Neuroendocrine tumors (NETs) are a rare type of tumor, originating from dispersed neuroendocrine cells distributed throughout the body. These cells have the ability to synthesise, store and secrete neurohormones, neurotransmitters and neuromodulators and can be either functioning or non-functioning. Functioning NETs may lead to carcinoid syndrome due to the secretion of serotonin and other vasoactive hormones including gastrin, insulin, glucagon and somatostatin. The symptoms of NETs may lead to misdiagnosis as may manifest in the abdominal organs in addition to the neuroendocrine system, thereby complicating patient treatment. Therefore researchers are attempting to diagnose this tumor type early in order to commence treatment sooner. This tumor type predominantly affects the gastrointestinal tract and pancreas rather than the liver. Primary hepatic neuroendocrine carcinomas (PHNEC) are a rare tumor type which are reported to have an incidence of 1.5/100,000 (1), accounting for <1% of all malignancies (2). Alternatively, due to carcinoid syndrome the symptoms of PHNEC may be varied and different to those for primary hepatocellular carcinoma (HCC) or those of other liver tumors. This feature and the rarity of PHNEC make it difficult to diagnose the PHNEC early and accurately prior to performing biopsies or tumor resectioning. To date, PHNEC is often misdiagnosed prior to performing a pathological examination. Computed tomography (CT) and magnetic resonance imaging (MRI) are emerging as two clinically usefully techniques in oncology. These techniques may be used for diagnosis, treatment monitoring and pathophysiologic understanding of PHNEC. However, it is often impossible to diagnose PHNEC accurately by relying solely on CT or MRI and pathological examination is currently the gold standard for diagnosis. To improve knowledge and diagnosis of PHNEC, the present study analyzed the imaging results and pathological features of nine pathologically diagnosed cases.

Neuroendocrine carcinomas most commonly develop in the gastrointestinal tract and pancreas. Those seen in the liver are metastasized from primary carcinomas of the gastrointestinal tract or pancreas in the majority of cases, and primary neuroendocrine carcinomas originating from the liver itself are rare (3). Symptoms and signs are not obvious in the early stages of this disease type. A number of patients may exhibit nonspecific symptoms, including abdominal pain and distension, whilst several suffer from carcinoid syndrome (4). The condition worsens with progression of the disease, with a number of manifestations, including symptoms caused by tumors compressed in adjacent organs, dyspepsia, weight loss and fatigue. Patients usually deny histories of hepatitis or cirrhosis (5) and exhibit AFP-negative serum levels. In addition, conventional tumor markers, for example CEA, CA125 and CA19-9, are usually negative.

Neuroendocrine tumors originating from neuroendocrine cells may be divided into two types, neurological and epithelial (6). Hepatic neuroendocrine tumors fall into the epithelial subtype but there are conflicting opinions, as it has been hypothesized that hepatic neuroendocrine tumors are formed by proliferation of neuroendocrine cells dispersed within the hepatic biliary epithelium (7). According to the latest World Health Organization criteria (2010) (8), neuroendocrine carcinomas may be subcategorized into three groups: Well-differentiated neuroendocrine tumors (carcinoid), moderately differentiated neuroendocrine carcinomas (atypical carcinoid) and poorly differentiated neuroendocrine carcinomas (small cell neuroendocrine carcinoma).

Pathological results, particularly immunohistochemical results, are required for the definitive diagnosis of a neuroendocrine carcinoma. It is generally accepted that positive expression of CgA, Syn and NSE represents definite evidence for diagnosis (9–11). Among the immunohistochemical results, CgA and Syn staining were positive in the nine patients, which was consistent with the aforementioned studies. NSE testing was performed in three patients, all of which were positive. All nine patients demonstrated negative results for CEA, HPC and AFP, whereas the majority of CK results were positive. Irregular data were obtained in Vim and EMA tests. However, in contrast to the immunohistochemical results, serum NSE tests were negative in all six patients tested, which indicated that NSE was expressed in tumor cells but not in serum. Therefore, this mechanism must be investigated further.

It is difficult to distinguish primary hepatic neuroendocrine carcinomas from metastases using pathological evidence alone. Therefore, clinical features are also important for this clarification. Thorough testing prior to surgery, examination during surgery and follow-ups after surgery are important in determining whether a primary focus is present outside the liver (12).

Neuroendocrine carcinomas are receiving considerable attention and pathological examination techniques, particularly the applications of electron microscopy and immunohistochemistry, are being developed rapidly. Although imaging methods, including CT and MRI, are unable to definitively diagnose neuroendocrine carcinomas (13,14), they remain useful for the preliminary diagnosis of a tumor. This is particularly true when combined with clinical features and other supporting information, for example no patient history of hepatic cirrhosis and an absence of tumor markers, i.e., AFP (3).

The patients of the present study exhibited single and multiple low-density masses with undefined boundaries, the majority of which had uniform density. Liquefaction necrosis was observed in the center of specific larger lesions. Contrast-enhanced CT scanning showed annular enhancement or small-sized heterogeneous enhancement in the arterial phase. The area of enhancement enlarged in the portal venous phase and the density remained almost constant in this phase. There was mild enhancement in the delayed phase. These results are consistent with previous observations (15,16).

In the present study, one patient exhibited lesions only in the left lobe of the liver, while the other eight exhibited multiple lesions in the whole liver, indicating diffuse growth of the tumor. In addition, the majority of the tumors showed annular enhancement. Two patients showed enlargement of the hepatic portal lymph nodes; one showed abdominal lymph node enlargement and the other showed retroperitoneal lymph node enlargement. Portal vein tumor thrombi and cirrhosis were not observed in any of the patients. CT scanning was unable to conclusively diagnose hepatic neuroendocrine carcinomas due to its non-specificity. However, it was able to clearly reveal the internal structure, blood supply, association with neighboring organs and metastasis of the tumor. This indicates that CT may improve preliminary differential diagnosis and determine whether a mass is primary or secondary, the correct treatment and the prognosis.

Two of the nine patients were examined by MRI and showed marginally different appearances. One showed low signal lesions at T1WI whilst the other did not show any abnormal signal in the same MRI sequence. The two patients showed high signal lesions at T2WI, consistent with previous studies (17–20).

This neuroendocrine carcinoma tumor type should be distinguished from primary hepatocellular carcinoma (HCC) irrespective of whether single or multiple in number. A typical HCC often accompanies hepatitis and hepatic cirrhosis, and the majority of patients have elevated serum AFP levels. In addition, HCCs show well-defined enhancement in the arterial phase and rapid loss of enhancement during the portal venous and delayed phases known as the ‘quick in and out of contrast medium’. These factors are important for differential diagnosis. However, specific neuroendocrine carcinomas, with diffuse lesions, are difficult to distinguish from diffuse HCCs. Multiple lesions with ring-shaped enhancements are commonly found, which should be distinguished from metastatic tumors by clinical and immunohistochemical analyses. In addition, HCC should be distinguished from focal nodular hyperplasia (FNH). FNH has a lower degree of enhancement and approximately one-third of FNH patients exhibit a central fibrous scar in lesions, showing a star-shaped low-density shadow in plain and enhanced scanning.

Early detection and resection of primary lesions is the preferred treatment for the improvement of survival rate. For patients without indications for surgery, hepatic artery chemotherapy embolism is a preferred non-operative treatment that results in a good prognosis (21). Radiofrequency ablation, cryotherapy, microwaving and anhydrous alcohol injection also exert therapeutic effects (3,22). Liver transplantation is considered in special cases (23,24). Previous studies have indicated that interferon and somatostatin, as well as its analogs, may be used in the treatment of carcinomas (25,26).

As with other malignant tumors, early detection and treatment are the key to achieving a good prognosis. The prognosis is associated with a number aspects, including pathological type, degree of differentiation, size and boundary of the tumor, metastasis and the physical status of the patient.