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

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.

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.

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.