Diagnosis and management of indeterminate liver nodules in patients with cirrhosis

Abstract

BACKGROUND

HCC is the third cause of cancer-related mortality worldwide and one of the leading causes of cancer-related death in patients with compensated cirrhosis. Although HCC has a dismal prognosis with 5-year survival below 20%, the prognosis strongly depends on the tumor stage. Patients with early-stage HCC have a median survival over 10 years, compared to 1–3 years for those with more advanced tumor burden. Professional society guidelines recommend HCC surveillance in patients with cirrhosis, given associations with early tumor detection, curative treatment receipt, and reduced cancer-related mortality.¹

Surveillance is performed using semi-annual ultrasound and alpha-fetoprotein, with diagnostic contrast-enhanced CT or MRI recommended for any patients with positive surveillance results.² HCC can be diagnosed radiographically without the need for confirmatory biopsy in the setting of characteristic imaging (eg, arterial phase hyperenhancement and delayed washout). However, indeterminate liver nodules (ILNs) are commonly observed in diagnostic imaging and can pose a diagnostic and management dilemma.

Diagnosis and natural history of ILNs

The Liver Imaging Reporting and Data System (LI-RADS) classifies liver observations on diagnostic imaging for patients at risk for developing HCC, that is, those with cirrhosis, chronic HBV infection, or a history of HCC. LI-RADS uses an ordinal scale from LR-1 (definitely benign) to LR-5 (definitely HCC) and LR-5 (definite malignancy) (Figure 1). Observations with some but not all imaging features of LR-5 are classified as LR-3 or LR-4 and are considered as indeterminate liver nodules (ILNs). ILNs are commonly encountered in clinical practice, with false positive or indeterminate results observed in up to 20% of patients undergoing HCC surveillance, of whom 25%–30% are found to have ILNs on diagnostic imaging.^3,4 However, clinical evaluation of ILNs is variable, with some patients undergoing close monitoring with cross-sectional imaging every 3–6 months and others not having any follow-up imaging.⁵ Surveillance underuse can be related to multiple reasons, including provider uncertainty about managing these patients and failing to order repeat imaging, patients having limited access to imaging or other logistical barriers, and costs of surveillance.

FIGURE 1.

Summary of LI-RADS categories and recommended management with diagnostic CT/MRI. Note: *Major features represent: enhancing capsule appearance, nonperipheral washout, threshold growth (size increase of a mass by ≥ 50% in 6 mo) **LI-RADS categories not included in figure: LR-NC: Noncategorizable (due to image degradation or omission), LR-TIV: Malignancy with tumor in vein. Abbreviation: APHE, arterial phase hyperenhancement.

Several studies have highlighted that LR-3 and LR-4 observations vary in pathology and natural history. A single-center cohort study reported over 50% of LR-3 observations had no histologic correlate, although 31% were HCC and 10% had a dysplastic nodule.⁶ In contrast, two-thirds of patients with LR-4 observations had HCC on explant, 6% had a dysplastic nodule, and 28% had no histologic correlation.⁶ Beyond the risk of prevalent HCC, ILNs also carry a high but variable risk of incident HCC during follow-up, with the strongest risk factor for HCC being the type of ILN (LR-3 vs. LR-4 observation). A systematic review demonstrated that 11.1%–24.5% of patients with LR-3 observations develop HCC over time, compared to 30.9%–71.0% of LR-4 observations.⁷ Most patients with LR-4 observations who develop HCC do so in the first 6 months of follow-up, highlighting that most HCC are prevalent. Conversely, a regression can be observed in some patients, including LR-4 observations being downgraded to LR-3 observations or LR-3 observations no longer being observed.

There are few patient-level or observation-level factors consistently associated with HCC development in patients with ILNs (Table 1).⁷ Patient-level factors potentially associated with increased HCC include older age, male sex, higher alpha-fetoprotein (AFP) levels, viral etiology, and history of HCC; observation-level risk factors include the maximum diameter of the ILN, threshold growth, T2 hyperintensity, and visibility on ultrasound. Clinical risk factors alone likely do not have sufficient predictive accuracy to guide tailored surveillance or management strategies, highlighting a potential role for radiomics based on imaging features of the ILN, blood-based biomarkers, or liquid biopsy techniques.^8,9 Early work using artificial intelligence methods, such as convoluted neural networks, can help identify LR-3 and LR-4 observations, particularly when incorporating LI-RADS ancillary features; however, there have been fewer studies examining risk stratification among patients with ILNs.¹⁰

TABLE 1.

Factors associated with the development of HCC in patients with ILNs⁷

Patient-level factors	Observation-level factors
Older age	Diameter > 1 cm
Male sex	Delayed washout
Viral liver disease etiology	Threshold growth
Co-existing or history of HCC	Mild-to-moderate T2 hyperintensity
AFP > 10 ng/mL	Arterial phase hyperenhancement
LI-RADS v2017 vs. v2018	Interval growth
Follow-up duration	Presence of pseudocapsule

Abbreviations: AFP, alpha-fetoprotein; LI-RADS, Liver Imaging Reporting and Data System.

Management of ILNs

Given an increased risk of HCC, patients with ILNs are recommended to undergo close monitoring with or without biopsy. AASLD recommends repeat multi-phase CT or contrast-enhanced MRI every 3–6 months in patients with LR-3 observations, although ultrasound-based surveillance may be reasonable to consider in select patients with sub-centimeter LR-3 observations.² In patients with LR-4 observations, multidisciplinary discussions regarding treatment implications can help decide optimal follow-up, including repeat imaging within 3 months or immediate biopsy.² A routine biopsy of every LR-4 observation is not recommended given the risk of bleeding, tumor seeding, and false negative results; however, a biopsy may be warranted depending on factors including the size of the observation, transplant eligibility, and tumor marker levels. For example, a biopsy could be important for patients in whom liver transplant exception points would be awarded (eg, patients with decompensated cirrhosis and LR-4 observation ≥2 cm in maximum diameter). Similarly, a biopsy may be considered in patients with marked elevations in alpha-fetoprotein or other tumor markers. Empiric treatment with local ablation is occasionally considered in transplant-ineligible patients if there is high suspicion for HCC, although this must be weighed against the physical, psychological, and financial harms of overdiagnosis in a subset of patients.¹¹

SUMMARY

Indeterminate liver nodules (LR-3 and LR-4 observations) are commonly observed in clinical practice and have an intermediate, albeit variable, risk of HCC. These patients should be monitored closely with contrast-enhanced imaging every 3–6 months in most cases, although biopsy plays an important role in select patients.

FUNDING INFORMATION

Amit G. Singal’s research is conducted with support from National Cancer Institute U01 CA271887. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health. The funding agencies had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation of the manuscript.

CONFLICTS OF INTEREST

Amit G. Singal has served as a consultant or on advisory boards for Bayer, FujiFilm Medical Sciences, Exact Sciences, Roche, Glycotest, Universal Dx and GRAIL. Mounika Kanneganti has no conflicts to report.

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