に限局する場合に選択される．最も確実な治療法ではあるが侵襲が大きい点と，たとえ初回の局在病巣を完全に切除し得ても他部位への再発率は局所治療と変わらず，最終的な長期予後は単発小型の場合には局所治療法と大きくは変わらない．
2）ラジオ波焼灼療法（radiofrequency ablation：RFA）：
超音波ガイド下にラジオ波焼灼のための凝固針を腫瘍内に挿入し，腫瘍を焼灼する方法である．RFAは450～480 kHzの長い波長の高周波を使用している．3 cm程度の腫瘍であれば完全に一回の焼灼で治療することができるため，現在経皮的治療の主流となっている．凝固針には内部冷却水還流下のsingle needleと展開針の二種類がある．RFAは経皮的のみならず腹腔鏡下，胸腔鏡下，術中にも行われることがある．
3）エタノール注入療法（percutaneous ethanol injection therapy：PEIT）：
腫瘍径3 cm個数3病巣以内の場合が適応であり，超音波ガイド下に細径針を用いて腫瘍を穿刺し，99.9％エタノールを直接注入することにより，癌部を凝固壊死させる方法である．完全壊死が高率に得られるが，近年ラジオ波治療との比較試験でラジオ波治療の方がPEITよりも長期予後においてすぐれるとの結果が確認され，局所治療の中心はラジオ波に移行しつつある．
4）マイクロ波凝固療法（percutaneous microwave coagulation therapy：PMCT）：
MCTはRFAよりも短い波長（2450 MHz）の高周波を使用して腫瘍を焼灼する方法である．RFAよりも凝固範囲は狭く，また合併症も多いため最近ではRFAの登場に伴い一部の施設や開腹術中のMCTを除き，あまり用いられなくなってきた．
5）経カテーテル肝動脈塞栓療法（transcatheter arterial chemoembolization：TACE）：
Seldinger法によりカテーテルを腫瘍支配動脈に選択的に挿入し，通常リピオドールと抗癌薬を混和させた懸濁液を注入した後ゼラチンスポンジやジェルパートなどで塞栓して腫瘍を虚血壊死に至らせる治療法である．通常，門脈本幹ないし一次分枝に腫瘍栓がなく，難治性腹水や黄疸などの合併症がない症例が適応となる．多発病巣を有する症例に対しても適応となる．大型の肝癌に対してはTACEを行った後RFAを追加することにより治療効果が高まる．
6）放射線治療：
放射治療は骨転移などには疼痛緩和目的でよく行われる．原発巣に対しては肝障害が軽度で，単発で大きさ5～10 cm程度の腫瘍が肝内に限局して存在する場合に適応となる．リニアック照射が通常行われるが，陽子線や重粒子線などを用いた治療が最近試みられており，良好な成績を収めているが治療施設が限られているという難点があり，あくまで実験的治療の段階である．
7）動注化学療法（hepatic arterial infusion chemotherapy：HAIC）：
門脈腫瘍栓を有するような高度進行肝癌に対して動注化学療法が行われている．肝癌診療ガイドラインでも治療アルゴリズムが4個以上の肝癌に対してはTACEと並んでこの動注化学療法が推奨されている．レジメとしてはシスプラチン（CDDP）と5FUを組み合わせるlow-dose FP療法および5FU動注とインターフェロン皮下注を組み合わせるインターフェロン併用5FU動注化学療法の2種類が主として行われている．また，頻回に経動脈性に動注を行うリピオドール TAIも行われている．
8）全身化学療法：
通常，殺細胞性の全身化学療法は標準治療としては行われず，試験的治療の域を出ない．しかしながら，近年登場した分子標的薬ソラフェニブは積極的に肝癌にも使用されている．ソラフェニブは血管新生に関与するVEGFやPDGFの受容体チロシンキナーゼと細胞増殖にかかわるMAPキナーゼ系のRAFを選択的に阻害することにより，抗腫瘍効果を発揮し，患者の予後の延長効果がある．ソラフェニブは①遠隔転移や脈管浸潤を伴う進行肝癌，および②TACEや動注化学療法に不応のChild-Pugh Aの肝癌患者が対象となる．
9）肝移植：
欧米では一般に肝癌の治療法として肝移植が定着しているが，日本では脳死肝移植は脳死ドナーの不足によりきわめて少ない．しかしながら，日本においては，生体ドナーによる生体肝移植が積極的に行われている．この点がごく一般の標準治療として脳死肝移植が行われている欧米との大きな差である．日本における生体肝移植は2005年の集計で3246例であり，うち肝癌に対する肝移植は479例（15％）である．この生体肝移植は肝癌の発生母地である肝硬変と肝癌を一度に治してしまうことのできるすぐれた治療法であり，日本における5年生存率は80％ときわめて良好である．
10）肝癌根治後のインターフェロン治療：
現在，肝切除やラジオ波治療後のC型肝炎患者に対してはインターフェロン治療によりウイルス排除を行うと予後が著明に改善することが知られているため積極的に行われている．また，たとえウイルス学的著効が得られなくともインターフェロンを比較的長期投与すると肝癌根治後の患者の予後が改善することも報告されており，現在一般診療として行われている．
定義・概念
　まれな良性上皮性腫瘍で，正常肝細胞と類似した細胞からなり非硬変肝に発生する．20～40歳の女性に多く，女性では経口避妊薬，男性では蛋白同化ホルモンの長期服用に関連している．病理学的には，正常肝に発生し，多くは単発性で，比較的柔らかい．腫瘍径は1 cm前後から30 cmに及ぶ．割面は淡赤褐色～灰白色でほぼ均一な性状を示し，周囲肝組織との境界は明瞭で，大きな腺腫は薄い線維性被膜を有する．腫瘍内には門脈や胆管はなく，部分的に壊死あるいは出血巣などを認めることが多い．
原因・病因
　経口避妊薬の服用との密接な関係や1型糖原病（von Gierke病）に合併することが報告されている．
疫学
　日本ではきわめて少ないが，欧米では比較的多い．
診断
　腫瘍内や腫瘍の破裂による腹腔内出血とそれに伴う腹痛で発見されることが少なくない．　腫瘍内出血のない場合は，超音波では内部均一な高エコー，造影CTや血管造影では均一はhypervascularな病変として描出される．腫瘍割面像は比較的均一で，線維性被膜を認めない．　しかし，腫瘍内出血のある場合は，単純CTで高吸収域，MRIのT₁強調像で高信号を呈する．若い女性で，しかもB型・C型の肝炎ウイルスが陰性で正常肝に発生した場合は，本疾患の可能性を考慮する．
鑑別診断
　肝細胞癌および，肝限局性結節性過形成，もしくは血管筋脂肪腫などと鑑別を要する場合がある．特に肝細胞癌との鑑別は画像診断上は不可能である．
治療
　経口避妊薬，あるいは蛋白同化ホルモンを服用している場合は中止させ，腫瘍出血がみられる場合は緊急外科的切除適応となる．悪性転化のサブタイプも存在するとされているため，生検にて肝細胞腺腫と診断されれば自然腫瘍破裂のリスクもあるため，基本的には切除の対象である．
（3）限局性結節性過形成（focal nodular hyperplasia）
定義・概念
　WHO分類では腫瘍類似病変に分類され，20～50歳の女性で非硬変肝に表在性に単発し，長経5 cm以下の腫瘤としてみられる．病理学的特徴は中心に膠原線維からなる星芒状瘢痕（central scar）があり，周辺に向かう放射状の線維性隔壁により粗大結節性に区分されていることである．組織学的には細胞に異型性はなく，中心の瘢痕部には異常な壁肥厚を示す血管，炎症性細胞浸潤を伴う小胆管の増生をみる．臨床的には無症状である．限局性結節性過形成は肝の新生物というよりは過誤腫ないし血管奇形とそれに伴った反応性の病変と考えられる．肝細胞腺腫と異なって，経口避妊薬の服用は原因とならないとする考え方が最近では一般的である．
疫学
　肝細胞腺腫と比較すると日本では圧倒的に高頻度である．
検査所見
　画像診断上，超音波検査では，比較的周囲肝実質に近い低～等エコーを示し，中央部に星芒状瘢痕を疑わせる低エコー域を示すこともある．単純CTでは結節状の低～等濃度域のことが多く，造影CTでは早期で高濃度域，後期で等濃度域を示し，中心部に星芒状瘢痕に一致して低濃度域がみられる．MRIではT₁強調像でほぼ等信号，T₂強調像で等信号からやや高信号を示すことが多い．Kupffer細胞を有するため，SPIO-MRIやソナゾイドを用いた造影超音波Kupffer相では腫瘤内に造影剤が取り込まれ，周囲肝と等信号となる．血管造影では境界明瞭な血流に富んだ腫瘤（hypervasccular nodule）として描出され，屈曲・拡張した栄養動脈が腫瘍内部に入り込み，末梢に向かう車軸状血管（spoke wheel appearance）を認めることが特徴である．造影超音波検査では，動脈相で腫瘍の中心に血流を認め，急速に腫瘤辺縁に向かって染まりKupffer相では取り込みがみられるという特徴的所見を呈する．
診断
　正常肝で各種画像で車軸状構築を認める多血性腫瘍が検出され，Kupffer細胞の存在がソナゾイド造影エコーで確認されれば，本症の診断は困難ではない．
治療
　以前は肝細胞癌との鑑別が問題となっていたが，最近では確定診断されることが多い．確定診断がされれば治療は不要である．
（4）肝血管筋脂肪腫（angiomyolipoma）
定義・概念
　肝血管筋脂肪腫は脂肪，血管，平滑筋の3成分よりなる良性腫瘍である．血管成分があればhypervascularで，脂肪成分があれば単純CTで低信号，超音波で高エコーとなる．典型例ではT₁強調像で高信号，T₁強調のopposed phase（逆位相）で低信号を呈する．しかし，脂肪成分が少ない場合は診断はやや困難である．生検標本のHMB-45染色は特異的で確定診断の根拠となる．［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9-12-5
日本肝臓学会提唱のコンセンサスに基づく肝細胞癌治療アルゴリズム">

図9-12-5

出典　内科学第10版内科学第10版について　情報

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