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Review

Imaging of Liver Metastases from GEP-NETs: A Narrative Review

by
Alessandro Posa
1,*,
Enza Genco
1,
Pierluigi Barbieri
1,
Mario Ariano
1,
Marcello Lippi
1,
Alessandro Maresca
1 and
Roberto Iezzi
1,2
1
Department of Diagnostic Imaging, Radiation Oncology, and Hematology, A. Gemelli University Hospital Foundation, IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
2
Faculty of Medicine and Surgery, Università Cattolica del Sacro Cuore sede di Roma, Largo Francesco Vito 1, 00168 Rome, Italy
*
Author to whom correspondence should be addressed.
Onco 2025, 5(3), 36; https://doi.org/10.3390/onco5030036
Submission received: 27 April 2025 / Revised: 6 July 2025 / Accepted: 11 July 2025 / Published: 17 July 2025
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Simple Summary

To provide an overview of how liver metastases from gastro-entero-pancreatic neuroendocrine tumors look in diagnostic imaging examinations (i.e., computed tomography, magnetic resonance imaging, ultrasound, and PET-TC) and how to differentiate them from other focal liver lesions based on their characteristics. Detection and differential diagnosis of these lesions are crucial to make the best therapeutic choice for each patient.

Abstract

Prompt and accurate identification of liver metastases from neuroendocrine tumors, arising from the gastrointestinal system and from the pancreas, through the means of both anatomical and functional diagnostic imaging techniques is mandatory. A patient’s prognosis and treatment planning are dependent on these diagnostic procedures. The aim of this narrative review is to depict the common appearance of liver metastases, as well as to depict atypical imaging patterns. Moreover, this review will cover the differential diagnosis between liver metastases from neuroendocrine tumors and other primary and secondary malignant liver lesions, as well as benign liver lesions.

1. Introduction

Neuroendocrine tumors (NETs) represent a heterogeneous group of neoplasms that originate from the cells of the neuroendocrine system and are characterized by variable degrees of malignancy. NETs account for around 0.5% of all cancers, and for approximately 1.5% of all gastro-entero-pancreatic tumors, with a slight male predominance [1,2]. Around 60–70% of NETs can be found in the gastro-entero-pancreatic (GEP) system. In particular, GEP-NETs are primarily located in the pancreas (in the Islets of Langerhans), stomach, duodenum, appendix, jejunum, and colon, as well as in the rectum [3]. More than 50% of GEP-NETs are often discovered incidentally, either during surgical interventions or pre-procedural diagnostic imaging for other purposes, or after incidental diagnosis of distant metastases [4,5].
In the past 2 decades, the World Health Organization (WHO) classifications have undergone significant changes, especially for digestive NETs. These changes have occurred alongside the identification of new markers for various applications, as in the diagnostic (i.e., to differentiate or identify a primary GEP-NET) and prognostic field, with the publication of an increasing number of studies utilizing high-throughput genomic and/or transcriptomic technologies [6]. The majority of GEP-NETs occur sporadically, while less than 10% are linked to hereditary syndromes [7]. GEP-NETs may occur at any age: the highest incidence of GEP-NETs is among individuals 50 years old and above [8].

1.1. Clinical Manifestation

GEP-NETs are generally categorized into functional and non-functional tumors. Most GEP-NETs are non-functional tumors and may produce inactive substances like chromogranin, calcitonin, ghrelin, neuron-specific enolase, or pancreatic polypeptide, without a clinical syndrome associated with hormone secretion [9]. Due to the non-specific clinical symptoms, non-functional GEP-NETs typically present with mass effect symptoms as the primary tumor grows, such as abdominal pain, early fullness, as well as obstructive jaundice, or as the disease spreads to other organs [10,11,12]. In contrast, functional GEP-NETs have the characteristic ability to produce and secrete hormones and neuropeptides that cause clinical syndromes [13,14,15,16,17,18]. A smaller percentage of GEP-NETs (about 30%) are the functioning type and can show earlier manifestation due to clinical symptoms. Among functioning GEP-NETs, insulinomas (which present with symptoms of hypoglycemia such as palpitations, diaphoresis, altered mental status) and gastrinomas (which determine Zollinger-Ellison’s syndrome with peptic ulcer disease, gastroesophageal reflux disease, and chronic diarrhea) are the most common types of pancreatic NETs, while carcinoid syndrome (characterized by episodic flushing, wheezing, and diarrhea) is the most common clinical syndrome associated with NETs and is determined by serotonin secretion from small-bowel NETs [13,18].

1.2. Grading and Diagnostic Implications of Liver Metastases

All GEP-NETs should be graded based on the mitotic count and the assessment of proliferation index (Ki-67 index) at immunohistochemical evaluation of the tumor tissue [19]. According to the grading system made by the WHO and the European Neuroendocrine Tumor Society (ENETS), well-differentiated GEP-NETs can be divided into three grades, namely grade 1 (with less than 2/10 mitoses per high power field (HPF) and/or Ki-67 less than 2%), grade 2 (with 2/10 to 20/10 mitoses per HPF and/or Ki-67 ranging from 3 to 20%), and grade 3 (with more than 20/20 mitoses per HPF and/or Ki-67 greater than 20%), while poorly differentiated GEP-NETs (so-called neuroendocrine carcinomas—NECs) are characterized by more than 20/20 mitoses per HPF and/or Ki67 greater than 20% (often higher than 70%) [20,21]. Due to the physiological drainage of the gastrointestinal tract and pancreas in the portal vein, the hematogenous diffusion of GEP-NET neoplastic cells to the liver, determining metastases, is quite common. In particular, dissemination from a GEP-NET to the liver parenchyma occurs in more than 40% of these patients [4,22]. Liver involvement at the time of diagnosis, in contrast to metastatic disease in other sites, has been shown to be correlated to the prognosis and is considered a parameter of great importance for the patient’s treatment and overall management [23]. Other metastatic sites of GEP-NET metastases are represented by the abdominal and mediastinal lymph nodes, as well as the peritoneum and bone. More rarely, the metastases from GEP-NETs can involve the lungs, and even more rarely, the spleen, the brain, the thyroid and the pituitary glands, the breast, the heart, the meninges, and the orbit [24].
An accurate and timely diagnosis is of great importance to impact the prognosis of patients with liver metastases from GEP-NETs, as a late diagnosis or a misdiagnosis can result in a higher tumor burden, which consequently can hinder curative treatment and also lead to unsatisfactory treatment outcomes. Moreover, a high liver tumor burden may compromise liver function, limiting the treatment options, with an impact on the patient’s quality of life. Computed tomography (CT) is a useful tool to detect the primary tumor and identify metastatic sites in GEP-NETs. Magnetic Resonance Imaging (MRI) represents an added value in the characterization of both the primary lesion and the liver metastases. Several studies tried to identify the imaging characteristics to estimate the grade of the lesions, in particular, in the distinction between well-differentiated and poorly differentiated tumors. Diagnosis should ideally be made as soon as the clinical symptoms appear, to grant prompt treatment, also considering that some patients could be suitable for surgical resection of liver metastases or for locoregional treatments such as ablation or endovascular therapies (i.e., transarterial embolization—TAE, or chemoembolization—TACE, as well as transarterial radioembolization—TARE) [25]. It is also of great importance to perform a good differential diagnosis between liver metastases from GEP-NETs and other primary and secondary liver cancers (i.e., hepatocellular carcinoma, metastases from breast or melanoma), as well as benign liver lesions (i.e., hemangiomas, focal nodular hyperplasia). The aim of this narrative review is to comprehensively review the current knowledge on imaging of liver metastases from GEP-NETs, with a special emphasis on a multi-diagnostic approach to assess metastases detection, differential diagnosis, and prognosis.

2. Diagnosis

Diagnostic imaging techniques play a major role in the diagnostic work-up of GEP-NETs, both in the identification of the primary tumor, in its characterization and prognosis determination, as well as in the locoregional and distant staging. Imaging is also crucial in the diagnosis of a cancer predisposition syndrome and is mandatory in guiding the multidisciplinary choice of the most appropriate treatment, when performing treatment planning, and also in follow-up of treated patients. Patient prognosis is related to the metastatic tumor burden, as liver metastases from NETs can dramatically impact patient prognosis, with a 5-year overall survival ranging from 30 to 70% based on tumor grade and burden: a high tumor burden related to the liver volume is linked to a lower patient survival and a worse treatment response [20].
The diagnostic imaging of GEP-NETs is very rich and varied, combining conventional techniques of morphological imaging (ultrasound—US, CT, MRI) with functional imaging using radiopharmaceutical imaging techniques as positron emission tomography (PET), and endoscopic or laparoscopic exploration [26]. Liver metastases from GEP-NETs are often incidentally detected during first-level imaging examinations, such as a US, sometimes even before identification of the primary tumor. A US is useful for a general assessment of the liver parenchyma and tumor burden. However, lesion characterization based on a US alone requires integration with contrast-enhanced techniques, like contrast-enhanced ultrasound (CEUS), and correlation with second-line imaging modalities like CT and/or MRI. Accurate characterization and staging of liver metastases from GEP-NETs primarily rely on CT and PET-CT with dedicated tracers; the latter is also essential for assessing the metabolic activity of the disease. These imaging techniques are equally valuable during follow-up and for evaluating treatment response, as they allow assessment of tumor burden, lesion vascularity, and metabolic activity. MRI, on the other hand, is a particularly useful tool for lesion characterization and differential diagnosis—especially in cases where CT findings are inconclusive—as well as for evaluating the extent of liver involvement, notably in cases of small metastases.

2.1. US and CEUS

Grey-scale US imaging is a valuable first-line imaging modality for the abdomen and is often responsible for the incidental detection of focal liver lesions, pancreatic masses, or abdominal lymphadenopathy. It can also be useful as a tool for initial characterization of focal liver lesions, although not specific. In a US, liver metastases from GEP-NETs can appear as multiple hypoechoic and well-circumscribed lesions. However, US appearance can be highly heterogeneous (Figure 1).
CEUS can help in increasing the diagnostic accuracy of the US, with a high sensitivity, estimated at approximately 99%, providing a real-time dynamic evaluation of arterial and portal-venous enhancement of the lesions and of the surrounding healthy liver parenchyma, as well as lesion characterization (Figure 2) [27,28].
Hoeffel and colleagues showed that CEUS has a higher sensitivity than the US (99% versus 68%, p < 0.0001) in detecting liver metastases and a low false-positive rate [29]. In CEUS imaging, the vascular enhancement patterns of tumors can be evaluated during arterial (at 10–20 s from contrast medium injection), capillary (20–25 s), portal venous (25–120 s), and late venous phases (>120 s). Liver metastases from GEP-NETs show intense enhancement in the arterial and at the beginning of the capillary phase, with rapid wash-out in the portal phase [30,31].
The use of CEUS is particularly advantageous in the follow-up of liver and pancreatic lesions (either active surveillance or post-ablative treatment), or in cases in which CT and/or MRI examination cannot be safely performed (i.e., allergy to contrast medium, pacemaker, acute or chronic kidney injury, retroperitoneal fibrosis), as it reduces the need for repeated iodine-based contrast administration and minimizes patient exposure to ionizing radiation.

2.2. CT

Contrast-enhanced CT is the most available and commonly used second-line imaging modality in the approach to NETs. It is valuable in diagnosis, staging, and follow-up during and after treatment. In particular, it plays a key role in the assessment of the liver, in the characterization of focal hepatic lesions, and in evaluating treatment response. Initial characterization of focal liver lesions should be performed with quadriphasic CT imaging, including the unenhanced phase, arterial phase (at 25–30 s), portal-venous phase (at 60–70 s), and delayed phase (between 3 and 5 min). Non-contrast imaging identifies calcifications and necrosis; the arterial phase evaluates lesion enhancement and vascularity; and the portal and delayed phases assess wash-out, a feature which correlates with malignancy. Certain lesions exhibit delayed wash-out, aiding differential diagnosis. In a follow-up of patients with GEP-NET liver metastases, a limited protocol, including non-contrast, arterial, and venous phases, is generally sufficient for monitoring treatment-related changes and lesion evolution. Liver metastases are typically hypodense in the unenhanced phase and may exhibit, like the primary tumor, calcifications or, if large in size, areas of necrosis or hemorrhage. After a contrast medium injection, liver metastases can present highly variable enhancement patterns, with typical hyperdensity in the post-contrast arterial phase due to their hypervascularity, and fast wash-out in the portal-venous or delayed phases. However, portal-venous and delayed phase wash-out can vary based on the primary site of origin of the metastases. In particular, liver metastases from pancreatic NETs (P-NETs) are mostly iso-attenuating on portal-venous phase images, while liver metastases from gastroenteric NETs (GE-NETs) are frequently hypoattenuating on portal-venous and delayed phase images (Figure 3 and Figure 4) [32].
A study by Ronot and colleagues on CT appearance of liver metastases from GEP-NETs showed that in the unenhanced phase, 72% of them were hypodense relative to the surrounding parenchyma. Seventy percent of lesions were hypervascular in the arterial phase, and 44% of them had washout, which is usually considered to be the typical pattern. Persistence of hypervascularity in the portal-venous phase was seen only in 9% of lesions [33].
A multiphasic CT with arterial phase is suggested to perform a more accurate detection of GEP-NET liver metastases (Figure 5) [34].
However, a portal-venous phase is mandatory, as, in a series of hypervascular liver metastases of various origins (breast cancer, NET, melanoma, renal cell carcinoma, and thyroid cancer), the majority of lesions were detected on portal-venous phase than arterial phase images; this can be explained as some metastatic lesions can have reduced vascular supply, distorted microvasculature texture, and/or stromal desmoplasia, which may limit contrast delivery, making the lesion more visible in the portal-venous phase [33].
Contrast-enhanced CT can provide insights into tumor features that reflect pathological grade: some studies on GEP-NET have shown that well-differentiated tumors are more vascularized than poorly differentiated ones, whereas more feeding arteries and intratumoral neovascularity were found in the liver metastasis of poorly differentiated GEP-NET than in well-differentiated ones, probably due to a higher proliferation rate and a higher need for blood supply. Based on this, quantitative CT ratio parameters (i.e., tumor-to-aorta ratio in the hepatic arterial phase, and tumor-to-liver ratio in the hepatic arterial phase) can be useful in providing an estimation of the tumor grade [28]. CT is a key technique in defining the treatment strategy (i.e., for surgical planning or locoregional therapies), as well as for evaluating treatment response. In particular, during follow-up after systemic therapy, it may reveal not only a reduction in lesion size but also a decrease in hypervascularization (Figure 6).

2.3. MRI

Contrast-enhanced MRI scans have a high sensitivity for identifying liver metastases from GEP-NETs. An MRI is, therefore, regarded as the gold standard and minimal requirement prior to consideration of any hepatic surgery [35]. Moreover, MRI scans do not imply the use of X-rays. Therefore, it can be repeated without risks. In addition, the high contrast between healthy liver parenchyma and metastasis in the unenhanced phase grants a precise detection and measurement of the lesions [36].
Liver metastases from GEP-NETs are typically hypointense in T1-weighted images, and hyperintense in T2-weighted images, with a strong arterial enhancement after contrast medium administration due to their hypervascularization and early wash-out. In particular, metastases from well-differentiated GEP-NETs tend to be hypervascular and include hyperenhancement in the arterial phase with high apparent diffusion coefficient (ADC), while poorly differentiated neoplasms show more heterogeneous patterns, as hypo-/isoattenuation, low ADC, and more irregular enhancement. Therefore, a “standard” MRI protocol for detection and follow-up of liver metastases from GEP-NETs should include the following sequences: axial T2-weighted images (non-fat-suppressed and fat-suppressed imaging), axial T1-weighted in-phase and out-of-phase images, diffusion-weighted imaging (DWI) images (b = 0, 50, 400, and 800 s/mm2) and their corresponding ADC map, and dynamic contrast-enhanced images, with T1-weighted axial contrast-enhanced images (fat-suppressed, three-dimensional gradient-recalled-echo sequences) before and after gadolinium-based contrast-agent administration, during arterial (at 20–40 s), portal-venous (45–65 s), and equilibrium (from 3 to 5 min) phases after injection of contrast agent [37]. The European Society of Gastrointestinal and Abdominal Radiology (ESGAR) has recommended the use of liver-specific contrast agents, including gadobenate dimeglumine (Gd-BOPTA) and gadoxetic acid (Gd-EOB-DTPA) in liver metastases from GEP-NETs [38,39]. After a contrast medium administration, the arterial phase hyperenhancement can be heterogeneous and can be observed in the whole or part of the lesions, or it can be more pronounced at the periphery (e.g., “rim” arterial phase hyperenhancement) (Figure 7) [40].
The use of the hepatospecific contrast medium can show absent enhancement in the hepatobiliary phase, as there are no functioning hepatocytes in these lesions. However, this feature is not specific for GEP-NET metastases [41,42].
A study by Dromain and colleagues on MRI appearance of liver metastases from GEP-NETs showed that in the T1-weighted unenhanced images, 93–94% of them were hypointense relative to the surrounding parenchyma. In the T2-weighted unenhanced phase, 85–86% of them were moderately or highly hyperintense, and in the post-contrast arterial and venous phases, 80% and 70% of them were hyperintense, respectively [35]. DWI has been demonstrated to be more sensitive in detecting and characterizing GEP-NET liver metastases than T2-weighted or post-contrast images (Figure 8) [43].
Moreover, DWI sequences are valuable for accurately monitoring size variations of GEP-NET liver metastases from NETs [44]. Conversely, fat-saturated post-contrast T1-weighted arterial phase sequences are considered to be the least reliable sequence for lesion accurate measurement. Hayoz and colleagues showed that the combination of DWI and hepatobiliary phase images had the highest sensitivity and specificity for GEP-NET liver metastases detection and could be used in combination for a “short” MRI protocol in follow-up examination in these patients [39]. Nonetheless, as good practice, it is advised to perform the same acquisition protocol at every follow-up examination to avoid mismatches and biases [45].
In addition to dynamic contrast study, T2-weighted images and DWI studies play a crucial role in facilitating the characterization of liver lesions, evaluating the cellularity of the tissue. DWI reflects tissue cellularity and cell membrane consistency, which allows for the distinction between benign and malignant lesions, as they are able to detect subtle neoplastic tissue changes on a cellular level. T2-weighted images, due to their high sensitivity to variations in tissue water content, are useful in detecting lesions with high fluid content, such as necrotic tumors. In contrast, DWI images and ADC maps are based on the Brownian motion of water molecules. In highly cellular tissues—such as malignant tumors and metastatic lesions—water diffusion is restricted by the dense cellular architecture, resulting in increased signal intensity on DWI and low ADC values. Therefore, DWI is valuable for assessing the microstructural characteristics of liver tissue, such as cellular density, allowing the detection of pathological changes even before they become apparent on conventional imaging sequences. In particular, some studies correlate the type of signal in T2-weighted images and DWI with the secretory capacity of the tumor and the degree of differentiation. Diffusion restriction (with high signal on DWI and low signal on ADC map) can provide a correlation between imaging features and pathological classification in terms of lesion size, growth, intra- or extra-intestinal involvement, zone of intralesional alterations, mesenteric fat infiltration, and metastases [46].

2.4. PET-CT

PET-CT scans are helpful in the localization and staging of distant metastases from GEP-NETs. Usefulness of PET-CT examination varies based on the tracer: 68Ga-DOTATATE or -DOTATOC is useful in identifying liver metastases from well-differentiated (G1) GEP-NETs, as they express somatostatin receptors (SSTR), with high sensitivity and specificity. 18F-FDG is used for less (G2) or poorly differentiated (G3) GEP-NETs, which have increased glycolysis.
Gallium-68 (68Ga)-DOTATATE or -DOTATOC PET-CT represent an advanced functional imaging modality for assessment and staging of well-differentiated (grade 1—G1) GEP-NETs. DOTATATE and DOTATOC are the two somatostatin analogues that are most often used in functional imaging with PET-CT: these two ligands have a similar somatostatin binding profile and possess a similar diagnostic accuracy in identifying NET lesions [47].
Further, 68Ga-DOTATATE PET-CT should be the preferred imaging modality for initial diagnosis of GEP-NET, as well as for localization of unknown primary tumors and for selection of patients for peptide receptor radionuclide therapy (PRRT, also known as radioligand therapy) [33]. Also, 68Ga-DOTATATE PET-CT has an improved sensitivity and specificity for the detection of liver metastases from GEP-NETs, which are approximately 94% and 89%, respectively [33]. The National Comprehensive Cancer Network (NCCN) guidelines added the 68Ga-DOTATATE PET-CT as an appropriate test in the management of NETs (Figure 9) [33].
In G2 and G3 GEP-NETs, both 68Ga-DOTATATE and 18F-FDG PET-TC are employed due to their lower differentiation compared to G1 GEP-NETs and can perform a non-invasive assessment of tumor heterogeneity [48,49]. The reduction or loss of SSTR expression was found to coincide with an increase in glucose metabolism of GEP-NETs, leading to the suggestion that 18F-FDG PET-CT should be reserved for patients with SSTR-negative GEP-NET [50,51]. The fluorodeoxyglucose (FDG) uptake on an FDG PET-CT is a powerful and independent prognostic factor in patients with neuroendocrine tumors. Recent studies involving larger patient cohorts have evaluated the sensitivity of 18F-FDG PET-CT in comparison with 68Ga-DOTATATE PET-CT and how it is linked with patient survival, finding that the prevalence of glucose-avid tumors increases with GEP-NET grade and is associated with more aggressive disease features, including a higher risk of mortality [52]. In particular, Binderup and colleagues found in their prospective study that FDG uptake was a strong prognostic indicator of GEP-NET progression. Moreover, FDG avidity (SUV) was found to be associated with a shorter overall survival rate [53]. In general, well-differentiated NETs show high SSTR expression and are effectively imaged with 68Ga-DOTA-peptides (DOTANOC, DOTATOC, DOTATATE). SSTR-PET/CT is recommended for staging, restaging, follow-up, therapy response assessment, and PRRT eligibility. Further, 18F-FDG is used for high-grade tumors (G2, G3, NEC), especially when CT findings are not matched by SSTR imaging. Also, 18F-DOPA is reserved for selected tumors like medullary thyroid carcinoma, neuroblastoma, pheochromocytoma, and paraganglioma. Emerging tracers—such as 68Ga-FAPI, SSTR antagonists, 64Cu-SARTATE, 68Ga-PSMA, and 68Ga-CXCR4—are under investigation for their diagnostic and therapeutic potential, although their clinical impact is still being defined [54].
Well-differentiated GEP-NETs and their liver metastases usually present as small, round/oval, well-defined masses due to a more expansive growth pattern than infiltrative, with preserved architecture. Moreover, their rich vascularity, with a dense capillary network, corresponds to arterial phase hypervascularity and venous/delayed phase wash-out on dynamic imaging techniques (i.e., CT, MRI, CEUS). In case of large or long-standing liver metastases, calcifications can be present, corresponding to dystrophic changes in areas of necrosis and fibrosis, or after treatment [28,29]. On the other hand, poorly differentiated GEP-NETs present as large and poorly circumscribed with ill-defined margins, heterogeneously enhancing masses with frequent areas of necrosis [28,29,38]. On MRI T2-weighted images, a mild/moderate hyperintensity (less than cysts) corresponds to a high cellularity and intracellular water content. High cellular density also produces an intense restricted diffusion on DWI/ADC, especially in poorly differentiated lesions [38]. Regarding functional techniques, liver metastases from GEP-NET can have a high expression of somatostatin receptors, corresponding to a strong uptake of 68Ga-DOTA-peptides PET-CT in well-differentiated lesions. On the other hand, in poorly differentiated GEP-NETs, metastatic lesions can show a high glucose metabolism due to poor differentiation and proliferation, with FDG uptake on FDG PET-CT [54].

3. Differential Diagnosis

The differential diagnosis of liver metastases from GEP-NETs is crucial and can be sometimes challenging, as it can be difficult to differentiate them at a baseline examination from other primary or secondary liver tumors. Liver metastases from GEP-NET usually present as hypervascular lesions after contrast medium administration. However, this characteristic can be also frequent in other types of liver lesions, both primary and secondary (i.e., hepatocellular carcinoma—HCC, colorectal cancer, breast cancer, clear cell renal carcinoma, thyroid cancer, sarcoma, GISTs, and melanoma), and even from benign liver lesions (i.e., hemangiomas, hemorrhagic cysts, focal nodular hyperplasia—FNH). Therefore, differential diagnosis of liver metastases from GEP-NETs is crucial and can be sometimes challenging. Image-guided differential diagnosis requires an accurate analysis of imaging findings obtained with US and CEUS, CT, MRI, and PET-CT.
The hypervascular CT pattern of GEP-NETs, although typical, is not pathognomonic: liver metastases from various other neoplasms can have this appearance; these lesions can demonstrate early wash-out on the portal-venous phase or, more rarely, fading or persistent enhancement on post-arterial phases; the wash-out phenomenon of liver metastases from GEP-NETs is determined by their intricate net of capillaries and by their low fibrous stroma content [38]. In particular, liver metastases from clear cell renal carcinoma can be challenging to distinguish from GEP-NET metastases. In these cases, anamnesis, a history of previous nephrectomy, or evidence of kidney lesions can help in the diagnosis [55]. Gastrointestinal stromal tumors (GIST) can present with hypervascular liver metastases, even though they usually present with a necrotic core and irregular margins, with a different enhancement between the lesion’s core and periphery. Moreover, they can show hypermetabolism at 18F-FDG PET-CT [56]. Liver metastases from melanoma can present as hypervascular and can have dynamic behavior similar to GEP-NETs. When performing differential diagnosis, great care must be taken in evaluating a patient’s skin lesions, as well as ocular and cerebral ones [57]. Differentiated thyroid gland carcinoma can present with hypervascular liver metastases, in particular, the follicular type; laboratory exams (i.e., thyroglobulin, thyroid-stimulating hormone—TSH) and thyroid nodules seen at ultrasound can help in the differential diagnosis [58]. Liver metastases from mucinous colorectal adenocarcinoma or from pancreatic adenocarcinoma can appear as hypervascular, in particular, when small, due to their “rim” enhancement [59,60].
HCC is more often seen as a single encapsulated nodule, usually in a cirrhotic liver, and can show vascular invasion and mass effect on the adjacent structures. Moreover, tumor markers as alpha-fetoprotein (AFP) and evidence of regenerating nodules can help in differential diagnosis (Figure 10) [61].
Dual energy CT (DECT), being able to assess the iodine uptake of organs and lesions, can improve the differentiation between liver metastases from GEP-NETs and HCC in a non-cirrhotic liver. Moreover, histological sampling is always mandatory in non-cirrhotic livers to perform a correct diagnosis [62].
MRI examination of liver metastases from GEP-NETs can be hypointense in T1-weighted images and hyperintense in T2-weighted ones, with great hypervascularity in the post-contrast arterial phase and can show great signal restriction in DWI scans, as in case of high cellularity. However, these findings, even if typical in high-grade NETs, are not pathognomonic. In particular, HCC can present with hypervascular nodules and partial enhancement in the hepatobiliary phase, depending on the grade. Usually, HCC nodules are accompanied by mass effect or vascular invasion of the adjacent hepatic veins [56]. Intrahepatic cholangiocarcinoma (ICC) is usually hypovascular, although in a few cases, it can be moderately vascularized. However, ICC has a typical centripetal enhancement and central fibrosis, which can be seen as moderate T2 hyperintensity, and determined mass effect on the adjacent biliary ducts [63]. Liver metastases from mucinous tumors can appear as hyperintense in T2-weighted images but present peripheral or “rim” enhancement after contrast-medium administration, in contrast to the homogeneous enhancement pattern of GEP-NET metastases [64].
At MRI examination, liver metastases from melanoma are typically hyperintense in non-enhanced T1-weighted images (Figure 11), with the exception of uveal melanoma metastases, which are usually hypointense in T1-weighted images [65].
Hypervascular liver metastases from breast cancer can present with a homogeneous or peripheral post-contrast enhancement (Figure 12) [66].
Among benign liver lesions, hepatic hemangiomas typically have a globular, progressive, and centripetal “filling-in” (Figure 13). On MRI, hemangiomas are hypointense on T1-weighted images and firmly hyperintense on T2-weighted images, often described as “light bulb bright,” and similarly demonstrate the progressive centripetal enhancement pattern. Moreover, they do not show uptake in functional imaging.
Hemorrhagic cysts are seen as hyperdense in unenhanced CT scans. FNH, although hypervascular, is more often seen in younger patients, is hyperintense in the hepatobiliary phase, and has a hyperintense T2 central scar with a persistent delayed enhancement after contrast medium administration. Hepatocellular adenoma is a benign lesion that can present as hypervascular, although generally inferior and more gradual compared to GEP-NETs, and does not exhibit a wash-out. Even though differential diagnosis can be difficult, the adenoma often shows intralesional fat or blood signal that can be useful in distinguishing it from GEP-NETs. Moreover, on MRI, adenomas tend to be isointense to hypointense on T1-weighted images and mildly hyperintense on T2-weighted images, with no necrosis and rare calcifications. In addition, they do not exhibit somatostatin receptor expression or uptake at functional imaging [67]. Liver primary angiomyolipomas represent another benign hypervascular lesion that, like NETs, can occur sporadically or in association with tuberous sclerosis. These lesions contain smooth muscle, blood vessels, and fat components to different degrees. Due to their hypervascular appearance, lipid-poor angiomyolipomas must be differentiated from liver metastases from GEP-NETs using functional imaging [68].
The use of ADC and ADCmean values obtained from liver metastases during MRI examinations may be used to differentiate liver metastases from GEP-NETs from those originating from adenocarcinomas [69].
PET-CT is of great help in performing a differential diagnosis between liver metastases from GEP-NETs and other metastatic tumors. Lymphomas, HCCs, ICCs, and liver metastases from clear cell renal carcinoma and from gastrointestinal adenocarcinomas show an uptake of 18F-FDG but no or poor uptake of 68Ga-DOTATATE [70]. FNH, hepatic hemangiomas, and adenomas have no uptake of both 18F-FDG and 68Ga-DOTATATE [71]. Medullary thyroid cancer can show uptake of both 18F-FDG and 68Ga-DOTATATE [72].
US and CEUS often represent the first imaging modalities to assess liver lesions and to perform an initial staging of NETs, being cost-effective, widely available, and rapid. It can also be used to assess the effectiveness of ablative treatment for liver metastases [31]. When performing CEUS, liver metastases from GEP-NETs show hypervascularity in the arterial phase, with portal-venous and delayed wash-out. Liver metastases from adenocarcinomas usually present with a more rapid and intense wash-out, while HCC nodules have a smoother and slower wash-out. FNH has centrifugal enhancement and no wash-out, while hepatic adenoma can present with portal-venous wash-out, even though less intense than liver metastases [73]. Table 1 summarizes the key characteristics of the main primary and secondary liver lesions that are included in the differential diagnosis of GEP-NETs.

4. Conclusions

In conclusion, GEP-NETs are heterogeneous tumors that commonly metastasize to the liver. Imaging techniques play a fundamental role in the diagnosis and follow-up of patients with GEP-NETs, and an even crucial one in the differential diagnosis between liver metastases from GEP-NETs and other focal benign or malignant liver lesions. Radiological characteristics of liver metastases in patients affected by GEP-NETs can influence their prognosis, as seen in the case of FDG avidity at PET-CT scans. Diagnostic imaging also plays a fundamental role in the multidisciplinary choice of the best treatment individualized for each patient (i.e., surgery, systemic treatment, locoregional treatments), as well as in treatment planning. However, due to the relative rarity of this disease, more studies and research are needed to further ameliorate imaging techniques, which will guide diagnosis, prognosis, treatment, and follow-up of these patients. Differential diagnosis is crucial in a patient with liver lesions of unknown origin, and it is mandatory to provide the most correct clinical approach to patients with liver metastases from GEP-NETs.

Author Contributions

Conceptualization, A.P. and E.G.; methodology, A.P., P.B. and E.G.; software, M.A., M.L. and E.G.; validation, A.P. and E.G.; investigation, P.B., M.A. and M.L.; resources, M.A. and E.G.; data curation, E.G.; writing—original draft preparation, P.B., M.A., A.M. and M.L.; writing—review and editing, A.P. and E.G.; visualization, E.G.; supervision, R.I.; project administration, A.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
NETsNeuroendocrine tumors
GEPGastro-entero-pancreatic
WHOWorld Health Organization
P-NETsPancreatic NETs
ENETSEuropean Neuroendocrine Tumor Society
HPFHigh-Power Field
NECNeuroendocrine Carcinoma
USUltrasound
CTComputed Tomography
MRIMagnetic Resonance Imaging
PETPositron Emission Tomography
GE-NETsGastro-Enteric NETs
ESGAREuropean Society of Gastrointestinal and Abdominal Radiology
DWIDiffusion Weighted Imaging
ADCApparent Diffusion Coefficient
Gd-BOPTAGadobenate dimeglumine
Gd-EOB-DTPAGadoxetic acid
CEUSContrast-Enhanced Ultrasound
FDGFluorodeoxyglucose
PRRTPeptide Receptor Radionuclide Therapy
NCCNNational Comprehensive Cancer Network
SSTRSomatostatin Receptor
FNHFocal Nodular Hyperplasia
HCCHepatocellular Carcinoma
GISTGastrointestinal Stromal Tumor
TSHThyroid-Stimulating Hormone
AFPAlpha-Fetoprotein
DECTDual-Energy CT
ICCIntrahepatic Cholangiocarcinoma

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Figure 1. Sixty-four-year-old female patient with liver metastasis from pancreatic NET (G2). US shows a focal lesion in the V segment of the liver (crosses), with heterogeneous structure and necrotic core.
Figure 1. Sixty-four-year-old female patient with liver metastasis from pancreatic NET (G2). US shows a focal lesion in the V segment of the liver (crosses), with heterogeneous structure and necrotic core.
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Figure 2. Fifty-six-year-old male patient with liver metastasis from pancreatic NET (G2). CEUS shows a 30 mm focal lesion in the VI segment of the liver (arrows), which is hypervascular in the arterial phase after contrast medium administration (a) and has a mild wash-out in the delayed phase (b). A large hepatic cyst (*) with typical posterior acoustic enhancement is located adjacent to the metastatic lesion.
Figure 2. Fifty-six-year-old male patient with liver metastasis from pancreatic NET (G2). CEUS shows a 30 mm focal lesion in the VI segment of the liver (arrows), which is hypervascular in the arterial phase after contrast medium administration (a) and has a mild wash-out in the delayed phase (b). A large hepatic cyst (*) with typical posterior acoustic enhancement is located adjacent to the metastatic lesion.
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Figure 3. Seventy-year-old male patient with liver metastasis from pancreatic NET (G1). CT scan shows a focal lesion in the IV segment of the liver (arrow), hypervascular in the arterial phase (a), slightly hyperdense in portal phase (b) and late phase (c). Large hypervascular lesion of the pancreatic tail ((d), arrowhead). Further, 68Ga-DOTATOC PET-CT shows uptake corresponding to the focal area in segment IV (e) and to the pancreatic neoplasm (f).
Figure 3. Seventy-year-old male patient with liver metastasis from pancreatic NET (G1). CT scan shows a focal lesion in the IV segment of the liver (arrow), hypervascular in the arterial phase (a), slightly hyperdense in portal phase (b) and late phase (c). Large hypervascular lesion of the pancreatic tail ((d), arrowhead). Further, 68Ga-DOTATOC PET-CT shows uptake corresponding to the focal area in segment IV (e) and to the pancreatic neoplasm (f).
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Figure 4. Seventy-six-year-old male patient with liver metastases from ileal NET. CT images in the arterial (a) and venous phases (b,c) demonstrate two hypervascular nodules in segments II and IV (arrowhead), showing venous washout. Small nodule in the wall of an ileal bowel loop (d). Further, 68Ga-DOTATOC PET-CT shows uptake of the hepatic lesions (e) and of the ileal nodule (f).
Figure 4. Seventy-six-year-old male patient with liver metastases from ileal NET. CT images in the arterial (a) and venous phases (b,c) demonstrate two hypervascular nodules in segments II and IV (arrowhead), showing venous washout. Small nodule in the wall of an ileal bowel loop (d). Further, 68Ga-DOTATOC PET-CT shows uptake of the hepatic lesions (e) and of the ileal nodule (f).
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Figure 5. Seventy-one-year-old male patient with liver, lung, and bone metastases from pancreatic NET (G2). CT images show multiple liver lesions without arterial-phase enhancement—which can be due to tumor necrosis, fibrosis, or poor vascular supply within the tumor—(a), more clearly visible in the portal phase as numerous hypodense lesions. Arrows indicate the larger lesions (b). 68Ga-DOTATOC PET-CT showing an intense uptake of the multiple hepatic lesions (arrows) and of the secondary bone lesions in the right rib and vertebral body (c).
Figure 5. Seventy-one-year-old male patient with liver, lung, and bone metastases from pancreatic NET (G2). CT images show multiple liver lesions without arterial-phase enhancement—which can be due to tumor necrosis, fibrosis, or poor vascular supply within the tumor—(a), more clearly visible in the portal phase as numerous hypodense lesions. Arrows indicate the larger lesions (b). 68Ga-DOTATOC PET-CT showing an intense uptake of the multiple hepatic lesions (arrows) and of the secondary bone lesions in the right rib and vertebral body (c).
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Figure 6. Seventy-five-year-old female patient with liver metastases from pancreatic NET (G2) under radiometabolic therapy. CT scans show multiple large liver lesions in both lobes, some hypervascular in the arterial phase, others with low arterial enhancement (arrow) (a), others better seen as hypodense nodules in the late phase (b). The lesions show an intense uptake on 18F-FDG PET-CT (c,d), but some of them also show an uptake on 68Ga-DOTATOC PET-CT (e,f).
Figure 6. Seventy-five-year-old female patient with liver metastases from pancreatic NET (G2) under radiometabolic therapy. CT scans show multiple large liver lesions in both lobes, some hypervascular in the arterial phase, others with low arterial enhancement (arrow) (a), others better seen as hypodense nodules in the late phase (b). The lesions show an intense uptake on 18F-FDG PET-CT (c,d), but some of them also show an uptake on 68Ga-DOTATOC PET-CT (e,f).
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Figure 7. Seventy-one-year-old female patient with liver metastases from pancreatic NET (G2). MRI images show a focal lesion in the hepatic dome with homogeneous, moderately hyperintense signal in T2-weighted scans (arrow) (a). Diffusion-weighted imaging (DWI) (b) with apparent diffusion coefficient (ADC) map (c) demonstrates mild restriction of proton diffusion of the nodule. On unenhanced T1-weighted images, the lesion appears hypointense (d), with marked arterial enhancement (arrowhead) (e) and progressive washout in the portal venous (f) and delayed (g) phases.
Figure 7. Seventy-one-year-old female patient with liver metastases from pancreatic NET (G2). MRI images show a focal lesion in the hepatic dome with homogeneous, moderately hyperintense signal in T2-weighted scans (arrow) (a). Diffusion-weighted imaging (DWI) (b) with apparent diffusion coefficient (ADC) map (c) demonstrates mild restriction of proton diffusion of the nodule. On unenhanced T1-weighted images, the lesion appears hypointense (d), with marked arterial enhancement (arrowhead) (e) and progressive washout in the portal venous (f) and delayed (g) phases.
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Figure 8. Sixty-two-year-old female patient with liver metastasis from a histologically confirmed NET, with an occult primary lesion most likely originating from the gastro-entero-pancreatic tract. MRI images show a large lesion in segment VIII with a markedly heterogeneous signal intensity on T2-weighted scans (arrow) (a). The lesion demonstrates intense diffusion restriction (b,c). The nodule appears hypointense on pre-contrast images (d), and dynamic contrast-enhanced imaging reveals marked and heterogeneous arterial enhancement (arrowhead) (e), with portal phase washout (f).
Figure 8. Sixty-two-year-old female patient with liver metastasis from a histologically confirmed NET, with an occult primary lesion most likely originating from the gastro-entero-pancreatic tract. MRI images show a large lesion in segment VIII with a markedly heterogeneous signal intensity on T2-weighted scans (arrow) (a). The lesion demonstrates intense diffusion restriction (b,c). The nodule appears hypointense on pre-contrast images (d), and dynamic contrast-enhanced imaging reveals marked and heterogeneous arterial enhancement (arrowhead) (e), with portal phase washout (f).
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Figure 9. Fifty-year-old male patient with a liver metastasis from an ileal NET (G1), which has an atypical appearance. MRI scans show a lesion with well-defined margins located in segment VIII, which is markedly hyperintense in T2-weighted imaging (a). Diffusion-weighted imaging (DWI) on b = 800 (b) and apparent diffusion coefficient (ADC) map (c) demonstrate intense restriction of proton diffusion in the nodule. In the T1-weighted pre-contrast scan is hypointense (d), while in the post-contrast scans, the lesion demonstrates initial enhancement during the arterial phase (arrowhead) (e), which becomes more pronounced in the portal (f) and delayed phases (arrow) (g). The lesion mimics the appearance of a hepatic hemangioma, but the 68Ga-DOTATOC PET-CT shows intense radiotracer uptake, consistent with neuroendocrine metastasis (h).
Figure 9. Fifty-year-old male patient with a liver metastasis from an ileal NET (G1), which has an atypical appearance. MRI scans show a lesion with well-defined margins located in segment VIII, which is markedly hyperintense in T2-weighted imaging (a). Diffusion-weighted imaging (DWI) on b = 800 (b) and apparent diffusion coefficient (ADC) map (c) demonstrate intense restriction of proton diffusion in the nodule. In the T1-weighted pre-contrast scan is hypointense (d), while in the post-contrast scans, the lesion demonstrates initial enhancement during the arterial phase (arrowhead) (e), which becomes more pronounced in the portal (f) and delayed phases (arrow) (g). The lesion mimics the appearance of a hepatic hemangioma, but the 68Ga-DOTATOC PET-CT shows intense radiotracer uptake, consistent with neuroendocrine metastasis (h).
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Figure 10. Sixty-five-year-old male patient with hepatitis C virus (HCV)-related chronic liver disease. CT images show a hypodense lesion in hepatic segments V-VI (a), with arterial enhancement ((b), arrow), washout in the portal phase (c), and washout with a pseudocapsule in the delayed phase (d), consistent with hepatocellular carcinoma (HCC). Note the rounded hepatic margins and the presence of collateral venous circulation in the periesophageal and perigastric regions, suggestive of portal hypertension in the context of cirrhosis ((c), arrowhead).
Figure 10. Sixty-five-year-old male patient with hepatitis C virus (HCV)-related chronic liver disease. CT images show a hypodense lesion in hepatic segments V-VI (a), with arterial enhancement ((b), arrow), washout in the portal phase (c), and washout with a pseudocapsule in the delayed phase (d), consistent with hepatocellular carcinoma (HCC). Note the rounded hepatic margins and the presence of collateral venous circulation in the periesophageal and perigastric regions, suggestive of portal hypertension in the context of cirrhosis ((c), arrowhead).
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Figure 11. Sixty-two-year-old male patient with liver metastases from skin melanoma: CT images show several hypervascular liver lesions in the arterial phase (a), which remain slightly hyperdense in the portal phase (b). MRI scans reveal multiple hepatic lesions, some millimetric with a miliary appearance, showing hyperintense signal on unenhanced T1-weighted sequences (the major showed by arrows) (c), a characteristic feature of melanoma content. The lesions demonstrate marked diffusion restriction on diffusion-weighted imaging (DWI) sequences at b = 800 (d,e).
Figure 11. Sixty-two-year-old male patient with liver metastases from skin melanoma: CT images show several hypervascular liver lesions in the arterial phase (a), which remain slightly hyperdense in the portal phase (b). MRI scans reveal multiple hepatic lesions, some millimetric with a miliary appearance, showing hyperintense signal on unenhanced T1-weighted sequences (the major showed by arrows) (c), a characteristic feature of melanoma content. The lesions demonstrate marked diffusion restriction on diffusion-weighted imaging (DWI) sequences at b = 800 (d,e).
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Figure 12. Sixty-seven-year-old female patient with liver metastasis from infiltrating ductal carcinoma of the breast. CT images show a focal lesion in segment VII, characterized by peripheral arterial enhancement ((a), arrow) and washout in the portal (b) and delayed phases (c), in a patient with a vascularized solid mass in the left breast ((d), asterisk). A focal metabolic–perfusional alteration is present in segment IV ((b), arrowhead).
Figure 12. Sixty-seven-year-old female patient with liver metastasis from infiltrating ductal carcinoma of the breast. CT images show a focal lesion in segment VII, characterized by peripheral arterial enhancement ((a), arrow) and washout in the portal (b) and delayed phases (c), in a patient with a vascularized solid mass in the left breast ((d), asterisk). A focal metabolic–perfusional alteration is present in segment IV ((b), arrowhead).
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Figure 13. Fifty-six-year-old female patient with multiple hepatic hemangiomas. MRI images show three focal lesions in segments VII and IV (arrows), characterized by moderately hyperintense signal on T2-weighted images (a,b), with peripheral arterial enhancement (c,d) and a characteristic progressive centripetal filling in the subsequent phases (e,f). In the portal phase, the smallest lesion shows a small eccentric vascular spot, consistent with slow filling ((f), arrowhead).
Figure 13. Fifty-six-year-old female patient with multiple hepatic hemangiomas. MRI images show three focal lesions in segments VII and IV (arrows), characterized by moderately hyperintense signal on T2-weighted images (a,b), with peripheral arterial enhancement (c,d) and a characteristic progressive centripetal filling in the subsequent phases (e,f). In the portal phase, the smallest lesion shows a small eccentric vascular spot, consistent with slow filling ((f), arrowhead).
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Table 1. Summary of imaging findings for differential diagnosis of GEP-NETs.
Table 1. Summary of imaging findings for differential diagnosis of GEP-NETs.
LesionCTMRI18F-FDG PET-CTFeatures
Differentiated thyroid carcinoma metastasisHypervascular, possible wash-outT1: hypo
T2: hyper
CM: arterial enhancement		Variable uptakeLess frequent than NETs
Clear cell renal carcinoma metastasisHypervascular, portal-phase wash-outT1: hypo
T2: heterogeneous
DWI: restriction		Variable uptakeIrregular vascularization, heterogeneous lesion
Melanoma metastasisHypervascular, often multipleT1: hyper
T2: hypo/heterogeneous		High uptakeHyperintense in T1 due to melanin or blood
Breast cancer metastasisSome histotypes can be hypervascularT1: usually hypo
T2: heterogeneous		Good uptakeUsually multiple lesions
Liver hemangiomaPeripheral globular enhancement with progressive fill-inT1: hypo
T2: highly hyper		No uptakeTypical globular centripetal enhancement
Liver adenomaHypervascular, possible wash-outT1: variable
T2: variable		No uptakeUsually a single lesion, can contain fat or blood
Focal nodular hyperplasia (FNH)Hypervascular, iso or hypodense in the delayed phaseT2: hypercentral scar
CM: progressive enhancement		No uptakeCentral scar, hepatobiliary enhancement after hepatospecific contrast medium
AngiomyolipomaHypervascular due to angioid componentT1 IN/OUT: foci of macroscopic fat
CM: hyper		No uptakeAngioid and fat content
Hepatocellular carcinoma (HCC)Hypervascular, delayed wash-outT1: hypo
T2: variable		Variable uptakeOften in a cirrhotic liver
Hypervascular intrahepatic cholangiocarcinomaHypervascular in the arterial phaseT1: hypo
T2: hyper CM: arterial enhancement		Usually good uptakeAssociation with bile duct enlargement
Hypovascular intrahepatic cholangiocarcinomaHypovascular, progressive peripheral enhancementT1: hypo
T2: hyper CM: progressive enhancement		Usually good uptakeAssociation with bile duct enlargement
Legend: CT, Computed Tomography; MRI, Magnetic Resonance Imaging; FDG: FluoroDeoxyGlucose; PET: Positron-Emission Tomography; hyper, hyperintense; hypo, hypointense; CM, Contrast Medium; NET: NeuroEndocrine Tumors.
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Posa, A.; Genco, E.; Barbieri, P.; Ariano, M.; Lippi, M.; Maresca, A.; Iezzi, R. Imaging of Liver Metastases from GEP-NETs: A Narrative Review. Onco 2025, 5, 36. https://doi.org/10.3390/onco5030036

AMA Style

Posa A, Genco E, Barbieri P, Ariano M, Lippi M, Maresca A, Iezzi R. Imaging of Liver Metastases from GEP-NETs: A Narrative Review. Onco. 2025; 5(3):36. https://doi.org/10.3390/onco5030036

Chicago/Turabian Style

Posa, Alessandro, Enza Genco, Pierluigi Barbieri, Mario Ariano, Marcello Lippi, Alessandro Maresca, and Roberto Iezzi. 2025. "Imaging of Liver Metastases from GEP-NETs: A Narrative Review" Onco 5, no. 3: 36. https://doi.org/10.3390/onco5030036

APA Style

Posa, A., Genco, E., Barbieri, P., Ariano, M., Lippi, M., Maresca, A., & Iezzi, R. (2025). Imaging of Liver Metastases from GEP-NETs: A Narrative Review. Onco, 5(3), 36. https://doi.org/10.3390/onco5030036

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