Background
Primary hepatic neuroendocrine carcinoma (PHNEC) is a rare neuroendocrine carcinoma (NEC) that originates from the liver, whereas the vast majority NECs in the liver are the result of metastases that arise from the gastrointestinal tract and lungs [
1‐
6]. Symptoms of PHNEC are not specific, and patients normally present with abdominal pain [
7]. Thus, diagnosis of PHNEC is very challenging. Liver cancer is commonly diagnosed initially, typically relying on imaging methods such as ultrasound, enhanced computer tomography (CT), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). A diagnosis of NEC then results from pathological examination of pre-operative liver tumor biopsy or the surgically resected tumor, and a final diagnosis of PHNEC largely depends on ruling out non-hepatic origins [
7‐
9]. Treatment of PHNEC includes surgical resection of liver (partial hepatectomy), transcatheter arterial chemoembolization (TACE) therapy, liver transplantation, chemotherapy, radiotherapy or radiofrequency ablation, and administration of somatostatin (i.e., growth hormone-inhibiting hormone) analogues, with the choice of treatment depending on tumor stage, location of the tumor in the liver, and whether the carcinoma secretes hormones [
7]. Partial hepatectomy is the most common used treatment, particularly for localized PHNECs [
8,
9], while TACE is normally performed for advanced PHNEC cases that are poor candidates for resection [
7,
10]. By interrupting the blood supply to the tumor while directly delivering chemotherapeutics, TACE inhibits tumor growth and extends survival. Somatostatin analogues, such as octreotide, can inhibit secretion of growth hormone by NECs and prevent tumor proliferation [
11].
Here, we report two PHNEC cases that were diagnosed and treated at our hospital. Since PHNEC is extremely rare and lacks specific diagnostic symptoms, diagnosis of each case proceeded through several important stages of examination. Imaging methods (DCE-MRI and enhanced CT) revealed a mass in the liver, supporting an initial diagnosis of liver cancer. Subsequent immunohistochemical (IHC) examination of liver biopsies confirmed the diagnosis of poorly differentiated NEC. Finally, the primary hepatic origin of the detected NEC in each case was arrived at when gastroscopy, colonoscopy, and positron emission tomography-computer tomography (PET-CT) examinations eliminated the possibility of the NEC having metastasized to the liver from elsewhere in the body. We present discussion of the diagnosis, pathology, treatment, and prognosis of PHNEC.
Discussion
Primary liver cancers are usually hepatocellular carcinoma (HCC) and rarely neuroendocrine carcinoma, as NEC normally metastasizes to the liver rather than originating from it [
12‐
15]. Differential diagnosis of PHNEC versus metastatic hepatic NEC is important to guide treatment options and predict outcomes [
16‐
19]. The two cases reported here were both diagnosed as grade 3 poorly differentiated PHNEC.
PHNEC shows no gender predominance [
6,
20] and no risk factors have been reported. A review of PHNEC cases estimated a mean age of 49.8 (standard deviation: ±16.0) at the time of diagnosis and that 58.5% (55/94; confidence interval, CI, 47.9%–68.6%) of patients were female [
7]. In contrast, another literature review estimated a median age of 66.5 (range: 37–80) and 58.3% (7/12; CI 27%–84%) male patients [
1]. Both cases we presented here were male with a mean age of 65 (61 and 69) and had been smokers for at least 20 years; case one had chronic hepatitis B, and case two had a long history of hypertension and diabetes.
PHNEC is normally detected at a late stage when the tumor is large, because patients normally present non-specific clinical symptoms. A review showed that 44% (37/84; CI 33.2%–55.3%) of patients presented abdominal discomfort, 13.1% (11/84; CI 6.8%–22.2%) of patients exhibited no symptoms, and 4.8% (4/84; CI 1.3%–11.8%) had jaundice [
7]. No standard markers have been reported to be unique for PHNEC [
14]. Both cases we reported here presented with abdominal pain, and serum studies showed abnormal tumor markers of AFP, NSE, CA–125, and SF for case one and CA19–9 for case two.
We diagnosed both patients as having hepatic NEC using imaging and pathological examination of biopsies. Based on imaging alone, it is challenging to distinguish hepatic NEC from other hepatic carcinomas such as HCC or distinguish primary hepatic from metastatic hepatic NEC [
21]. However, some hepatic NECs exhibit distinctive cyst-like changes in the liver on MRI and CT images that can differentiate hepatic NEC from HCC [
1,
2,
15,
22‐
25]. Retrospective investigation showed that both of our cases presented cyst-like changes in the liver that are similar to those described in the literature, which suggested a diagnosis of neuroendocrine carcinoma in the liver. With respect to pathological examination of the biopsies, IHC markers are effective for identification of primary hepatic neuroendocrine tumors, and positive staining for Syn and CgA has been used to support diagnosis of PHNEC [
15,
25‐
27]. A review reported that 84% (26 out of 31) of PHNEC cases showed positive staining for CgA [
13]. Another review reported that 95% (90 out of 95) of PHNEC cases showed positive staining for CgA [
6]. For the two cases we reported here, case one exhibited positive staining for Syn, but negative staining for CgA; whereas case two exhibited positive staining for both Syn and CgA.
While the general diagnosis of hepatic NEC normally relies on unique imaging characteristics, IHC markers, and biopsy, the primary hepatic origin of the NEC is normally determined by excluding evidence of origins from other organs [
28] given that most hepatic NECs originate from other tissues and later metastasize to the liver [
29]. Therefore gastroscopy, colonoscopy, and chest CT including PET-CT are used to finalize the diagnosis of the hepatic origin of NEC [
30]. We diagnosed both cases with PHNEC accordingly.
The possibility of co-occurrence of HCC and PHNEC is extremely rare, and we found only 12 cases in the English literature [
31‐
34] and one in the Korean literature [
35]. Interestingly, all 12 cases in the English literature are male patients in the age distributions of 40 s (one case), 50 s (2 cases), 60 s (4 cases), and 70 s (5 cases), and the Korean literature reported a case of a 68-year-old female. Almost all patients (11 out of 13) had documented liver disease, chronic hepatitis C (6 cases), chronic hepatitis B (4 cases), and cirrhosis of unknown cause (one case). Our patients were both males around 60 years of age, and case one had hepatitis B and was positive for the HCC marker HepPar-1, suggesting the possibility of co-occurring HCC and PHNEC. Due to the lack of autopsy samples, we cannot absolutely exclude this possibility.
While case two presented with symptoms of yellow skin and sclera, as well as fever and rash during hospitalization, suggesting a diagnosis of autoimmune liver disease, we excluded this possibility after performing liver biopsy. We concluded that the yellow skin and sclera were caused by obstructive jaundice, suggested by an elevated level of total bilirubin with an increased direct bilirubin and normal indirect bilirubin, which is consistent with the imaging results from enhanced-CT that revealed dilation of the bile duct. However, the degree of dilation of the extrahepatic bile duct seemed insufficient to explain the high level of bilirubin. Thus, we concluded that intrahepatic obstructive jaundice arose as a consequence of the neuroendocrine carcinoma having invaded intrahepatic small bile ducts, leading to severe small bile duct obstruction and high levels of direct bilirubin. Case two indicates that yellow skin and sclera from obstructive jaundice are clinical manifestations arising as a consequence of bile duct invasion by neuroendocrine carcinoma. Thus, jaundice can be consistent with diagnosis of neuroendocrine carcinoma having originated in the liver and metastasized to the bile duct. However, we could not rule out the possibility of cholangiocarcinoma or independent primary origin of biliary NEC in addition to PHNEC, and it is nearly impossible to distinguish between biliary NEC and cholangiocarcinoma without biopsy or autopsy [
36]. As for case one, since we did not see either lesions of the bile duct through multiple imaging approaches or symptoms suggesting obstruction of the bile duct, we excluded the possibility of cholangiocarcinoma or biliary NEC.
Furthermore, the PHNEC of case two was found to be bilobar, with tumors in both lobes of the liver, suggesting the multifocality of the primary. One review reported that 37.2% (35 out of 94) of PHNEC cases had multiple tumors involved, and 23.4% (22 out of 94) PHNEC were bilobar [
7]; another review reported that 23.7% (28 out of 118 cases) of PHNEC were ‘multicentric’ with a right lobe bias (48.4%, 60/124), and 18.5% (23/124) were bilobar PHNEC [
37].
There are multiple treatment options for PHNEC. For early stage PHNEC, surgical resection of liver tumor tissue or partial hepatectomy is the most common treatment [
7], with a five-year survival of 74–78% [
4]. Otherwise, treatment options are limited to liver transplantation, TACE, or administration of somatostatin [
11,
38‐
42]. Neither of our two cases was eligible for surgical resection of the tumor, and liver transplantation was not performed due to a lack of matched donor livers or financial concerns. Accordingly, case one received TACE treatment. As TACE was contraindicated for case two, this patient received somatostatin treatment, but his allergic reaction forced us to resort to a supportive therapy of albumin administration to protect the liver.
While the inhibitory hormone somatostatin is useful for alleviating the symptoms of the excessive hormones released by many NECs and inhibiting tumor growth. Particularly, administration of a high dose of the radiolabeled somatostatin analogue
111indium-octreotide, which is typically used to detect neuroendocrine tumors, may hold promise as a therapeutic agent [
43,
44]. However, it has been reported that PHNEC is normally endocrinologically silent (i.e. the tumors do not present with carcinoid syndrome) due to the rapid degradation of neoplastic-derived hormones via portal circulation, and only 6.8% (6 out of 88 cases) of PHNEC presented with classic carcinoid syndrome [
37], although another review reported slightly higher 16.7% (14 out of 84) carcinoid syndrome-presenting cases [
7]. Consistently, neither of our cases presented classic carcinoid syndrome, and case two was allergic to somatostatin analogue octreotide. Thus, somatostatin analogues have not been demonstrated to be therapeutically effective in the treatment of PHNEC [
45,
46], and the potential for allergic reaction to somatostatin analogues should be anticipated.
Targeted therapies such as treatment with mTOR inhibitor (everolimus) or tyrosine kinase inhibitor (ranitidine) have shown promise for the treatment of advanced pancreatic neuroendocrine tumors [
47‐
49]. Everolimus is currently approved by the FDA for targeted therapy of well-differentiated, nonfunctional neuroendocrine tumors of gastrointestinal origin [
50]. However, for PHNEC, there are no approved targeted therapies available [
51].
The prognosis of PHNEC depends on the size of the tumor, the degree of differentiation (well, moderately or poorly differentiated), histologic grade, Ki-67 index, and status of metastasis [
37,
52‐
54]. Currently, the overall prognosis of PHNEC is better than other types of liver cancer [
41,
55]. Median survival is 16.5 months (range, 0.7 to 41.7 months) based on a review of 12 PHNEC patients [
1]. The five-year survival following surgery for all three differentiation subtypes of PHNEC is about 75% [
37]. After surgical resection, PHNEC can recur or metastasize in one to 10 years [
1,
56,
57]. For poorly differentiated NEC, the five-year survival rate is only 6% [
52]. Both cases we reported exhibited the most aggressive and malignant grade 3 poorly differentiated PHNEC with a high Ki-67 index, surviving only 61 and 109 days, respectively, after initial hospital admission.