Abstract
Simultaneous occurrence of primary hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) is rare. We report two cases of synchronous double primary HCC and ICC (sdpHCC-ICC), both associated with chronic hepatitis B. Case 1 involves a 63-year-old man whose liver lesions were incidentally found during routine screening. Preoperative imaging revealed lesions in the S4 and S5 liver segments, with postoperative confirmation of sdpHCC-ICC. He received hepatic arterial infusion chemotherapy (HAIC) and transcatheter arterial chemoembolization (TACE) combined with gemcitabine and oral S-1 over 26 months, with no recurrence observed. Case 2 describes a 48-year-old woman presenting with right upper abdominal pain. Preoperative imaging identified a lesion at the S6/7 and S8 junction, later confirmed as sdpHCC-ICC. Postoperative TACE was performed at 1.5 and 3 months, and lenvatinib was introduced at 3.5 months. She remained recurrence-free at the 21-month follow-up. While the precise pathogenesis of sdpHCC-ICC remains unclear, chronic HBV infection plays a pivotal role. Surgical resection remains the primary treatment, though prognosis is generally poor due to the ICC component.
1 Introduction
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the two most common pathological types of primary liver cancer, with HCC accounting for 75% to 85% and ICC for 10% to 15% (, ). Mixed hepatocellular carcinoma, containing both HCC and ICC components, is rare. In 1949, Allen et al. classified this tumor into three subtypes (): Type A, where HCC and ICC grow independently in different liver regions; Type B, where both components form a continuous tumor; and Type C, where both components mix within the same tumor. In 1985, Goodman et al. proposed another classification (): Type I for collision tumors, Type II for transitional tumors, and Type III for fibrolamellar tumors. Allen Type A and Goodman Type I are known as synchronous double primary hepatocellular carcinoma and intrahepatic cholangiocarcinoma (sdpHCC-ICC), with an incidence of less than 0.8% in primary liver cancer (–).
Surgical resection is the preferred treatment for sdpHCC-ICC. However, due to challenges in preoperative diagnosis, some patients are diagnosed at an advanced stage or are undergoing other localized treatments, resulting in missed surgical opportunities and poor prognosis (). Reports on sdpHCC-ICC are scarce, but studies indicate that hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are associated with its development (–). In this study, we reviewed the literature and analyzed two cases of sdpHCC-ICC associated with chronic HBV infection from our center, aiming to enhance clinical understanding and provide insights into its diagnosis and management. In addition to comprehensive clinical data—including preoperative imaging, histopathological features, and immunohistochemical profiles—we incorporated next-generation sequencing (NGS) to characterize molecular alterations and explore potential pathogenic mechanisms and therapeutic targets. Compared to prior case reports primarily focused on pathological findings, this study integrates clinical, pathological, and molecular perspectives to enhance understanding of the biological heterogeneity of sdpHCC-ICC and support the development of precise diagnostic and therapeutic strategies.
2 Case presentation
2.1 Case 1
A 63-year-old man was found to have hepatic lesions during an abdominal ultrasound examination performed as part of a routine physical check-up six months ago. Due to the small size of the lesions, regular follow-up was recommended. A recent review at an outside hospital revealed lesion enlargement, though the patient reported no symptoms such as abdominal pain, distension, nausea, vomiting, or significant weight change. He had a long history of chronic hepatitis B without antiviral treatment and began oral entecavir after admission. He also had a history of alcohol consumption but no history of metabolic diseases. Laboratory tests showed a normal platelet count and liver function indicators. The results also included positive HBV surface antigen (HBsAg), positive anti-HBV core antibody (anti-HBc), an HBV-DNA level of 928 IU/ml, and a negative anti-HCV antibody. Tumor marker results were as follows: alpha-fetoprotein (AFP) 2.91 ng/ml, protein induced by vitamin K antagonist-II (PIVKA-II) 45.08 mAU/ml, carcinoembryonic antigen (CEA) 1.61 ng/ml, and carbohydrate antigen 19-9 (CA19-9) 12.10 U/ml.
The patient completed Dynamic Contrast-Enhanced Computed Tomography (DCE-CT) and Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI). DCE-MRI revealed a blood-rich space-occupying lesion in the S4 segment of the liver, measuring approximately 5.1×3.7 cm. The lesion exhibited inhomogeneous enhancement in the arterial phase and homogeneous enhancement in the venous phase. A subcapsular lesion with a strip-like low signal was observed in segment 5 of the liver, with ill-defined margins. On contrast-enhanced imaging, the lesion demonstrated marked enhancement in all phases, accompanied by mild atrophy of the surrounding hepatic parenchyma and capsular retraction. See Figure 1. On the 9th day of admission, laparoscopic resection of the S4 segment of the liver, partial resection of the S5 segment, and cholecystectomy were performed. Postoperative pathology revealed that the mass in the S4 segment of the liver was highly differentiated HCC, measuring 3.7 cm × 3.2 cm × 3.6 cm. Immunohistochemical results were: CK7 (–), CK19 (–), hepatocyte (+), AFP (+), Arg (+), and GPC3 (+).The mass in the S5 segment of the liver was moderately differentiated ICC, measuring 3.2 cm × 3.5 cm × 1.1 cm. Immunohistochemistry results were: CK7 (weakly +), CK19 (weakly +), hepatocyte (–), AFP (–), Arg (–), and GPC3 (–).The cholecystectomy specimen showed chronic cholecystitis, with no carcinoma observed at the severed end. The pathological diagnosis was consistent with sdpHCC-ICC. See Figure 2.
Figure 1
Figure 2
Following surgical resection, the patient received eight sessions of intra-arterial therapy, comprising five sessions of hepatic arterial infusion chemotherapy (HAIC) and three of transcatheter arterial chemoembolization (TACE), administered at 1 to 1.5-month intervals. In each session, 100 mg of oxaliplatin was infused via microcatheter into the right hepatic artery, followed by diagnostic embolization using 1–2 mL of ultra-fluid lipiodol. Gemcitabine (1400 mg) was co-administered during each cycle, along with oral S-1 as part of the combination chemotherapy regimen. At 26 months postoperatively, follow-up imaging showed no evidence of tumor recurrence.
2.2 Case 2
A 48-year-old woman was admitted to the hospital with a 3-week history of right upper abdominal pain. An external abdominal ultrasound suggested cirrhosis with multiple intrahepatic nodules. At admission, the patient experienced loss of appetite without abdominal distension, nausea, or vomiting, and had recently lost 4 kg of body weight. She had a 15-year history of chronic hepatitis B and started taking tenofovir orally in the past 3 weeks. She had no history of alcohol consumption or metabolic diseases. Laboratory tests showed normal platelet count and liver function indexes, positive HBsAg, positive HBV e antigen (HBeAg), positive anti-HBc, an HBV-DNA level of 103,000 IU/ml, and a negative anti-HCV antibody. Tumor marker results were as follows: AFP 652.00 ng/ml, PIVKA-II 23.55 mAU/ml, CEA 0.44 ng/ml, and CA19-9 52.80 U/ml.
Both CT and MRI revealed a space-occupying lesion at the junction of hepatic segments S8 and S6/7, measuring approximately 3.5×2.5 cm. The lesion showed multiple vascular-like enhancements in the arterial phase and slightly higher enhancement in the venous phase compared to the surrounding hepatic parenchyma, initially suggesting HCC. Additionally, multiple regenerative nodules, the largest measuring about 0.7 cm, were present in the liver, some of which could not be ruled out as early-stage hepatocellular carcinoma. See Figure 3. On the 3rd day of admission, laparoscopic partial resection of liver segments S8 and S6/7 was performed. Postoperative pathology revealed that the mass in segment S8 was moderately differentiated ICC, measuring 3 cm × 2 cm × 2 cm, with immunohistochemical results: CK7 (+), CK19 (+), hepatocyte (–), GS (+), GPC3 (–), and Arg (–). The mass in segment S6/7 was moderately differentiated HCC, measuring 2.5 cm × 2 cm × 2 cm, with immunohistochemical results: CK7 (–), CK19 (–), hepatocyte (+), GS (+), GPC3 (+), and Arg (+). The pathological diagnosis was consistent with sdpHCC-ICC. See Figure 4.
Figure 3
Figure 4
The patient underwent two sessions of TACE at 1.5 and 3 months after resection, with epirubicin 30 mg as the chemotherapy drug. Starting at 3.5 months postoperatively, the patient began taking oral lenvatinib, which has been continued to date. There were no signs of recurrence at the 21-month postoperative follow-up.
3 Literature review
A review of 16 reported cases of sdpHCC-ICC, including two from the present study (Table 1), showed that patients were predominantly middle-aged to elderly (41–77 years), with a peak incidence between 50 and 70 years. The male-to-female ratio was approximately 1:1, suggesting no significant sex-related predisposition. HBV infection was the most common etiological factor (11/16), followed by HCV (3/16), with a minority lacking a history of viral infection. Underlying liver disease was primarily chronic hepatitis (8/16) or cirrhosis (5/16), supporting the hypothesis that chronic liver inflammation, especially of viral origin, contributes significantly to tumorigenesis. Imaging revealed that most HCC lesions were located in the right hepatic lobe (segments 5–8, ~75%), whereas ICC lesions were more diffusely distributed across segments 2–4 and junctional regions, suggesting that the two tumor components may originate from distinct biliary progenitor lineages. The average diameter of HCC lesions was generally larger than that of ICC (up to 10 cm vs. 5 cm), indicating that HCC often dominates the clinical manifestation. Symptomatically, 10 patients presented with liver mass or abdominal pain, whereas 6 were asymptomatic and diagnosed incidentally, emphasizing the importance of imaging-based detection and pathological confirmation, particularly immunohistochemistry, for accurate diagnosis.
Table 1
| No. | Age | Gender | Viral infection | Underlying liver disease | Localization HCC/ICC | Size (cm) HCC/ICC | Symptom | Treatment | Follow-up | Prognosis | Author | Year |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 70 | M | HCV | Chronic hepatitis | S4/S7 | 4/2.2 | Liver mass | Segmentectomy | 30 months | Alive without recurrence | Matsuda et al. () | 2006 |
| 2 | 67 | M | HCV | Liver cirrhosis | S7/S8 | 1.3/1.2 | Liver mass | Partial resection + TACE | 84 months | Recurrence occurred | Inaba et al. () | 2007 |
| 3 | 66 | F | HBV | Chronic hepatitis | S7/S2-3 | N/A | Liver mass | Partial resection+ Chemotherapy | 7 months | Alive without recurrence | Jung et al. () | 2013 |
| 4 | 68 | F | HBV | Chronic hepatitis | S5/S3 | 4.3/1.1 | Liver mass | Segmentectomy | 24 months | Alive without recurrence | ||
| 5 | 58 | M | Negative | None | S5/S8 | 6/4 | Abdominal pain | Partial resection | 11 months | Alive without recurrence | Wu et al. () | 2014 |
| 6 | 48 | M | HBV | Chronic hepatitis | S5, S7/S2-3 | 5, 10/8 | Liver mass | Segmentectomy + Chemotherapy | 6 months | Alive without recurrence | Topaloğlu et al. () | 2014 |
| 7 | 56 | M | Negative | None | S7/S6 | 7/4.5 | Right lumbago | Partial resection | 12 months | Alive without recurrence | Hu et al. () | 2016 |
| 8 | 41 | M | HBV | Chronic hepatitis | S7/S6 | 4/1 | None | Segmentectomy | 8 months | Alive without recurrence | Zhou et al. () | 2016 |
| 9 | 45 | M | HBV | Liver cirrhosis | S6/S7 | 2.3/1 | None | Segmentectomy | 20 months | Alive without recurrence | Suzumura et al. () | 2016 |
| 10 | 58 | M | HBV, HCV | Chronic hepatitis | S7/S3 | 1.4/0.8 | None | Partial resection | 24 months | Alive without recurrence | Yamamoto et al. () | 2018 |
| 11 | 49 | F | HBV | Liver cirrhosis | S6/S4 | 2.5/5 | Abdominal pain | Partial resection | 16 months | Died of liver failure | Qu et al. () | 2021 |
| 12 | 69 | F | HBV | Liver cirrhosis | S4/S6 | 2.1/3 | Abdominal pain | Partial resection | 7 months | Recurrence occurred | Gao et al. () | 2022 |
| 13 | 75 | F | HCV | Liver cirrhosis | S8/S5 | 1.5/2 | None | Segmentectomy | 6 months | Alive without recurrence | Khessairi et al. () | 2024 |
| 14 | 77 | F | HBV | Chronic hepatitis | S5/S8, S4 | 1.5/3.6 | None | Partial resection + Chemotherapy | 12 months | Alive without recurrence | Fukuda et al. () | 2024 |
| 15 | 63 | M | HBV | Chronic hepatitis | S4/S5 | 3.7/3.5 | None | Partial resection + Chemotherapy + HAIC + TACE | 26 months | Alive without recurrence | Present Case 1 | 2024 |
| 16 | 48 | F | HBV | Chronic hepatitis | S6-7/S8 | 2.5/3 | Abdominal pain | Partial resection + TACE + Lenvatinib | 21 months | Alive without recurrence | Present Case 2 | 2024 |
Reported cases of synchronous double primary hepatocellular carcinoma and intrahepatic cholangiocarcinoma (sdpHCC-ICC) undergoing surgical resection, including the present cases.
M, male; F, female; HCV, hepatitis C virus; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; ICC, intrahepatic cholangiocarcinoma; N/A, not available; TACE, transarterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy.
All patients underwent curative surgical resection, either via anatomical segmentectomy or partial hepatectomy. Six patients received postoperative adjuvant therapy, including TACE, HAIC, systemic chemotherapy, or targeted therapy. Within this subgroup, only one recurrence occurred during a follow-up period of 6 to 84 months, suggesting that adjuvant therapy may improve prognosis. In contrast, among the ten patients treated with surgery alone, two experienced recurrence and one died of liver failure, suggesting that postoperative adjuvant therapy may prolong disease-free survival (DFS) and overall survival (OS), despite the small sample size. The median follow-up duration was 15 months (range: 6–84 months), with most patients remaining recurrence-free within two years post-surgery. In the present study, both cases were HBV-related, with tumors located in segments S4/S5 and S6-7/S8, respectively. Both patients received surgical resection combined with adjuvant TACE plus HAIC and chemotherapy, or TACE plus lenvatinib, and remained recurrence-free at 21 and 26 months of follow-up, respectively. These findings further support the potential benefit of comprehensive treatment strategies in improving outcomes for HBV-related sdpHCC-ICC and offer clinical evidence to guide diagnostic and adjuvant treatment strategies in future practice.
4 Discussion
In 2004, the World Health Organization (WHO) excluded stand-alone HCC and ICC occurring simultaneously in the liver from combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Since then, the classification mechanism for primary liver cancer has been continuously refined. The 2019 WHO Classification of Tumors of the Digestive System further clarified the classification of primary liver cancer based on molecular studies, identifying different pathogenic mechanisms for various pathological types (, ). The pathogenesis of sdpHCC-ICC, a rare primary liver cancer, is unclear, with long-standing controversy regarding the origin of tumor cells. One view suggests that liver tumor cells originate from hepatic progenitor cells (HPC) with bipotent differentiation potential, capable of differentiating into hepatocytes or cholangiocytes and undergoing malignant proliferation (–). Another view proposes that the tumor cells of HCC and ICC originate independently, or that HCC initially emerges and transforms into ICC, and vice versa (). Xue et al. demonstrated that sdpHCC-ICC may have both monoclonal and polyclonal origins, with foci of different phenotypes originating from the same clone, suggesting a phenotypic shift (). Genetic testing was conducted on the ICC and HCC lesions of the patients, with 1021 tumor-related genes sequenced using NGS. The details are provided in Tables 2, 3, and Figure 5. In Case 1, the mutation profiles of the two tumor lesions shared only a PDGFRA and DNMT3A missense mutation and a CHEK2 frameshift mutation. In Case 2, the two tumor lesions shared only a DUSP22 missense mutation and a TP53 copy number loss in their mutation profiles. These findings indicate that the ICC and HCC lesions in these two cases likely arose from distinct clones.
Table 2
| Cancer Type | Gene | Mutation Result | Variant Type | Abundance | Mutation Grade |
|---|---|---|---|---|---|
| ICC | DICER1 | p.F1677L | Missense mutation | 19.8% | III |
| EPHB1 | p.P420S | Missense mutation | 19.3% | III | |
| ARID2 | p.R1754Efs*11 | Frame shift | 17.7% | III | |
| CYP19A1 | p.M356V | Missense mutation | 16.2% | III | |
| IDH1 | p.R132C | Missense mutation | 14.5% | I | |
| EPHA2 | p.I619Mfs*13 | Frame shift | 12.3% | III | |
| CDKN1B | Amplification | Copy number gain | 5.4% | III | |
| MCL1 | Amplification | Copy number gain | 5.2% | II | |
| SRSF2 | Amplification | Copy number gain | 4.2% | III | |
| BTG1 | Amplification | Copy number gain | 4.0% | III | |
| PDGFRA | p.A146V | Missense mutation | 2.4% | III | |
| DNMT3A | p.R771Q | Missense mutation | 2.2% | III | |
| CHEK2 | p.R523Vfs*43 | Frame shift | 1.6% | II | |
| JAK1 | p.R108Q | Missense mutation | 1.0% | III | |
| HCC | ZNF703 | p.R222_S225del | In frame del | 31.5% | III |
| TERT | c.-58-u66C>T | Missense mutation | 26.2% | III | |
| STAT3 | p.Q361P | Missense mutation | 21.5% | III | |
| KIT | p.Y221C | Missense mutation | 21.4% | III | |
| CDH18 | p.R689K | Missense mutation | 20.0% | III | |
| JAK1 | p.S703I | Missense mutation | 14.1% | II | |
| POLE | p.R2016K | Missense mutation | 3.9% | III | |
| FAT2 | p.Q3494R | Missense mutation | 3.8% | III | |
| PIK3CA | p.H1047R | Missense mutation | 3.5% | II | |
| MYC | Amplification | Copy number gain | 3.0% | III | |
| MET | Amplification | Copy number gain | 2.8% | II | |
| MAP2K4 | p.K357T | Missense mutation | 2.5% | III | |
| JAK1 | p.K924M | Missense mutation | 2.3% | III | |
| MSH6 | p.C779* | Missense mutation | 2.2% | III | |
| ALB | p.E525Vfs*2 | Missense mutation | 2.1% | III | |
| DNMT3A | p.R771Q | Missense mutation | 1.7% | III | |
| AR | Amplification | Copy number gain | 1.7% | III | |
| MPL | p.P227Lfs*4 | Frame shift | 1.6% | III | |
| PARP1 | p.A884T | Missense mutation | 1.5% | III | |
| PDGFRA | p.A146V | Missense mutation | 1.5% | III | |
| SPTA1 | p.T635N | Missense mutation | 1.5% | III | |
| SPTA1 | p.D318G | Missense mutation | 1.2% | III | |
| CHEK2 | p.R523Vfs*43 | Frame shift | 1.1% | II |
The results of the next-generation sequencing (NGS) analysis of 1021 relevant genes from the liver tumor resection specimen in Case 1.
ICC, intrahepatic cholangiocarcinoma; HCC, hepatocellular carcinoma.
Table 3
| Cancer Type | Gene | Mutation Result | Variant Type | Abundance | Mutation Grade |
|---|---|---|---|---|---|
| ICC | DUSP22 | p.V129M | Missense mutation | 32.5% | III |
| MIB1 | p.S300T | Missense mutation | 19.5% | III | |
| EGFR | Amplification | Copy number gain | 10.6% | II | |
| TP53 | p.C176F | Missense mutation | 8.9% | II | |
| MYC | Amplification | Copy number gain | 7.8% | III | |
| MCL1 | Amplification | Copy number gain | 4.8% | II | |
| RECQL | Amplification | Copy number gain | 4.6% | III | |
| CDKN1B | Amplification | Copy number gain | 4.0% | III | |
| KRAS | Amplification | Copy number gain | 3.0% | II | |
| TP53 | Deletion | Copy number loss | 1.4% | II | |
| HCC | PTPRD | p.M1164I | Missense mutation | 73.5% | III |
| KIT | p.A777V | Missense mutation | 41.3% | III | |
| TERT | c.-58-u66C>T | Missense mutation | 32.6% | III | |
| DUSP22 | p.V129M | Missense mutation | 32.0% | III | |
| CREBBP | p.0? | Nonsense mutation | 21.2% | III | |
| NRXN1 | p.W183R | Missense mutation | 19.9% | III | |
| ERBB3 | p.Q1301K | Missense mutation | 19.2% | III | |
| LRP1B | p.L700I | Missense mutation | 17.8% | III | |
| PMS2 | p.Q342R | Missense mutation | 14.0% | III | |
| MET | Amplification | Copy number gain | 2.8% | II | |
| CHEK2 | Deletion | Copy number loss | 1.4% | II | |
| RAD51 | Deletion | Copy number loss | 1.2% | II | |
| TP53 | Deletion | Copy number loss | 1.2% | II | |
| TSC2 | Deletion | Copy number loss | 1.2% | II | |
| CDKN2B | Deletion | Copy number loss | 1.2% | III | |
| CREBBP | Deletion | Copy number loss | 1.2% | III | |
| CDKN2A | Deletion | Copy number loss | 1.0% | II | |
| MAP3K1 | p.R58W | Missense mutation | 1.0% | III |
The results of the next-generation sequencing (NGS) analysis of 1021 relevant genes from the liver tumor resection specimen in case 2.
ICC, intrahepatic cholangiocarcinoma; HCC, hepatocellular carcinoma.
Figure 5
An in-depth understanding of tumor pathogenesis is crucial for identifying clinicopathological factors associated with tumorigenesis and development. In China, high-risk groups for HCC primarily include those with HBV or HCV infections (), while ICC is mostly associated with bile duct inflammation, viral hepatitis, intrahepatic bile duct stones, and other diseases (, ). Previous reports indicate that chronic liver inflammation is closely associated with multiple primary liver tumors, as most cases involve chronic hepatitis, which plays a key role in primary hepatocarcinogenesis at the molecular level (, ). Therefore, any factor causing chronic liver inflammation may be a potential risk factor for sdpHCC-ICC. Studies have shown that sdpHCC-ICC patients in Japan, Europe, and the United States tend to be co-infected with HCV (, ), while those in China are more often co-infected with HBV (). This may be related to geographical differences in virus distribution. In this study, both patients had chronic hepatitis B and were not treated regularly for a long period before the liver tumor was discovered, which facilitated tumor progression. After resection, both patients were on long-term oral antiviral medication, with no recurrence observed to date. This suggests that HBV infection is closely associated with the development of sdpHCC-ICC, and antiviral therapy plays a key role in reducing the risk of tumorigenesis in such patients.
Most sdpHCC-ICC patients present with nonspecific clinical symptoms. In this study, Case 1 was identified as a liver lesion during a routine health checkup. The lesion was initially small, prompting a recommendation for regular follow-up. Subsequent imaging showed lesion enlargement, although the patient remained asymptomatic. In contrast, Case 2 presented with symptoms of abdominal pain and decreased appetite. These findings underscore the nonspecific clinical manifestations of sdpHCC-ICC, which complicate early diagnosis. Routine biochemical tests in sdpHCC-ICC patients are nonspecific. Some patients may exhibit abnormal liver function, such as mild elevation of aminotransferases, correlating with the level of viral load (). In this study, liver function indices were normal in both patients. sdpHCC-ICC lacks specific serum tumor markers. Since it has components of both HCC and ICC, theoretically, tumor markers AFP and PIVKA II for HCC and CA19–9 and CEA for ICC could be used. Concomitant elevation of AFP and CA19–9 aids in diagnosing sdpHCC-ICC but requires imaging to differentiate it from cHCC-CCA (, ). However, the extremely low incidence of sdpHCC-ICC and lack of clinician awareness result in a low rate of preoperative imaging diagnosis. Physicians often diagnose larger tumors as the primary disease and smaller ones as intrahepatic metastases (). On DCE-CT and DCE-MRI, HCC typically shows “fast-in-fast-out” enhancement (), while ICC shows peripheral enhancement in the arterial phase, peripheral contouring in the portal vein phase, and delayed enhancement in the central delayed phase (). The imaging manifestation of sdpHCC-ICC combines both features. Clinicians should consider the possibility of sdpHCC-ICC when observing this pattern, despite its low incidence. Reviewing the imaging data in this study, the preoperative diagnosis in both cases initially considered HCC and overlooked ICC. Therefore, improving understanding of sdpHCC-ICC, considering medical history and tumor marker characteristics, and accumulating experience can enhance the preoperative diagnosis rate.
Surgical resection remains the preferred treatment for sdpHCC-ICC, with the principle of performing radical R0 resection while ensuring residual liver function (, ). However, the principle of lymph node dissection differs between HCC and ICC. In HCC, surgery typically requires only liver tumor resection due to the low incidence of lymph node metastasis. In ICC, lymph node metastasis is common, necessitating lymph node dissection (). Previous studies reported a case where a patient did not undergo lymph node dissection, developed lymph node metastasis after surgery, and eventually died (). Additionally, extensive use of intraoperative frozen biopsy is recommended for lesions preoperatively and intraoperatively considered atypical HCC with suspected sdpHCC-ICC. HCC and ICC components are located in different tumor foci, independent of each other, with distinct morphologies under the microscope. Hep Par-1 and GPC-3 are reliable markers for HCC, while CK7 and CK19 are valuable for distinguishing ICC from HCC, especially when combined with immunohistochemistry (, ). Recently, liver transplantation has been used as a curative option for some patients (, ), but its long-term efficacy needs further study. Additionally, ablation therapy is an effective localized treatment for patients with severe cirrhosis who cannot tolerate surgery, offering advantages such as low impact on liver function, minimal trauma, and precise therapeutic efficacy (). HAIC and TACE are commonly used for unresectable and recurrent tumors, though their use in sdpHCC-ICC is less frequently reported as a complement to surgical treatment (, ). Vidili et al. described a case of a patient presenting with jaundice and dyspepsia, diagnosed with sdpHCC-ICC and a concurrent right kidney tumor. They emphasized the critical role of ultrasound technology in tumor diagnosis and minimally invasive treatment, offering valuable insights for managing this rare disease (). Both patients in this study underwent radical R0 resection followed by postoperative prophylactic TACE combined with chemotherapy or targeted therapy as a comprehensive treatment approach. Case 1 received multiple sessions of HAIC and TACE, given the high risk of tumor recurrence and good treatment compliance, with the aim of improving local tumor control and delaying recurrence. The necessity of postoperative adjuvant therapy, such as chemotherapy, targeted therapy, or immunotherapy, for patients with high-risk recurrence factors still needs further investigation, and this will be the focus of future research.
Few reports exist on the prognosis of sdpHCC-ICC. Available studies suggest that the prognosis is worse than HCC and comparable to ICC (, ). Cao et al. retrospectively analyzed the survival prognosis of 35 patients with sdpHCC-ICC and found that the OS at 1, 3, and 5 years after surgery was 60.0%, 28.9%, and 23.1%, respectively. Among these patients, ICC tumor size, lymph node metastasis, and histological differentiation of ICC components were independent risk factors affecting OS (). Li et al. noted that tumor size affects OS in both ICC and HCC, while tumor size and postoperative prophylactic TACE treatment in ICC also affect DFS (). We hypothesize that ICC has a greater impact on the survival prognosis of patients with sdpHCC-ICC than HCC. Therefore, more attention needs to be paid to the progression of ICC in clinical practice. The two patients in this study had a good survival prognosis and no recurrence at the time of writing, likely due to their low tumor stage, high degree of differentiation, and prophylactic TACE treatment after surgery. With new advances and breakthroughs in treatment, the survival prognosis of patients has significantly improved. In the future, more multidisciplinary basic and clinical studies are needed to explore safer and more efficient diagnostic and treatment methods. By synergizing diagnosis and treatment and leveraging the professional advantages of various disciplines, we can provide more evidence-based medical evidence and clinical references to improve the prognosis of sdpHCC-ICC patients.
5 Conclusion
In this study, we investigated the clinical and pathological features of sdpHCC-ICC through two cases with chronic hepatitis B. The pathogenesis of sdpHCC-ICC is unclear and may involve both monoclonal and polyclonal origins. HBV infection is an important risk factor, and antiviral therapy plays a key role in reducing the risk of tumorigenesis. sdpHCC-ICC lacks specific clinical manifestations and serum tumor markers, resulting in a low preoperative imaging diagnosis rate. Surgical resection remains the treatment of choice, but the prognosis is poor, with the ICC component having a greater impact on prognosis. Postoperative prophylactic TACE, along with adjuvant therapies such as chemotherapy and targeted therapy, plays an important role in improving prognosis.
Statements
Data availability statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Ethics statement
The studies involving humans were approved by The Institutional Review Board of Peking University People’s Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author contributions
PW: Data curation, Investigation, Writing – original draft, Writing – review & editing. NK: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft. CL: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft. YL: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft. JG: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing – original draft. JZ: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Writing – original draft. ZL: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Supervision, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by the Capital Health Research and Development of Special Fund (2022–2–4084).
Acknowledgments
The authors would like to extend their deepest gratitude to Prof. Zhao Li and Prof. Nan Kang for their invaluable guidance and mentorship throughout the course of this research. Additionally, we wish to thank all the colleagues at Peking University People’s Hospital who participated in and supported this work. Their contributions were instrumental in the completion of this study.
Conflict of interest
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.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
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Summary
Keywords
double primary hepatic cancer, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, chronic liver disease, hepatitis B virus
Citation
Wei P, Kang N, Lo C, Luo Y, Gao J, Zhu J and Li Z (2025) Synchronous double primary hepatocellular carcinoma and intrahepatic cholangiocarcinoma in a single patient with chronic hepatitis B: two case reports and literature review. Front. Oncol. 15:1507454. doi: 10.3389/fonc.2025.1507454
Received
07 October 2024
Accepted
27 May 2025
Published
16 June 2025
Volume
15 - 2025
Edited by
Liang Qiao, The University of Sydney, Australia
Reviewed by
Lin Yang, Affiliated Hospital of North Sichuan Medical College, China
Cristina Felicani, Sant’Orsola-Malpighi Polyclinic, Italy
Marco Arru, University of Sassari, Italy
Updates
Copyright
© 2025 Wei, Kang, Lo, Luo, Gao, Zhu and Li.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhao Li, goodlizhao@sina.com
†These authors have contributed equally to this work and share first authorship
Disclaimer
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