Misdiagnosis of Primary Hepatic Neuroendocrine Carcinoma: A Case Report and Literature Review

Background: Primary hepatic neuroendocrine carcinoma (PHNEC) is relatively rare and has high malignancy and poor prognosis, but the rate of clinical diagnosis is low. The clinical symptoms, signs, and ultrasound images are not specic. Diagnosis is mainly based on pathological manifestations and immunophenotyping analysis. Here, we present a case of PHNEC with rectal adenoma. Case presentation: A 63-year-old male patient complained of dull pain and discomfort in his right upper abdomen that had persisted for over 1 month. This individual was initially diagnosed with rectal cancer with liver metastasis because of unclear and inconclusive imaging examination results. The biopsy of rectal polyps indicated tubular villous adenoma, and the liver biopsy and immunohistochemical examinations suggested PHNEC. Conclusions: When a patient has not been diagnosed with hepatitis or cirrhosis, the AFP value is not high, and imaging shows solid space-occupying lesions, liquefaction, and clear liver tumor boundaries, we can exclude tumors of non-hepatic origin using gastroscopy, colonoscopy, and PET-CT, and other tests. We can then consider Primary hepatic neuroendocrine tumor and conrm this with pathological examinations and immunophenotyping.


Background
Primary hepatic neuroendocrine carcinoma (PHNEC) is a relatively rare cancer with high malignancy and poor prognosis [1] . PHNEC can secrete various polypeptides and biological amines. The average age of onset is approximately 40-50 years old, but there is no signi cant difference in its incidence between men and women. In addition, the diagnosis rate is low and its clinical symptoms, signs, and ultrasound images are not speci c [2] . Diagnosis is mainly based on pathological manifestations and immunophenotype. No cases of PHNEC with rectal adenoma have been previously published. Here, we present such a case.

Case Presentation
Clinical summary A 63-year-old male patient complained of dull pain and discomfort in his right upper abdomen that had persisted for over 1 month. The patient did not report any other symptoms. A computed tomography (CT) scan of the upper abdomen indicated multiple liver lesions. The patient had a history of hypertension for 5 years with no regular treatment for it. Physical examinations showed deep tenderness in the right upper abdomen.
Laboratory examinations showed the following: concentrations of tumor markers CA724, NSE, FRT, CA199, and Ca50 were increased to 49.22 U/mL (normal range 0-6.9 U/mL), 275.2 ng/mL (normal range 0-16.3 ng/mL), 631.10 µg/L (normal range 30-400 µg/L), 73.77 U/mL (normal range 0-27 U/mL), and 49.15 U/mL (normal range < 20 U/mL), respectively. The hepatic biochemical index gamma-glutamyl transpeptidase was increased to 455 U/L (normal range 15-73 U/L). Results of other blood tests were normal. Both CT and PET-CT scans ( Figure 1) indicated that the patient was suffering from rectal cancer with distant metastasis to sites such as the liver. Further examinations were performed and a colonoscopy suggested rectal polyps were present. A biopsy of these rectal polyps indicated tubular villous adenoma of the rectum nests. PET-CT excluded other primary lesions of neuroendocrine carcinoma in the pancreas, digestive tract, and other sites.

Treatments
The patient treated by transcatheter arterial embolization,but nally gave up follow-up treatment for personal reasons.

Discussion
A neuroendocrine tumor (NET) was originally de ned 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 classi cation in 2010, NET is classi ed into three grades based on the mitotic rate and Ki-67 proliferation index: G1, mitotic rate < 2 per 10 high power elds (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% [3] . 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 [4] . The liver is the most common metastatic organ of NETs, but PHNEC is rare, accounting for only 0.3-4.0% of all NETs [1] .
Primary hepatic neuroendocrine tumors (PHNETs) frequently stem from intrahepatic bile duct epithelial cells, adrenal tissue, or ectopic pancreatic cells [5] . 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 speci c, 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 ushing, abdominal pain, and diarrhea [2] . 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 speci city 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 [6] . 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 [7] . 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 18Fuoro-deoxygenated glucose uptake [8] . 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% [9] . The diagnosis of PHNEC is dependent on histological ndings 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 [10] . 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 ndings 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 classi cation 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 speci c diagnostic value in either group [11] .
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 [12] . TP53 mutations have been reported in approximately 80% of poorly differentiated neuroendocrine cancers [13] . As part of the PI3K-AKT-mTOR pathway, PI3KCA is considered to be a molecular target for the treatments of advanced NET [14] . Kwon et al. rst 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 [15] . 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 [1] .

Conclusions
When a patient has not been diagnosed with hepatitis or cirrhosis, the AFP value is not high, and imaging shows solid space-occupying lesions, liquefaction, and clear liver tumor boundaries, we can exclude tumors of non-hepatic origin using gastroscopy, colonoscopy, and PET-CT, and other tests. We can then consider PHNET and con rm this with pathological examinations and immunophenotyping.