Primary hepatic neuroendocrine tumor with a suspicious pulmonary nodule: A case report and literature review

Abstract

BACKGROUND

Primary hepatic neuroendocrine tumors (PHNETs) are extremely rare tumors originating from neuroendocrine cells. Due to lack of neuroendocrine symptoms and specific radiographic characteristics, PHNETs are challenging to differentiate from other liver tumors.

CASE SUMMARY

This case involved a 67-year-old male who was admitted with a discovered hepatic mass and a suspicious lung lesion. Primary hepatic carcinoma was initially speculated based on the characteristic magnetic resonance imaging findings. The patient underwent a laparoscopic right partial hepatectomy, and subsequent immunohistochemical examination revealed a HNET. To exclude other potential origins, a positron emission tomography-computed tomography scan and gastrointestinal endoscopy were performed, leading to a final diagnosis of PHNETs. Then we conducted a literature review using the PubMed database, identifying 99 articles and 317 cases related to PHNETs. The characteristics, diagnostic methods, and treatment of PHNETs have been described. Finally, we elaborate on the presumed origins, pathological grades, clinical features, diagnosed methods, and treatments associated with PHNETs.

CONCLUSION

The diagnosis of PHNETs was primarily an exclusionary process. A definitive diagnosis of PHNETs relied mainly on immunohistochemical markers (chromogranin A, synaptophysin, and cluster of differentiation 56) and exclusion of primary foci in other organs. Radical surgery was the preferred treatment for early-stage tumors.

Key Words: Primary hepatic neuroendocrine tumors; Pulmonary nodule; Neuroendocrine neoplasms; Liver; Surgical resection; Case report

Core Tip: This paper reports a case of a rare primary hepatic neuroendocrine tumor (PHNET). Subsequently, we conducted a literature review using the PubMed database to describe the characteristics, diagnostic methods, and treatment of PHNETs. The diagnosis of PHNETs relies on definitive pathological findings, with the primary objective of preoperative examinations being the exclusion of extrahepatic primary sources. Radical surgery is the preferred treatment for early-stage tumors, and overall outcomes of PHNETs are generally better than those of gastrointestinal NETs with liver metastasis.

INTRODUCTION

Neuroendocrine tumors (NETs) are a rare type of tumor originating from neuroendocrine cells and distributing throughout the body, with the lung and gastrointestinal tract being the most common sites of origin[1]. Hepatic NETs (HNETs) are primarily caused by metastases from other organs, while primary HNETs (PHNETs) account for only 0.3% of all NETs[2]. The etiology and pathogenesis of PHNETs remain unclear. Diagnosing PHNET is challenging due to the absence of typical imaging or serological markers. Based on imaging characteristics, differentiating PHNETs from other hepatic malignancies, such as hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCC), is difficult. Most patients do not exhibit overt clinical symptoms, leading to incidental discovery during physical examinations or treatment for other conditions. As a result, the diagnosis and treatment of PHNETs are often delayed, posing significant risks to patient health.

This paper reported the case of a 67-year-old male who was admitted to our hospital because of a discovered hepatic mass. Hepatic carcinoma was initially suspected based on the magnetic resonance imaging (MRI) findings. Until a pathological examination after surgical resection, along with positron emission tomography-computed tomography (PET-CT) and gastrointestinal endoscopy to exclude other origins, the hepatic mass was ultimately diagnosed as a PHNET.

CASE PRESENTATION

Chief complaints

A 67-year-old male discovered a hepatic mass 6 days prior.

History of present illness

The patient’s routine examination revealed a hepatic mass, without abdominal pain, bloating, diarrhea, jaundice, or other symptoms.

History of past illness

The patient has had a nodule in the left lung for several years, with no significant changes noted during regular reexaminations.

Personal and family history

The patient denied any family history of malignant tumors.

Physical examination

On physical examination, the vital signs were as follows: Body temperature, 36.5 °C; blood pressure, 135/86 mmHg; heart rate, 82 beats per minute; respiratory rate, 19 breaths per minute. Additionally, no mass was touched on the abdominal examination. There was no pressure, rebound pain, or muscle tension on palpation over the whole abdomen.

Laboratory examinations

The liver function indicators were within the normal range. Among the tumor-related markers, the gastrin-releasing peptide precursor level increased to 93.87 pg/mL (> 63 pg/mL). Both hepatitis B surface antigen and hepatitis C antibody tests were negative.

Imaging examinations

Hepatic MRI with contrast enhancement and diffusion-weighted imaging (DWI) indicated a nodule measuring 20 mm × 18 mm in hepatic segment VIII. The nodule exhibited long T1 and long T2 signals, along with hyperintensity on DWI. The enhanced scan demonstrated the circumferential enhancement, raising concerns for potential malignancy and metastasis (Figure 1). A high-resolution chest CT (HRCT) scan showed a solid nodule in the basal segment of the left lung’s lower lobe (Im163), measuring approximately 15 mm × 13 mm, and CT enhancement was recommended. The enhanced chest CT scan indicated that the nodule displayed mild to moderate inhomogeneous enhancement.

Figure 1 Liver magnetic resonance imaging enhanced findings. Showing a 20 mm × 18 mm nodule in the hepatic segment VIII with A: Long T1; B: Long T2; and C: Hyperintensity in diffusion-weighted imaging.

After consulting with the multidisciplinary treatment team, primary hepatic tumor was considered as a temporary diagnosis. To determine whether the pulmonary nodule was benign or malignant and to exclude the possibility of metastasis, we carried out PET-CT and gastrointestinal endoscopy. The PET-CT demonstrated a slightly hypodense nodule in the hepatic segment VIII with low glucose metabolism, which was considered malignancy (Figure 2). By contrast, the pulmonary nodule exhibited slightly elevated glucose metabolism, suggesting it was a benign lesion. The gastrointestinal endoscopy showed no significant abnormalities.

Figure 2 Positron emission tomography-computed tomography findings. A: Hepatic segment VIII hypodense nodule with a low glucose metabolism; B: Pulmonary nodule with slightly elevated glucose metabolism.

FINAL DIAGNOSIS

Based on the combined pathological and immunohistochemical results, the tumor was consistent with a PHNET and was classified as small cell carcinoma.

TREATMENT

Based on the examinations conducted, primary hepatic cancer was diagnosed, and a laparoscopic right partial hepatectomy was performed. Intraoperative pathology suggested the presence of HCC with size of 2 cm × 1.9 cm × 1.2 cm. Subsequent microscopy analysis of the mass revealed that the tumor cells exhibited small cell morphology. Immunohistochemical analysis indicated that the tumor cells were positive for synaptophysin (Syn), chromogranin A (CgA), cluster of differentiation 56 (CD56) and somatostatin receptor 2 (endocrine markers), as well as pan cytokeratin (an epithelial keratin marker), suggesting the presence of NETs. Liver tumor-related markers, including hepatocyte paraffin 1, heat shock protein 70, arginase-1 and glutamine synthetase, were negative. The Ki67 proliferation index was 10% (Figure 3).

Figure 3 Microscopic findings. A: Hematoxylin and eosin staining; B: Synaptophysin immunohistochemistry; C: Chromogranin A immunohistochemistry; D: Ki67 immunohistochemistry.

OUTCOME AND FOLLOW-UP

After the operation, the lung mass underwent a puncture biopsy, which revealed no tumor cells. Additionally, there was no signs of liver recurrence or emergence of another PHNET at the 1-year follow-up.

LITERATURE REVIEW

Epidemiological and clinical manifestations

We have summarized cases reported in the English literature over the past 15 years. A systematic search was conducted in the PubMed database using the term ‘primary hepatic neuroendocrine tumor’. The search produced 99 publications and reported 317 cases. The mean age of patients was 52 years, with the oldest patient being 87 years old[3] and the youngest 17 years[4]. The literature review showed that the age at diagnosis of PHNETs was generally older. One patient had a preoperative course lasting 26 years. She was initially diagnosed with a benign hepatic tumor, and was later found to have PHNETs after tumor recurrence following resection[5]. The male-to-female ratio for PHNET was 1.01:1 (148 males to 146 females), indicating no significant sex difference. Approximately 34.3% of the tumors were multiple, while 65.7% were single, with tumors in the right liver being more common. There were seven cases of giant tumors, with a maximum diameter of 35 cm[6-12]. PHNET metastasis primarily involved multiple intrahepatic sites[13,14], with some cases presenting in the lungs, mesentery, spleen, adrenal glands, bone marrow, and brain[11,15-17]. Rasmussen et al[6] reported a unique case of PHNET with orbital metastasis.

Complementary examinations

In most cases, patients underwent hepatitis viruses test, tumor marker test [carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9)], chest and upper abdominal CT scans, and hepatic MRI. A total of 50.2% of patients received ¹⁸F-fludeoxyglucose PET/CT scans to exclude extrahepatic lesions and to assist in diagnosing whether the lesions were benign or malignant[18,19]. Twenty-five percent of patients underwent somatostatin receptor scintigraphy (SRS), some of which were performed postoperatively. This may be associated with preoperative susceptibility to the diagnosis of HCC or hepatic hemangioma[20-22]. To clarify the nature of the lesions preoperatively, 62.8% of patients underwent ultrasound (US)- or CT-guided liver puncture[23,24]. A total of 48.6% of patients underwent gastrointestinal endoscopy to exclude primary foci of gastrointestinal origin[25,26].

Treatment strategies

Regarding treatment strategies, 170 patients underwent surgery, predominantly radical resection[27,28]. Twenty-seven patients received transcatheter arterial chemoembolization (TACE)[24,29], and six patients underwent liver transplants due to giant tumors or liver failure[30,31]. A study by Qiu et al[32] study demonstrated that radical surgery was significantly associated with overall survival. TACE following surgery was found to be superior to surgery combined with microwave ablation, chemotherapy, and other treatments[33]. According to their multivariate analysis, Ki67, histological types, albumin levels and treatments were identified as independent prognostic factors[34,35]. Patients in the early stage (G1/G2) exhibited a better prognosis, while most patients who died were in the G3 stage with systemic metastases and multiple organ failure. However, PHNET had a lower cumulative survival rate compared to pancreatic neuroendocrine neoplasm (NEN)[35]. Previous literature has reported 14 cases of primary hepatic mixed neuroendocrine and non-NENs, including combined with HCC, CCC, adenocarcinoma, gall bladder adenocarcinoma, and gallbladder carcinosarcoma[36-40].

DISCUSSION

NENs are a heterogeneous group of tumors originating from diffuse NETs. NENs are mostly found in the gastrointestinal tract, pancreas, and lungs, with a lower incidence in the liver, accounting for only 0.3% of all NEN cases and 0.28%-0.46% of all hepatic cancers[2].

The origin of PHNETs remains unclear, with three hypotheses proposed in the literature. First, PHNETs may originate from ectopic tissues with endocrine functions in the liver, such as the pancreas and adrenal glands[41,42]. Second, they may arise from the neuroendocrine differentiation of malignant stem cells within the liver. Third, PHNETs could originate from neuroendocrine cells located in the epithelium of the intrahepatic capillary bile ducts[2,43]. The third hypothesis is the most widely accepted. Nakano described a case of HCC combined with the neuroendocrine carcinoma (NEC). Microscopic examination revealed that HCC and NEC are closely intermingled, with a transitional area evident between them. Therefore, the author proposed that moderately or poorly differentiated HCC transdifferentiate into a neuroendocrine phenotype, which aligns with third hypothesis[44].

NENs are classified into well-differentiated (NETs) and poorly differentiated (NECs). NETs are further categorized into three grades based on mitotic count and/or the Ki67 proliferation index: Low-grade (G1), intermediate-grade (G2), and high-grade (G3). By definition, NECs are considered high-grade, characterized by early dissemination and a poor prognosis[45]. The latest World Health Organization 2022 classification of endocrine and NETs, distinguished NECs and subclasses them into small cell NEC (SCNEC) and large cell NEC (LCNEC), each defined by cytological features (Table 1)[46,47]. SCNECs exhibit highly atypical with small cell morphology, forming solid proliferations with prominent necrosis. LCNECs display large cell morphology with vesicular chromatin or prominent nucleoli, consisting of large nodules arranged in an organoid pattern with focal necrosis[48].

Table 1 World Health Organization 2022 neuroendocrine neoplasm classification for different anatomic sites.

Neuroendocrine neoplasm	Classification	Diagnostic criteria
Well-differentiated neuroendocrine neoplasm	Grade 1 (G1)	< 2 mitoses/2 mm2 and/or Ki67 < 3%
	Grade 2 (G2)	2-20 mitoses/2 mm2 and/or Ki67 3%-20%
	Grade 3 (G3)	> 20 mitoses/2 mm2 and/or Ki67 > 20%
Poorly differentiated neuroendocrine neoplasm	Small cell NEC	> 20 mitoses/2 mm2 and/or Ki67 > 20% (often > 70%), and small cell cytomorphology
	Large cell NEC	> 20 mitoses/2 mm2 and/or Ki67 > 20% (often > 70%), and large cell cytomorphology

NEC: Neuroendocrine carcinoma.

PHNETs grow slowly, and most patients are clinically asymptomatic. These tumors are often discovered incidentally, with common symptoms including abdominal pain, jaundice, and a palpable mass in the right upper quadrant, which may result from mass effects on the liver and adjacent organs[49]. Metastatic HNETs (MHNETs) present with flushing, diarrhea, and abdominal pain, which are associated with the typical carcinoid syndrome due to the secretion of vasoactive hormones[50]. Most PHNETs lack endocrine function, which is speculated that the biopeptides or amines released by these tumors are degraded by hepatic enzymes and directly enter the circulation to avoid activation[51].

PHNETs lack of definitive imaging and characteristic serological markers to facilitate the diagnosis. Conventional tumor markers, such as AFP, CEA, and CA19-9, are generally within normal ranges or mildly elevated in patients with PHNETs. For functional PHNETs, the metabolic products of biogenic amines and peptides, such as serotonin, insulin, and gastrin, are useful to disease diagnosis. However, most PHNETs are non-functional and do not have specific serological markers. In our case, elevated level of gastrin-releasing peptide precursor was associated with NETs. CT imaging reveals single or multiple low-density nodules or heterogeneous masses in the liver, often accompanied by cystic degeneration or liquefied necrosis. MRI imaging demonstrates slightly long T1 and T2 signals, as well as hyperintensity on DWI. Following a dynamic enhanced scan, the lesions exhibit heterogeneous enhancement with irregular internal margins in the arterial phase. In the portal venous phase, the lesions show continuous enhancement with irregular, non-enhanced low-density foci at the center[52]. Solid PHNETs are frequently misdiagnosed preoperatively as the HCC or cholangiocarcinoma (CCC) due to imaging similarities. HCC typically displays a ‘fast-in-fast-out’ enhancement pattern on CT/MRI, characterized by marked enhancement in the arterial phase followed by rapid clearance in the portal venous phase. CCC is radiographically characterized by bile duct dilation, thickening of the bile duct wall, or periductal infiltration, and usually demonstrates a slowly progressive enhancement on enhanced imaging (Table 2). Cystic PHNETs easily confused with hepatic mucinous cystadenoma, cystadenocarcinoma, and Echinococcus cysts on CT and MRI[50,53,54]. Wang et al[55] compared pathological grading with CT and MRI features, revealing that G1 tumors were singular solid nodules, while G2 and G3 tumors exhibit multiple diffuse lesions or a large tumor with multiple satellite lesions characterized by focal hemorrhage, necrosis, and portal vein thrombosis. PHNETs show significant enhancement in the arterial phase, indicating that they are tumors with a rich blood supply. On US, PHNET lesions are predominantly hyperechoic, exhibiting strong arterial hyperenhancement on contrast-enhanced US (CEUS). By contrast, CEUS in patients with MHNETs showed arterial hypo-enhancement or iso-enhancement[56]. The somatostatin analogue octreotide receptor scintigraphy (SRS) can also be used in the diagnosis of NENs, with a sensitivity of 90% and specificity of 80%[57]. PET/CT offers superior specificity and sensitivity compared to SRS for the diagnosis of NENs. Gallium-dotatate PET/CT not only clarifies the location of the primary tumor, but it also highly sensitive to microscopic metastatic lesions, which is essential for the staging and prognosis of patients with PHNETs[58,59].

Table 2 Differential diagnosis of pancreatic neuroendocrine neoplasms with hepatocellular carcinoma and cholangiocarcinoma.

	PHNENs	HCC	CCC
Source	Neuroendocrine cells	Liver cells	Bile duct cells
Incidence rate (of all hepatic cancers)	0.28%-0.46%	80%	15%
Risk factors	Un clear	Viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, aflatoxin	Cholangitis, bile duct stones, bile duct cysts, hepatic schistosome infection
Clinical manifestations	No manifestations in the early stage. Abdominal pain, jaundice and an epigastric mass in the late stage. Functional PHNENs may be associated with carcinoid syndrome	No manifestations in the early stage. The first symptom is abdominal pain, followed by an epigastric mass, fatigue, lethargy and abdominal distension	No manifestations in the early stage. Abdominal discomfort, abdominal pain, fatigue, nausea, an epigastric mass, jaundice and fever in the late stage
Imaging manifestations	Single or multiple low-density nodules or inhomogeneous masses in the liver, often with cystic degeneration or liquefied necrosis	‘Fast-in-fast-out’ enhancement pattern on CT/MRI	Bile duct dilatation, thickening of the bile duct wall or periductal infiltration on CT/MRI, and a slowly progressive enhancement on enhanced imaging
Serum tumor markers	No specific tumor markers. Serotonin, insulin and gastrin elevated in the functional PHNENs	AFP, PIVKA II, AFP-L3, microRNA elevated	No specific tumor markers. CA19-9, CA125 and CEA elevated
Immunohistochemical markers	CgA, Syn, NSE, CD56	HepPar1, CD34, pCEA, COX-2, arginase-1	MUC-1, CK19, AQP-1
Treatment	Preferred surgery	Preferred surgery	Preferred surgery

AFP: Alpha-fetoprotein; AQP-1: Aquaporin 1; CA: Carbohydrate antigen; CCC: Cholangiocarcinoma; CD: Cluster of differentiation; CEA: Carcinoembryonic antigen; CgA: Chromogranin A; CK19: Cytokeratin 19; COX-2: Cyclooxygenase 2; CT: Computed tomography; HCC: Hepatocellular carcinoma; MRI: Magnetic resonance imaging; MUC-1: Mucin 1; NSE: Neuron-specific enolase; pCEA: Monoclonal carcinoembryonic antigen; PHNENs: Pancreatic neuroendocrine neoplasms; PIVKA II: Protein induced by vitamin K absence or antagonist-II; Syn: Synaptophysin.

The diagnosis of PHNETs relies on definitive pathological findings, with the primary objective of preoperative examinations being the exclusion of extrahepatic primary sources. Gastroscopy and colonoscopy are performed to exclude gastrointestinal NETs. Lung evaluations, including (HRCT and bronchoscopy, are conducted to identify any primary pulmonary lesions. PET/CT has gained popularity prior to surgery because of its comprehensive whole-body imaging findings. While assessing the hepatic lesion through abdominal MRI and CT scans, it is crucial to consider the possibility of a primary pancreatic mass. Consequently, the diagnosis of PHNETs can be regarded as an exclusionary diagnosis.

Preoperative puncture biopsy is not recommended, as several literatures indicate that it has a low diagnostic accuracy, with only 11.3% reported[2,60]. Postoperative histological and immunohistochemical evaluations are the most essential method for definitive diagnosis. Mitoses and the Ki67 proliferation index serve as the fundamental criteria for tumor staging and grading. CgA, Syn, and CD56 are widely recognized as the most specific immunohistochemical markers. CgA is predominantly found in the neuroendocrine cells and is considered a highly specific neuroendocrine marker[61]. It exhibits strong and diffuse immunostaining in NETs, but may be weak or even absent in NECs[62]. CgA also correlates with tumor burden and patient prognosis, making it a valuable indicator for postoperative follow-up observations[63]. Neuron-specific enolase (NSE) is a glycolytic enzyme involved in neurons and neuroendocrine cells. However, the sensitivity of NSE, which ranges from 39%-43%, and its specificity, which ranges from 65% to 73%, limit its clinical application in distinguishing NENs from non-NENs[64]. Syn is a primary component of synaptic vesicles in neurons and is expressed in both NETs and NECs. It is the most sensitive neuroendocrine marker rather than the specific marker[65,66]. The CD56, a neural cell adhesion molecule, exhibits high sensitivity in identifying the neuroendocrine phenotype of tumors, but it is also not a specific neuroendocrine marker[61,67]. Additional neuroendocrine markers are summarized in the Table 3[68-71]. In conclusion, a variety of immunological markers are necessary for the accurate diagnosis of NETs.

Table 3 Commonly used immunohistochemical markers in neuroendocrine neoplasms[68-71].

Immunohistological markers	Interpretation
Chromogranin A	The major constituents of neuroendocrine secretory granules, the first-choice marker to confirm nets, responding prognosis
Synaptophysin	The main constituent of synaptic vesicles of neurons, most sensitive but no specific nets marker
Neuron-specific enolase	A glycolytic enzyme produced in neurons and neuroendocrine cells, with low sensitivity and specificity
CD56	The neural cell adhesion molecule, a sensitive but no specific neuroendocrine marker
ASH1	The key transcription factor in neuroendocrine cell differentiation, used as a differential diagnosis for high-grade extra-pulmonary NECs[68,69]
CK AE1/AE3	Marking the epithelial and epithelial-derived tumors[61,70]
SSTR 2/5	The most frequently expressed SSTR subtypes in NENs, with type-specific differences[71]

ASH1: Achaete-scute homolog-1; CD: Cluster of differentiation; CK AE1/AE3: Cytokeratin AE1/AE3; NECs: Neuroendocrine cancers; NENs: Neuroendocrine neoplasms; SSTR: Somatostatin receptor.

Although there is no treatment guidelines of PHNETs, surgical resection is the main treatment for both primary and secondary HNETs[72,73]. Achieving an R0 resection to ensure negative margins and appropriate lymph node dissection is considered the optimal surgical approach. Overall survival outcomes of PHNETs were generally better than those of HCC (mean survival time: 30.64 vs 25.11 months) and gastrointestinal NETs with liver metastasis (5-year survival rate: 18.57% vs 8.63%). However, the mean survival time of PHNETs was inferior to gastrointestinal NETs without metastasis (30.64 months vs 41.62 months)[74]. Knox reviewed the long-term survival following PHNET resection, and the results showed that the 10-year survival rate was 68%. There was no significant influence on survival associated with preoperative chemotherapy, radiation therapy, or chemoembolization[75]. Qu et al[76] utilized associating liver partition and portal vein ligation for staged hepatectomy to treat a PHNET that was too large to be resected in a single operation. Iwao et al[77] reported a 5-year survival rate of 74% and a recurrence rate of 18% in a follow-up study of 53 patients with PHNETs. Given that PHNETs are blood-rich tumors and sensitive to ischemia, TACE may be recommended for unresectable and recurrent cases[77]. Liver transplantation could also be taken into consideration for unresectable PHNETs that otherwise poorly treated and do not have extrahepatic metastases[78,79]. A study by Moris et al[80] indicated that the 5-year overall survival rate following liver transplantation was 63%. However, the widespread application of liver transplantation is limited by high costs, a scarcity of donor organs, and a high recurrence rate.

CONCLUSION

As shown in our case, PHNETs are extremely rare tumors for which early detection and diagnosis are particularly important. Due to the absence of neuroendocrine symptoms and their nonspecific radiographic appearance, PHNETs are challenging to differentiate from other liver tumors. The diagnosis of PHNETs is a continuum that spans from the preoperative to the postoperative stage, necessitating long-term follow-up to exclude a primary extrahepatic source. Immunohistochemical markers of the postoperative mass, such as CgA, Syn, and CD56, represent the most accurate method for diagnosing the PHNETs. Surgical resection is the preferred treatment, and most patients tend to recover well after surgery.

ACKNOWLEDGEMENTS

We are grateful for the support from the participant and his family.