Primary hepatic alpha-fetoprotein-producing neuroendocrine neoplasm harboring 
Case presentation A 45-year-old man presented with intermittent back and epigastric pain. Upper gastrointestinal endoscopy revealed gastritis, the symptoms of which persisted post-treatment. Subsequently, contrast-enhanced computed tomography (CT) revealed multiple lesions in the liver (Fig. a, b). The largest tumor (nearly 12 cm in diameter) was located in the lateral segment of the left lobe and was accompanied by multiple additional tumors measuring 1–6 cm. Dynamic contrast-enhanced imaging showed intense early-phase enhancement along the periphery of the occupying lesions. However, the internal areas appeared to be hypovascular. Moreover, the tumor periphery exposed to the liver surface exhibited a concave indentation, consistent with intrahepatic cholangiocarcinoma. The largest tumor was assumed to be the primary site, and the others were deemed metastases. The differential diagnosis included multiple liver metastases from malignancies originating outside the liver; however, no extrahepatic lesions suggestive of a primary tumor were identified. The clinical findings at admission are summarized in Table . Blood tests revealed elevated levels of alpha-fetoprotein (AFP; 7683.0 ng/mL) and neuron-specific enolase (21.4 ng/mL). Histopathological examination of the liver biopsy specimen showed proliferating atypical cells with abundant cytoplasm and enlarged nuclei, forming cord-like structures or a nested organoid growth pattern with surrounding fibrosis (Fig. a, b). Tumor necrosis or degeneration was not apparent (Fig. a). Immunohistochemical analysis revealed cells positive for neuroendocrine markers, including synaptophysin (Fig. c, d), chromogranin A (Fig. e), CK19 (Fig. f), and AFP (Fig. g, h). Most neoplastic cells were positive for synaptophysin (Fig. c, d), and about half of the neoplastic cells were positive for AFP (Fig. g). The Ki-67 labeling index was 25% (hot spot). Therefore, the patient was diagnosed with an AFP-producing neuroendocrine neoplasm. Foundation One Liquid CDx test results were as follows: microsatellite instability-high, not detected; tumor mutational burden, intermediate (7.59 Muts/Mb); FGFR2 missense variant, c.1144T>C; PTEN missense variant, c.335T>C; and TP53 missense variant, c.722C>T. FGFR2 and TP53 mutations are common in intrahepatic cholangiocarcinomas. The coexistence of these genetic abnormalities with radiographic features resembling intrahepatic cholangiocarcinoma implied the possibility of mixed neuroendocrine neoplasm (MINEN) with concomitant intrahepatic cholangiocarcinoma.   A 45-year-old man presented with intermittent back and epigastric pain. Upper gastrointestinal endoscopy revealed gastritis, the symptoms of which persisted post-treatment. Subsequently, contrast-enhanced computed tomography (CT) revealed multiple lesions in the liver (Fig. a, b). The largest tumor (nearly 12 cm in diameter) was located in the lateral segment of the left lobe and was accompanied by multiple additional tumors measuring 1–6 cm. Dynamic contrast-enhanced imaging showed intense early-phase enhancement along the periphery of the occupying lesions. However, the internal areas appeared to be hypovascular. Moreover, the tumor periphery exposed to the liver surface exhibited a concave indentation, consistent with intrahepatic cholangiocarcinoma. The largest tumor was assumed to be the primary site, and the others were deemed metastases. The differential diagnosis included multiple liver metastases from malignancies originating outside the liver; however, no extrahepatic lesions suggestive of a primary tumor were identified. The clinical findings at admission are summarized in Table . Blood tests revealed elevated levels of alpha-fetoprotein (AFP; 7683.0 ng/mL) and neuron-specific enolase (21.4 ng/mL). Histopathological examination of the liver biopsy specimen showed proliferating atypical cells with abundant cytoplasm and enlarged nuclei, forming cord-like structures or a nested organoid growth pattern with surrounding fibrosis (Fig. a, b). Tumor necrosis or degeneration was not apparent (Fig. a). Immunohistochemical analysis revealed cells positive for neuroendocrine markers, including synaptophysin (Fig. c, d), chromogranin A (Fig. e), CK19 (Fig. f), and AFP (Fig. g, h). Most neoplastic cells were positive for synaptophysin (Fig. c, d), and about half of the neoplastic cells were positive for AFP (Fig. g). The Ki-67 labeling index was 25% (hot spot). Therefore, the patient was diagnosed with an AFP-producing neuroendocrine neoplasm. Foundation One Liquid CDx test results were as follows: microsatellite instability-high, not detected; tumor mutational burden, intermediate (7.59 Muts/Mb); FGFR2 missense variant, c.1144T>C; PTEN missense variant, c.335T>C; and TP53 missense variant, c.722C>T. FGFR2 and TP53 mutations are common in intrahepatic cholangiocarcinomas. The coexistence of these genetic abnormalities with radiographic features resembling intrahepatic cholangiocarcinoma implied the possibility of mixed neuroendocrine neoplasm (MINEN) with concomitant intrahepatic cholangiocarcinoma.   This report describes a rare case of a patient diagnosed with primary hepatic AFP-producing neuroendocrine neoplasm. Prior to this study, only one case of an AFP-producing neuroendocrine neoplasm originating from the liver has been reported in the literature  (Table ). Primary hepatic neuroendocrine neoplasms are rare and present diagnostic challenges; hence, accurate diagnostic differentiation from other primary malignant liver tumors, such as hepatocellular carcinoma and intrahepatic cholangiocarcinoma, is crucial. The neoplasm in this study showed neuroendocrine differentiation on immunohistochemistry and FGFR2 and TP53 mutations on genetic analysis. The mechanisms underlying the acquisition of AFP production in neuroendocrine neoplasms remain unclear; however, the identification of genetic abnormalities commonly associated with intrahepatic cholangiocarcinoma suggests a potential derivation from AFP-producing intrahepatic cholangiocarcinoma . TP53 mutations are suggestive of neuroendocrine carcinoma rather than neuroendocrine tumor . Therefore, this neoplasm may be a partial MINEN lesion with concomitant intrahepatic cholangiocarcinoma. However, despite the extremely high serum AFP levels, the AFP expression on tumor cells appeared relatively weak (Fig. g, h). A limitation of this study is the inability to exclude the possibility of hepatocellular carcinoma at sites other than the biopsy site. In addition, AFP may serve as a prognostic factor for neuroendocrine tumors . In this case, chemotherapeutic regimens comprising gemcitabine/cisplatin, S-1 (tegafur, gimeracil, and oteracil potassium), and pemigatinib were administered; however, all yielded a treatment response categorized as progressive disease (Table ). AFP-producing hepatic neoplasms warrant extra caution, and this case emphasizes the importance of considering primary hepatic neuroendocrine neoplasms in the differential diagnosis of liver tumors. The presence of AFP production and genetic abnormalities reiterates the importance of accurate differentiation from hepatocellular carcinoma and intrahepatic cholangiocarcinoma, as their treatment approaches and prognoses differ. Moreover, detailed histopathological evaluation, immunohistochemical profiling, and genetic analysis are crucial for accurate diagnosis. Further studies are warranted to elucidate the underlying molecular mechanisms and to develop targeted therapeutic strategies for this subtype of primary hepatic neuroendocrine neoplasm. Increased awareness among clinicians and pathologists can ensure early recognition and appropriate tumor management.   