Research ArticleClinical Studies
Open Access

Albumin-bilirubin (ALBI) and Platelet-ALBI (PALBI) Grades: Novel Prognostic Factors for Cholangiocellular Carcinoma

ERGİN AYDEMİR, FUNDA YILMAZ, ALPER TÜRKEL, ÖZTÜRK ATEŞ and MUTLU DOĞAN
In Vivo September 2025, 39 (5) 2976-2985; DOI: https://doi.org/10.21873/invivo.14098

Abstract

Background/Aim: Cholangiocarcinoma (CCA) is the second most frequently occurring primary malignant tumor of the liver, characterized by poor survival due to late diagnosis and limited treatment options. The albumin-bilirubin (ALBI) and platelet-ALBI (PALBI) scores, which reflect liver function and inflammation, have emerged as potential prognostic markers in hepatocellular carcinoma (HCC). Their prognostic significance in CCA, however, remains less established.

Patients and Methods: A retrospective analysis was conducted on 184 patients diagnosed with CCA between 2007 and 2024. The study evaluated the relationship between tumor location, ALBI/PALBI grades, and overall survival (OS). Patients were categorized into three groups based on their ALBI and PALBI scores, and survival outcomes were analyzed.

Results: Tumor location significantly impacted OS. The median OS (mOS) was 18 months for distal CCA, 13 months for perihilar CCA, and 7 months for intrahepatic CCA (p<0.001). When stratified by ALBI grade, mOS was 17 months for Grade 1, 8 months for Grade 2, and 2 months for Grade 3 (p=0.001). Similarly, for PALBI grade, mOS was 13 months for Grade A1, 11 months for Grade A2, and 8 months for Grade A3 (p=0.037). Among the variables included in the multivariate analysis, only the ALBI grade retained its significance as an independent prognostic factor for overall survival.

Conclusion: ALBI and PALBI grades serve as effective prognostic indicators in CCA, with lower grades associated with enhanced survival rates. Notably, ALBI grade was found to be an independent predictor of OS, presenting a cost-efficient biomarker that may support clinical decision-making by providing crucial prognostic information insights.

Keywords:

Introduction

Cholangiocellular carcinoma (CCA) represents a significant oncologic challenge as the second most common liver malignancy, following hepatocellular carcinoma (HCC). Cholangiocellular carcinoma originates from biliary epithelium along any segment of the bile duct, leading to various clinical presentations (1). It predominantly presents as adenocarcinoma, which accounts for 90% of all cases. Cholangiocarcinoma is classified as intrahepatic cholangiocellular carcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA). The extrahepatic type is divided into distal cholangiocarcinoma (dCCA) and perihilar cholangiocarcinoma (pCCA), with distinct risk profiles and epidemiological characteristics (2). Perihilar cholangiocarcinoma is the most common subtype, representing around 50% of cases. In contrast, dCCA accounts for about 40%, while iCCA is the least common, comprising around 10% of cases (3). CCA may develop as a result of various underlying conditions that trigger biliary tract inflammation and cholestasis, including hepatitis B and C, Opisthorchis viverrini infection, liver cirrhosis, primary sclerosing cholangitis, non-alcoholic fatty liver disease, and Caroli’s disease (4, 5).

Surgical resection is the primary treatment modality in CCA at early stages. Chemotherapy, immunotherapy, and radiation therapy are other options in selected patients. Median overall survival (OS) is around 24-36 months (6, 7).

Tumor extent, cellular differentiation, lymph node involvement, and vascular invasion are prognostic factors for CCA. Tumor markers, like carbohydrate antigen 19-9 (Ca 19-9) and carcinoembryonic antigen (CEA), may have clinical significance as biomarkers when elevated at diagnosis (8-10). However, new prognostic and predictive biomarkers are needed because CCA has a poor prognosis, especially in advanced stages.

Albumin-bilirubin (ALBI) grade and platelet-ALBI (PALBI) grade were shown to have prognostic significance in HCC (10-12). These grades reflect liver function and provide insight into the inflammatory response and the extent of fibrosis. Given the prognostic value of ALBI grade demonstrated in HCC and limited studies in cholangio-carcinoma, this study aimed to comprehensively evaluate both ALBI and PALBI grades as prognostic markers in CCA patients across all tumor subtypes.

Patients and Methods

Patient selection. Patients aged ≥18 years diagnosed with CCA between February 2007 and February 2024, whose diagnosis, treatment, or follow-up was conducted at Dr. Abdurrahman Yurtaslan Ankara Oncology Research and Training Hospital were retrospectively assessed. Clinical records were retrieved from the institutional FONET® patient database. Those with adequate data were included in the study. They were analyzed for prognostic factors and survival outcomes. Based on clinical staging, individuals were classified as having either early-stage or more advanced forms of the disease (i.e., locally advanced stage & advanced stage) according to the current editions of ‘The American Joint Committee on Cancer (AJCC) Staging System [6th Ed. (2003), 7th Ed. (2010) & 8th Ed. (2017)]’ due to their diagnosis dates, between 2007 and 2024.

The albumin-bilirubin (ALBI) index was calculated using the following equation: ALBI=0.66×log10(bilirubin) −0.0852×albumin. The platelet-albumin-bilirubin (PALBI) score was determined using the following formula: PALBI =2.02×log10(bilirubin)-0.37×(log10(bilirubin))2-0.04× albumin-3.48×log10(platelet count)+1.01×log10(platelet count). Based on ALBI calculation, patients were categorized into three distinct classes: Grade 1 for scores ≤−2.60, Grade 2 for scores between −2.60 and −1.39, and Grade 3 for scores >−1.39. Similarly, patients were grouped accordingly: Grade 1 if PALBI ≤−2.53, Grade 2 if PALBI was between −2.53 and −2.09, and Grade 3 if PALBI >−2.09 (13).

Statistical analysis. Descriptive statistics were expressed as proportions for nominal variables, and as either arithmetic mean±SD for normally distributed variables or median (with minimum-maximum) for non-normally distributed numerical variables, based on distribution profiles. The distribution of continuous data was examined by the Kolmogorov–Smirnov test. Depending on the normality outcome, parametric (Student’s t) or non-parametric (Mann–Whitney U) tests were conducted for continuous variables. Group-wise comparisons of categorical parameters were analyzed through Pearson’s chi-squared test. Independent predictors identified by univariate screening (p<0.05) were subsequently incorporated into the multivariable regression model. Multivariate Cox regression analysis was performed to assess the independent prognostic significance of variables found to be statistically significant in univariate analysis. Overall survival (OS) was calculated as the time from initial clinical diagnosis to either the occurrence of death or the most recent follow-up point available. Disease-free interval (DFS) was defined as the interval from the date of diagnosis until the recurrence or death among individuals with early-stage CCA. Progression-free survival (PFS) represents the time from initial diagnosis until disease advancement or death in cases initially identified as advanced-stage. Survival analysis was conducted through the Kaplan-Meier method, and comparison of survival curves was performed via log-rank test. All p-values <0.05 were considered statistically significant. All statistical computations were executed via the SPSS program (version X; IBM, Armonk, NY, USA).

Ethics approval and consent to participate. This study involved a retrospective review of previously gathered records. As the design did not require direct patient interaction, the obligation for informed consent was waived by the Ethics Committee of Dr. Abdurrahman Yurtaslan Oncology Hospital (Approval No: 2024-02/03, dated February 2, 2024). All information was de-identified to protect privacy. The research was conducted in line with institutional ethical standards and followed the guidelines of the Declaration of Helsinki and its updates.

Patient consent. Due to the retrospective design of the study, the Clinical Research Ethics Committee granted an exemption from obtaining informed consent. All patient information was anonymized to maintain confidentiality.

Results

A total of 184 patients diagnosed with CCA were analyzed retrospectively. Of these, 102 (55.4%) were female, and 82 (44.6%) were male. Patients were observed for a median duration of 10 months (95% CI=16.2-23.8), and the median age at diagnosis was 64 years (range=33-87). Ninety-six (52.1%) patients were <64 years. The tumor was located in pCCA in 87 (47.3%) patients, iCCA in 52 (28.3%) patients, and dCCA in 45 (24.4%) patients. Staging data was missing for 8 (4.3%) patients, rendering them unclassifiable. Among the remaining ones, 8 (4.3%) patients were in stage 1, 33 (17.9%) in stage 2, 66 (35.9%) in stage 3 and 69 (37.5%) in stage 4. Most patients had advanced stage CCA (n=135, stages 3 & 4). Ninety-five (51.6%) patients had de novo metastasis.

Surgery was performed on all early-stage patients (n=41), as well as on 58 patients with advanced-stage disease. Among patients with early-stage disease, 37 patients (90.5%) achieved R0 resection with clear surgical margins, whereas 4 patients (9.5%) had R1 resection with positive margins. Additionally, among the 55 advanced-stage patients who underwent surgery, 40 (72.7%) patients achieved R0 resection, 12 (21.8%) had R1 resection, and 3 (5.5%) had R2 resection. Among advanced-stage patients who underwent surgery, 18 (43.9%) patients received postoperative chemotherapy, with 14 of them (77.7%) experiencing relapse during follow-up. Gemcitabine with/without platinum was initiated as first-line systemic therapy in 52 (42.4%) patients with unresectable advanced-stage disease. Nineteen (10.3%) patients were alive at analysis.

ALBI grade could be calculated for 147 (65.2%) patients, while the PALBI grade could be calculated for 118 (64.2%) patients at diagnosis since the others had missing parameters for calculating these scores. Based on the ALBI score, 46 (31.2%) patients were classified as grade 1, while 86 (58.6%) were as grade 2 and 15 (10.2%) were as grade 3. According to the PALBI score, 26 (17.9%) were categorized as grade A1, 44 (30.3%) as grade A2, and 75 (51.7%) as grade A3, respectively.

Survival analysis. Univariate analysis in early-stage patients revealed that median DFS was significantly longer in patients aged >64 years compared to those aged ≤64 years. ALBI grade 2 and PALBI grade A3 were also significantly associated with longer DFS. Conversely, DFS did not differ significantly by sex, tumor location, or R status. These prognostic factors lost their significance for PFS in relapsed patients receiving first-line systemic therapy (Table I). In advanced-stage patients, univariate analysis revealed that de novo metastasis, surgical intervention, and R1 residual tumor status were significantly associated with longer PFS, while age, sex, tumor location, ALBI grade, and PALBI grade showed no significant association with PFS (Table II). Additionally, in the whole population, univariate analysis revealed that all parameters including age, tumor location, diagnosis stage, de novo metastasis status, surgical intervention, residual tumor status, ALBI grade, and PALBI grade were significantly associated with OS, while sex showed no significant impact (Table III). Specifically, older (>64 years old) patients with distal CCA, at early stages (stage I-II) and R0 resections had longer OS (Table III). In univariate analysis, ALBI and PALBI grades were statistically significant prognostic factors for DFS for early-staged patients and OS for the whole population. Overall survival curves based on ALBI-PALBI grades are presented in Figure 1. Additionally, OS curves according to patient characteristics (age, tumor location, diagnosis stage and surgical resection) are shown in Figure 2.

View this table:
Table I.

Univariate analysis of possible prognostic factors for early stage patients (n=41).

View this table:
Table II.

Univariate analysis of possible prognostic factors for advanced stage patients (n=135).

View this table:
Table III.

Univariate analysis for patients’ characteristics, ALBI-PALBI grades and OS in all patients (N=184).

Figure 1.
Figure 1.

Kaplan-Meier overall survival (OS) curves. OS curves in patients with cholangiocellular carcinoma (n=184) according to ALBI (A) and PALBI (B). ALBI: Albumin-bilirubin; PALBI: platelet-ALBI.

Figure 2.
Figure 2.

Overall survival (OS) based on demographic characteristics. Kaplan-Meier OS curves in patients with cholangiocarcinoma (n=184) according to age (A), tumor location (B), diagnosis stage (C) and surgical resection (D). CCA: Cholangiocarcinoma.

The significant variables identified in the univariate analysis were included in the multivariate model. Cox regression analysis demonstrated that advanced stage at diagnosis and ALBI grade emerged as independent prognostic factors for overall survival. Advanced stage disease (stage 3-4) was significantly associated with inferior survival outcomes [hazard ratio (HR)=2.421, 95% confidence interval (CI)=1.244-4.710]. Additionally, ALBI Grade 3 was identified as a significant independent predictor of poor prognosis (HR=4.355, 95% CI=1.207-15.70). Other variables including age, residual tumor status, de novo metastasis, surgical intervention, and PALBI grade did not demonstrate independent prognostic significance in the multivariate analysis (all p>0.05) (Table IV).

View this table:
Table IV.

Multivariate analysis of patients’ characteristics and ALBI-PALBI grades for overall survival.

Discussion

Cholangiocarcinoma remains a challenging malignancy characterized by poor prognosis, delayed diagnosis, and limited treatment options, with surgical resection being the only curative approach available to approximately one-third of patients at diagnosis (8). Current prognostic factors are often limited to region-specific or resectable CCA cases (9, 10), and the heterogeneous nature of CCA across different anatomical locations and underlying etiologies, combined with its relative rarity, complicates the identification and validation of reliable prognostic markers for predicting treatment efficacy. While ALBI and PALBI grades have demonstrated prognostic value in hepatocellular carcinoma, their utility in cholangio-carcinoma remains inadequately explored. This study aimed to evaluate these liver function-based scoring systems as potential prognostic markers across all CCA subtypes. Our analysis revealed that ALBI grade serves as a significant independent predictor of survival outcomes, while PALBI grade did not show independent prognostic significance. These findings suggest that ALBI grade may serve as a valuable tool for risk stratification and treatment planning in cholangiocarcinoma patients.

In this retrospective study, the median age was 64 years, parallel to the literature (11). Although CCA is typically 1.2-1.5 times more common in men, our study revealed a male-to-female ratio of 1:1.24 (14). This difference might be due to geographical variations or unique demographic traits of our study group. In the literature, iCCA is the least common subtype, with a prevalence of only 10%. iCCA has been more frequently linked to underlying conditions like liver cirrhosis, PSC, and NAFLD (15). Tumor location may have prognostic significance. In our study, survival outcomes were better in dCCA, followed by pCCA, and lowest in iCCA, similar to Hang et al. (16). Survival outcomes can vary depending on stage, resectability at diagnosis, and tumor burden. Our findings were in line with literature regarding longer OS in early stage and R0 resected CCA patients (17).

As CCA typically remains asymptomatic in its early stages, most of the patients were diagnosed at an advanced stage. In our cohort, 41 patients at early stage reflected this, whereas 135 patients were at advanced stage. Additionally, most patients had ‘de novo’ metastasis (18). As surgery is currently the only curative treatment, it is unsurprising that 42.9% of advanced-stage patients were operated, besides the operation of all early-stage patients. The R0 resection rate is reported as 30-60%, depending on the tumor location and surgical challenges at advanced stage CCA (6). In our study, the R0 resection rate was 66% for patients with advanced-stage CCA, probably related to the experienced surgical oncology team of our institution. Achievement of R0 resection is difficult due to the potential microscopic spread of the disease beyond the surgical margins (19). Despite R0 resection, even with adjuvant treatment, most of the patients tend to relapse, probably due to aggressive tumor biology in CCA.

Younger (<64 years old) patients with CCA have better OS in the literature (20). In our study, older (>64 years old) patients had better OS in univariate analysis. However, this significance was not maintained in multivariate Cox regression analysis, likely due to the limited sample size and the influence of confounding variables when adjusted for other prognostic factors. Higher rate of de novo metastasis in younger patients might have contributed to this outcome, since the patients with de novo metastasis had worse OS outcome in the whole population (Table IV). Although we could not show a relationship between sex and survival outcomes, a higher mortality rate was indicated in male patients in the literature (21).

As previously noted, inflammatory markers may carry prognostic value. In our cohort, the majority of patients were categorized as ALBI grade 2 and PALBI grade 3. Liver dysfunction often contributes to the disease course, leading to thrombocytopenia that worsens ALBI and PALBI grades, as in our retrospective analysis. Though the analysis of inflammatory indices as possible prognostic factors for the survival of early-stage patients was encouraging, the small sample size (n=41) prevented us from conducting detailed subgroup analyses and achieving statistically significant results for these parameters. Nonetheless, ALBI and PALBI grades were significant prognostic factors for DFS following R0 resection. Similar outcomes were reported for HCC in the literature (22). Additionally, the prognostic value of ALBI/PALBI grades may vary according to tumor localization, with potential differences in survival prediction across different cholangiocarcinoma subtypes. The patients with iCCA and higher ALBI grade following resection were shown to have higher mortality rates (23). However, ALBI/PALBI grades were not independent prognostic factors for PFS in early-stage patients who experienced relapse after first-line treatment, nor in patients with advanced disease. As tumors progress and become metastatic, factors such as increased tumor burden and the presence of more resistant clones may overshadow and diminish the prognostic impact of liver function-based scoring systems like ALBI/PALBI on survival outcomes (24).

In multivariate analysis, only ALBI grade and disease stage at diagnosis were significant prognostic factors for OS. Although the literature has limited data on this topic, most studies have focused on iCCA and ALBI grade (25, 26). However, our study evaluated not only ALBI grade but also PALBI grade in CCA, regardless of specific tumor localization (i.e., iCCA, eCCA). Our results showed that ALBI and not PALBI grade was as independent predictor of OS in patients with CCA.

This study has several limitations that should be acknowledged. The retrospective design inherently carries the risk of selection bias and incomplete data collection. Although we analyzed 184 patients, ALBI and PALBI scores could only be calculated for 147 (79.9%) and 118 (64.1%) patients, respectively, due to missing laboratory parameters, which may have influenced our results. As a single-center study, our findings may not be generalizable to other populations or healthcare settings. Furthermore, the relatively small sample size, particularly for early-stage patients (n=41), limited our ability to perform robust subgroup analyses based on individual disease stages (stage 1, 2, 3, and 4 separately), age groups, systemic chemotherapy protocols, performance status, CA 19-9 levels, and adjuvant treatment status. We also acknowledge that we did not evaluate underlying etiologic factors such as hepatitis, primary sclerosing cholangitis, or non-alcoholic fatty liver disease, which may independently influence prognosis in cholangiocarcinoma patients. Furthermore, we did not perform comparative analyses between ALBI/PALBI grades and other established liver function assessment models such as Child-Pugh classification or Model for End-Stage Liver Disease (MELD) score, which could have strengthened the clinical relevance of our findings and provided better benchmarking for prognostic performance. Future multicenter studies with larger patient populations are needed to confirm the clinical utility of ALBI and PALBI grades across diverse cholangiocarcinoma populations.

Conclusion

ALBI and PALBI scores emerge as practical prognostic indicators in CCA patients, with lower scoring categories demonstrating a clear association with prolonged survival durations. Notably, the ALBI score was identified as an independent predictor of overall survival alongside tumor stage. These accessible and cost-effective biomarkers hold promise for enhancing treatment planning and guiding therapeutic decisions in daily clinical practice. However, further clinical trials with larger patient cohorts and more robust data are needed to validate these outcomes for the prognostic value of ALBI and PALBI in this context.

Footnotes

  • Authors’ Contributions

    EA: Conceptualization, Patient Recruitment and Screening, Study Design, Writing and Editing, Critical Review. FY: Conceptualization, Literature Review, Patient Recruitment and Screening. AT: Conceptualization, Study Design, Supervision. ÖA: Study Design, Supervision, Critical Review. MD: Study Design, Supervision, Critical Review. All Authors have read and approved the final version of the manuscript.

  • Conflicts of Interest

    The Authors state that there are no conflicts of interest related to this publication.

  • Artificial Intelligence (AI) Disclosure

    During the preparation of this manuscript, a large language model (Claude Sonnet 4) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning–based image enhancement tools.

  • Received May 3, 2025.
  • Revision received June 22, 2025.
  • Accepted June 26, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Albumin-bilirubin (ALBI) and Platelet-ALBI (PALBI) Grades: Novel Prognostic Factors for Cholangiocellular Carcinoma
ERGİN AYDEMİR, FUNDA YILMAZ, ALPER TÜRKEL, ÖZTÜRK ATEŞ, MUTLU DOĞAN
In Vivo Sep 2025, 39 (5) 2976-2985; DOI: 10.21873/invivo.14098
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