社论 AFP与超声联合检测可改善早期肝癌检测

StephenW

Editorial
Testing for AFP in combination with ultrasound improves early liver cancer detection
Kristina Tzartzeva & Amit G. Singal
Pages 947-949 | Received 15 Jun 2018, Accepted 14 Aug 2018, Accepted author version posted online: 17 Aug 2018, Published online: 21 Aug 2018

    Download citation https://doi.org/10.1080/17474124.2018.1512855

Hepatocellular carcinoma (HCC) is the fastest rising cause of cancer-related death in the United States and a leading cause of death in patients with cirrhosis [1 El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142(6):1264–1273.e1.[Crossref], [Web of Science ®], [Google Scholar]]. Tumor stage at diagnosis is of prognostic and therapeutic significance. Patients with early-stage HCC are eligible for curative therapies such as surgical resection or liver transplantation and can achieve 5-year survival rates of nearly 70% [2 Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999;30(6):1434–1440.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]]. More advanced HCCs, on the other hand, have a poor prognosis and are primarily managed with palliative measures. Given that symptomatic presentation is almost universally indicative of advanced tumor burden, effective implementation of HCC surveillance during its subclinical course is critical. Several studies have demonstrated that HCC surveillance is associated with significant improvements in early tumor detection, curative treatment receipt, and overall survival in patients with cirrhosis [3 Singal AG, Pillai A, Tiro J. Early detection, curative treatment, and survival rates for hepatocellular carcinoma surveillance in patients with cirrhosis: a meta-analysis. PLoS Med. 2014;11(4):e1001624.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]].

Although the American Association for the Study of Liver Disease (AASLD) and European Association for the Study of the Liver (EASL) agree on the need for HCC surveillance in at-risk patients including those with cirrhosis, they differ in recommended surveillance tests. Both societies recommend abdominal ultrasound every 6 months but disagree about using the serum biomarker, alpha-fetoprotein (AFP), as an adjunct surveillance test [4 Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358–380.[Crossref], [PubMed], [Web of Science ®], [Google Scholar],5 Galle PR, Forner A, Llovet JM, et al. European association for study of liver clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]]. The recently updated AASLD guidelines recommend ultrasound with or without AFP, because the authors believed it was not possible to determine if ultrasound alone or ultrasound with AFP would lead to a greater survival benefit based on current data [4 Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358–380.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]]. In contrast, EASL continues to recommend ultrasound alone for surveillance and discourages the use of AFP due to reports of minimal improvement in sensitivity with potential increase in cost [5 Galle PR, Forner A, Llovet JM, et al. European association for study of liver clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]].

A number of factors must be examined when considering ultrasound as a surveillance modality. Ultrasound has many advantages including being cheap, readily available, and noninvasive. It does, however, face a number of shortcomings. First, increasing data highlight the variability in ultrasound performance between patients and centers. Ultrasound is well known to be operator dependent, with image quality affected by the experience and skill of the person completing the exam [6 Stasi G, Ruoti EM. A critical evaluation in the delivery of the ultrasound practice: the point of view of the radiologist. Italian J Med. 2015;9(1):5–10.[Crossref], [Web of Science ®], [Google Scholar]]. In the United States, ultrasound exams are performed by trained technicians and frozen ultrasound images are interpreted later by radiologists, whereas in other parts of the world, physicians perform the surveillance exams themselves. Second, ultrasound quality may be impacted by patient characteristics. A recent study found ultrasound quality was inadequate for HCC evaluation in one in five patients, with poor ultrasound quality seen more commonly in obese patients, those with increased liver nodularity, and patients with cirrhosis due to nonalcoholic steatohepatitis (NASH), amongst other characteristics [7 Simmons O, Fetzer DT, Yokoo T, et al. Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis. Aliment Pharmacol Ther. 2017;45(1):169–177.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]]. Third, poor quality or indeterminate exams can lead to screening-related harms including additional use of cross-sectional imaging, such as computed tomography (CT) or magnetic resonance imaging (MRI), and increased patient anxiety [8 Atiq O, Tiro J, Yopp AC, et al. An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis. Hepatology. 2017;65(4):1196–1205.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]]. These factors lead to inconsistency in screening adequacy between sites and patients. With the rise of metabolic syndrome and increasing incidence of NASH cirrhosis, ultrasound quality concerns and failure are anticipated to become more problematic. While interventions such as using expert ultrasound operators, developing specific surveillance protocols, and standardizing reporting methods may improve ultrasound quality and reduce surveillance failure, they would not address the patient-related issues. Therefore, surveillance strategies other than, or in addition to, ultrasound should be considered. While CT- or MRI-based surveillance are not as operator dependent and may improve sensitivity for early tumor detection, their routine use is limited by cost-effectiveness and issues such as contrast or radiation exposure. Therefore, use of serum biomarkers, such as AFP, which are thought to be more objective, provides a potential solution to this growing issue.

A randomized controlled trial comparing ultrasound alone and ultrasound with AFP was attempted as part of a French multicenter study [9]. However, there were high rates of AFP contamination in the ultrasound-alone group, precluding any meaningful comparisons. This high rate of contamination not only reflects providers’ hesitance to abandon AFP but also suggests that a randomized controlled trial will not be possible and we will be forced to rely on comparisons within cohort studies. A recent meta-analysis of cohort studies evaluating the benefit of using AFP with ultrasound for HCC surveillance in patients with cirrhosis found a significant increase in sensitivity for early-stage HCC detection when AFP was used with ultrasound (63%, 95% CI 48%–75%) compared to ultrasound alone (45%, 95% CI 30%–62%) [10 Tzartzeva K, Obi J, Rich NE, et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Gastroenterology. 2018;154(6):1706–1718.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]]. This observed increase in sensitivity was consistently noted across included studies despite a wide variation in reported sensitivities for ultrasound. Specifically, the benefit of AFP was observed in prospective studies, studies in the United States, and studies conducted after the year 2000. Although studies did not directly evaluate downstream benefits, such as improved survival, it is reasonable to infer that increased early tumor detection would translate into a survival benefit given that curative therapies are only available for early tumor stage. The benefit of adding AFP may be particularly notable in patients with increased ultrasound echogenicity and nodularity [11 Soresi M, Terranova A, Licata A, et al. Surveillance program for diagnosis of HCC in liver cirrhosis: role of ultrasound echo patterns. BioMed Res Int. 2017;1–8.[Crossref], [Web of Science ®], [Google Scholar]].

Of note, the increased sensitivity for early HCC detection observed in the meta-analysis was accompanied by a small but statistically significant decrease in specificity. Though a rise in AFP levels can be a sign of HCC, it is necessary to recognize that AFP can also be elevated in other clinical scenarios, including other malignancies, or undergo benign variability, contributing to false-positive and indeterminant results. AFP-related false-positive results have been found to be more commonly associated with specific characteristics, including hepatitis C (HCV) infection and elevated alanine aminotransferase (ALT) levels [12 Gopal P, Yopp AC, Waljee AK, et al. Factors that affect accuracy of alpha-fetoprotein test in detection of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 2014;12(5):870–877.[Crossref], [PubMed], [Web of Science ®], [Google Scholar],13 Sterling RK, Wright EC, Morgan TR, et al. Frequency of elevated hepatocellular carcinoma (HCC) biomarkers in patients with advanced hepatitis C. Am J Gastroenterol. 2012;107(1):64–74.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]]. Therefore, the decrease in specificity with AFP may be less noteworthy as the epidemiology of cirrhosis changes to reflect increasing treatment of HCV infection and the rising prevalence of NASH. Further, there are several methods to decrease AFP-related false-positive results, improving its value when implemented in clinical practice. The AFP cutoff for upper limit of normal, usually set at a single threshold of 20ng/mL, can be tailored to cirrhosis etiology, with higher cutoffs in viral than nonviral cirrhosis [12 Gopal P, Yopp AC, Waljee AK, et al. Factors that affect accuracy of alpha-fetoprotein test in detection of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 2014;12(5):870–877.[Crossref], [PubMed], [Web of Science ®], [Google Scholar],14 Soresi M, Magliarisi C, Campagna P, et al. Usefulness of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma. Anticancer Res. 2003;23(2C):1747–1753.[PubMed], [Web of Science ®], [Google Scholar]]. Alternatively, interpreting AFP trends over time rather than as individual values and using algorithms to adjust for high baseline AFP levels can also better guide clinical interpretation of this biomarker [15 Tayob N, Lok AS, Do KA, et al. Improved detection of hepatocellular carcinoma by using a longitudinal alpha-fetoprotein screening algorithm. Clin Gastroenterol Hepatol. 2016;14(3):469–475.e2.[Crossref], [PubMed], [Web of Science ®], [Google Scholar],16 Lee E, Edward S, Singal AG, et al. Improving screening for hepatocellular carcinoma by incorporating data on levels of alpha-fetoprotein, over time. Clin Gastroenterol Hepatol. 2013;11(4):437–440.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]]. Therefore, further evaluation is needed to discern whether the observed decrease in specificity translates clinically into a significant increase in physical harms (e.g. further diagnostic imaging or biopsy), financial harms (e.g. direct costs of testing or indirect costs of missed work), or psychological harms (e.g. anxiety or depression related to false-positive results). A single-center study characterizing screening-related harms suggested AFP-related physical harms due to false-positives are lower than those related to ultrasound, likely due to providers using clinical judgement when interpreting positive AFP levels but not being able to do so with ultrasound results; however, these results still require validation in other practice settings [8 Atiq O, Tiro J, Yopp AC, et al. An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis. Hepatology. 2017;65(4):1196–1205.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]].

The benefit of combining AFP with ultrasound is a proof of concept for the potential value of biomarkers but unlikely to be the long-term solution. Using the two tests, ultrasound and AFP, in combination still misses up to one-third of HCCs at an early stage, underscoring the continued need for improved biomarkers. Several other biomarkers such as des-gamma carboxyprothrombin (DCP) and lectin-bound alpha-fetoprotein (AFP-L3) have been proposed and are undergoing phase III biomarker evaluation [17 Chaiteerakij R, Addissie BD, Roberts LR. Update on biomarkers of hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2015;13(2):237–245.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]]. Given the heterogeneity between and even within tumors, a single biomarker is unlikely to be sufficient and a panel of biomarkers may be necessary to achieve adequate sensitivity for early tumor detection. One of the best studied biomarker panels to date, GALAD, combines three biomarkers (AFP, AFP-L3, and DCP) with patient age and gender and has been shown to have high accuracy (AUROC ~0.90) in large case–control studies; however, this panel still requires validation in large cohort studies prior to routine use [18 Berhane S, Toyoda H, Tada T, et al. Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients. Clin Gastroenterol Hepatol. 2016;14(6):875–886.e6.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]]. While awaiting these data evaluating novel biomarkers, including biomarker panels, we should use the best of our currently validated surveillance tests.

In summary, ultrasound appears to be suboptimal for detecting HCC at an early stage when used alone. The addition of AFP to ultrasound significantly increases the sensitivity for HCC detection at an early stage, which can translate to increased curative treatment eligibility and improved survival. The increase in sensitivity is accompanied by a small, albeit statistically significant, decrease in specificity which could potentially be ameliorated with optimized AFP thresholds, longitudinal evaluation, and clinical interpretation. Additional evaluation is needed to determine whether the decrease in specificity relates to a clinical increase in physical, financial, or psychological harms. Until more optimal imaging modalities or biomarkers are available, we believe AFP should be used with ultrasound in all patients with cirrhosis undergoing HCC surveillance.

StephenW

肝细胞癌（HCC）是美国癌症相关死亡的最快起因，也是肝硬化患者死亡的主要原因[1 El-Serag HB。病毒性肝炎和肝细胞癌的流行病学。消化内科。 2012; 142（6）：1264-1273.e1。[Crossref]，[Web ofScience®]，[Google Scholar]]。诊断时的肿瘤阶段具有预后和治疗意义。早期HCC患者有资格接受手术切除或肝移植等治愈性治疗，可实现近70％的5年生存率[2 Llovet JM，Fuster J，Bruix J.手术治疗的意向治疗分析对于早期肝细胞癌：切除与移植。肝病。 1999; 30（6）：1434-1440。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]]。另一方面，更先进的HCC预后不良，主要通过姑息治疗措施进行管理。鉴于症状表现几乎普遍表明晚期肿瘤负担，在其亚临床过程中有效实施HCC监测至关重要。一些研究表明，HCC监测与肝硬化患者的早期肿瘤检出，治愈性治疗和总生存率有显着改善[3 Singal AG，Pillai A，Tiro J.早期检测，治愈性治疗和肝细胞存活率肝硬化患者的癌症监测：荟萃分析。 PLoS Med。 2014; 11（4）：e1001624。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]]。

虽然美国肝病研究协会（AASLD）和欧洲肝脏研究协会（EASL）同意需要对高风险患者（包括肝硬化患者）进行HCC监测，但他们在推荐的监测试验中存在差异。两个社团都建议每6个月进行腹部超声检查，但不同意使用血清生物标志物甲胎蛋白（AFP）作为辅助监测试验[4 Heimbach JK，Kulik LM，Finn RS，et al。 AASLD治疗肝细胞癌的指南。肝病。 2018; 67（1）：358-380。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]，5 Galle PR，Forner A，Llovet JM，et al。欧洲肝脏临床实践指南研究协会：肝细胞癌的治疗。 J Hepatol。 2018; 69：182-236。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]]。最近更新的AASLD指南建议使用或不使用AFP进行超声检查，因为作者认为根据当前数据无法确定单独超声或AFP超声是否会带来更大的生存获益[4 Heimbach JK，Kulik LM，Finn RS ，等。 AASLD治疗肝细胞癌的指南。肝病。 2018; 67（1）：358-380。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]]。相比之下，EASL继续建议单独使用超声波进行监测，并且不鼓励使用AFP，因为有报道称灵敏度的改善极小，可能会增加成本[5 Galle PR，Forner A，Llovet JM，et al。欧洲肝脏临床实践指南研究协会：肝细胞癌的治疗。 J Hepatol。 2018; 69：182-236。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]]。

在将超声波视为监视模式时，必须考虑许多因素。超声具有许多优点，包括便宜，容易获得和非侵入性。但是，它确实面临许多缺点。首先，增加数据突出了患者和中心之间超声性能的变化。众所周知，超声是依赖于操作者的，图像质量受完成检查的人的经验和技能的影响[6 Stasi G，Ruoti EM。超声波实践的一项关键评估：放射科医师的观点。意大利人J Med。 2015; 9（1）：5-10。[Crossref]，[Web ofScience®]，[Google Scholar]]。在美国，超声检查由经过培训的技术人员进行，冰冻超声图像后来由放射科医师解释，而在世界其他地方，医生自己进行监测检查。其次，超声质量可能受到患者特征的影响。最近的一项研究发现，五分之一的患者的超声质量不足以进行HCC评估，肥胖患者更常见的超声质量较差，肝脏结节性增加，以及非酒精性脂肪性肝炎（NASH）引起的肝硬化患者，以及其他特征[ 7 Simmons O，Fetzer DT，Yokoo T，et al。肝硬化患者肝细胞癌监测的足够超声质量的预测因子。 Aliment Pharmacol Ther。 2017; 45（1）：169-177。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]]。第三，质量差或不确定的检查可能导致筛查相关的危害，包括额外使用横断面成像，如计算机断层扫描（CT）或磁共振成像（MRI），以及患者焦虑增加[8 Atiq O，Tiro J， Yopp AC，et al。肝硬化患者肝细胞癌监测的益处和危害评估。肝病。 2017; 65（4）：1196-1205。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]]。这些因素导致网站和患者之间筛查充分性的不一致。随着代谢综合征的增加和NASH肝硬化发病率的增加，预计超声质量问题和失败将变得更成问题。虽然使用专家超声操作员，制定特定监测方案和标准化报告方法等干预措施可以提高超声质量并减少监测失败，但它们无法解决与患者相关的问题。因此，应考虑除超声波之外或除超声波之外的监测策略。虽然基于CT或MRI的监测不依赖于操作者并且可以提高早期肿瘤检测的灵敏度，但是它们的常规使用受到成本效益和诸如对比或辐射暴露等问题的限制。因此，使用被认为更客观的血清生物标志物，例如AFP，为这一日益严重的问题提供了潜在的解决方案。

一项随机对照试验比较了单独超声和超声与AFP，作为法国多中心研究的一部分[9]。然而，单独超声组中的AFP污染率很高，排除了任何有意义的比较。这种高污染率不仅反映了医疗服务提供者放弃AFP的犹豫不决，而且还表明无法进行随机对照试验，我们将不得不依赖于队列研究中的比较。最近对队列研究进行的荟萃分析评估了使用AFP和超声波对肝硬化患者进行HCC监测的益处，发现当AFP与超声检查一起使用时，早期HCC检测的敏感性显着增加（63％，95％CI 48％）与单独超声相比（-75％）（45％，95％CI 30％-62％）[10 Tzartzeva K，Obi J，Rich NE，et al。监测成像和甲胎蛋白用于肝硬化患者肝细胞癌的早期检测：荟萃分析。消化内科。 2018; 154（6）：1706-1718。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]]。尽管所报告的超声敏感性存在很大差异，但在所纳入的研究中始终注意到这种观察到的敏感性增加。具体而言，在美国的前瞻性研究，研究和2000年后进行的研究中观察到AFP的益处。尽管研究没有直接评估下游益处，例如改善生存率，但推断早期肿瘤检测增加是合理的。鉴于治疗疗法仅适用于早期肿瘤阶段，将转化为生存益处。添加AFP的益处在超声回声和结节性增加的患者中尤为显着[11 Soresi M，Terranova A，Licata A，et al。诊断肝硬化HCC的监测程序：超声回声模式的作用。 BioMed Res Int。 2017; 1-8。[Crossref]，[Web ofScience®]，[Google Scholar]]。
值得注意的是，在荟萃分析中观察到的早期HCC检测的灵敏度增加伴随着特异性的小但统计学上显着的降低。虽然AFP水平的升高可能是HCC的征兆，但有必要认识到AFP在其他临床情况下也可能升高，包括其他恶性肿瘤，或者经历良性变异，导致假阳性和不确定结果。已发现AFP相关的假阳性结果更常见于特定的特征，包括丙型肝炎（HCV）感染和丙氨酸氨基转移酶（ALT）水平升高[12 Gopal P，Yopp AC，Waljee AK，et al。影响肝硬化患者肝细胞癌甲胎蛋白检测准确性的因素。 Clin Gastroenterol Hepatol。 2014; 12（5）：870-877。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]，13 Sterling RK，Wright EC，Morgan TR，et al。晚期丙型肝炎患者升高的肝细胞癌（HCC）生物标志物的频率.Am J Gastroenterol。 2012; 107（1）：64-74。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]]。因此，随着肝硬化的流行病学变化以反映HCV感染的治疗增加和NASH的流行率增加，与AFP的特异性降低可能不那么值得注意。此外，有几种方法可以降低AFP相关的假阳性结果，在临床实践中提高其价值。正常上限的AFP临界值，通常设定在20ng / mL的单一阈值，可以适应肝硬化病因，病毒的截止值高于非病毒性肝硬化[12 Gopal P，Yopp AC，Waljee AK，et al。影响肝硬化患者肝细胞癌甲胎蛋白检测准确性的因素。 Clin Gastroenterol Hepatol。 2014; 12（5）：870-877。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]，14 Soresi M，Magliarisi C，Campagna P，et al。甲胎蛋白在肝细胞癌诊断中的应用。 Anticancer Res。 2003; 23（2C）：1747-1753。[PubMed]，[Web ofScience®]，[Google Scholar]]。或者，解释AFP随时间而不是单个值的趋势，并使用算法调整高基线AFP水平也可以更好地指导该生物标志物的临床解释[15 Tayob N，Lok AS，Do KA，et al。通过使用纵向甲胎蛋白筛选算法改进肝细胞癌的检测。 Clin Gastroenterol Hepatol。 2016; 14（3）：469-475.e2。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]，16 Lee E，Edward S，Singal AG，et al。通过纳入甲胎蛋白水平的数据，随着时间的推移改进对肝细胞癌的筛查。 Clin Gastroenterol Hepatol。 2013; 11（4）：437-440。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]]。因此，需要进一步评估以辨别观察到的特异性降低是否在临床上转化为物理危害的显着增加（例如进一步的诊断成像或活组织检查），经济危害（例如测试的直接成本或错过工作的间接成本），或心理危害（例如与假阳性结果相关的焦虑或抑郁）。一项以筛查相关危害为特征的单中心研究表明，由于假阳性导致的与AFP相关的物理伤害低于与超声相关的物理伤害，可能是由于提供者在解释AFP阳性水平时使用临床判断而不能通过超声检查进行临床判断结果;然而，这些结果仍需要在其他实践环境中进行验证[8 Atiq O，Tiro J，Yopp AC，et al。肝硬化患者肝细胞癌监测的益处和危害评估。肝病。 2017; 65（4）：1196-1205。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]]。
将AFP与超声结合的益处是生物标志物潜在价值的概念证明，但不太可能是长期解决方案。使用这两项测试，超声和AFP联合使用仍然在早期阶段错过了三分之一的HCC，这突显了对改进生物标志物的持续需求。已经提出了几种其他生物标志物，例如des-γ羧基凝血酶原（DCP）和凝集素结合的甲胎蛋白（AFP-L3），并且正在进行III期生物标志物评估[17 Chaiteerakij R，Addissie BD，Roberts LR。肝细胞癌生物标志物的最新进展。 Clin Gastroenterol Hepatol。 2015; 13（2）：237-245。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]]。鉴于肿瘤之间甚至肿瘤内的异质性，单个生物标志物不太可能是足够的，并且可能需要一组生物标志物来实现对早期肿瘤检测的足够敏感性。迄今为止研究最好的生物标志物组之一GALAD将三种生物标志物（AFP，AFP-L3和DCP）与患者年龄和性别结合起来，并且在大型病例对照研究中已被证明具有高准确度（AUROC~0.90）;然而，在常规使用之前，该小组仍需要在大型队列研究中进行验证[18 Berhane S，Toyoda H，Tada T，et al。 GALAD和BALAD-2血清学模型在肝细胞癌诊断和患者生存预测中的作用。 Clin Gastroenterol Hepatol。 2016; 14（6）：875-886.e6。[Crossref]，[PubMed]，[Web ofScience®]，[Google Scholar]]。在等待评估新生物标记物（包括生物标记物组）的这些数据时，我们应该使用我们目前最有效的监测测试。

总之，当单独使用时，超声在早期检测HCC时似乎不是最理想的。在超声中添加AFP显着提高了早期HCC检测的灵敏度，这可以转化为治愈性治疗的合格性和提高的生存率。敏感性的增加伴随着一个小的，尽管具有统计学意义的特异性降低，特异性降低，可能通过优化的AFP阈值，纵向评估和临床解释得到改善。需要进一步评估以确定特异性降低是否与身体，经济或心理危害的临床增加有关。在获得更多最佳成像方式或生物标记物之前，我们认为AFP应该用于所有接受HCC监测的肝硬化患者的超声检查