A neuroendocrine tumor (NET) was originally defined as a carcinoid tumor derived from mucosal or submucosal gland epithelial cells that can synthesize and secrete peptide hormones. According to the World Health Organization classification in 2010, NET is classified into three grades based on the mitotic rate and Ki-67 proliferation index: G1, mitotic rate < 2 per 10 high power fields (HPFs) and/or Ki-67 index ≤ 3%; G2, mitotic rate 2–20 per 10 HPFs and/or Ki-67 index 3–20%; and G3, mitotic rate > 20 per 10 HPFs and/or Ki-67 index > 20%. Highly differentiated NETs of grades G1 and G2 are considered benign, and poorly differentiated NETs of grade G3 are named neuroendocrine carcinoma. Studies in the literature have reported that 45% of NETs originate from the small intestine, 20% from the rectum, 17% from the appendix, 11% from the colon, and 7% from the stomach. The liver is the most common metastatic organ of NETs, but PHNEC is rare, accounting for only 0.3–4.0% of all NETs.
Primary hepatic neuroendocrine tumors (PHNETs) frequently stem from intrahepatic bile duct epithelial cells, adrenal tissue, or ectopic pancreatic cells. PHNEC usually occurs in the right lobe of the liver. Vascular invasion is common because of the abundant blood supply in the liver, but distant metastases are rare. These lesions are often single (approximately 66%), and about 70.33% of them have a diameter greater than 5 mm. Most clinical features of PHNEC are no specific, and some patients show abdominal pain, an abdominal mass, or weight loss without hormone-related syndrome. A few patients with PHNEC may have carcinoid syndrome, but only approximately 5% show its obvious biological signs and symptoms, such as skin flushing, abdominal pain, and diarrhea. Because PHNEC grows slowly compared with other NETs, many patients only seek treatment when certain late stage clinical symptoms and signs appear. For example, in the case presented here, the patient saw a doctor because he felt pain and discomfort in his upper abdomen. Unfortunately, by that point the lesions had spread throughout his liver.
PHNEC has high malignancy and poor prognosis, but the diagnosis rate is very low. PHNETs show no obvious specificity in ultrasound, CT, or magnetic resonance imaging (MRI) examinations. PHNEC lesions are often hypoechoic, hyperechoic, or mixed with a surrounding ring in the ultrasound images, which may be easily misdiagnosed as a hemangioma because of the blood echo signals in the lesions. Researchers have reported that grade 1 PHNETs tend to be solitary and rapidly enhanced in the arterial phase. Grade 2 PHNETs can be either single or multiple masses with necrosis and ring-shaped enhancement. Grade 3 PHNETs are multiple masses with internal necrosis and bleeding. Kai Yang analyzed the image data of 11 PHNEC patients and found that the abdominal CT scans of eight patients showed multiple round or oval masses with clear boundaries. Enhancing images revealed diffuse heterogeneity during the arterial phase, and the enhancement was slightly higher than that in peripheral normal liver parenchyma. There were also indistinct edges in the small lesions in the portal phase. The MRI of eight patients showed characteristic lobular or segmental masses,and multiple lesions with clear edges and rich with vcasculature were observed at the arterial stage with digital subtraction angiography. Additionally, the role of PET-CT in the grading of PHNEC is not yet clear, but PHNEC is often characterized by high 18F-fluoro-deoxygenated glucose uptake. In the case presented here, PET-CT showed increased glucose metabolism in the liver, which is consistent with the literature. Finally, octreotide scintigraphy is more sensitive to tumor localization than other methods, with a reported sensitivity of approximately 85–90%. The diagnosis of PHNEC is dependent on histological findings and immunostaining for neuroendocrine markers, and requires comprehensive examinations to exclude extrahepatic primary lesions.
In addition, postoperative long-term follow-up is critical to further identify the primary tumor sites. The CT and PET-CT of the patient discussed here showed diffuse lesions of whole liver and uneven thickening of the rectal wall. Because the imaging findings suggested that rectal cancer with liver metastasis could not be ruled out, this case was easily misdiagnosed as intrahepatic metastatic disease by clinicians. Immunohistochemistry is the key method for the diagnosis and classification of NETs. CgA, Syn and Ki-67 are routine detection markers. Syn expression is one of the characteristic signs of NETs, and can be used to mark neuroendocrine tumors of neural and epithelial origin. CgA is part of a group of soluble acidic proteins that are used to label neuroendocrine cells and tumors of their origin. Syn and CgA represent the differentiation characteristics of neuroendocrine cells. Ki-67 is a proliferation-associated nuclear antigen and is used to assess cell proliferation rates. The higher the Ki-67 index is, the lower the survival rate of patients and the worse the prognosis. CD56 is a neural cell adhesion molecule that is frequently strongly positively expressed in neuroendocrine tissues, tumors, and a few lymphomas. Qiu et al. compared 34 cases of neuroendocrine carcinoma with liver metastasis with 14 cases of PHNEC and found the positive rates of Syn, CgA, CD56, PCK, CK19, and EMA were 100%, 75%, 90%, 87.5%, 66.67%, and 80%, respectively, in PHNEC lesions, and 91.18%, 69.70%, 76.47%, 100%, 68.18%, and 78.57%, respectively, in metastatic liver neuroendocrine cancer. The author also found serum AFP, CEA, CA199, and other tumor markers had no specific diagnostic value in either group.
In the case presented here, the liver biopsy showed a heterocystic nest, and immunohistochemistry analysis suggested that Syn, CgA, CD56, Ki67, and EMA were all positive, which is consistent with previous reports. Laura et al. reported two large PHNETs with tumor diameters of 18 cm and 24 cm, and genetic testing revealed that both patients had DNA mutations in tumor protein P53(TP53), including one with phosphatidylinositol 3-kinase (PI3KCA) mutations. TP53 mutations have been reported in approximately 80% of poorly differentiated neuroendocrine cancers. As part of the PI3K-AKT-mTOR pathway, PI3KCA is considered to be a molecular target for the treatments of advanced NET . Kwon et al. first reported a case combined hepatocellular carcinoma and neuroendocrine carcinoma with ectopic secretion of parathyroid hormone. This report suggested that PHNEC may cause ectopic parathyroid hormone secretion, leading to hypercalcemia. This demonstrates the importance of considering neuroendocrine differentiation when diagnosing liver cancer with low differentiation. Additionally, through a retrospective analysis of 28 patients with PHNETs, Chen et al. found that G3 grade tumors, high Ki-67 expression, poor liver function, anemia, abnormal CA125, and lack of radical surgery were positively associated with shorter survival times and poor prognosis .