Hepatocellular Carcinoma Cholangiocarcinoma Research Articles

Abstract 44: Global Incidence of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma in 2018

Abstract Purpose: The two main subtypes of primary liver cancer are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). We aimed to produce worldwide and regional estimates of the distribution of these subtypes based on high quality data. Methods: Population-based cancer registry data were used to compute sex-specific proportions of HCC, iCCA, and other specified histology. The proportions were applied to sex- and age-specific liver cancer estimates from GLOBOCAN 2018 and age-standardized incidence rates were calculated. Results: Of an estimated 826,000 cases of liver cancer in 2018, 661,000 (80.0%) were HCC, 123,000 (14.9%) were iCCA and 42,000 (5.1%) were other specified histology. In nearly all world regions, HCC was more common than iCCA, except in women in Northern Europe where iCCA was more common than HCC. The highest rates of HCC were found in Eastern Asia (14.8 cases per 100,000 person-years), Northern Africa (13.2) and South-Eastern Asia (9.5). The highest rates of iCCA were in South-Eastern Asia (2.9), Eastern Asia (2.0), Northern Europe, the Caribbean and Central America, and Oceania (all 1.8). HCC was more often diagnosed in males (M:F rate ratio ranged from 1.6 to 5.0), while the sex difference in iCCA rates was much smaller (M:F between 0.7 and 1.7). Conclusion: Uncovering the distinct patterns of HCC and iCCA by sex, country and world region is critical to further develop public health policy to reduce liver cancer burden and monitor progress in controlling the disease globally. Improved completeness of liver cancer histology registration would provide more reliable estimates for policymakers to base decisions on. Citation Format: Harriet Rumgay, Jacques Ferlay, Catherine de Martel, Damien Georges, Amal Samy Ibrahim, Rongshou Zheng, Wenqiang Wei, Valery Lemmens, Isabelle Soerjomataram. Global Incidence of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma in 2018 [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 44.

Post-resection prognosis of combined hepatocellular carcinoma-cholangiocarcinoma according to the 2019 WHO classification

Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA) has wide histologic diversity. This study investigated the prognostic impacts of cHCC-CCA histology according to the 2019 World Health Organization (WHO) classification. This retrospective observational study included 153 patients who underwent surgical resection for cHCC-CCA at Asan Medical Center between August 2012 and July 2019. During the study period, 153 patients, 112 (73.2%) men and 41 (26.8%) women with a mean age of 56.4 ± 10.8 years, underwent R0 resection for cHCC-CCA. Mean tumor diameter was 4.2 ± 2.6 cm, and 147 (96.1%) patients had solitary tumors. According to 2019 World Health Organization (WHO) classification, 111 (72.5%) patients had cHCC-CCA alone, and 29 of them (26.1%) showed stem cell features. cHCC-CCA-intermediate cell carcinoma and cHCC-CCA-cholangiolocellular carcinoma were identified in 27 (17.6%) and 15 (9.8%), respectively. The 1-, 3-, and 5-year tumor recurrence and patient survival rates were 31.8% and 92.1%, 49.8% and 70.9%, and 59.0% and 61.7%, respectively. Univariate analyses revealed that significant prognostic factors were tumor size > 5 cm, microscopic and macroscopic vascular invasion, lymph node metastasis, 8th American Joint Committee on Cancer (AJCC) tumor stage, and status of stem cell feature. Multivariate analysis revealed 8th AJCC tumor stage and status of stem cell features as independent prognostic factors. The 2019 WHO classification was not associated with post-resection prognosis. The 2019 WHO classification was not associated with post-resection prognosis, thus was considered as a simple histologic classification. We suggest that stem cell features should be included as an essential component of the pathology report for cHCC-CCA.

Dynamic 18F-FDG PET imaging of liver lesions: evaluation of a two-tissue compartment model with dual blood input function

BackgroundDynamic PET with kinetic modeling was reported to be potentially helpful in the assessment of hepatic malignancy. In this study, a kinetic modeling analysis was performed on hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) from dynamic FDG positron emission tomography/computer tomography (PET/CT) scans.MethodsA reversible two-tissue compartment model with dual blood input function, which takes into consideration the blood supply from both hepatic artery and portal vein, was used for accurate kinetic modeling of liver dynamic 18F-FDG PET imaging. The blood input functions were directly measured as the mean values over the VOIs on descending aorta and portal vein respectively. And the contribution of hepatic artery to the blood input function was optimization-derived in the process of model fitting. The kinetic model was evaluated using dynamic PET data acquired on 24 patients with identified hepatobiliary malignancy. 38 HCC or ICC identified lesions and 24 healthy liver regions were analyzed.ResultsResults showed significant differences in kinetic parameters {K}_{1}-{k}_{4}, blood supplying fraction {f}_{A}, and metabolic rate constant {K}_{i} between malignant lesions and healthy liver tissue. And significant differences were also observed in {K}_{1}, {k}_{3}, {f}_{A} and {K}_{i} between HCC and ICC lesions. Further investigations of the effect of SUV measurements on the derived kinetic parameters were conducted. And results showed comparable effectiveness of the kinetic modeling using either SUVmean or SUVmax measurements.ConclusionsDynamic 18F-FDG PET imaging with optimization-derived hepatic artery blood supply fraction dual-blood input function kinetic modeling can effectively distinguish malignant lesions from healthy liver tissue, as well as HCC and ICC lesions.

Combined hepatocellular carcinoma-cholangiocarcinoma: A misdiagnosed case preoperatively.

Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CC) is a rare subtype in primary liver cancer, which is difficult to diagnose in clinics. In this report, we present a case of a 62-year-old male with abdominal pain and slightly elevated alpha-fetoprotein. The contrast-enhanced computed tomography scans showed a left liver mass, which showed adherence to the imaging characteristics of hepatocellular carcinoma. However, with the treatment of laparoscopic liver resection, the following histological examination displayed two distinct components, which were consistent with the diagnosis of cHCC-CC.

Post-resection prognosis of combined hepatocellular carcinoma-cholangiocarcinoma cannot be predicted by the 2019 World Health Organization classification

BackgroundCombined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA) has wide histologic diversity. This study investigated the prognostic impacts of cHCC-CCA histology according to the 2019 World Health Organization (WHO) classification. MethodsThis retrospective observational study included 153 patients who underwent surgical resection for cHCC-CCA at Asan Medical Center between August 2012 and July 2019. ResultsDuring the study period, 153 patients, 112 (73.2%) men and 41 (26.8%) women with a mean age of 56.4 ± 10.8 years, underwent R0 resection for cHCC-CCA. Mean tumor diameter was 4.2 ± 2.6 cm, and 147 (96.1%) patients had solitary tumors. According to 2019 WHO classification, 111 (72.5%) patients had cHCC-CCA alone, and 29 of them (26.1%) showed stem cell features. cHCC-CCA-intermediate cell carcinoma and cHCC-CCA-cholangiolocellular carcinoma were identified in 27 (17.6%) and 15 (9.8%), respectively. The 1-, 3-, and 5-year tumor recurrence and patient survival rates were 31.8% and 92.1%, 49.8% and 70.9%, and 59.0% and 61.7%, respectively. Univariate analyses revealed that significant prognostic factors were tumor size >5 cm, microscopic and macroscopic vascular invasion, lymph node metastasis, 8th American Joint Committee on Cancer (AJCC) tumor stage, and status of stem cell features. Multivariate analysis revealed 8th AJCC tumor stage and status of stem cell features as independent prognostic factors. 2019 WHO classification was not associated with post-resection prognosis. Conclusions2019 WHO classification was not associated with post-resection prognosis, thus was considered as simplified histologic classification requiring prognostic validation. We suggest that stem cell features should be included as an essential component of the pathology report for cHCC-CCA.

Long-term risk of primary liver cancers in entecavir versus tenofovir treatment for chronic hepatitis B

It remains controversial whether entecavir (ETV) and tenofovir disoproxil fumarate (TDF) is associated with different clinical outcomes for chronic hepatitis B (CHB). This study aimed to compare the long-term risk of ETV versus TDF on hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) in CHB patients from a large multi-institutional database in Taiwan. From 2011 to 2018, a total of 21,222 CHB patients receiving ETV or TDF were screened for eligibility. Patients with coinfection, preexisting cancer and less than 6 months of follow-up were excluded. Finally, 7248 patients (5348 and 1900 in the ETV and TDF groups, respectively) were linked to the National Cancer Registry database for the development of HCC or ICC. Propensity score matching (PSM) (2:1) analysis was used to adjust for baseline differences. The HCC incidence between two groups was not different in the entire population (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.66–1.02, p = 0.078) and in the PSM population (HR 0.83; 95% CI 0.65–1.06, p = 0.129). Among decompensated cirrhotic patients, a lower risk of HCC was observed in TDF group than in ETV group (HR 0.54; 95% CI 0.30–0.98, p = 0.043, PSM model). There were no differences between ETV and TDF groups in the ICC incidence (HR 1.84; 95% CI 0.54–6.29, p = 0.330 in the entire population and HR 1.04; 95% CI 0.31–3.52, p = 0.954 in the PSM population, respectively). In conclusion, treatment with ETV and TDF showed a comparable long-term risk of HCC and ICC in CHB patients.

Postresection prognosis of combined hepatocellular carcinoma-cholangiocarcinoma according to the 2010 World Health Organization classification: single-center experience of 168 patients.

PurposeCombined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) has wide histologic diversity. This study investigated the effects of cHCC-CC histology, according to the 2010 World Health Organization (WHO) classification, on patient prognosis.MethodsThe medical records of patients who underwent surgical resection for cHCC-CC at our institution between July 2012 and June 2019 were retrospectively evaluated.ResultsDuring the study period, 168 patients, 122 males (72.6%) and 46 females (27.4%), underwent surgical resection for cHCC-CC, including 159 patients (94.6%) who underwent R0 resection. Mean tumor diameter was 4.4 ± 2.8 cm, and 161 patients (95.8%) had solitary tumors. Histologically, 86 patients (51.2%) had classical type, and 82 (48.8%) had tumors with stem cell (SC) features, including 33 (19.6%) with intermediate-cell and 23 (13.7%) each with typical SC and cholangiolocellular features; 3 tumors (1.8%) were unclassifiable. At 1, 3, and 5 years, tumor recurrence rates were 31.9%, 49.6%, and 58.1%, respectively, and patient survival rates were 91.0%, 70.2%, and 60.3%, respectively. Univariate analysis showed that tumor size of >5 cm, microscopic and macroscopic vascular invasion, lymph node metastasis, 8th edition of the American Joint Committee on Cancer (AJCC) tumor stage, and 2010 WHO classification were significantly prognostic. Multivariate analysis showed that the 8th AJCC tumor stage and 2010 WHO histologic classification were independently prognostic for tumor recurrence and patient survival. There were no significant prognostic differences among the 3 SC subtypes.ConclusionPostresection outcomes are better in patients with SC-type than with classical-type cHCC-CC.

Construction and validation of a nomogram for predicting cancer-specific survival in hepatocellular carcinoma patients

The prognosis of patients with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) is a research hotspot. This study aimed to incorporate important factors obtained from SEER database to construct and validate a nomogram for predicting the cancer-specific survival (CSS) of patients with HCC and ICC. We obtained patient data from SEER database. The nomogram was constructed base on six prognostic factors for predicting CSS rates in HCC patients. The nomogram was validated by concordance index (C-index), the receiver operating characteristic (ROC) curve and calibration curves. A total of 3227 patients diagnosed with HCC (3038) and ICC (189) between 2010 and 2015 were included in this study. The C-index of the nomogram for HCC patients was 0.790 in the training cohort and 0.806 in the validation cohort. The 3- and 5-year AUCs were 0.811 and 0.793 in the training cohort. The calibration plots indicated that there was good agreement between the actual observations and predictions. In conclusion, we constructed and validated a nomogram for predicting the 3- and 5-year CSS in HCC patients. We have confirmed the precise calibration and excellent discrimination power of our nomogram.

Abstract PR04: Understanding tumor clonal evolution by single-cell transcriptomic analysis in liver cancer

Abstract Tumor evolution is a key feature intrinsic to tumor biology and contributes to intratumor heterogeneity, escape of immune surveillance, treatment failure, and patients’ prognosis. The evolutionary process of tumor is driven by selecting favorable phenotypes in terms of their fitness and survival in a tumor ecosystem. While genomic alterations provide rich materials for tumor evolution, only a few can induce a recognizable phenotypic change with even fewer for a fitness advantage. Thus, transcriptomics, a major molecular feature reflecting functional activities, will be informative in modeling tumor heterogeneity and crucial in understanding tumor evolution. Here, we aim to study tumor clonal evolution by single-cell transcriptomic profiling of hepatocellular carcinoma and intrahepatic cholangiocarcinoma from 37 patients participating the immune checkpoint inhibition trials. By analyzing core biopsies before or after treatment, we determined the single-cell atlas of liver tumors and confidently separated malignant cells and non-malignant cells by inferring chromosomal copy number variations. We developed a consensus clustering model based on machine learning algorithms and statistical methods to identify functional clones from malignant cells within each tumor. We further determined the clonal relationship by constructing the phylogenetic tree of the clones from all tumors. The clonal relationship within each tumor was independently assessed by manifold based single-cell trajectory and RNA-velocity based cell lineage. The analyses revealed a tumor branching evolutionary architecture of the clones. Noticeably, tumor branching evolution was associated with patient outcomes, which was also validated by using bulk transcriptomic data from 765 liver tumors. We found tumors in the poor prognosis branch were enriched in the pathways of hypoxia, epithelial-mesenchymal transition and angiogenesis. Remarkably, the functional role of the clones within a tumor varied, indicating a cooperative tumor cell community. We found a polarization of immune landscape associated with tumor branching evolution driven by tumor cell-specific cytokines. Our results offer insight into the collective behavior of tumor cell communities in liver cancer as well as potential drivers for tumor evolution in response to immunotherapy. Citation Format: Lichun Ma, Limin Wang, Ching-Wen Chang, Sophia Franck, Dana Dominguez, Marshonna Forgues, Julian Candia, Maria O. Hernandez, Michael Kelly, Yongmei Zhao, Bao Tran, Jonathan M. Hernandez, Jeremy L. Davis, David E. Kleiner, Bradford J. Wood, Tim F. Greten, Xin Wei Wang. Understanding tumor clonal evolution by single-cell transcriptomic analysis in liver cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PR04.

Adjuvant Transarterial chemoembolization does not influence recurrence-free or overall survival in patients with combined hepatocellular carcinoma and Cholangiocarcinoma after curative resection: a propensity score matching analysis

BackgroundThe prognosis of patients with combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma (CHC) is usually poor, and effective adjuvant therapy is missing making it important to investigate whether these patients may benefit from adjuvant transarterial chemoembolization (TACE). We aimed to evaluate the efficiency of adjuvant TACE for long-term recurrence and survival after curative resection before and after propensity score matching (PSM) analysis.MethodsIn this retrospective study, of 230 patients who underwent resection for CHC between January 1994 and December 2014, 46 (18.0%) patients received adjuvant TACE. Univariate and multivariate regression analyses were used to identify the independent predictive factors of survival. Cox regression analyses and log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS) between patients who did or did not receive adjuvant TACE.ResultsA total of 230 patients (mean age 52.2 ± 11.9 years; 172 men) were enrolled, and 46 (mean age 52.7 ± 11.1 years; 38 men) patients received TACE. Before PSM, in multivariate regression analysis, γ-glutamyl transpeptidase (γ-GT), tumour nodularity, macrovascular invasion (MVI), lymphoid metastasis, and extrahepatic metastasis were associated with OS. Alanine aminotransferase (ALT), MVI, lymphoid metastasis, and preventive TACE (HR: 2.763, 95% CI: 1.769–4.314, p < 0.001) were independent prognostic factors for DFS. PSM created 46 pairs of patients. Before PSM, adjuvant preventive TACE was not associated with an increased risk of OS (HR: 0.911, 95% CI: 0.545–1.520, p = 0.720) or DFS (HR: 3.345, 95% CI: 1.686–6.638, p = 0.001). After PSM, the 5-year OS and DFS rates were comparable in the TACE group and the non-TACE group (OS: 22.7% vs 14.9%, respectively, p = 0.75; DFS: 11.2% vs 14.4%, respectively, p = 0.06).ConclusionsThe present study identified that adjuvant preventive TACE did not influence DFS or OS after curative resection of CHC.

Abstract IA40: Race-related liver tumor subtypes are associated with gut microbiome-mediated metabolism

Abstract Liver cancer has one of the fastest-rising incidence rates in the United States and across the world. It disproportionally affects men and individuals of Asian and African descent. Liver cancer consists of two main histologically distinct subtypes, i.e., hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) confined within the liver, whose diagnoses and treatment decisions are uniquely based on their baseline clinical features. However, both HCC and iCCA are genetically, etiologically, and biologically heterogeneous, and have a complex mutational landscape with vast intertumor and intratumor heterogeneity, which poses a major challenge to define actionable drivers. With the need of a well-annotated biobank to improve our understanding of disease susceptibility, progression, and outcome at a global level, we established the Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC) consortium to create a comprehensive biorepository with biospecimens linked to etiologies and clinical features from 3,000 patients with liver cancer and 3,000 high-risk and healthy individuals who reside in Thailand. Here, by characterizing the first 199 sequentially enrolled Thai patients, we could demonstrate the presence of common molecular subtypes among HCC and iCCA patients in Thailand using state-of-the-art systems integration of genomics, transcriptomics, and metabolomics. While HCC and iCCA share recurrently mutated genes (TP53, ARID1A, and ARID2), mitotic checkpoint anomalies distinguish the C1 subtype with key drivers PLK1 and ECT2 from the C2 subtype, which is mainly linked to obesity, T-cell infiltration, and gut microbiome-mediated bile acid metabolism. Intriguingly, however, certain molecular subtypes were found in Asian, but less so in Caucasian, patients in our study, indicating geographic differences in disease presentation. Notably, Thai patients with the common C2 subtype showed elevated serum microbial metabolites, consistent with a potential effect of the local microbiome on tumor biology. In support of this hypothesis, we could demonstrate that gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells in mice. Thus, HCC and iCCA, while clinically treated as separate entities, shared common molecular subtypes with similar actionable drivers and underlying tumor biology in an Asian patient population. However, our study also provides evidence of geographic disease heterogeneity and a rationale for liver cancer intervention based on regulating the balance of gut microflora. Citation Format: Xin W. Wang, Anuradha Budhu, Jittiporn Chaisaingmongkol, Yotsawat Pomyen, Mathuros Ruchirawat, Tim F. Greten. Race-related liver tumor subtypes are associated with gut microbiome-mediated metabolism [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr IA40.

Genomics and Interventional Oncology in Primary Liver Cancer

AbstractPersonalized medicine is revolutionizing oncologic care. Molecular and imaging “fingerprinting” of cancer through genomics, radiomics, and radiogenomics has allowed for the meticulous characterization of many forms of malignancy, including primary liver cancers. With this data, treatments are being developed that precisely target and exploit key variations in individual tumors. As these methods continue to evolve, interventional oncologists are well positioned to capitalize on the advances being made. This article will provide a concise overview of the genomic, radiomic, and radiogenomic research on hepatocellular carcinoma and intrahepatic cholangiocarcinoma, in addition to discussions on how precision medicine would relate to interventional oncology.

Locoregional and local ablative treatment options for liver tumors

Interventional radiology offers alarge variety of locoregional and local ablative treatment options for liver tumors. These can be applied as stand-alone minimally invasive procedures or in combination with other treatment options and with curative as well as palliative intent depending on the respective tumor stage. This review article presents the various locoregional and local ablative treatment techniques and describes the clinical value in the treatment of hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

Usefulness of18F-FDG PET/CT and Multiphase CT in the Differential Diagnosis of Hepatocellular Carcinoma and Combined Hepatocellular Carcinoma-Cholangiocarcinoma

PurposeThe purpose of this study was to evaluate the usefulness of multiphasic CT and 18F-fluorodeoxyglucose (FDG) PET/CT for the differentiation of combined hepatocellular carcinomacholangiocarcinoma (cHCC-CCA) from hepatocellular carcinoma (HCC).Materials and Methods From January 2007 to April 2016, 93 patients with pathologically confirmed HCC (n = 84) or cHCC-CCA (n = 9) underwent CT and PET/CT imaging. Contrast enhancement patterns were divided into three types based on the attenuation of the surrounding liver parenchyma: type I (early arterial enhancement with delayed washout), type II (early arterial enhancement without delayed washout), and type III (early hypovascular, infiltrative appearance, or peripheral rim enhancement).ResultscHCC-CCAs (89%) had a higher PET/CT positive rate than did HCCs (61%), but the PET/CT positive rate did not differ significantly (p = 0.095). Among the 19 cases of the type II enhancement pattern, 3 (21%) of 14 HCCs and 4 (80%) of 5 cHCC-CCAs were PET/CT positive. cHCC-CCAs had a significantly higher PET/CT positive rate (p = 0.020) in the type II enhancement pattern.ConclusionThe PET/CT positive rate of cHCC-CCA was significantly higher than that of HCC in lesions with a type II enhancement pattern. The 18F-FDG PET/CT can be useful for the differentiation of cHCC-CCA from HCC in lesions with a type II enhancement pattern on multiphasic CT.

An exceptional response to immunotherapy doublet in combined hepatocellular carcinoma-cholangiocarcinoma

Abstract Background We present here a case of a 67-year-old male. He presented in May 2018 with severe abdominal pain and weight loss of 25%. Alpha-feto protein (AFP) and Carbohydrate antigen 19-9 (CA19-9) were within normal limits, and CA125 was 5 times upper normal limit (ULN). Computed tomography showed liver masses and enlarged retroperitoneal lymph nodes. Biopsy from a liver mass showed Combined Hepatocellular Carcinoma (HCC)-Cholangiocarcinoma (CC) (CHC). This a rare tumor, with an incidence of less than 10% of primary liver tumors. In whole exome analysis, mutations suggested the bipotent cell origin and stem cell origin. There are no guidelines or randomized trials regarding treatment. In an analysis of 36 patients who were treated with chemotherapy, the progression-free survival was 2.8 months, with an overall response rate of 5.6%. Targeted agents had minimal effect on survival. Methods In our case, extensive genomic, transcriptomic and proteomic testing was performed. No genomic alterations were identified, tumor mutational burden was low and microsatellite status was stable. 7 of 9 immune checkpoint genes were overexpressed. A variant in CDK12 was noted, which was shown to be associated with elevated neoantigen burden and may predict benefit from immune checkpoint therapy. Results The patient began immunotherapy with ipilimumab and nivolumab followed by nivolumab, which he is continuing. The only side effects were hypothyroidism and Addison’s disease which are being treated. His clinical response was dramatic, he regained all the lost weight, and discontinued high dose opiate treatment. ECOG performance status improved from 3 to 0. Repeated PET-CT showed near complete response, ca125 decreased by 90% and liver function tests normalized. Table: 49P . Blood tests of case Before immunotherapy After 11 months of immunotherapy Normal range Alk Phos 456 83 38-150 GGT 588 72 15-73 Ca125 210 21 2-35 Conclusions We present here an exceptional case of a rare tumor, where the patient had a clinical, laboratory and radiological response and a significant improvement in quality of life, suggesting that these tumors are sensitive to immunotherapy. No published cases of this tumor have yet been treated with immunotherapy doublet. Legal entity responsible for the study The author. Funding Has not received any funding. Disclosure The author has declared no conflicts of interest.

2222 Primary Combined Hepatocellular Carcinoma-cholangiocarcinoma: A Case Report for Under-Diagnosed Primary Liver Cancer

INTRODUCTION: Combined hepatocellular carcinoma- cholangiocarcinoma (HCC-CC) was first classified in 1949 by Allen and Lisa et al. It composes less than 1% of primary hepatic malignancies. HCC-CC is being increasingly identified given the advances in immunohistochemistry (IHC) techniques. Due to its rarity, there are no formal treatment guidelines. However, a national cancer database review reported a worse prognosis. CASE DESCRIPTION/METHODS: A 73-year-old man with history of alcohol dependence presented with 2-week history of sharp right upper abdominal pain (RUQ). Review of systems was negative. Examination revealed RUQ tenderness. Hepatitis B and C serology were negative. Abdominal ultrasound showed two heterogeneous, hypoechoic liver lesions. Abdominal MRI showed enhancing masses in the left and right liver lobes. CT-guided liver biopsy confirmed the diagnosis of HCC -CC. The left sided tumor was treated with yttrium 90 radioembolization. Unfortunately, his restaging MRI showed progressive enlargement of the right hepatic lobe tumor and complete venous thrombosis of the portal vein. With rapidly worsening performance status, he was not a candidate for any further treatment and was enrolled in hospice care. DISCUSSION: HCC-CC is a primary liver tumor which presents diagnostic challenges to the pathologist, radiologist and clinician. Adequate tissue sampling is crucial to capture enough tumor to allow recognition of both histologies. Hence, core needle sampling would be preferable to fine needle aspiration. Triphasic CT/ MRI imaging may have characteristics of either tumor type. Tumor markers are often discordant with the imaging findings, which should raise suspicion for this entity. Histology and IHC are the only definitive way to establish diagnosis, which reveal a spectrum from both histologies occurring independently yet concurrently in the liver, to mixed cells of both histologies in same lesion to a fibrolamellar HCC like histology. Notably, the World Health Organization histological classification does not have prognostic or treatment impact. Although the prognosis of HCC-CC tends to be worse than both HCC and CC, there is uncertainty if it should be treated more like HCC or CC. Surgical resection and liver transplantation are the only curative option. For resected patient, survival was substantially worse than those with HCC. Inoperable patient and unresectable tumors can be treated locally with trans-arterial chemoembolization, radioembolization, and systemic therapy.

Abstract 4875: Clinical importance and clarification of the WHO subclassification of combined hepatocellular and cholangiocarcinoma

Abstract Introduction: Combined hepatocellular and cholangiocarcinoma, classical type (Comb HCC-CCC) is defined as a single tumor, in which hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are clearly differentiated. However, combined hepatocellular-cholangiocarcinoma with stem-cell features, cholangiolocellular type (CoCC) was added to the WHO Classification in 2010. This has caused a great deal of confusion and raised many questions for clinicians and pathologists. The aim of this study was to answer these questions and evaluate the clinical importance of the WHO classification. Subjects: The subjects were 1,002 patients with primary liver cancer who underwent hepatectomy from 2010 to 2016, including 931 with HCC, 6 with Comb HCC-CCC, 50 with ICC, and 15 with CoCC. Pathological evaluation using immunohistochemical staining was mainly used for CoCC. Results: The CoCC cases had similar serum total bilirubin and serum albumin to those in other types of hepatic cancer, but with a low ICGR15 level. AFP, PIVKA-II, and CEA were 4.4 (1.3 - 3,689) ng/mL, 18 (9 - 15,933) mAU/mL, and 3.8 (0.2 - 33) ng/mL, respectively. In preoperative CT diagnosis of CoCC, HCC, Comb HCC-CCC, and ICC were diagnosed in 20%, 40%, and 40% of the cases, respectively, suggesting difficulty with this diagnosis. The resected specimen showed the number of tumors (1 [1 - 16]), tumor diameter (4 [1.7 - 12] cm), microscopic-portal venous invasion (43%), microscopic venous invasion (36%), and cirrhosis (22%), suggesting a higher level of invasion to vascular channels compared to other types of cancer. In pathological findings, both transitional HCC and cholangiocarcinoma were found in HE staining, in addition to fibrosis and necrosis in the tumor. Among the subjects, 40%, 100%, 100%, and 100% had biliary cell markers of positive CD117 (c-Kit), positive CD56 (NCAM), positive CK7, and positive CK19, respectively, in addition to high expression of neural cell adhesion molecules. Levels of hepatocytes (10%) and glypican 3 (25%) were low. Cumulative survival was lower than that in other types of liver cancer, with 1- and 3-year survival rates of 67% and 57%, respectively. [Conclusion] The development mechanism of Comb HCC-CCC is thought to be genetic transformation of HCC or ICC, while that of CoCC with stem-cell features is believed to be cancerization of stem cells. However, stem-cell features are just characteristics, and thus do not serve as definitive evidence for stem cell-derived cancer. In addition, since there are various types of CoCC in Comb HCC-CCC, actual classification is extremely difficult in many cases. The clinical importance of clear differentiation between Comb HCC-CCC and CoCC is unclear, and thus the WHO classification of these tumors may be in a transition period. Citation Format: Hisashi NAKAYAMA, Tadatoshi TAKAYAMA, Yutaka Midorikawa, Masahiko Sugitani. Clinical importance and clarification of the WHO subclassification of combined hepatocellular and cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4875.

Oncology precision medicine for hepatobiliary and pancreatic cancer: An institutional review.

e14626 Background: Hepatobiliary cancers - hepatocellular carcinoma (HCC), intra or extrahepatic cholangiocarcinoma (I/EC), and gallbladder carcinoma (GB) - and pancreatic adenocarcinoma (PC) remain a leading cause of death with little improvement in long-term outcome. Recent studies have suggested that these cancers harbor actionable mutations to varying degrees. The aim of our study was to examine the number of patients (Pts) with these primary tumors who underwent molecular testing in a large vertically integrated health system. Subsequently, we analyzed the percentage of that population who may be candidates for oncology precision medicine (OPM) directed therapy. Methods: We identified Pts with HCC, IC, EC, GB in an IRB reviewed OPM database of our system over a one year period. Pts who underwent molecular panel testing were selected out, and their molecular alterations were identified and stratified by cancer type. Results: 304 total Pts were identified. 61 (20%) underwent molecular testing broken down as follows: 17/132 (13%) I/EC and HCC, 3/11 (27%) GB, and 41/161 (25%) PC. Quantity not sufficient for testing was in 10/61 (16%), of which 5/10 (50%) were resubmitted and tested successfully. 6/61 (10%) were cancelled or deemed not appropriate. Test recommended potential actionability was 8/17 (47%) of I/EC and HCC, 2/3 (67%) of GB, and 25/41 (61%) of PC. Conclusions: OPM is a dynamic area of increasing testing and learning. We found 13-27% of hepatobiliary and pancreatic Pts had molecular testing, which suggests the potential to increase molecular screening for this difficult group of tumors. Total genetic alterations (TGA) and clinically relevant genomic alterations (CRGA) per patient are similar to Ross et al. ( http://ow.ly/k52a30nBMnU ) for GB. Final interpretation regarding pragmatic actionability (patient on drug) and clinical outcomes are still under investigation.[Table: see text]

Epidemiology, prevalence and national trends of combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) in hospitalized US patients between 2002-2014.

e15616 Background: cHCC-CCA represents a rare type of primary liver cancer that was first identified in 1949. The aim of this study is to evaluate epidemiology, clinical outcomes and national trends of cHCC-CCA in hospitalized US patients using the Nationwide Inpatient Sample database (NIS). Methods: NIS database was inquired to identify patients with HCC between 2002 and 2014 using ICD9-CM codes. Patients with HCC were classified into two groups, one group with cholangiocarcinoma (CCA) and the other group without CCA. SPSS version 25 was used for statistical analysis. Results: We identified 525,699 patients with HCC between 2002-2014. Of them, 2,158 patients (0.4%) had CCA. In the cHCC-CCA group, 87.8% of the patients were above 50 years old, 58.1% were male, 63.7% were Caucasian, and 10% were African American. Mortality in patients hospitalized with cHCC-CCA was 8.5% compared to 11.1% in patients with HCC (OR 0.74, 95% CI 0.64-0.86, P &lt; 0.0001). Mortality in cHCC-CCA patients decreased from 19.1% in 2002 to 7.9% in 2014. The median length of stay (LOS) in patients with cHCC-CCA was 6 days compared to 4 days in patients with HCC (P &lt; 0.0001). Median LOS for patients with cHCC-CCA was unchanged between 2002 and 2014. The median hospitalization cost of charge in cHCC-CCA patients was 41,012 USD compared to 28,371 USD in HCC patients. In the cHCC-CCA group, it increased from 17,243 USD in 2002 to 37,234 USD in 2014. Only 0.9% of patients with cHCC-CCA underwent liver transplantation compared to 3.5% of HCC patients (OR 0.26, 95% CI (0.17-0.41), P &lt; 0.0001). Conclusions: Prevalence of cHCC-CCA was 0.4% of patients with HCC during the study period. cHCC-CCA was unexpectedly associated with less mortality; possibly because of limitations in comparison due to the smaller number of patients compared to HCC alone. cHCC-CCA was also associated with lower rates of liver transplantation but more prolonged LOS and higher hospitalization cost of charge compared to HCC patients. In the same period, mortality decreased in cHCC-CCA patients and cost of charge increased while prevalence and LOS were unchanged. Further studies are needed to evaluate and understand cHCC-CCA as a separate entity.

Management of combined hepatocellular carcinoma-cholangiocarcinoma.

To review the recent consensus on the nomenclature, clinical features, diagnosis, and treatment of combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA). cHCC-CCA is a primary liver carcinoma with varying degrees of hepatocytic and cholangiocytic cytology and architecture within the same tumor. The diagnosis of cHCC-CCA can only be established based on histologic examination. Surgical resection should be considered in patients with resectable tumors who do not have underlying liver disease or clinically significant portal hypertension. While treatment by liver transplantation (LT) is controversial due to the high risk of post LT recurrence, LT should remain as a potentially curative option in a highly selected group of patients. Little data exist for the outcome of other treatments. High quality multicenter prospective studies should be conducted to better understand this rare, but increasingly recognized tumor.