超声标记物可预测肝硬化患者的肝癌 造影剂摄取和结节生长

StephenW

Markers on Ultrasound May Predict HCC in Cirrhosis Patients
Timing of contrast uptake and nodule growth rate tied to malignancy risk

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    by Diana Swift, Contributing Writer
    October 29, 2019

In cirrhosis patients at risk for hepatocellular carcinoma (HCC), differences in contrast uptake during an initial ultrasound and a nodule's growth rate on follow-up imaging may be noninvasive diagnostic predictors of progression to carcinoma, a small retrospective study from China suggested.

In a sample of 39 patients with confirmed cirrhotic nodules on contrast-enhanced ultrasound (CEUS), a contrast arrival time difference between the nodule and liver of more than half a second predicted transformation to HCC (HR 4.35, P=0.011), Ming Kuang, MD, PhD, of Sun Yat-Sen University in Guangzhou, China, and colleagues reported.

"For patients at risk for HCC, the contrast arrival time difference between the nodule and liver on CEUS was useful in stratifying the eventual malignant transformation risk of cirrhotic nodules, which may enable a more customized surveillance strategy," they wrote in the American Journal of Roentgenology.

Their findings also confirmed initial nodule size as an independent predictor of transformation to HCC (HR 1.07, P=0.019). Incorporating both initial nodule size as well as difference in contrast arrival time yielded an area under the receiver operating curve of 0.75 (P=0.002).

During surveillance, a relative growth rate of 30% or greater over 6 months or an absolute growth rate of 5 mm or more during that span proved highly indicative of malignant transformation. These markers could be taken as "threshold growth" indicators for identifying malignant transformation risk (specificity 100%, positive predictive value 100%).

Conversely, the absence of echogenicity change and threshold growth was highly accurate in excluding malignant transformation (sensitivity 100%, negative predictive value 100%).

"These additional imaging features may have the potential to be adopted as ancillary or even major features to stratify probability for HCC in the CEUS LI-RADS system," Kuang's group suggested.

They noted that 80% of HCCs develop in patients with underlying chronic hepatitis or cirrhosis and most follow a multi-step process in which regenerative nodules can become dysplastic and evolve into early HCC. Although the degree of dysplasia also correlates with malignant transformation risk, biopsy is rare for nodules that are not overtly suspicious and hence, the authors stated, it is important to stratify transformation risk on the basis of imaging findings at initial detection.

Asked for his perspective on the study, Amit Singal, MD, MS, of the University of Texas Southwestern Medical Center in Dallas, noted that HCC risk varies widely among patients with cirrhotic nodules, highlighting the need for risk stratification tools among these patients.

"Accurate risk stratification markers would enable more intensive surveillance of the highest risk patients and less intensive surveillance of low-risk patients," said Singal, who was not involved in the research. "If validated in larger studies, radiomic features such as timing of contrast uptake could enable a precision surveillance approach to patients with cirrhotic nodules."

Jonathan M. Schwartz, MD, of the Children's Hospital at Montefiore in New York City, said, "This exciting observation that dynamic imaging criteria can be predictive of HCC has the potential to customize tumor surveillance and focus on patients at greatest risk for tumor development while reassuring patients at low risk."

But Schwartz, who was not involved in the research, cautioned that it is unclear whether the findings in Asian patients with hepatitis B infection would predict HCC in U.S. patients, in whom HCC is typically a complication of liver injury from hepatitis C, alcoholic liver disease, and non-alcoholic steatohepatitis.

"Furthermore, differences in body habitus may influence imaging findings," said Schwartz. "Hopefully these observations will be validated in a prospective cohort of U.S. patients."

The study from Kuang's group involved 39 consecutive patients (28 of whom were men) with 44 pathologically confirmed cirrhotic nodules (mean size 17.5 mm). Average age at enrollment was 60 years. All participants had underlying hepatitis B. After initial CEUS examination, patients had conventional ultrasound every 3 to 4 months.

Malignant transformation was identified by noninvasive diagnostic criteria for HCC or by rebiopsy, and biomarkers were identified from clinical and sonographic variables.

Over a median follow-up of 26.7 months, 14 nodules progressed to HCC -- six within 1 year, five within 2 years, and three within 3 years. The incidence of HCC per 100 person-years of follow-up was 18.2%. The other 30 nodules remained stable.

Study limitations included the use of noninvasive criteria to diagnose malignant transformation in most nodules. In addition, the authors said, reliable and consistent size measurements can be challenging and time-consuming in the case of irregularly shaped nodule or isoechogenicity.

Since CEUS was not the usual surveillance technique at the study site, the researchers could not analyze the dynamic evolution of the differences in contrast arrival time during the carcinogenic process. And because of the study's limited size and single-center retrospective design, confounding bias might have resulted from the use of two different ultrasound systems. Additionally, selection bias could not be avoided.

Lastly, since the underlying chronic liver disease was hepatitis B virus in all patients, multicenter prospective studies are needed to validate the current findings in other liver disease related to hepatitis C, alcohol, and cholestasis.

This study was supported by the Science and Technology Development Special Fund of Guangdong Province, China. Kuang and coauthors disclosed no competing interests, as did Singal and Schwartz.

StephenW

超声标记物可预测肝硬化患者的肝癌
造影剂摄取和结节生长时间与恶性肿瘤风险有关

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    作者：戴安娜·斯威夫特（Diana Swift），撰稿人
    十月29，2019

来自中国的一项小型回顾性研究表明，在有肝细胞癌（HCC）风险的肝硬化患者中，初次超声检查期间造影剂摄取的差异以及后续影像学检查中结节的增长率可能是无创性诊断为癌症进展的诊断指标。

在39例经超声造影确诊为肝硬化结节的患者中，结节与肝脏之间的造影剂到达时间差超过了半秒的预测转化为肝癌（HR 4.35，P = 0.011），Ming Kuang中国广州中山大学的医学博士，博士及其同事报道。

他们在《美国杂志》上写道：“对于有HCC风险的患者，CEUS结节与肝脏之间的造影剂到达时间差可用于对肝硬化结节的最终恶性转化风险进行分层，这可能有助于制定更具针对性的监测策略。”放射线学。

他们的发现还证实了初始结节大小是转化为肝癌的独立预测因子（HR 1.07，P = 0.019）。结合初始结节大小和造影剂到达时间的差异，得出接收器工作曲线下的面积为0.75（P = 0.002）。

在监视过程中，六个月内的相对增长率为30％或更高，或者在该跨度内的绝对增长率为5 mm或更高，证明了恶变的高度迹象。这些标记可以用作“阈值增长”指标，以识别恶性转化风险（特异性100％，阳性预测值100％）。

相反，不存在回声性变化和阈值增长，可以高度准确地排除恶性转化（敏感性为100％，阴性预测值为100％）。

Kuang的研究小组建议：“这些额外的影像学特征可能有可能被用作辅助甚至主要特征，以对CEUS LI-RADS系统中HCC的可能性进行分层。”

他们指出，80％的HCC在潜在的慢性肝炎或肝硬化患者中发展，并且大多数遵循多步骤过程，其中再生性结节可能会发育不良并演变为早期HCC。尽管不典型增生的程度也与恶性转化风险相关，但活检对于结节不是很可疑的肿瘤很少见，因此，作者指出，在初始检测时根据影像学发现对转化风险进行分层非常重要。

达拉斯的德克萨斯大学西南医学中心医学博士Amit Singal医师被问及对这项研究的看法时指出，肝硬化结节患者的HCC风险差异很大，突显了这些患者对风险分层工具的需求。

未参与这项研究的辛格说：“准确的风险分层标记将使对高风险患者的监视更加深入，而对低风险患者的监视则更加少。” “如果在较大的研究中得到证实，放射学特征（例如造影剂摄取的时间）可以为肝硬化结节患者提供一种精确的监测方法。”

纽约蒙特菲尔儿童医院的医学博士乔纳森·施瓦兹说：“这一令人振奋的观察表明，动态影像学标准可以预测肝癌，因此有可能对肿瘤进行个性化监测，并将重点放在肿瘤发生风险最大的患者身上同时使低风险患者放心。”

但是未参与该研究的施瓦兹警告说，目前尚不清楚亚洲乙型肝炎患者的发现是否可以预测美国患者的肝癌，其中，肝癌通常是丙型肝炎，酒精性肝病引起的肝损伤的并发症和非酒精性脂肪性肝炎。

Schwartz说：“此外，身体习性的差异可能会影响成像结果。” “希望这些观察结果将在美国患者的预期队列中得到验证。”

Kuang小组的研究涉及39例连续患者（其中28例为男性），其中44例经病理证实为肝硬化结节（平均大小为17.5 mm）。入学的平均年龄为60岁。所有参与者均患有基础乙型肝炎。在最初的CEUS检查后，患者每3-4个月进行常规超声检查。

恶性转化是通过HCC的非侵入性诊断标准或通过活检来确定的，并从临床和超声检查中确定了生物标志物。

在平均26.7个月的随访中，有14个结节发展为肝癌-一年内六个结节，两年内五个结节，三年内三个结节。每100人年随访的HCC发生率为18.2％。其他30个结节保持稳定。

研究局限性包括使用非侵入性标准来诊断大多数结节中的恶性转化。作者说，此外，在不规则形状的结节或等回声的情况下，可靠且一致的尺寸测量可能具有挑战性且耗时。

由于CEUS并不是研究现场常用的监视技术，因此研究人员无法分析致癌过程中造影剂到达时间差异的动态演变。并且由于研究的规模有限和单中心回顾性设计，使用两个不同的超声系统可能会造成混淆。另外，无法避免选择偏差。

最后，由于所有患者的潜在慢性肝病都是乙型肝炎病毒，因此需要进行多中心前瞻性研究来验证与丙型肝炎，酒精和胆汁淤积有关的其他肝病的最新发现。

这项研究得到了中国广东省科学技术发展专项基金的支持。与Singal和Schwartz一样，Kuang和合著者也没有透露任何竞争利益。