注: 目前已有关于成人原发性肝癌治疗和儿童肝癌治疗的单独PDQ总结。
基于一般推荐性证据，高危人群筛查并不能降低肝细胞癌的死亡率。
效应强度：不能降低死亡率
基于一般推荐性证据，细针穿刺细胞学筛查可导致罕见但严重的副作用，如针道种植（尤其是直径大于2cm的病灶）、出血、胆汁性腹膜炎和气胸。经颈静脉肝活检很少引起如肝包膜穿孔或胆管炎等严重并发症。
效应强度：充分的证据证明，有少见但严重的危害
Note: Separate PDQ summaries on Adult Primary Liver Cancer Treatment and Childhood Liver Cancer Treatment are also available.
Based on fair evidence, screening of persons at elevated risk does not result in a decrease in mortality from hepatocellular cancer.
Magnitude of Effect: No reduction in mortality.
Based on fair evidence, screening would result in rare but serious side effects associated with needle aspiration cytology such as needle-track seeding, particularly of lesions more than 2 cm in diameter, and hemorrhage, bile peritonitis, and pneumothorax. Transjugular liver biopsy is rarely associated with major complications such as perforation of the hepatic capsule or cholangitis.
Magnitude of Effect: Good evidence for uncommon but serious harms.
肝细胞癌（HCC）是世界第四常见的癌症。肝细胞癌（HCC）也是中国第四常见的癌症。
年龄标化发病率从北美的2.1/10万到中国的80/10万之间不等。在中国，2015年肝癌发病的中标率为17.64/10万，世标率为17.35/10万。
2020年，预计美国将有新发肝癌病例42,810例，同时将有30,160例患者死于肝癌。据估计，2015年中国肝癌新发病例和死亡病例分别为：37.0万例和32.6万例。
在美国所有种族人群中均为男性高发，特别在华裔男性中更为高发。其男性HCC年发病率为20.8/10万，女性为7.6/10万。在中国，男性发病率远远高于女性。2015年男性HCC发病率为26.63/10万，8.64/10万（按2000年中国人口标化）。
慢性乙型肝炎和丙型肝炎是世界公认的HCC主要危险因素，两者合并感染时危险更高。
慢性肝炎患者的HCC年发病率高达0.46%。在美国，30%-40%的HCC由慢性乙型肝炎和丙型肝炎引起。无论是在乙型肝炎表面抗原阳性的携带者中还是在非携带者中，慢性庚型肝炎感染均与HCC无关。
各种病因的肝硬化均为HCC的危险因素。肝硬化患者的HCC年发生率在1%至6%之间。
其他危险因素包括酒精性肝硬化、血色素沉着症、α-1抗胰蛋白酶缺乏症、糖原贮积病、迟发型皮肤卟啉病、酪氨酸血症和Wilson病，
但胆汁性肝硬化导致HCC很罕见
一项回顾性病例对照研究表明，相比病毒感染或饮酒引起的HCC患者，在隐匿性肝硬化引起的HCC患者中，非酒精性脂肪肝的危险因素如肥胖、2型糖尿病、血脂异常、胰岛素抵抗等更常见。
黄曲霉毒素是一种由特定曲霉菌形成的霉菌毒素，其污染常见于储藏不当的谷物和坚果中。非洲部分地区的HCC发生率高可能与摄入被黄曲霉毒素污染的食品有关。然而，这种关联尚不明确，因为这些人群多合并乙型肝炎病毒感染。HCC可能的病因总结如下表。
| 致病因子 | 主要地理区域 |
| 乙型肝炎病毒 | 亚洲与非洲 |
| 丙型肝炎病毒 | 欧洲、美国与日本 |
| 酒精 | 欧洲与美国 |
| 黄曲霉毒素 | 东亚与非洲 |
Hepatocellular cancer (HCC) is the fourth most common cancer in the world.
Age-standardized incidence rates vary from 2.1 per 100,000 in North America to 80 per 100,000 in China.
In the United States, it is estimated that there will be 42,810 new cases diagnosed in 2020 and 30,160 deaths due to this disease.
There is a distinct male preponderance among all ethnic groups in the United States, although this trend is most marked among Chinese Americans, in whom the annualized rate of HCC among men is 20.8 per 100,000 and among women is 7.6 per 100,000 population.
Chronic hepatitis B and C are recognized as the major factors worldwide increasing the risk of HCC, with risk being greater in the presence of coinfection with hepatitis B virus and hepatitis C virus.
The incidence of HCC in individuals with chronic hepatitis is as high as 0.46% per year. In the United States, chronic hepatitis B and C account for about 30% to 40% of HCC. Chronic hepatitis G infection is not associated with HCC in either hepatitis B surface antigen–positive carriers or noncarriers.
Cirrhosis is also a risk factor for HCC, irrespective of the etiology of the cirrhosis. The annual risk of developing HCC among persons with cirrhosis is between 1% and 6%.
Other risk factors include alcoholic cirrhosis, hemochromatosis, alpha-l-antitrypsin deficiency, glycogen storage disease, porphyria cutanea tarda, tyrosinemia, and Wilson disease,
but rarely biliary cirrhosis.
A retrospective case-control study found that features suggestive of nonalcoholic steatohepatitis, including obesity, type 2 diabetes, dyslipidemia, and insulin resistance, were more frequently observed in patients with HCC associated with cryptogenic cirrhosis than in those with HCC of viral or alcohol etiology.
Aflatoxins, which are mycotoxins formed by certain Aspergillus species, are a frequent contaminant of improperly stored grains and nuts. In parts of Africa, the high incidence of HCC in humans may by related to ingestion of foods contaminated with aflatoxins. This association, however, is blurred by the frequent coexistence of hepatitis B infection in those population groups. The likely etiology of HCC is summarized in the following table.
| Causative Agents | Dominant Geographical Area |
| Hepatitis B virus | Asia and Africa |
| Hepatitis C virus | Europe, United States, and Japan |
| Alcohol | Europe and United States |
| Aflatoxins | East Asia and Africa |
对肝细胞癌(HCC)的筛查，是基于肝癌高危人群(如肝硬化患者)可以被识别出来的原理。然而，20%到50%的HCC患者在此前并未被诊断患有肝硬化。
如果将肝硬化患者作为目标人群，那么这些未被诊断的肝硬化人群将不被纳入监测范围。
目前可用的筛查方法包括血清甲胎蛋白（AFP）检测和超声。若筛查结果存在异常，可行肝活检确诊。据报道，约有0.06%-0.32%的患者会在行肝活检时发生并发症，且主要发生于活检后的数小时内。
目前常用于肝细胞癌检查或研究中的肿瘤标志物有四种。包括癌胚抗原和糖蛋白抗原、酶和同工酶、基因和细胞因子。
血清AFP是一种胚胎特异性糖蛋白抗原，也是检测HCC最常用的一种肿瘤标记物。各个文献报道的AFP检测灵敏度，无论在乙型肝炎病毒（HBV）阳性人群中，还是在HBV阴性的人群中均差异较大，主要由于研究设计不同，有的是筛查研究，有的是诊断研究。
AFP用于高危人群的筛查时，灵敏度为39%-97%，特异度为76%-95%，阳性预测值（PPV）为9%-32%。
AFP对HCC特异性不高，在急性或慢性肝炎、妊娠和生殖细胞瘤等情况下，AFP滴度也可升高。
一项前瞻性的、为期16年、基于人群的观察性研究对1487例慢性感染HBV的阿拉斯加原住民进行了肝细胞癌筛查，并将筛查出HCC患者的生存与由既往临床诊断HCC患者组成的对照组进行了比较。
该筛查项目的目标是每6个月检测一次AFP水平。AFP对HCC的灵敏度和特异度分别达到了97%和95%（妊娠期女性除外）。但在其他高危人群如肝硬化患者中，并未发现如此高的灵敏度和特异度。
筛查是否确实改善了肝癌生存，目前尚不明确。
在美国退伍军人事务部(VA)卫生保健系统进行的一项病例对照研究评估了AFP和/或超声筛查是否能降低HCC死亡率。病例组为2013年至2015年间的238例死于HCC的肝硬化患者，这些患者确诊HCC前已经被VA诊断为肝硬化超过4年。对照组未死于HCC，同样被VA诊断为肝硬化超过4年，且与对照组在入院日期（或发现病灶的时间）、年龄、性别，种族、终末期肝病模型(MELD)评分和肝硬化病因（主要是丙型肝炎病毒）等相匹配。研究人员在不知道结局的情况下，用提取的病历数据对患者既往是否行超声和AFP检查继进行盲法评估。研究发现，病例组和对照组之间接受超声筛查（52.9%对54.2%）、AFP筛查（74.8%对73.5%）或两种检查都接受的患者比例均没有差异。在确诊HCC前的1，2或3年内进行比较，结果均无差异。
正如本章其他地方所指出的，随机对照试验较少并且证据强度不足。因此这项尽可能控制偏倚的病例对照研究，为AFP或超声筛查HCC的有效性提供了最强证据；然而，其结果仍表明在降低HCC死亡率方面，筛查并无益处。
鉴于AFP在高危人群的监测中灵敏度和特异度有限，肝脏超声也被用作检测HCC的额外方法。
对健康的乙型肝炎表面抗原携带者和肝硬化患者的研究确定了超声作为一种HCC筛查方法的性能特点，超声的灵敏度在前者中为71%，在后者中为78%，特异性为93%。阳性预测值分别为14%和73%。一项在等待肝移植的患者中进行的研究显示，肝脏超声的灵敏度为58%，特异性为94%，阴性预测值为91%，阳性预测值为68%。
一项在VA人群中进行的病例对照研究评估了AFP和/或超声筛查是否能降低HCC死亡率（更多信息请参阅本总结的甲胎蛋白一章）。
鉴于AFP与超声在高危人群（如肝硬化患者）筛查中的灵敏度和特异性有限，计算机断层扫描（CT）也被做为检测HCC的另一种方法。在肝硬化患者中进行的研究表明，CT比超声和AFP（大于20μg/L）在检测HCC时更敏感。
在上海进行的一项对照试验纳入了18,816例35-59岁的乙型肝炎感染者，将其随机分为接受AFP和超声的筛查组（每6个月进行一次）和常规监测组。筛查组HCC死亡率低于常规监测组（83.2/10万 vs 131.5/10万；死亡率之比为0.63[95%置信区间（CI）0.41–0.98]）。虽然这些结果很有前景，但是也存在如下问题：
一项随机对照试验于1989年至1995年间，在中国启东市纳入了5,581例30-69岁的慢性HBV携带者。将其随机分配至筛查组3,712例，对照组1,869例。筛查组每6个月进行一次AFP检测，并对结果异常(≥20μg/L）的患者进行随访，记录肝癌发病或死亡的信息。研究的总体灵敏度和特异度分别为55.3%和86.5%。在全部完成筛查计划的患者中，灵敏度和特异度分别为80%和80.9%。尽管AFP筛查可以更早地诊断肝癌（筛查组的I期肝癌占比29.0%，显著高于对照组的6%），但筛查组的死亡率（1138/10万人年）和对照组的死亡率（1114/10万人年）差异无统计学意义。
一项综述认为，AFP检测HCC不够灵敏是导致本试验阴性结果的解释。
The rationale for screening for hepatocellular carcinoma (HCC) is based on the concept that populations at high risk for HCC, such as those with cirrhosis, can be identified. However, 20% to 50% of patients presenting with HCC have previously undiagnosed cirrhosis.
These patients would not be recruited into a surveillance program if the presence of cirrhosis is used to define a target population.
The modalities potentially available for screening include serum alpha-fetoprotein (AFP) and ultrasonography. Abnormal screening results may lead to liver biopsy for diagnosis. Complications of liver biopsy are reported in 0.06% to 0.32% of patients, and typically occur within the first few hours after the biopsy.
There are four categories of tumor markers that are currently being used or studied for the detection of hepatocellular carcinoma. These include oncofetal antigens and glycoprotein antigens; enzymes and isoenzymes; genes; and cytokines.
Serum AFP, a fetal-specific glycoprotein antigen, is the most widely used tumor marker for detecting patients with HCC. The reported sensitivity of AFP for detecting HCC varies widely in both hepatitis B virus (HBV)-positive and HBV-negative populations, which is attributable to overlap between screening and diagnosis study designs.
When AFP is used for screening of high-risk populations, a sensitivity of 39% to 97%, specificity of 76% to 95%, and a positive predictive value (PPV) of 9% to 32% have been reported.
AFP is not specific for HCC. Titers also rise in acute or chronic hepatitis, in pregnancy, and in the presence of germ cell tumors.
A prospective, 16-year, population-based, observational study of screening for hepatocellular cancer among 1,487 Alaska Natives chronically infected with HBV compared survival among screen-detected HCC patients with a historical comparison group of clinically diagnosed HCC patients.
The screening program’s target was AFP determination every 6 months. It achieved 97% sensitivity and 95% specificity (excluding pregnant women) for HCC. Such high sensitivity and specificity have not been found for other high-risk groups, such as individuals with cirrhosis.
Whether screening actually improved survival is not clear.
A case-control study conducted within the U.S. Veterans Affairs (VA) health care system assessed whether screening with AFP and/or ultrasound reduced HCC mortality. The cases were 238 patients with cirrhosis who died of HCC from 2013 to 2015 and who had been in VA care with a diagnosis of cirrhosis for 4 years or more before the diagnosis of HCC. The controls, who did not die of HCC and had also been in VA care for 4 years or more, were matched for date of entry (or focal time) and for age, gender, race, model for end-stage liver disease (MELD) score, and etiology of cirrhosis (mainly hepatitis C virus). The study examiners, blinded to outcome status, used chart extraction to assess exposure to ultrasound and AFP screening. The reason for testing (screening vs. other indication) was assessed, also blinded to outcome. The study found that there was no difference between cases and controls regarding the proportion of patients who underwent screening ultrasound (52.9% vs. 54.2%), AFP screening (74.8% vs. 73.5%), or both. The lack of difference persisted for tests within 1, 2, or 3 years of the outcome.
Given the paucity of randomized controlled trials and their lack of strength, as noted elsewhere in this section, this case-control study—done with great care to avoid bias—comprised perhaps the strongest evidence about the efficacy of AFP or ultrasound screening; however, it showed no benefit in HCC mortality.
Limitations in the sensitivity and specificity of AFP in surveillance of high-risk populations led to the use of ultrasound as an additional method for detection of HCC.
Studies in both healthy hepatitis B surface antigen carriers and in patients with cirrhosis have defined the performance characteristics of ultrasound as a screening test for HCC. Sensitivity in the former was 71% and in the latter 78%, with 93% specificity. The PPVs were 14% and 73%, respectively. In a study of patients who were on a waiting list for liver transplantation, ultrasonography was found to have a sensitivity of 58%, a specificity of 94%, a negative predictive value of 91%, and a PPV of 68%.
A case-control study conducted in the VA population assessed whether screening with AFP and/or ultrasound reduced HCC mortality (refer to the Alpha-fetoprotein section of this summary for more information).
Limitations in the sensitivity and specificity of AFP and ultrasound in surveillance of high-risk populations, such as individuals with cirrhosis, led to the assessment of computed tomography (CT) as an additional method for detection of HCC. Studies in patients with cirrhosis suggest that CT may be a more sensitive test for HCC than ultrasound or AFP more than 20 μg/L.
A controlled trial of 18,816 persons aged 35 to 59 years with hepatitis B in Shanghai randomly assigned patients to a screening group using AFP and ultrasound every 6 months versus a usual-care group. HCC mortality was lower in the screened group (83.2 vs. 131.5 per 100,000; mortality rate ratio of 0.63 [95% confidence interval (CI), 0.41–0.98]). While these results are promising, there were problems, including the following:
A randomized controlled trial studied 5,581 men aged 30 to 69 years who were chronic carriers of HBV between 1989 and 1995 in Qidong County, China. Of these men, 3,712 were randomly assigned to a screening group and 1,869 to a control group. Screening entailed 6-monthly AFP assays, with follow-up of patients having an abnormal (≥20 μg/L) test result. All patients were followed up for liver cancer and/or death. The overall sensitivity and specificity of the program were 55.3% and 86.5%, respectively. In patients who complied with all scheduled screening tests, sensitivity was 80% and specificity was 80.9%. The mortality rate in the screening group (1,138 per 100,000 person-years) was not significantly different from that in the control group (1,114 per 100,000 person-years), although AFP screening resulted in an earlier diagnosis of liver cancer (i.e., percentage of cases in stage I was significantly higher in the screened group [29.0%] than in the control group [6%]).
A review concluded that the method of measuring AFP was not sensitive enough to detect HCC, affecting interpretation of the negative result of this trial.
筛查可能导致两类危害或并发症。作为进一步诊断肝癌的方法，肝活检可能会造成直接的伤害。据报道，0.06%-0.32%的患者在接受肝活检后会发生并发症，并且多发生在活检后的数小时内。并发症包括出血、胆汁性腹膜炎、脏器穿孔和气胸。肝活检很少直接导致死亡（0.009%-0.12%）。约三分之一的患者右上腹或右肩穿刺部位会出现疼痛。
细针穿刺细胞学检查和肝活检很少导致恶性细胞的针道种植转移。筛查带来的5年和10年生存率的提高，全部或部分归因于领先时间偏倚（在HCC自然病程中被早期诊断，而非通过早期诊断与治疗提高生存率）、病程长短偏倚（筛查可以早期发现进展缓慢、侵袭性低的肿瘤）和/或HCC的过度诊断（检出肿瘤并不影响肿瘤的发病率和死亡率）
Two kinds of harms or complications may result from screening. Direct harms may result from complications of liver biopsy done as part of the diagnostic workup. Such complications are reported in 0.06% to 0.32% of patients, and typically occur within the first few hours after the biopsy. Complications include hemorrhage, bile peritonitis, penetration of viscera, and pneumothorax. Rarely, death occurs as a direct result of liver biopsy (0.009%–0.12%). About one third of patients experience pain at the site of entry, in the right upper quadrant, or in the right shoulder.
Needle aspiration cytology and liver biopsy are rarely associated with needle-track implantation of malignant cells. Lead-time bias (earlier diagnosis in the natural history of HCC rather than improved survival from earlier diagnosis and treatment), length bias (earlier detection of slower-growing and less aggressive tumors through screening), and/or overdiagnosis of HCC (detection of tumors that will not affect morbidity or mortality) may wholly or partially account for the improved 5-year and 10-year survival rates reported.
定期审查PDQ癌症信息总结，并在获得新信息时进行更新。本节描述了截至上述日期对该总结所做的最新更改。
更新了2020年预计新发病例与死亡病例的统计数据（引自美国癌症协会数据，见参考文献3）。
该总结由PDQ筛查和预防编辑委员会撰写和维护，该委员会在编辑上独立于NCI。本总结为独立的文献综述，不作为NCI或NIH的政策声明。关于总结政策和PDQ编辑委员会的更多信息请参见关于本PDQ总结和 PDQ® - NCI综合性癌症数据库页面。
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Updated statistics with estimated new cases and deaths for 2020 (cited American Cancer Society as reference 3).
This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about liver (hepatocellular) cancer screening. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
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PDQ® Screening and Prevention Editorial Board. PDQ Liver (Hepatocellular) Cancer Screening. Bethesda, MD: National Cancer Institute. Updated
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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about liver (hepatocellular) cancer screening. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Screening and Prevention Editorial Board. PDQ Liver (Hepatocellular) Cancer Screening. Bethesda, MD: National Cancer Institute. Updated
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