Hepatocellular carcinoma-cholangiocarcinoma collision tumor with excellent therapeutic response: a case report and literature review

Abstract

This article reports a rare case of a collision tumor composed of intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC). The patient is a 54-year-old male with hepatitis B virus-related cirrhosis and three focal lesions located in liver segments S8, S7, and S4. Contrast-enhanced computed tomography (CT) revealed the following imaging features: the S8 lesion demonstrated marked arterial phase enhancement, consistent with typical HCC; the S7 lesion exhibited rim-like arterial enhancement, characteristic of ICC; and the S4 lesion showed peripheral nodular enhancement in the arterial phase, indicative of a hemangioma. Laboratory findings showed a mildly elevated alpha-fetoprotein level (15.39 IU/mL)and significantly abnormal transaminase levels. Due to the patient’s overall condition being unsuitable for surgical resection, an ultrasound-guided biopsy was performed after excluding extrahepatic metastases. Histopathological examination confirmed that the S7 nodule was moderately differentiated cholangiocarcinoma, while the S8 nodule was hepatocellular carcinoma. Following diagnosis, the patient underwent interventional therapy, immunotherapy, and chemotherapy. At the 9-month follow-up after diagnosis, the patient was in good general condition with no significant abnormalities in liver and kidney function, complete blood count, or other routine tests. Follow-up contrast-enhanced abdominal CT demonstrated a reduction in tumor diameter from 6.7 cm to 2.8 cm in segment S7, representing approximately 60% decrease in tumor burden and from 3.5 cm to 1.0 cm in segment S8, corresponding to roughly 72% decrease in tumor burden. This disease entity is extremely rare. To date, it has been definitively reported in the literature only by Hong, Chang Kyun, et al. in 2007 and Al Hamoudi, Waleed, et al. in 2012. By analyzing the clinical, imaging, and pathological characteristics of this case and reviewing the relevant literature, we aim to offers a valuable clinical reference for the formulation of comprehensive treatment regimens for unresectable HCC-ICC collision tumors.

Introduction

In the liver, both combined and collision tumors are relatively rare and are classified based on their distinct pathological characteristics. Although these tumors may occur simultaneously in multiple organs, their coexistence within the liver is uncommon. Specifically, collision tumors in the liver are infrequent, with an estimated incidence ranging from 0.1% to 1% [1]. Most patients are either asymptomatic or present with non-specific symptoms such as abdominal pain or bloating [2]. For suspected cases, guided biopsy demonstrates high sensitivity and nearly absolute specificity; however, the procedure carries a potential risk of tumor seeding along the needle tract [3]. Regarding the treatment of such patients, the number of recently reported cases and available literature is limited. Based on previous clinical experience, surgical resection is often considered the primary treatment option. If surgery is not feasible, aggressive chemotherapy and immunotherapy are highly recommended alternatives. We report this case for two key reasons: First, given the extreme rarity of hepatic collision tumors and the current absence of standardized treatment guidelines, our study provides valuable clinical insights for developing comprehensive therapeutic strategies for unresectable HCC-ICC collision tumors. Second, this aggressive synchronous malignancy combining hepatocellular carcinoma and intrahepatic cholangiocarcinoma represents a significant therapeutic challenge. Our integrated treatment approach - combining immunotherapy (sintilimab plus bevacizumab) with chemotherapy (gemcitabine plus cisplatin) after careful consideration of both tumor characteristics and current first-line options - resulted in favorable outcomes. This suggests that immune checkpoint inhibitors (ICIs) may offer substantial therapeutic potential for this difficult-to-treat disease entity.

Case report

A 54-year-old male patient was admitted on August 30, 2024, due to a 10-day history of fatigue, anorexia, and jaundice. He had a 10-year history of chronic hepatitis B virus (HBV) infection and had not received prior antiviral therapy. On physical examination, the patient presented with a hepatopathic facies and mild abdominal distention. Laboratory findings upon admission revealed: Alpha-fetoprotein (AFP) 15.39 IU/ml, abnormal prothrombin (DCP) 13402.11 mAU/ml, with markedly elevated transaminases: ALT 685.9 U/L and AST 558.9 U/L. Contrast-enhanced abdominal computed tomography (CT) scan demonstrated: (1) a nodular lesion in hepatic segment S7 with ring-like arterial phase enhancement, (2) a nodular lesion in segment S8 with marked homogeneous arterial phase enhancement, and (3) a nodular lesion in segment S4 with punctate peripheral arterial phase enhancement (Fig. 1A). The patient was diagnosed with multiple hepatic hilar and peritoneal lymph node metastases, rendering the disease unresectable for radical surgery. An ultrasound-guided core needle biopsy of the hepatic lesions was performed. Pathological examination revealed that the lesion in segment S7 was cholangiocarcinoma (Fig. 2C), while the lesion in segment S8 was hepatocellular carcinoma (Fig. 2D). Immunohistochemical analysis revealed the following findings:1) Liver segment S7 nodule: CK19 (+) Hepatocyte (-), Arg-1 (-), CK7 (+) 2) Liver segment S8 nodule: CK19 (-), Hepatocyte (-), Arg-1 (focal weak +), CK7 (focal +) .Given the rarity of primary collision tumors in the liver and the lack of a standardized treatment protocol for unresectable cases, a multidisciplinary team (MDT) discussion was held. The patient was initially treated with transarterial chemoembolization (TACE), followed by systemic immunotherapy combined with chemotherapy. The regimen consisted of 3-week cycles: intravenous immunotherapy (sintilimab plus bevacizumab) and chemotherapy (gemcitabine plus cisplatin) on day one of each cycle, with a second dose of gemcitabine administered intravenously on day eight. Throughout the treatment period, the patient adhered to a prescribed oral regimen of tenofovir disoproxil fumarate (TDF) for his chronic HBV infection. After completing nine cycles of therapy, a follow-up contrast-enhanced CT scan showed a significant reduction in tumor burden in segments S7 and S8 (Fig. 1B). The patient’s condition is currently stable, and he is undergoing regular subsequent treatment.

Fig. 1.

Enhanced abdominal CT demonstrates a poorly-defined, round-like nodule measuring approximately 6.7 cm in diameter in segment S7, showing ring-like arterial phase enhancement. In segment S8, a round-like mass, approximately 3.5 cm in diameter, is observed, showing marked homogeneous enhancement in the arterial phase (A). The mass in segment S7 has significantly decreased in size to approximately 2.8 cm in diameter and shows no significant enhancement in the arterial phase. The mass in segment S8 has also significantly reduced in size to approximately 1.0 cm in diameter, with markedly diminished arterial phase enhancement compared to the previous scan (B)

Fig. 2.

Ultrasound-guided biopsy was performed on the SVII segment lesion (Fig. 1A). Histological examination of the sections shows diffuse distribution of cuboidal-like cells with scant cytoplasm and focal irregular, slit-like lumen formation, consistent with the features of cholangiocarcinoma (C) (Hematoxylin and eosin staining, ×200); Ultrasound-guided biopsy was performed on the SVIII segment lesion (Fig. 1A). The histological sections also reveal tumor cells with eosinophilic cytoplasm arranged in irregular trabecular patterns with sinusoidal spaces, characteristic of hepatocellular carcinoma (D) (Hematoxylin and eosin staining, ×200)

Discussion

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer characterized by the concurrent presence of histological components of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Allen and Lisa [4] first classified cHCC-CCA into three types: (1) Separate type tumors: distinct lesions composed of a single cell type; (2) Collision type tumors: adjacent lesions of different cell types that may become intermingled during growth; and (3) Mixed type lesions: a single lesion containing both cell types, suggesting a common origin. The case we present is a typical example of a hepatic collision tumor, a category that is exceedingly rare. A PubMed search (www.pubmed.gov; search terms: Liver collision or hepatocellular collision or hepatocellular carcinoma concomitant) reveals that only two previous cases of HCC-ICC collision tumors have been reported by Chang Kyun Hong et al. [5] and Waleed Al Hamoudi et al. [6] (Table 1). The pathogenesis of collision tumors remains unclear. In 1995, Maeda et al. [7] proposed three hypotheses regarding their development: (1) Two types of cancer cells form independently; (2) The tumor originates from either hepatocytes or cholangiocytes and subsequently transdifferentiates into the other type; (3) The tumor arises from an intermediate progenitor cell that differentiates into both distinct lineages. There are no abnormal detection results related to hepatic progenitor cells in this case, so the third hypothesis cannot be verified for the time being. It is speculated that chronic liver injury induced by HBV may independently induce malignant transformation of hepatocytes and cholangiocytes, supporting the possibility of the first hypothesis.However, many researchers currently favor the third hypothesis, suggesting that HCC-ICC collision tumors most likely originate from a common progenitor cell.Nofar Rosenberg et al. [8] found that cHCC-CCA originates from hepatic progenitor cells (HPCs), which differentiate into the two distinct cancer types under the influence of inflammatory signals, such as the cytokine interleukin-6 (IL-6). Reports on the formation mechanism of collision-type tumors are scarce, and the role of chance cannot be excluded; further research is warranted in the future. The patients reported by Chang Kyun Hong [5] and Waleed Al Hamoudi [6] had a history of chronic schistosomiasis and chronic hepatitis C with cirrhosis, respectively. In contrast, our patient had a decades-long history of chronic hepatitis B virus infection with cirrhosis. We therefore speculate that, similar to HCC, HCC-ICC collision tumors may also be associated with infections such as hepatitis B virus (HBV), hepatitis C virus (HCV), and schistosomiasis. On imaging, the lesion in hepatic segment S7 in our case demonstrated marked homogeneous enhancement in the arterial phase, which is typical for HCC. The mass in segment S8 showed rim enhancement, a characteristic feature of ICC. The lesion in segment S4 appeared as a slightly hypodense mass with punctate peripheral enhancement, consistent with the imaging appearance of a hemangioma. The tumors in segments S7 and S8 were adjacent to each other yet maintained a very clear demarcation. To our knowledge, this represents the first report of such a direct and typical imaging presentation of a hepatic collision tumor. Compared with the imaging findings from the cases reported by Chang Kyun Hong [5] and Waleed Al Hamoudi [6], the imaging manifestations in our study appear more prototypical.In the management of malignant tumors, a complete R0 resection is the most effective therapeutic modality. Unfortunately, the patient in this report presented with multiple lymph node metastases in the hepatic hilar and retroperitoneal regions, precluding the possibility of radical resection. In patients with unresectable hepatocellular carcinoma (HCC), traditional chemotherapy is not recommended as a first-line treatment due to the inherent insensitivity of HCC to conventional cytotoxic agents (e.g., doxorubicin, cisplatin). Consequently, immunotherapy and targeted therapy have become the mainstays of HCC treatment. The immune system plays a pivotal role in the progression of unresectable HCC. A paradigm shift in systemic treatment strategies occurred in 2017: previously, therapeutic options were limited to anti-angiogenic tyrosine kinase inhibitors (TKIs). The advent of immune checkpoint inhibitors (ICIs) has since transformed the landscape, demonstrating potent efficacy in a subset of patients [9]. Among these, the combination of atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) has become the new standard of first-line therapy. Nivolumab and pembrolizumab (anti-PD-1 agents) are widely utilized in subsequent lines of therapy following TKI treatment [10]. For patients with advanced cholangiocarcinoma (CCA), the doublet chemotherapy regimen combining gemcitabine (Gem) and cisplatin (Cis) is considered the most effective first-line option [11–12]. Based on the ABC-06 study, a randomized Phase III trial, the combination of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) can serve as the standard second-line treatment for unresectable CCA [13]. Furthermore, the integration of immunotherapy with chemotherapy has achieved remarkable success, offering greater benefits to patients. According to the latest survival data from the TOPAZ-1 trial, the addition of durvalumab to gemcitabine and cisplatin improved overall survival (OS) rates at 12 months (54.3% vs. 47.1%), 18 months (34.8% vs. 24.1%), and 24 months (23.6% vs. 11.5%), and prolonged the median OS (mOS) duration (12.9 months vs. 11.3 months) compared to the placebo group [14]. In a Phase II trial of 37 evaluable patients with advanced BTC, the combination of GEMOX and camrelizumab yielded an objective response rate (ORR) of 54%, with a median progression-free survival (mPFS) and median overall survival (mOS) of 6.1 months and 11.8 months, respectively. This regimen was found to be effective and tolerable for patients with unresectable CCA [15]. Specifically, the ORR was 80% in patients with a PD-L1 tumor proportion score (TPS) ≥ 1%, compared to 53.8% in those with a PD-L1 TPS < 1%. With rapid advancements, targeted therapy and immunotherapy have emerged as important treatment options for CCA, alongside surgery, chemotherapy, and radiotherapy. For patients with resectable cHCC-CCA, the prognosis may be similar to that of iCCA but worse than that of HCC [16–17], with reported 1-year and 3-year survival rates of 81.9% and 47.0%, respectively, compared to 47.3% and 18.3% for iCCA, and 92.4% and 77.1% for HCC [18–19]. However, for unresectable cHCC-CCA collision tumors, there is currently no established standard of care due to the rarity of this cancer entity. Consequently, treatment strategies are often individualized, and the ultimate therapeutic approach may be tailored toward the dominant tumor component. In our case, following a multidisciplinary team (MDT) discussion and considering the larger volume of the cholangiocarcinoma component, we initially performed transarterial chemoembolization (TACE) for cytoreduction. Subsequently, the patient received the standard first-line chemotherapy regimen for cholangiocarcinoma, gemcitabine plus cisplatin, administered every three weeks. This was combined with immunotherapy using sintilimab and bevacizumab, which target pathways relevant to both cholangiocarcinoma and hepatocellular carcinoma. Concurrently, long-term antiviral therapy with oral tenofovir disoproxil fumarate was administered to treat the underlying chronic hepatitis B virus infection. After nine cycles of this combined treatment, a significant reduction in the overall tumor burden was observed.

Table 1.

Previously Reported Collision Tumor Cases

	Sex	Age	Relevant PMH	Largest TD	Treatment modality	Overall survival
Case one	Female	39	Chronic HCV infection	4.8 cm	Surgery	2 months
Case two	Female	56	Schistosomiasis	3 cm	Liver transplantation	9 months
Our study	Male	54	Chronic HBV infection	6.7 cm	Systemic and local therapy	At least one year

Relevant PMH: Past Medical History, Largest TD: Largest tumor diameter, Case one: Chang Kyun Hong’s report, Case two: Waleed Al Hamoudi’s report

Author contributions

Zhiguo Tan: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data; also participated substantially in the drafting and editing of the manuscript. Zengpeng Sun: Participated substantially in conception, design, and execution of the study and in the analysis and inter pretation of data.Yutao Wang: Participated substantially in conception, design, and execution of the study and in the analysis and interpretation of data.Chuang Peng： Participated substantially in execution of the study.

Funding

This work was supported by the Leading talent project of Hunan Provincial People’s Hospital (20230327-1012); the National Clinical Key Specialty Construction Project (20191127-1001); Cancer-Free Initiative of Sichuan Xinxin Charity Foundation(SCF251028).

Data availability

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

Declarations

Ethics approval and consent to participate

The studies involving humans were approved by the Ethics Committee of Hunan Provincial People’s Hospital/The First Affliated Hospital of Hunan Normal University. The studies were conducted in accordance with the local legislation and institutional requirements. The patient gave written informed consent for their personal or clinical details along with any identifying images to be published in this study.

Consent for publication

The patient has provided informed consent for the publication of his medical information. All authors, including Zengpeng Sun, Yutao Wang, Chuang Peng, Zhiguo Tan, have given their informed consent for the publication of this manuscript.

Competing interests

The authors declare no competing interests.