Abstract
Background
Hepatic metastases are the most common malignant tumors in the liver. Conventional contrast-enhanced CT examinations face challenges in distinguishing between benign and malignant atypical metastatic liver lesions with a diameter <3 cm, and evaluating their therapeutic efficacy remains particularly difficult.
Objective
To assess the clinical value of quantitative iodine analysis and spectral curves for diagnosing and differentiating liver metastases using gemstone spectral CT.
Methods
Among 915 patients with suspected hepatic metastases, 140 cases (87 males, 53 females) were pathologically confirmed. Primary malignancies included colorectal cancer (41 cases), gastric cancer (21 cases), lung cancer (35 cases), pancreatic cancer (31 cases), and breast cancer (12 cases). A total of 425 small lesions (<3 cm) were detected. CT values at lesion centers and peripheries were measured and compared against normal liver parenchyma. Quantitative iodine concentrations and spectral curve slopes were analyzed to evaluate differences in small hepatic metastases originating from distinct primary malignancies
Results
In the differentiation of hepatic metastatic subtypes, mean CT values demonstrated diagnostic utility in distinguishing colorectal cancer from gastric in AP (Arterial Phase, P = 0.001) in the Center of lesions.On the contrary, the quantitative analysis of focus edge iodine reliably distinguished the AP (P < 0.000), lung cancer (P = 0.023) and pancreatic cancer (P < 0.000) of colorectal cancer and gastric cancer. The results have statistical significance.
Conclusions
GSI(Gemstone spectral Imaging)-derived spectral curve slope and quantitative iodine analysis may facilitate differential diagnosis of small hepatic metastatic lesions with diverse primary origins, especially the source of colorectal cancer.
Introduction
Liver metastases represent the most prevalent malignant liver tumors. 1 However, differentiating small hepatic metastases (<3 cm) from benign lesions remains challenging. These small metastases often lack typical enhancement patterns, making them difficult to distinguish visually from benign lesions such as atypical cavernous hemangiomas. Moreover, detecting metastatic liver tumors with atypical imaging features and assessing treatment response pose significant clinical difficulties.
While angiography, PET, MRI, and Doppler ultrasonography can aid in diagnosing and differentiating metastatic liver tumors, CT remains the primary imaging modality for clinical diagnosis, differential diagnosis, and follow-up of hepatic metastases. 2 In recent years, gemstone spectral CT has been validated as an effective modality for detecting small hepatic lesions.3,4 Prior studies indicate that spectral CT may improve diagnostic accuracy in hepatic tumor characterization.5–7 Studies demonstrate that spectral CT parameters - including the energy spectrum curve, optimal monoenergetic images, and iodine quantification - can improve metastatic lymph node detection and lesion characterization.8,9 The technique, introduced by P.J.Lv et al., 10 is applied to distinguish liver hemangioma, focal nodule hyperplasia (FNH), or hepatic vascular smooth muscle tumors from hepatocellular carcinoma.6,11,12
Given gemstone spectral CT's unique tissue characterization capabilities, its diagnostic value for hepatic tumors warrants further investigation.12,13 However, to our knowledge, no comparative study has evaluated different gemstone spectral imaging (GSI) parameters—such as iodine concentration and spectral curve slope—for differentiating metastatic liver tumors.This study aims to detect early-stage small hepatic metastases and characterize gemstone spectral imaging (GSI) features of metastases originating from different primary tumors.We present the following article in accordance with the MDAR reporting checklist.
Gemstone spectral CT enables scanning at 40–140 keV, allowing extraction of monoenergetic images at any energy level within this range. This optimizes lesion-to-background contrast while reducing beam-hardening artifacts, ensuring superior image quality.Gemstone spectral CT acquires mixed-energy images, monoenergetic images, and material decomposition images simultaneously through a single volumetric scan. This facilitates high-resolution spectral analysis and enables a multi-parameter diagnostic approach. The technology effectively minimizes hardening artifacts and enhances lesion detection in parenchymal organs, significantly improving tumor localization, characterization, and staging accuracy.
Materials and methods
Study population
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the institutional review board of Tongji hospital (ID:TJ-IRB20181123), and the requirement for formal informed consent was obtained from all patients. A total of 915 consecutive patients were enrolled in this study, and all patients underwent a CT scan (Discovery CT 750 HD; GE Healthcare, Waukesha, Wis) to evaluate metastatic hepatic tumors between December 2018 and December 2021. The inclusion criteria were as follows: (a) Solid hepatic tumors with a cancer history or suspected metastatic tumors; (b) CT GSI was performed in patients before the treatment of hepatic tumors; (c) histopathologic diagnosis or clinical follow-up was confirmed after the completion of the CT imaging examination according to current WHO guidelines. The exclusion criteria were as follows: (a) CT data were not available owing to patients’ movement artifacts; (b) the maximum diameter of the solid tumor was >3 cm.
The study excluded 192 patients without pathological confirmation, 536 patients with solid tumors exceeding 3 cm, 32 patients with rare metastasis subtypes (including 7 esophageal, 6 papillary RCC, 4 cervical/nasopharyngeal/ovarian cancers each, 3 renal carcinomas, and single cases of bladder cancer, melanoma, duodenal cancer, and sinus cancer), and 15 patients lacking histopathological diagnosis, ultimately enrolling 140 eligible patients for analysis (see Figure 1 for the enrollment flowchart).

Flow diagram showing the lesion exclusion criteria and final patient cohort.
All examinations were performed on a dual-energy 64 slice multi-detector CT system (Discovery CT 750 High Definition; GE Healthcare Technologies, Waukesha, Wisconsin, USA). The hepatic arterial phase (AP) was scanned by bolus tracking (Smartprep; GE Healthcare Technologies) when the threshold enhancement of 120 HU was reached in the abdominal aorta. The scanning of the portal venous phase (PVP, Portal Venous Phase;) was started 30 s after completing the AP scanning. Non-ionic iodinated contrast agent (Iopromide 370 mg I/mL) was injected via the antecubital vein using an 18-gauge intravenous cannula and a double tube high-pressure syringe (Stellant D; Medred Co., Pittsburgh, Pennsylvania, USA) followed by 20 mL of physiological saline, each at an injection rate of 3–4 mL/s. The patients were in the supine position. The total contrast volume was 0.8 mL/kg. AP and PVP scanning was performed in the spectral imaging mode with fast tube voltage switching between 140 kVp and 40 kVp. Other CT imaging parameters were as follows: rotation time 0.6 s; matrix 512 × 512; heli-cal pitch 0.984:1; slice thickness/interval 0.625 mm; and table speed 39.37 mm/rotation. Three kinds of images were reconstructed from the single spectral CT acquisition for analysis: conventional polychromatic images were obtained at 140 kVp, iodine-based and water-based, monochromatic images, and material-decomposition images were obtained at energies ranging from 40 to 140 keV.
Image processing and analysis
All CT data was transferred from the picture archiving and communication system (PACS) to a workstation (AW4.6; GE Healthcare). Two independent blinded CT scan technologists with 6 and 16 years of experience reviewed the quality of all images. Regions of interest (ROI) were drawn in the central and peripheral regions of hepatic metastatic lesions in AP and PVP by three experienced imaging diagnosicians. Normal liver tissue was analyzed as the control at the same time. The parameters derived from the analysis included: CT value, iodine value, and energy spectrum curve slope characteristics (λHU). We found that the slope of the spectral curve was higher at HU = 60. In general, the curve between 100 Kev and 140 Kev was almost flat, so we chose a series of high-slope 60 and 100 Kev sensitivity increases representing the spectral attenuation curves of different slopes over the entire range (details are provided in Figure 2). Receiver operating characteristic (ROC, Receiver Operating Characteristic) curves were obtained based on iodine quantitative analysis. According to the formula λHU = [CT60-kev1-CT100 KeV] / 60, the slope of the curve is calculated as the CT attenuation difference of two energy levels (60 KeV and 100 KeV) divided by the energy difference of the spectral HU curve (60 KeV).

Illustration of the calculation of the ratio. A. The primary imaging; To draw two vertical lines: x = 60 and x = 100, get two intersections A and B; To get the straight line which runs through intersections A and B. The slope of straight line AB served as the slope of the primary curve in imaging A.
Statistical analysis was performed with statistical software (PASW version 19.0, SPSS). One-way ANOVA was utilized to compare the CT value, the iodine value, and λHU between the 5 different hepatic metastatic tumor subtypes. Multiple comparisons between subtypes were accomplished using receiver operating characteristic curve. Sensitivity curve was used to compare the CT value, the iodine value, and λHU between the central regions and peripheral regions of hepatic metastatic lesions in the AP and PVP. P < 0.05 was considered statistically significantand with Bonferroni correction applied for multiple comparisons.
Results
Patient and lesion characteristics
This prospective study enrolled 140 patients (mean age 55.2 ± 12.3 years; range 26–81 years; 76 males, 64 females) with histologically confirmed hepatic metastases, comprising 109 lesions from 41 colorectal cancers, 73 from 31 pancreatic cancers, 58 from 21 gastric cancers, 31 from 35 lung cancers, and 26 from 12 breast cancers. Quantitative analysis (Figure 3) revealed significant differences (p < 0.01) in CT attenuation, iodine density, and λHU values between lesion cores, margins, and adjacent parenchyma during both arterial and portal venous phases, with pancreatic metastases demonstrating characteristic spectral curve patterns (Figures 4–6). The spectral CT parameters provided superior discriminative capacity for small (<3 cm) metastases compared to conventional enhancement CT, particularly through iodine quantification. Figure 4A–B, Figure 5A–C, and Figure 6A–F show the features of the colorectal, pancreatic, gastric, lung, and breast metastases on CT values, iodine values, and λHU, ROC curve, respectively.

A 56-year-old male patient with liver metastases from pancreatic cancer with abdominal pain. A: Routine computed tomography (CT) images showed that the CT values of the center, the marginal part of the lesion, and the normal liver tissue in the arterial phase were 19.88 HU, 49.56 HU, and 59.84 HU, respectively. B: Iodine base chart showed that the iodine values in the center of the lesion, the marginal part, and the normal liver tissue were 1.32 mg/mL, 5.08 mg/mL, and 4.48 mg/mL, respectively. C: The energy spectrum curve showed that the slopes of the energy spectrum curve of the center of the lesion, the edge part, and the normal liver tissue in the arterial phase were 0.181, 0.809, and 0.382, respectively. D: CT values of the center, the marginal part of the lesion, and the normal liver tissue in the venous phase were 20.2 HU, 48.72 HU, and 67.64 HU, respectively. E: Iodine values in the center, the edge of the lesion, and the normal liver tissue at the venous stage were 1.64 mg/mL, 4.6 mg/mL, and 6.28 mg/mL, respectively. F: The slopes of the energy spectrum curve of the center, the edge, and the normal liver tissue in the F venous stage were 0.423, 0.634, and 0.058, respectively. Note:The arrows indicate the measured hepatic metastatic mass from pancreatic cancer.

Receiver operating characteristic (ROC) curve analysis of computed tomography (CT) values in 5 hepatic metastatic tumor subtypes. CT values could only distinguish colorectal cancer from gastric cancer hepatic metastasis in the centers of the lesions (Figure 4A: Blue - (lesion center) - Colorectal cancer vs gastric cancer (AP); Green - (center of lesion) - Colorectal cancer vs gastric cancer (PVP)), and colorectal cancer from lung cancer hepatic metastasis in peripheral regions (Figure 4B: Blue (edge of lesion) - Colorectal cancer vs lung cancer (PVP)).

Receiver operating characteristic (ROC) curve analysis of iodine values in 5 hepatic metastatic tumor subtypes. Iodine values could distinguish colorectal cancer from gastric cancer hepatic metastasis in the arterial phase, both in peripheral regions and lesion centers (Figure 5A: Blue - (focus center) - colorectal cancer vs gastric cancer (AP); Green - (focus edge) - colorectal cancer vs gastric cancer (AP)). It also distinguished colorectal cancer from pancreatic cancer (Figure 5B: Blue - (focus edge) - colorectal cancer vs pancreatic cancer (AP) Green - (focus edge) - colorectal cancer vs pancreatic cancer (PVP)) and colorectal cancer from lung cancer, mainly in the peripheral regions (Figure 5C: Blue - (center of lesion) - Colorectal cancer vs lung cancer (PVP) Green - (edge of lesion) - Colorectal cancer vs lung cancer (AP) Yellow - (edge of lesion) - Colorectal cancer vs lung cancer (PVP)).

Receiver operating characteristic (ROC) curve analysis of the energy spectrum curve slope (λHU) in 5 hepatic metastatic tumor subtypes. The λHU could distinguish almost all the pairs of hepatic metastases, including colorectal cancer vs. gastric cancer (Figure 6A: Blue - (lesion center) - Colorectal cancer vs gastric cancer (AP); Green - (lesion edge) - Colorectal cancer vs lung cancer (AP)), colorectal cancer vs. lung cancer (Figure 6B: Blue - (lesion center) - Colorectal cancer vs lung cancer (AP); Green - (lesion center) - Colorectal cancer vs lung cancer (PVP); Yellow - (lesion edge) - Colorectal cancer vs lung cancer (AP); Purple - (focus edge) - colorectal cancer vs lung cancer (AP)), gastric cancer vs. pancreatic cancer (Figure 6C: Blue - (focus edge) - gastric cancer vs pancreatic cancer (AP); Green - (focus edge) - gastric cancer vs pancreatic cancer ((PVP)),), pancreatic cancer vs. lung cancer (Figure 6D: Blue - (focus center) - colorectal cancer vs lung cancer (PVP)), and gastric cancer vs. lung cancer (Figure 6E: Blue - (focus edge) - gastric cancer vs lung cancer (PVP)).
The CT values in the center and the periphery of the metastatic lesions in the AP and PVP in the GSI images were measured in 5 metastatic liver tumors with the LSD test (Table 1). In the center of the lesions, only the differences between colorectal cancer and gastric cancer were statistically significant in AP (P < 0.001) and PVP (P < 0.000). In the peripheral region of the lesions, only colorectal cancer and lung cancer showed a significant difference in CT value in PVP (P = 0.04). All the other groups were not statistically significant (all P > 0.05). Quantitative analysis of iodine concentrations in central and peripheral tumor regions across arterial (AP) and portal venous (PVP) phases (Table 2) demonstrated distinct patterns: In central regions, colorectal cancer metastases showed significantly higher iodine uptake than gastric cancer during AP (P < 0.001) and lung cancer during PVP (P < 0.000), with no other intergroup differences reaching significance (all P > 0.05). Peripheral region analysis revealed more pronounced differentiation, with colorectal cancer exhibiting statistically greater iodine values versus gastric cancer in AP (P = 0.006), pancreatic cancer in both AP (P < 0.000) and PVP (P = 0.03), and lung cancer in both AP (P = 0.023) and PVP (P = 0.02). No other comparative analyses achieved statistical significance (all P > 0.05), suggesting these specific iodine uptake patterns may serve as discriminative features for metastasis origin identification.
Comparison results of the CT values in 5 hepatic metastatic tumor subtypes.
Comparison results of the CT values in 5 hepatic metastatic tumor subtypes.
Comparison results of the iodine value in five hepatic metastatic tumor subtyes.
Multiphase contrast-enhanced CT is the primary imaging modality for liver tumor differentiation, but its ability to identify primary origins of hepatic metastases remains unclear; our results show limited diagnostic value of mean CT attenuation values in determining metastatic lesion origins due to (1) heterogeneous signal integration from tumor tissue, vascular enhancement, necrosis, and peritumoral inflammation, and (2) resultant obscuring of histology-specific imaging signatures, indicating that advanced quantitative imaging techniques are needed to characterize distinct radiomorphological patterns of metastases from different primary sites.
Recent studies have found that the iodine value of GSI CT can detect slight iodine concentration changes in tumor tissues and reflect the histopathological features more efficiently.6,14,15 For example, P.J.Lv reported that quantitative analysis of the iodine value could distinguish liver cancer from FNH, liver cancer from hepatic angiomyolipoma, and small hepatocellular carcinoma from small hepatic hemangioma. They also reported that CT spectral imaging enables material decomposition and analysis of several additional quantitative CT imaging parameters—namely, the normalized iodine concentration (NIC) and the lesion-to-normal hepatic tissue ratio (LNR)—that may be used to improve the sensitivity for differentiating hydropericardium hepatitis syndrome (HHs) from hepatocellular carcinoma (HCC) in two-phase scanning. At the same time, it may increase the sensitivity for differentiating small hemangiomas from small HCCs in two-phase scanning.6,10,11 Iodine value analysis can also be employed to identify stomach, lung, pancreas, mediastinum, cervix, adrenal, neck, prostate, and other benign and malignant tumors.2,16–24
The spectral curve is the attenuation of matter or structure with the X-ray energy curve. It has been reported that the spectral curve can reveal the characteristics of the material energy attenuation; thus, it reflects the characteristics of the lesion.12,24 However, at this point, no extensive research has been reported on the role of the spectral curve in the differentiation of hepatic metastases. The slope of the energy spectrum curve can identify the origins of the tumors more accurately. It can semi-quantitatively determine the similarity of lesion components, such as the similarity between metastases and primary lesions. In a limited disease classification, similar spectral curves may reflect the same or similar pathological class. This feature may help to identify the primary sources of the tumors.2,25–30
Compared with the CT value, the iodine value is a more valuable parameter and can better identify tumors of different origins. The possible reason is that the iodine value can better reflect the tumor's blood supply status than the CT value. During our study, compared with metastases from other sources, the iodine value of liver metastases from colon cancer was significantly different from the iodine value of most other metastatic tumors (except breast cancer). This may be because colon cancers are mainly the epithelium adenocarcinomas of the digestive duct, and most of them enhance with typical features (target signs and bull's eye sign). However, other tumor origins lack such a characteristic. Therefore, the iodine value does not help diagnose other cancer types, such as lung cancer, gastric cancer, pancreatic cancer, and breast cancer. Further investigations may be required.
We found that some atypical metastatic liver tumors were often difficult to distinguish from small metastatic liver tumors (diameter <3 cm). Although the hepatic artery supplies most hepatic metastases, a few small hepatic metastases (diameter <3 cm) are partially supplied by the Portal vein system. As a result, some small metastatic liver tumors do not have the enhancement signs of typical metastatic liver tumors, and metastatic liver tumors of different sources, such as breast cancer and RCC of the same rich blood supply origin, have the best imaging in the AP, showing peripheral ring or mixed enhancement. Colon cancer and gastric cancer were the sources of blood deficiency, and PVP imaging was the best. Metastatic liver tumors of this origin type have uniform enhancement characteristics and are difficult to distinguish. Therefore, traditional CT enhancement still has some defects. In this paper, by comparing and analyzing the characteristics of the CT value, iodine value, and λHU of small metastatic liver tumors from different sources, it was found that quantitative analysis of the CT iodine value could distinguish colorectal cancer versus gastric cancer, rectal cancer versus pancreatic cancer, and rectal cancer versus lung cancer.
In contrast, general CT could only distinguish colorectal cancer versus gastric cancer and gastric cancer versus lung cancer. Comparative analysis with Table 2 results demonstrates the superior diagnostic performance of spectral CT iodine quantification.The λHU is highly consistent with the iodine value (Tables 2 and 3), which further proves its credibility. With the help of the area under the ROC curve, we can conclude that colorectal cancer has significant specificity compared with several other sources of liver metastases. In primary tumor is not clear or no biopsy cases, or those who are not typical, lack of blood supply small metastatic liver tumors conventional CT enhancement is difficult to distinguish.
Comparison results of the energy spectrum curve slope (λHU) in 5 hepatic metastatic tumor subtypes.
Comparison results of the energy spectrum curve slope (λHU) in 5 hepatic metastatic tumor subtypes.
Another noteworthy finding in our study was that when comparing the diagnostic efficacy of hepatic metastases from different primary origins, colorectal cancer liver metastases consistently demonstrated the largest area under the ROC curve (AUC) compared to gastric and lung cancer metastases (Table 4 [0.697, 0.777, and 0.804]). This observation indicates that a larger AUC corresponds to greater diagnostic significance.The possible reason is that compared with other tumors, colorectal cancer liver metastases have different imaging characteristics. The classical “bull eye sign” and “target sign” may reflect these imaging features. The λHU may make it easier to quantitatively distinguish liver metastases from colorectal cancer and other liver metastases. Overall, energy spectrum analysis of metastatic liver tumors with distinct sources may provide some guidance in identifying the nature and origin of the lesions.
ROC analysis of CT value, iodine value, and spectrum curve slope (λHU) in 5 hepatic metastatic tumor subtypes.
Our study had several limitations. First, the small sample size requires future validation with larger cohorts to strengthen statistical power. Second, the retrospective design introduced inherent selection bias. Third, measurements were influenced by region-of-interest size, necessitating methodological refinement. Fourth, partial lesion sampling rather than comprehensive ROI analysis may have caused sampling error. Additionally, primary tumor classification was limited by insufficient pathological data. Finally, histopathology-CT correlations were excluded as they fell beyond our study scope.
In this study, using hepatic metastatic lesion subtype analysis, the mean CT value only detected colorectal from gastric metastasis and lung from gastric metastasis. However, there was no significant difference between other pairs regarding the mean CT value (Table 1). In this study, through comparative iodine value analysis of the 5 common metastatic liver tumors, it was observed that iodine values could be used to identify colorectal cancer versus gastric cancer, colorectal cancer versus lung cancer, and colorectal cancer versus pancreatic cancer (Table 2). And the detailed statistics about the different iodine values across different cancer sites: We concluded that Colorectal cancer VS Cancer of the stomach (Center lesions A Iodine value with :37.41 ± 10.75 mg/mL.), Colorectal cancer VS Pancreatic cancer (peripheral regions A and peripheral regions V, Iodine value with :10.22 ± 3.98 mg/mL and 17.73 ± 10.23 mg/mL.), Colorectal cancer VS Lung cancer (peripheral regions A and peripheral regions V, Iodine value with :10.32 ± 4.36 mg/mL and 18.58 ± 6.11 mg/mL.). Our findings provide a reliable basis for avoiding invasive procedures in tumor patients through spectral CT iodine quantification of small hepatic metastases (<3 cm), particularly facilitating early diagnosis and treatment of metastases from different primary origins, especially the source of colorectal cancer. This study highlights the need to develop more advanced techniques with expanded sample sizes to differentiate small metastases from various primary sites and even distinct pathological subtypes of the same origin. Due to limited sample size, small hepatic metastases of rare subtypes (lacking statistical representativeness and characteristic imaging features) were excluded. Future studies with expanded cohorts and optimized techniques to systematically characterize these lesions will be of significant clinical value.These advancements will establish a critical foundation for breakthroughs in clinical management and early-stage stratification, ultimately improving patient survival outcomes.
In summary, our quantitative analysis of GSI iodine values combined with auxiliary parameters may facilitate the diagnosis of small lesions and help determine the origin of metastatic liver tumors, especially the source of colorectal cancer.
Footnotes
Abbreviations
Ethical considerations and consent to participate
We confirm that this study complies with all regulations. This retrospective study was approved by the institutional review board of Tongji hospital (ID:TJ-IRB20181123), and the requirement for formal informed consent was obtained from all patients.
Consent for publication
All the listed authors have seen and approved the submitted manuscript.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was supported by The Chinese National Natural Science Funds (No. 81501447, 81771801) and Hubei Provincial Natural Science Foundation (No. 2025AFD863).
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data availability statement
The datasets analyzed during the current study are available from the corresponding author on reasonable request.
