Edited by: Alessandro Granito, University of Bologna, Italy
Reviewed by: Yandong Wang, Tianjin Third Central Hospital, China; U. Wai Francisco Lok, Mayo Clinic, United States
This article was submitted to Gastroenterology, a section of the journal Frontiers in Medicine
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Hepatocellular carcinoma (HCC) with the concurrent occurrence of primary hepatic neuroendocrine carcinoma (NEC) of the liver is extremely rare. Preoperative diagnosis of HCC combined with NEC is very difficult. Here, we presented a case report of HCC combined with NEC. A 33-year-old male was admitted to our hospital due to focal liver lesion. To further the diagnosis, he received laboratory tests, conventional ultrasound, contrast-enhanced ultrasound (CEUS), and magnetic resonance imaging (MRI). Grayscale ultrasound showed a hypoechoic nodule with peripheral hypoechoic halo and central small patches of anechoic area in the hepatic segment VI, and the liver background was cirrhosis. In the CEUS, the solid component of the nodule was rapidly homogeneous hyper-enhancement in the arterial phase. Then, the enhancement of the nodule was washed out slowly and gradually; the nodule presented heterogeneously mild enhancement in the portal phase, and slight hypo-enhancement was showed in the late phase. The hypo-enhanced area was mainly located in the surrounding space. Meanwhile, there was a small piece of non-enhanced area within the lesion center in the whole three-phase imaging. MRI showed a lobular contoured mass in segment VI. The patient underwent middle liver resection, splenectomy, and cholecystectomy. The pathological diagnosis was a HCC with NEC. At the time of the preparation of this manuscript, the patient has been alive without recurrence or distant metastases for 6 months since the surgery. We mainly focus on the ultrasound imaging characteristics, especially its enhancement manifestations on CEUS. In this report, since this article is a case report, which is based on the clinical information of the patient and does not involve the patient's privacy, informed consent is not necessary. In addition, the patient agreed to publish the case. To the best of our knowledge, this report is the first to describe the CEUS patterns of the HCC combined with NEC. Herein, we report a case that provides novel insights that will improve clinicians' awareness of the clinical and ultrasound manifestations of this mixed tumor, resulting in improved diagnosis, treatment, and outcomes.
Two or more new tumor tissue structures may be detected simultaneously in several organs, which is called a mixed tumor. In the liver, most of the mixed carcinomas consist of a combination of hepatocellular carcinoma (HCC) and cholangiocarcinoma (
A 33-year-old male, who claimed to have had a 5-year history of liver cirrhosis with antiviral treatment and liver protection drugs, was admitted to our hospital due to a “liver space-occupying lesion” for the past 2 weeks. Physical examination revealed abdominal flatness and no tenderness point, but the spleen was swollen. Laboratory studies detected infection by hepatitis B virus and almost normal liver function. However, serum examinations detected a level of alpha-fetoprotein (AFP) of 403 ng/ml. Then, the patient underwent an abdominal ultrasound examination by a Resona7 ultrasound system (Mindray Medical International, Shenzhen, China) equipped with an SC6-1U (1–6 MHz) and L9-3 (3–9 MHz) transducer. The conventional B-mode ultrasound image showed a malformation of the liver; the capsule of the liver was not smooth, and the echo of the liver parenchyma was rough and heterogeneous. Meanwhile, a hypoechoic nodule with peripheral hypoechoic halo, located in the hepatic segment VI, was found. The lesion had an approximate size of 2.7 cm × 2.2 cm, with an almost regular shape and slightly clear margins; small patches of anechoic area were detected within the tumor (
Findings of magnetic resonance imaging (MRI).
Soon afterward, middle liver resection, splenectomy, and cholecystectomy were performed. Severe liver cirrhosis changes were found during the operation. An intraoperative ultrasound revealed that the nodule was located in segment VI, extending to segment V, with an approximate size of 2.7 cm × 2.0 cm. No tumor changes were observed in the rest of the liver. Microscopic examination revealed that the tumor consisted of two components: a HCC and a NEC (
The coexistence of HCC and NEC is rare as compared with the mixed type of HCC with cholangiocarcinoma in the liver, which is mainly due to the relatively low incidence of primary hepatic NEC. With the aim to investigate more comprehensively and understand better the clinical characteristics, imaging performance, and treatment, here, we present a case of a liver tumor with classical HCC combined with NEC. In this case, the patient was young, male, and had a history of hepatitis B, which is consistent with previous evidence (
The precise diagnosis of this rare mixed tumor is based predominantly on postoperative pathological examination findings. The patient in the case was diagnosed with HCC of the liver complicated with NEC, established by postoperative pathology. The pathological diagnosis was based on the following findings: (1) morphologically, the tumor tissue was composed of two components, with HCC morphology and with NEC morphology. This tumor was a HCC with the features of a small NEC. The two types of tumor cells were separated by wide fibrous band, with no transition areas observed under a microscope; hence, a single disease could not explain the various morphologies; (2) immunohistochemical results: strongly positive HCC markers, HEPA(+) and GPC-3(+), and positive neuroendocrine markers, CgA(+), Syn(+), and CD56. (3) The tumor size was 2.5 cm ×2 cm, with most of the area occupied by the hepatocellular carcinoma tumor, accounting for ~98% of the whole tumor area. (4) The results of abdominal MRI did not support the diagnosis of metastasis to the liver from other sites. In addition, regarding the genetic analysis results of this mixed tumor, both tumor components contained genetic mutations in the CTNNB1 gene (S33F located in exon 3), which were shared in the PD-1, PGP, and SMO of this gene mutation (
The preoperative diagnosis of a mixed tumor is a major challenge. Our literature review showed that combined HCC and NEC, on the one hand, are similar to HCC in their clinical and hematological manifestations, such as the possible combination of hepatitis B or C, cirrhosis, and elevated levels of AFP in the blood. On the other hand, the vascular and extrahepatic metastases of the mixed tumor are similar to those of other mixed tumors such as cholangiocarcinoma, and it is difficult to obtain an accurate preoperative diagnosis. In terms of imaging findings, there have been few reports on ultrasound and CEUS. In this case, we report CEUS findings of a mixed tumor for the first time. Our analysis revealed that mixed carcinoma needs to be differentiated from HCC. These features of CEUS in the present case were similar to those of HCC, and the patient had a history of hepatitis B and cirrhosis in the liver. Thus, the mixed HCC–NEC diagnosis is difficult to make or differentiate from that of HCC alone. Retrospective analysis results showed that in this case, conventional ultrasound and CEUS revealed patches of cystic changes within the tumor and relatively regular morphology of the area. However, in small HCC ( ≤ 3 cm), similar cystic changes within the tumor are rarely found (
The prognosis and treatment of HCC accompanied by NEC are unclear due to the limited number of cases reported. Our analysis of the literature found that the presence of NEC components implicates the possibility of aggressive behavior of the mixed-type tumor (
In summary, although a mixed HCC and NEC tumor is a rare condition, in patients with chronic liver disease, the rare possibility of HCC–NEC needs to be considered in the differential diagnosis, regardless of the presence of cirrhosis even if diagnostic clinical signs are not manifested and imaging features are lacking. Although the final diagnosis is based mainly on pathological and immunohistochemical examinations, ultrasonography, including CEUS, is widely used for detection of liver lesions.
Our case is important as it is the first to highlight the value and utility of CEUS for diagnosis in patients with HCC tumor combined with NEC. Our report provides novel insights that can serve as a basis for further research and will improve clinicians' awareness of the clinical and ultrasound manifestations of this mixed tumor, resulting in improved diagnosis, treatment, and outcomes.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
HW collected, conducted, and interpreted the patient data and contributed significantly to the writing of the initial manuscript. WL revised the paper and had primary responsibility for the final content. ZW performed and analyzed pathological data. YL contributed to the conception of the study. DY was the major contributor in coordinating patient care and helped perform the analysis with constructive discussions. The final manuscript was read and approved by all authors.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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alpha-fetoprotein
hepatocellular carcinoma
neuroendocrine carcinoma
contrast-enhanced ultrasound
transcatheter arterial chemoembolization
percutaneous ethanol injection therapy.