With the increasing number of cancer survivors, it is crucial to diagnose new hepatic nodules that occur during follow-up accurately. Our study systematically reported 38 patients with 63 hepatic FNH lesions in breast cancer, colorectal cancer, and other scattered types of cancer (NHL and gastric cancer) after chemotherapy. To our knowledge, this is the first relatively large case series to focus on newly emerging hepatic FNH after chemotherapy in adult patients with cancer. This study demonstrated that in addition to paediatric tumours, adult tumours, especially breast and colorectal cancers, could also develop FNH after chemotherapy, particularly after using cyclophosphamide or oxaliplatin, which is very important for radiologists and oncologists to provide accurate diagnosis and treatment decisions.

FNH incidentally discovered on common physical examination usually has typical imaging findings for a relatively easy diagnosis [2]. MRI is an effective diagnostic method with a specificity and sensitivity of 98% and 70%, respectively [17]. Hepatic FNH primarily comprises hepatocytes and resembles the surrounding liver parenchyma on unenhanced MR. The feeding artery and branching vessels in the hepatic FNH accounted for the homogeneous hyperintensity on AP images. Although almost all FNH cases have central scars composed of myxomatous and fibrous elements, they are not always visible on CT and MRI, especially when the nodules are small [18]. The presence of a central scar, which always shows hypointensity on T1WI, hyperintensity on T2WI, and delayed enhancement on contrast-enhanced MR, can improve diagnostic accuracy. In addition, typical uptake patterns using hepatocyte-specific contrast agents on HBP images (iso-hyperintense) are essential to exclude malignancies. Bilreiro et al [19] found that peripheral ring-like hyperintensity on HBP images has excellent specificity (100%) for diagnosing FNH. In our study, approximately two-thirds of the lesions showed this sign on HBP images. The special expression pattern of OATP8 (peripheral rather than central hepatocytes) may be the pathological mechanism underlying the ring hyperintensity pattern in HBP images [20].

Previous studies [1, 15, 16] have found that FNH in cancer survivors has the following characteristics compared to FNH in the general population: multiplicity, small size, and relatively less incidence of the central scar. Approximately 55.3% (21/38) of the patients in our study presented with multiple hepatic FNH lesions at first diagnosis, and two newly presented with multiple lesions during follow-up. The frequency of FNH lesions with a central scar was relatively low (14.3%) in our study, similar to that reported in a previous study (11%) [14]. A plausible explanation is that central scar formation is related to lesion size, and imaging is insensitive to the central scar of small lesions. Kamel et al [21] reported that a central scar occurred in 35% of FNH lesions measuring < 3 cm in size. Strict posttreatment monitoring of patients with tumours allows earlier detection of hepatic FNH, and the FNH lesions in our study were smaller in size (median, 11.5 mm) than those reported in the general population (mean, 43.0 mm) [22].

Previous paediatric FNH studies [4, 14,15,16] have found that neuroblastoma treated with cyclophosphamide and cisplatin is the most common primary malignancy, accounting for 50–80% of cases. A commonly accepted explanation is that the use of chemotherapy drugs damages the sinusoidal integrity and microvascular function, resulting in the formation of hepatic FNH [1, 2, 23,24,25]. Particularly, in patients receiving alkylating agent chemotherapy, such as cyclophosphamide, depletion of reduced glutathione in hepatic sinusoidal endothelial cells may be associated with the occurrence of FNH [24,25,26]. Breast and colorectal cancer were the two main tumour types in our study for newly formed FNH during follow-up, and cyclophosphamide and oxaliplatin were two common chemotherapeutic drugs for these patients. The occurrence of FNH in appendiceal mucinous neoplasms, pancreatic cancer, gastric cancer, and ovarian cancer treated with chemotherapy has been previously reported [4, 11, 27]. However, our study is the first to report a patient with NHL who developed hepatic FNH approximately 2 years after receiving cyclophosphamide treatment. Therefore, the history of chemotherapy, especially the use of cyclophosphamide or oxaliplatin, should be considered a probable risk factor for the occurrence of FNH.

Our study provides a detailed analysis of 38 patients and a comparison of two different treatment groups. The patients in the cyclophosphamide-based chemotherapy group were significantly younger than those in the oxaliplatin-based chemotherapy group. The younger age of onset of breast cancer (approximately 45 years old) than colorectal cancer (approximately 55 years old) may be the main reason. Moreover, the median discovery interval in the cyclophosphamide-based chemotherapy group was 12.9 months, which was significantly shorter than the oxaliplatin-based chemotherapy group (36.0 months). Age and sex differences may account for this result, and the influence of hormone replacement therapy on breast cancer needs to be considered. Previous studies [28, 29] have reported side effects of hormonal medicines in humans, especially in the liver, including thrombosis, steatohepatitis, and hepatic cirrhosis. A higher probability of hepatic vascular injury and recanalization may have accelerated the early onset of FNH in the cyclophosphamide-based chemotherapy group. Oxidative stress, stimulated by hormonal drugs, could also promote FNH growth [30, 31].

None of the patients experienced disease progression (local recurrence or distant metastasis) during the follow-up period. Alteration of hepatic FNH in cancer survivors occurs in approximately 44.4–64.3% of patients [14, 27], and the detection of new hepatic nodules always raises concerns about metastasis, especially when the lesions grow during follow-up. In addition to the typical imaging characteristics, DWI plays a crucial role in differentiating FNH from hepatic metastasis, which is often markedly hyperintense on DWI. In our study, all hepatic nodules were isointense or slightly hyperintense on DWI at the initial diagnosis and subsequent follow-up. Eleven patients in our study experienced an increase in nodule size or number. Despite a history of cancer, a wait-and-see strategy may be the preferred treatment option for asymptomatic patients with typical imaging characteristics [14]. Therefore, knowledge of the possible occurrence of FNH in cancer patients treated with cyclophosphamide or oxaliplatin may effectively prevent aggressive or incorrect treatments. Besides, we noted the lesion shrinkage in four patients, and the same tendency was also seen in previous paediatric studies [6, 14]. We speculated that alternations in hepatic haemodynamics and iron overload in hepatic tissues may be potential reasons for FNH evolution [32].

This study had some limitations. First, most patients did not undergo surgical resection, and pathological information was lacking. Hepatic lesions were diagnosed as FNH based on imaging when they had typical characteristics, and follow-up provided additional information [14, 15]. In our study, three radiologists reviewed a series of imaging data from the remaining patients to ensure the accuracy of our results. Second, the influence of liver background was not included in the statistical analysis. Haemangioma, hepatic hemosiderosis, and iron overloading are associated with the occurrence of multiple FNH lesions and FNH evolution [31,32,33]. Our study focused on the imaging characteristics of new FNH in patients with cancer, and the influence of the liver background needs to be explored in the future. Finally, hormone replacement therapy in females may be a risk factor for FNH, which perhaps affects the size or number of FNH in imaging follow-up [6]. We did not include this information in our study because various drugs are available as hormonal replacement therapy for breast cancer.

In conclusion, cancer survivors, particularly those treated with cyclophosphamide or oxaliplatin, may present with benign FNH lesions during follow-up. In addition to metastasis, radiologists and clinicians should consider the possibility of FNH in the presence of hepatic nodules on imaging. Typical MRI findings and treatment histories can reduce misdiagnoses and avoid unnecessary invasive treatment.