Liver metastasis from pancreatic neuroendocrine tumor: A case report

Abstract

BACKGROUND

Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors with a pathological spectrum ranging from well-differentiated tumors (pancreatic neuroendocrine tumors) to poorly differentiated carcinomas (pancreatic neuroendocrine carcinomas). Optimal surgical management for locally advanced grade 3 pancreatic neuroendocrine tumors and pancreatic neuroendocrine carcinomas remains debated due to their differing biological behaviors and prognoses.

CASE SUMMARY

This report presents a case of a non-functional pNEN with type I liver metastasis. The patient underwent laparoscopic radical retrograde modular pancreatosplenectomy for a pancreatic body/tail tumor, followed by a staged laparoscopic partial hepatectomy 2 years later. Combined with adjuvant chemotherapy (initially mFOLFIRINOX, later CAPTEM regimen), a favorable clinical outcome was achieved.

CONCLUSION

This case suggests that a combined surgical and chemotherapeutic strategy can be effective for selected patients with an advanced pNEN and metachronous liver metastasis. It may assist surgeons in better understanding the management of such cases, helping to formulate precise treatment strategies while balancing surgical risks and benefits.

Key Words: Pancreatic neuroendocrine tumor; Liver metastasis; Invasion; Laparoscopic surgery; Case report

Core Tip: This study reports a case of a high-grade (grade 3) pancreatic neuroendocrine tumor with liver metastasis. The patient achieved a favorable outcome through staged laparoscopic radical pancreatic surgery, metastasectomy, and adjuvant chemotherapy. The case demonstrates that an aggressive sequential surgical approach combined with chemotherapy is a viable strategy for selected patients with a grade 3 pancreatic neuroendocrine tumor, providing a reference for individualized treatment planning by balancing surgical benefits and risks.

INTRODUCTION

Pancreatic neuroendocrine neoplasms (pNENs) are relatively rare epithelial malignant tumors arising from pancreatic neuroendocrine cells. They account for approximately 2% of all pancreatic tumors, although their overall incidence has been steadily increasing[1]. The pNENs typically develop insidiously and demonstrate marked heterogeneity in biological behavior. Based on the mitotic count and/or Ki-67 proliferation index, pNENs are classified into well-differentiated pancreatic neuroendocrine tumors (pNETs), graded as G1, G2, and G3, or poorly differentiated pancreatic neuroendocrine carcinomas (pNECs)[2]. As the disease progresses, pNENs may undergo biological transformation, ranging from indolent growth and low aggressiveness, to invasive and metastatic behavior[3]. Consequently, significant challenges and unresolved issues remain in their clinical diagnosis and management.

Surgical treatment remains one of the principal strategies for improving the prognosis of patients with a pNEN. According to tumor stage and surgical feasibility, these tumors are categorized as resectable, borderline resectable, or locally advanced[4]. Surgical complexity is usually greater for cases that are borderline resectable and metastatic due to adjacent organ involvement or high tumor burden, potentially necessitating extended resections and limiting the achievement of radical surgery[5]. The role of surgery in locally advanced and metastatic pNENs, especially for G3 pNETs and pNECs, remains controversial with respect to survival benefits and symptom control[6]. However, accumulating evidence suggests that surgical intervention may confer survival advantages and symptom relief compared with systemic therapy alone in some patients[7]. This case presentation reports a 75-year-old woman with a non-functional G3 pNET who experienced liver metastasis following radical retrograde modular pancreatic body and tail splenectomy. Subsequent staged surgical intervention and postoperative adjuvant therapy resulted in prolonged survival and improved quality of life.

CASE PRESENTATION

Chief complaints

A 75-year-old woman was admitted to our hospital after incidental detection of a liver mass during routine examination 1 month prior.

History of present illness

Six months prior to this admission, a pancreatic mass was identified during a routine examination. At that time, the patient was asymptomatic. However, with disease progression, she gradually developed symptoms related to tumor compression, including anorexia and postprandial abdominal distension. The patient subsequently underwent a laparoscopic radical pancreatosplenectomy for a resectable pancreatic body/tail tumor, with pathology confirming a pNET. Postoperatively, she received adjuvant chemotherapy (mFOLFIRINOX regimen). Five months after the initial surgery, follow-up magnetic resonance imaging (MRI) revealed a new lesion in the left hepatic lobe, suggestive of metastasis and leading to the current admission.

History of past illness

The patient’s medical history included hypertension and diabetes for > 12 years as well as coronary heart disease for 6 years.

Personal and family history

No significant family history was reported.

Physical examination upon admission

On admission, her vital signs were stable. Physical examination revealed a height of 160 cm, a weight of 54 kg, a blood pressure of 146/82 mmHg, and a pulse of 79 beats per minute. The patient was conscious, alert, and mentally oriented, with no evident jaundice of the skin or sclera. Abdominal examination showed a soft abdomen without tenderness, rebound tenderness, guarding, or palpable masses. No percussion tenderness was noted over the liver or kidney regions.

Laboratory examinations

Tumor marker testing at admission showed elevated levels of carcinoembryonic antigen (16.37 ng/mL) and carbohydrate antigen 19-9 (95.57 U/mL), while the levels of alpha-fetoprotein (2.04 ng/mL) and other tumor indicators were within normal limits. The patient’s Child-Turcotte-Pugh classification was grade A. Tumor indicator levels, biochemical test findings, and routine blood test results are summarized in Table 1.

Table 1 Laboratory parameters before and after surgical treatment.

Item	One month before the operation	One week before the operation	One day after the operation	Three days after the operation	One week after the operation	One month after the operation
Carbohydrate antigen 19-9 (U/mL)	76.76	223.01	214.25	205.13	217.45	96.94
Alpha-fetoprotein (ng/mL)	1.87	2.03	1.51	1.45	1.49	1.71
Carcinoembryonic antigen (ng/mL)	25.19	76.52	33.07	29.86	27.45	19.84
White blood cell count (109/L)	6.83	3.03	10.27	7.20	5.03	3.33
Red blood cell count (1012/L)	2.95	3.21	2.69	2.77	2.78	3.42
Hemoglobin (g/L)	96	101	88	90	88	106
Platelet count (109/L)	190	233	268	298	311	213
Total bilirubin (μmol/L)	17.5	16.3	11.9	12.6	8.8	18.5
Direct bilirubin (μmol/L)	6.0	6.7	3.0	5.1	1.7	7.8
Alanine aminotransferase (U/L)	33	42	60	27	53	10
Aspartate aminotransferase (U/L)	20	24	50	14	47	16
Alkaline phosphatase (U/L)	90	95	74	70	86	141
Gamma-glutamyl transferase (U/L)	17	23	17	22	23	28

Imaging examinations

Contrast-enhanced abdominal MRI revealed a patchy lesion in the pancreatic neck with hypointense T1 and mildly hyperintense T2 signals, and a high signal intensity on diffusion-weighted imaging, measuring approximately 22 mm × 16.5 mm. Atrophy of the pancreatic body and tail with irregular dilation of the pancreatic duct was noted. The lesion demonstrated progressive and heterogeneous enhancement on dynamic contrast imaging (Figure 1). Contrast enhanced computed tomography (CT) showed a poorly defined, mildly hypodense lesion in the pancreatic neck, with a maximum diameter of approximately 19 mm and mild heterogeneous enhancement. Similar atrophic changes of the pancreatic body and tail with irregular ductal dilation were observed (Figure 2). Based on imaging findings and clinical evaluation, the tumor was staged as T2N0M0 and classified as a resectable pancreatic malignancy. After a multidisciplinary team discussion and informed consent acquisition, laparoscopic radical anterograde modular pancreatosplenectomy was performed. The patient recovered uneventfully. Histopathological examination and immunohistochemistry confirmed the diagnosis of pNET (Figure 3). Postoperatively, the patient received adjuvant chemotherapy with a modified FOLFIRINOX (mFOLFIRINOX) regimen (oxaliplatin 100 mg + irinotecan 200 mg + calcium folinate 0.6 g + 5-fluorouracil 3 g). Regular follow-up with CT and MRI was conducted. Five months postoperatively, contrast-enhanced MRI detected a hepatic lesion in the left lobe, characterized by an oval lesion with hypointense T1 and hyperintense T2 signals, mildly increased diffusion-weighted imaging signal, and a size of approximately 2.4 cm × 3.3 cm. Ring-like enhancement was observed on contrast imaging. Intrahepatic vasculature appeared normal, and no dilation of intrahepatic or extrahepatic bile ducts was noted (Figure 4). Based on the imaging findings, the low-density mass in liver segment II was suspected to represent metastatic disease from the pancreatic mixed endocrine tumors. The postoperative CT findings are shown in Figure 5, and the postoperative pathological findings are presented in Figure 3.

Figure 1 Contrast-enhanced abdominal magnetic resonance imaging revealing a patchy lesion in the pancreatic neck with hypointense T1-weighted and mildly hyperintense T2-weighted signals. A: Magnetic resonance imaging (MRI) T1 with contrast enhancement (arrow); B: MRI T2 with contrast enhancement (arrow); C: MRI diffusion-weighted imaging with contrast enhancement (arrow). Diffusion-weighted imaging showed high signal intensity. The lesion measured approximately 22 mm × 16.5 mm. The pancreatic body and tail were atrophied with irregular dilation of the pancreatic duct. Progressive and heterogeneous enhancement was observed on contrast-enhanced sequences.

Figure 2 Contrast-enhanced abdominal computed tomography showing a poorly defined, mildly hypodense lesion in the pancreatic neck, with a maximum diameter of approximately 19 mm. A: Represents the arterial phase of the computed tomography (CT) scan (arrow); B: Represents the venous phase of the CT scan (arrow); C: Non-contrast CT scan (arrow). Mild heterogeneous enhancement was noted. Atrophy of the pancreatic body and tail with irregular dilation of the pancreatic duct was present.

Figure 3 Immunohistochemical findings for the pancreatic tumor. A: Tumor cell nests within pancreatic tissue; B: CD56 (+), 100 ×; C: Synaptophysin (+), 100 ×; D: Ki-67 (+, hotspot approximately 40%), 400 ×; E: Chromogranin A (+), 100 ×; F: Nest-like tumor cell infiltration was observed in the liver tissue.

Figure 4 Contrast-enhanced abdominal magnetic resonance imaging revealing a hepatic lesion in the left lobe characterized by hypointense T1-weighted and hyperintense T2-weighted signals with mildly increased diffusion-weighted imaging signal intensity. A: Magnetic resonance imaging (MRI) T1 with contrast enhancement (arrow); B: MRI T2 with contrast enhancement (arrow); C: MRI diffusion-weighted imaging with contrast enhancement (arrow); D: Venous phase magnetic resonance imaging (arrow). The lesion measured approximately 2.4 cm × 3.3 cm and demonstrated ring-like enhancement after contrast administration. Intrahepatic vessels were normal, with no dilation of the intrahepatic or extrahepatic bile ducts.

Figure 5 Postoperative contrast-enhanced abdominal computed tomography demonstrating changes following resection of the left-lobe liver metastasis, including postoperative exudation, localized effusion, gas accumulation, a turbid fat gap in the operative field, and a visible drainage tube in the upper abdomen. A: Represents the arterial phase of the computed tomography (CT) scan; B: Non-contrast CT scan; C: Represents the venous phase of the CT scan.

MULTIDISCIPLINARY EXPERT CONSULTATION

Following multidisciplinary team discussion, the diagnosis of liver metastasis from the pNET was established. After informed consent was obtained, a laparoscopic partial hepatectomy was performed.

FINAL DIAGNOSIS

The final diagnosis was pNET of G3 (Ki-67 approximately 40%) after pancreatosplenectomy with metachronous liver metastasis (type I) from the pNET.

TREATMENT

The patient underwent a laparoscopic partial hepatectomy for the left lobe metastasis. Following partial hepatectomy, the patient continued to receive chemotherapy. Capecitabine was administered at a dose of 750 mg/m² twice daily from day 1 to day 14, and temozolomide at 200 mg/m² once daily from day 10 to day 14. This regimen was repeated every 28 days for two cycles.

OUTCOME AND FOLLOW-UP

The patient recovered uneventfully from the hepatectomy and was discharged 10 days postoperatively. According to the Chinese Guidelines for the Diagnosis and Treatment of Pancreatic Neuroendocrine Tumors (2020), treatment response was evaluated using CT or MRI examinations, or both, every 3 months during follow-up. At the most recent follow-up, conducted 12 months after the second surgery, no evidence of disease recurrence was found. To date, no disease recurrence has been observed.

DISCUSSION

The pNETs typically exhibit an organoid growth pattern with characteristic neuroendocrine morphology, and clinical manifestations are highly heterogeneous. Most patients lack clinical symptoms during the early and intermediate stages, and lesions are frequently detected incidentally during routine imaging examinations, resulting in delayed diagnosis and missed opportunities for early intervention. In addition to conventional CT and MRI, endoscopic ultrasound is regarded as the gold standard for diagnosing pNENs[8]. Endoscopic ultrasound-guided fine needle aspiration allows cytological and histological assessment with high diagnostic sensitivity and reliable grading consistency, thereby facilitating appropriate treatment selection[9]. Notably, pNENs demonstrate marked heterogeneity in biological behavior and prognosis. Some patients, even in the presence of liver metastases, may experience prolonged disease stability. Conversely, other cases exhibit aggressive tumor behavior with extensive metastasis and rapid progression, leading to significantly reduced survival. The World Health Organization Classification of Digestive System Tumors (Fifth Edition) revised the classification of NENs based on advances in molecular pathology, clearly distinguishing well-differentiated G3 pNETs from poorly differentiated pNECs[2,10]. Well-differentiated G3 pNETs demonstrate significantly longer median overall survival (41-99 months) compared with poorly differentiated pNECs (approximately 17 months)[11,12]. Postoperative outcomes further indicate superior survival in patients with G3 pNETs without metastasis (median overall survival: 39.2 months) and with metastasis (19.5 months) compared with pNECs (16 months and 9.1 months, respectively)[13,14]. Conversely, no significant survival difference has been observed between surgically treated and non-surgically treated patients with pNECs[15]. Given the poor prognosis and limited treatment responsiveness of pNECs[16], management strategies for G3 pNETs should emphasize more aggressive approaches, with radical surgical resection prioritized when feasible.

The management of pNETs with liver metastases requires a multidisciplinary and individualized approach based on patient performance status, comorbidities, tumor burden, and prognostic factors. Treatment strategies for pNENs continue to evolve and include surgical resection, locoregional therapies such as radiofrequency ablation and transarterial interventions, and systemic treatments including chemotherapy, targeted therapy, immunotherapy, peptide receptor radionuclide therapy, and endocrine therapy[17]. Peptide receptor radionuclide therapy has emerged as an active area of research in recent years, with the development of an increasing number of novel radiopharmaceutical agents. For patients with unresectable liver metastases, locoregional liver-directed therapies may be considered, including radiofrequency ablation, cryoablation, alkalization, transarterial embolization, and transarterial chemoembolization[18]. Compared with pancreatic ductal adenocarcinoma, pNETs are generally associated with a more favorable prognosis and higher long-term survival rates.

In the presented case, based on a comprehensive preoperative evaluation, the feasibility of simultaneous resection of the primary tumor and metastatic lesions was assessed. During disease progression, the patient developed symptoms related to tumor compression, including anorexia and postprandial abdominal distension. Without surgical intervention, the patient’s quality of life would have been expected to decline significantly, with a corresponding reduction in survival. Therefore, surgical treatment was selected. Postoperative pathological examination confirmed achievement of R0 resection. Given the presence of multiorgan invasion and concomitant type I liver metastasis in this case, postoperative adjuvant therapy was considered essential. Initially, the mFOLFIRINOX regimen was administered to control disease progression, eradicate active cancer cells, and reduce metastatic burden, thereby creating an opportunity for surgical management of liver metastases. After hepatic resection, chemotherapy was transitioned to the CAPTEM regimen (capecitabine plus temozolomide) to reduce the risk of recurrence. Encouragingly, both the surgical outcome and postoperative disease control met clinical expectations. An important remaining question is whether neoadjuvant or conversion therapy can further improve R0 resection rates in patients with pNETs characterized by a high tumor burden and an elevated risk of recurrence or metastasis, thereby improving long-term survival. The present case of advanced metastatic pNET is reported to summarize our experience with its surgical management combined with sequential chemotherapy.

CONCLUSION

This case report demonstrates that a tailored, multimodal strategy involving staged minimally invasive surgical resections combined with sequenced adjuvant chemotherapy can achieve favorable oncologic outcomes in selected patients with a G3 pNET and metachronous liver metastasis. This case underscores the importance of accurate pathological grading (differentiating G3 pNET from pNEC), a multidisciplinary decision-making process, and the continued relevance of surgical management within the treatment arsenal for a well-differentiated, advanced pNET. Individualized treatment planning, balancing surgical risks with potential for long-term disease control, remains paramount.