Treatment of G1 Duodenal Neuroendocrine Tumors With Hepatic Metastasis: A Case Report

ABSTRACT

HAIC‐FOLFOX combined with lenvatinib induced complete liver metastasis response and partial primary tumor response in G1 duodenal neuroendocrine tumor, enabling curative resection (13 months recurrence free survival), highlighting a novel conversion strategy for advanced dNETs with liver metastases.

1. Background

Neuroendocrine tumors (NETs) are rare neoplasms originating from neuroendocrine cells, and their prevalence has increased in recent years. The overall incidence of duodenal neuroendocrine tumors (dNETs) remains relatively low, accounting for only 2.8% of all NETs and 2%–3% of gastrointestinal NETs [1, 2]. However, dNETs are highly invasive and carry a significant risk of distant metastasis. Studies have shown that 10%–15% of patients with dNETs present with liver metastases [3, 4]. In line with existing literature, we report a case of dNET with liver metastasis in a 66‐year‐old woman. We hope this report will improve the understanding of the diagnosis and treatment of this disease.

2. Case Report

2.1. Patient Information

The patient was a 66‐year‐old woman presenting with recurrent right upper abdominal pain that had persisted for 1 week. Previous examinations at a local hospital suggested “choledocholithiasis”. However, her symptoms continued despite analgesic and anti‐inflammatory therapy. Physical examination upon admission was unremarkable, except for tenderness in the upper abdomen. Laboratory tests revealed liver dysfunction, with ALT at 98 U/L, AST at 56 U/L, ALP at 141 U/L, and Alb at 39 g/L. Routine blood tests, biochemical analyses, and tumor marker assessments showed no significant abnormalities.

2.2. Imaging and Pathological Findings

Both magnetic resonance cholangiopancreatography (MRCP) and contrast‐enhanced abdominal computed tomography (CT) revealed a lobulated mass at the major duodenal papilla, measuring approximately 25 × 18 mm in diameter, which was suspected to be a malignant tumor (Figure 1). After discussion with the patient, an esophagogastroduodenoscopy (EGD) with biopsy was performed. The EGD revealed a prominent mass at the duodenal papilla (Figure 2), and tissue samples were obtained for pathological examination. Immunohistochemistry (IHC) confirmed the diagnosis of a dNET (Figure 3). Histologically, hematoxylin and eosin (H&E) staining revealed no heterogeneity in the mucosal layer, with cells arranged in nests, fuzzy tissue architecture, and focally hyperchromatic nuclei. The immunoprofile revealed the following: chromogranin A (CgA–), CD56–, synaptophysin (Syn+), cytokeratin (CK+), and a Ki‐67 proliferation index of approximately 2%. To assess the tumor staging, we performed PET‐CT, which revealed three areas of hypermetabolic lesions in the left lobe of the liver, the largest located in segment 4a (Figure 4). According to the WHO 2022 Classification of Neuroendocrine Tumors, the patient was diagnosed with an asymptomatic G1 duodenal neuroendocrine tumor (dNET) with hepatic metastases [5].

FIGURE 1.

Patient's imaging findings. (A) Noncontrast CT scan showing dilatation of the lower end of the common bile duct without high‐density stones. (B, C) Arterial and venous phase contrast‐enhanced CT images demonstrating a homogeneously enhancing 25 × 18 mm nodule at the common bile duct's distal duodenal papilla. (D) MRI (T1WI) image showing a lobate nodule at the major duodenal papilla. (E) MRI (T2WI) image showing a lobate nodule at the major duodenal papilla. (F) DWI showing a high signal in the major duodenal papilla.

FIGURE 2.

EGD image showing a nodular mass at the duodenal papilla with congestion and erosion on the surface.

FIGURE 3.

Immunohistochemical results of duodenal tumors. (A) Hematoxylin and eosin (H&E) stained tumor tissue sections under microscopic examination. (B) Chromogranin and (C) CD56 (×40). (D) Synaptophysin (×40). (E) CK immunohistochemical staining positive (×40). (F) The Ki‐67 proliferation index was approximately 2% (×40).

FIGURE 4.

PET–CT before treatment. (A–C) 18F‐FDG PET–CT image showing three nodular foci of increased metabolic abnormalities in the left lobe of the liver and (D) a patchy increased metabolic shadow in the major papilla of the duodenum. (E, F) Metabolic hyperactivity in the liver and duodenal major papilla, with absence of abnormal metabolism in metastatic lymph nodes.

2.3. Treatment

Following consensus by the multidisciplinary team (MDT), we implemented a conversion therapy protocol comprising hepatic artery infusion chemotherapy with mFOLFOX (HAIC‐mFOLFOX) and lenvatinib to induce tumor downstaging and facilitate subsequent radical surgery. The specific steps are as follows: under the guidance of digital subtraction angiography (DSA), an arterial catheter was inserted into the celiac trunk or superior mesenteric artery for angiography using the Seldinger technique. A microcatheter was selectively inserted into the tumor supplying artery, and a mFOLFOX‐based HAIC regimen was infused. The following chemotherapy drugs were used: oxaliplatin 85 mg/m² (adjusted to 130 mg/m² when the tumor diameter was > 10 cm), pumped for 2 h; calcium folinate 400 mg/m², pumped for 2 h; 5‐fluorouracil (5‐FU) 400 mg/m², infused over 30 min, followed by 2400 mg/m² administered continuously over more than 23 h. Patients received HAIC‐mFOLFOX treatment every 21 days. Lenvatinib was initiated on the third day after the first HAIC treatment. According to the prescribing guidelines for lenvatinib, patients received a daily dose of 8 mg (8 mg for those weighing < 60 kg; 12 mg for those ≥ 60 kg). If a grade 1 or 2 treatment‐related adverse reaction occurred, the lenvatinib should be reduced to 4 mg per day or temporarily discontinued, and resumed after symptom resolution. For grade 3 or 4 treatment‐related adverse reactions, lenvatinib was discontinued. The patient received four HAIC‐mFOLFOX treatments without any adverse reactions (Figure 5). Post‐treatment PET‐CT revealed that the liver metastases showed no metabolic activity, and the duodenal papillary tumor measured approximately 17 × 13 mm, with its longest diameter reduced by about 32% compared to the initial imaging examination (Figure 6). According to RECIST 1.1 and mRECIST criteria, dNET after four treatment courses was evaluated as a partial response (PR), and liver metastases were evaluated as a complete response (CR) [6, 7]. Ultimately, the patient underwent 3D laparoscopic pancreaticoduodenectomy (Figure 7). Postoperative pathology confirmed a well‐differentiated duodenal neuroendocrine tumor (G1) invading the pancreas and bile duct but without lymph node involvement. The AJCC stage was T3N0M1, Stage IV. The patient recovered and was subsequently discharged from the hospital. No tumor recurrence was observed during the 13‐month follow‐up.

FIGURE 5.

Tumor staining changes on angiography images before and after HAIC. (A) The angiography of the first HAIC treatment showed that multiple tumor staining was visible in the left and right lobes of the liver. (B) The angiography of the last HAIC treatment showed that the tumor staining in the left and right lobes of the liver decreased.

FIGURE 6.

PET–CT after HAIC treatment. (A–C) 18F‐FDG PET–CT revealed multiple hypermetabolic nodules in the original liver without metabolic abnormalities. (D) The nodule at the duodenal papilla has shrunk compared to before the initial treatment, approximately 17 × 13 mm, with increased radioactivity uptake, suggesting continued tumor activity. (E, F) Multiple hypermetabolic nodules in the liver showed no abnormal radioactive uptake and no abnormal increase in metastatic lymph nodes was observed.

FIGURE 7.

Gross specimens after the laparoscopic pancreaticoduodenectomy specimen. A gray‐white nodule (approximately 15 × 12 mm) with firm consistency is observed at the ampulla of Vater (indicated by white arrow), partially adherent to the pancreatic parenchyma.

3. Discussion

Duodenal neuroendocrine tumors (dNETs) are rare neoplasms originating from duodenal neuroendocrine cells and peptidergic neurons, accounting for 4% of all gastrointestinal NETs [5]. Epidemiological studies have shown that the incidence of dNETs has been increasing, with a 6.4‐fold increase in the past 50 years [1]. Most dNETs are located in the duodenal bulb and are well differentiated [8]. However, liver metastases are one of the most common sites of NETs progression and serve as an independent prognostic factor. Data indicate that the 5‐year survival rate for patients with liver metastases ranges from 13% to 54%, significantly lower than that of patients without liver metastases [9]. Generally, NETs with liver metastases are classified into three types: type 1 (single liver metastasis of any size), type 2 (larger liver metastasis accompanied by smaller metastases, often involving both lobes), and type 3 (diffuse multiple liver metastases) [10]. In this case, the patient was diagnosed with asymptomatic dNET combined with liver metastases (G1), TNM stage IV, dNET diameter > 1 cm, and three liver metastases localized in the left lobe. According to the latest National Comprehensive Cancer Network (NCCN) guidelines, pancreaticoduodenectomy with regional lymph node dissection is recommended for dNET. Resectable liver metastases should be surgically removed. If complete resection is not feasible, treatment options include somatostatin analogs (SSAs) or liver‐directed therapies such as transarterial embolization (TAE) or transarterial chemoembolization (TACE). However, this case presented several challenges. First, current evidence suggests that SSAs demonstrate suboptimal objective response rates (ORR) and limited tumor shrinkage efficacy in NETs treatment. Second, the patient had three liver metastases confined to the left lobe, with an insufficient future liver remnant (FLR) of < 40%, contraindicating radical surgical resection. Third, TACE carries risks of post‐embolization syndrome and biliary complications, which could worsen liver function [11, 12]. Therefore, we explored a translational treatment strategy beyond the current guideline paradigm and ultimately employed HAIC‐mFOLFOX combined with lenvatinib for tumor management.

Hepatic artery infusion chemotherapy (HAIC) is an interventional treatment method that has emerged in recent years. Since the blood supply to liver cancer tissue is almost entirely derived from the hepatic artery, effectively blocking the tumor's blood supply has become a key therapeutic strategy. Compared with transcatheter arterial chemoembolization (TACE), HAIC continuously delivers chemotherapy drugs through the artery, increasing the total dose of chemotherapy drugs and prolonging the exposure time to maximize the destruction of liver tumor cells. HAIC is also associated with fewer side effects, avoiding adverse events such as post‐embolization syndrome, and is associated with a low incidence of adverse reactions [13, 14]. HAIC therapy can induce tumor downstaging, enabling patients who were initially considered unresectable to become eligible for curative surgical resection. A retrospective study by Liu et al. included 50 patients with gastroenteropancreatic neuroendocrine tumors (GEP‐NETs) with liver metastases. HAIC treatment of liver metastases demonstrated significant efficacy. The data showed that the median overall survival (OS) of patients after HAIC treatment was extended to 19 months, and the best objective response rate (ORR) of liver metastases after HAIC treatment reached 64%, with four patients achieving complete response (CR). Multivariate analysis further revealed that patients who received more than three HAIC treatments could achieve longer liver progression‐free survival (PFS) (HR = 0.533; p = 0.043). This evidence confirms that HAIC can effectively reduce tumor burden in patients with GEP‐NET liver metastases and has a favorable safety profile [15].

SSAs have been widely used as the first‐line treatment for NETs. The PROMID study reported that octreotide LAR, used as a tumor treatment regimen for patients with midgut NETs, significantly delayed tumor progression. However, only one patient in the study experienced a PR after treatment, indicating that the objective response rate (ORR) was suboptimal. Similarly, the CLARINET study found that in patients with advanced G1 or G2 NET, lanreotide was associated with significantly prolonged PFS, but no tumor responses were observed. Several retrospective studies have also found that a greater proportion of NET patients treated with SSAs exhibited persistent stable disease (SD), suggesting that SSAs as a first‐line treatment provide a lasting effect in inhibiting tumor growth rather than downstaging the tumor [16, 17, 18].

Currently, international guidelines recommend tyrosine kinase inhibitors (TKIs) as treatment options for dNETs. Sunitinib and surufatinib are the most commonly used TKIs; both target the vascular endothelial growth factor receptor (VEGFR). However, it is noteworthy that in a phase 3 trial of sunitinib, although the median PFS was significantly improved in the treatment group compared with the placebo group (11.4 months vs. 5.5 months, p < 0.001), data showed that the overall ORR with sunitinib was only 9.3%, with 63% of patients experiencing SD after treatment. The SANET‐ep study enrolled 198 patients with NETs other than pancreatic NETs and randomly assigned them to surufatinib (n = 129) or placebo (n = 69). Of the surufatinib group, 97 patients (75%) had liver metastases. Data showed that 63% of patients achieved tumor shrinkage after treatment, but the overall ORR in the treatment group was only 8%, with 70% experiencing SD. These studies suggest that sunitinib and surufatinib, as targeted therapies, primarily inhibit tumor progression and maintain disease stability rather than induce tumor regression [19, 20, 21]. A recent multicenter, single‐arm phase II clinical trial demonstrated that lenvatinib exhibited significant efficacy in previously treated patients with advanced GEP‐NETs. The data revealed an ORR of 29.9% in the overall cohort, with the gastrointestinal neuroendocrine tumor (GI‐NET) subgroup achieving an ORR of 16.4%, significantly reducing tumor burden and showing better tumor shrinkage compared with surufatinib and sunitinib. Survival analysis revealed a PFS of 15.7 months in the GI‐NET subgroup, demonstrating favorable outcomes and indicating the potential therapeutic value of lenvatinib in treating advanced GEP‐NETs [22]. At the mechanism level, the study found that overexpression of HRAS in tumor tissue from GEP‐NET patients was associated with significant responsiveness to lenvatinib (p = 0.048). Although there are no relevant studies on HRAS overexpression and clinical outcomes in patients with NETs, it is speculated that HRAS overexpression may activate the downstream Ras–Raf–MEK–ERK pathway, contributing to NETs development. Lenvatinib inhibits angiogenesis, blocks tumor vascularization, and targets highly vascularized NETs, thereby achieving tumor control [23].

The imaging data in this study were collected retrospectively, and scale bars were not embedded in the imaging and pathology images, which may have affected the intuitive interpretation of lesion size. However, this case innovatively utilized HAIC‐mFOLFOX combined with lenvatinib treatment. After treatment, PET‐CT images revealed no abnormalities in liver metabolic nodules, suggesting tumor activity suppression. This treatment successfully achieved CR in the liver metastases, thereby meeting the criteria for radical surgery. This approach overcomes the limitations of traditional treatments through the synergistic effect of interventional therapy and targeted drugs: on one hand, it addresses the low ORR of SSAs or traditional targeted drugs and significantly improves tumor response; on the other hand, it avoids complications associated with TACE, such as post‐embolization syndrome. This case demonstrates that for patients with initially unresectable advanced G1 dNET with liver metastases, this combined treatment model is expected to achieve better tumor response in liver metastases, enable synchronous downstaging of primary and metastatic lesions, and ultimately facilitate radical surgery, thereby prolonging the patients' survival. Ultimately, the patient underwent laparoscopic pancreaticoduodenectomy, and postoperative pathology revealed a well‐differentiated, G1 dNET with no lymph node metastasis. The patient has been followed up in the outpatient clinic for 13 months with no signs of tumor recurrence.

4. Conclusion

Currently, dNETs are relatively rare, and patients with liver metastases have a poor prognosis. This patient achieved synergistic tumor downstaging through HAIC‐mFOLFOX plus lenvatinib, culminating in complete remission of liver metastases. Ultimately, the patient underwent a successful radical pancreaticoduodenectomy, offering a potentially transformative treatment strategy for patients with initially unresectable G1 dNET liver metastases.

Author Contributions

Yuhui Fang: conceptualization, writing – original draft, writing – review and editing. Yuquan Chang: data curation, investigation. Yilin Qiu: data curation, investigation. Ruiqin Huang: methodology. Feng Tian: data curation, investigation. Qijie Luo: methodology. Dongdong Huang: methodology. Kun He: conceptualization, writing – review and editing.

Funding

This study was funded by the Science and Technology Plan Project of Zhongshan, Guangdong Province (Project No. 2024B1039), but the funder was not involved in the study design or writing of the manuscript.

Ethics Statement

In compliance with the Helsinki Declaration, written and informed assent or consent was obtained from the patient before proceeding.

Conflicts of Interest

The authors declare no conflicts of interest.

Fang Y., Chang Y., Qiu Y., et al., “Treatment of G1 Duodenal Neuroendocrine Tumors With Hepatic Metastasis: A Case Report,” Clinical Case Reports 14, no. 1 (2026): e71764, 10.1002/ccr3.71764.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.