A prospective cohort study tracking 164 patients with cholangiocarcinoma at National Cheng Kung University Hospital in Taiwan demonstrated that systemic inflammatory markers and specific therapeutic interventions independently correlate with clinically meaningful depressive symptoms across distinct anatomical cancer classifications. Through repeated-measures assessments evaluated via multivariate generalized linear mixed models, higher circulating concentrations of log-transformed C-reactive protein and the absence of surgical resection were independently associated with depression across the entire cholangiocarcinoma cohort and within the intrahepatic cholangiocarcinoma subgroup. In contrast, among patients diagnosed with extrahepatic cholangiocarcinoma, the receipt of radiation therapy and lower serum albumin concentrations were independently associated with heightened depression risk, whereas C-reactive protein did not demonstrate an independent association in that anatomical subset. Over the longitudinal observation timeframe, the overall prevalence of depression among study participants stood at 19.9 percent at baseline before fluctuating during intermediate evaluations and ultimately decreasing to 10.4 percent at the twelve-month follow-up assessment.
Cholangiocarcinoma represents an aggressive and biologically challenging malignancy that continues to confer an unfavorable prognosis despite ongoing therapeutic advancements across modern oncology. Anatomically, this biliary cancer is classified into intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, which exhibit distinct pathological presentations, clinical behaviors, and therapeutic pathways. Intrahepatic cholangiocarcinoma originates within the intrahepatic biliary ductal network as adenocarcinomas presenting with mass-forming, periductal infiltrative, or intraductal growth morphologies, reaching peak incidence between fifty and sixty years of age and displaying heightened prevalence across East Asia. Conversely, extrahepatic cholangiocarcinoma primarily compromises the epithelial structures of the liver hilum, frequently producing biliary obstruction, obstructive jaundice, and secondary inflammatory complications. Global epidemiological trends reveal rising incidence rates, with population mortality ranging from 1 to 2 per 100,000 individuals across most geographic areas to nearly 100 per 100,000 individuals within endemic regions. Because initial disease phases generally produce no distinctive symptoms, late-stage diagnoses predominate, contributing to therapeutic failure, considerable caregiver burden, and liver and biliary tract cancers ranking as the third leading cause of cancer-related mortality globally.
The substantial physical burden of cholangiocarcinoma is compounded by severe psychological challenges, with oncological guidelines documenting that approximately 25 percent of cancer patients experience depressive disorders, starkly contrasting with the 4 percent prevalence recognized in the general public. While certain malignancy cohorts experience progressive declines in depressive symptomatology over their treatment course, phase-specific longitudinal evidence examining cholangiocarcinoma has remained scarce, with prior data suggesting psychological distress remains stable or demonstrates only modest early improvement while correlating with reduced survival duration, decreased treatment adherence, and degraded quality of life. To clarify the biological mechanisms driving these mood disorders, the investigators focused on peripheral inflammatory signaling, which has been implicated in cancer advancement and neuropsychiatric pathology. The study concentrated on four accessible inflammatory biomarkers obtainable from regular complete blood counts and metabolic panels without specialized processing or additional economic expense: C-reactive protein as an indicator of acute-phase inflammatory activity, the neutrophil-to-lymphocyte ratio capturing innate and adaptive immune activation, the platelet-to-lymphocyte ratio signaling inflammatory thrombocytosis, and serum albumin functioning as a negative acute-phase reactant.
Conducted under Institutional Review Board approval protocol B-ER-110-060 at National Cheng Kung University Hospital, the prospective investigation enrolled 164 adult patients aged twenty years or older who had received confirmed diagnoses of cholangiocarcinoma across stages I through IV between May 2021 and September 2024. All participants supplied written informed consent, and exclusion criteria removed individuals unable to furnish informed consent or lacking essential medical records for diagnostic verification. The study cohort comprised 97 patients with intrahepatic cholangiocarcinoma and 67 patients with extrahepatic cholangiocarcinoma, consisting predominantly of elderly men presenting with advanced clinical stages. Within the cohort, systemic chemotherapy served as the primary oncological treatment, whereas surgical resection was performed in only 30 patients, accounting for 18.3 percent of the study population, leaving 81.7 percent in the non-surgical category. Repeated-measures assessments were scheduled at baseline prior to therapeutic initiation and during treatment at two, three, four, six, nine, and twelve months, with 80 participants, representing 48.8 percent of the enrolled cohort, completing the full twelve-month evaluation timeline.
Screening and quantification of depressive symptoms were conducted using the Patient Health Questionnaire-9, a nine-item self-report instrument scoring depressive manifestations from zero for not at all to three for nearly every day, yielding total scores between zero and twenty-seven. The instrument delineates minimal symptoms at zero to four, mild symptoms at five to nine, moderate symptoms at ten to fourteen, moderately severe symptoms at fifteen to nineteen, and severe symptoms at twenty to twenty-seven, with a cutoff score of ten or greater defining clinically significant depression. This established threshold provides a sensitivity of 0.77 and a specificity of 0.94 in oncological screening environments, facilitating identification of patients requiring psychiatric intervention. Concurrent laboratory measures obtained from electronic medical records evaluated serum biomarker parameters, where C-reactive protein concentrations under 10 milligrams per liter represented normal physiological levels and concentrations at or exceeding 10 milligrams per liter denoted active inflammation, while normal serum albumin ranged between 3.5 and 5.0 grams per deciliter. To confirm regression reliability and rule out collinear distortions, variance inflation factor analyses demonstrated values of 2.07 for albumin, 1.97 for log-transformed C-reactive protein, 1.44 for the neutrophil-to-lymphocyte ratio, and 1.18 for the platelet-to-lymphocyte ratio, remaining well below the threshold of ten.
In the statistical analysis protocol, categorical variables were coded numerically, assigning one for male sex and zero for female reference, and one for cancer stage IV versus zero for stages I through III reference, with parallel numerical coding applied to surgical resection, chemotherapy, and radiation therapy. Because C-reactive protein values exhibited a non-normal distribution, natural logarithmic transformation was implemented prior to analytical modeling. Univariate screening evaluated demographic, clinical, and biomarker parameters, advancing variables exhibiting statistical significance at a two-tailed alpha below 0.05 into multivariate generalized linear mixed models using SPSS version 17 software. Tracking across the prospective intervals demonstrated that overall depression prevalence stood at 19.9 percent at baseline, experienced fluctuations over time, and declined to 10.4 percent at twelve months. Patients with extrahepatic cholangiocarcinoma exhibited higher baseline depression rates than intrahepatic cases. Throughout follow-up, circulating C-reactive protein, neutrophil-to-lymphocyte ratios, and platelet-to-lymphocyte ratios varied in parallel with depression rates, whereas serum albumin levels remained comparatively stable, and intrahepatic cases demonstrated greater longitudinal marker fluctuations than extrahepatic cases.
Multivariate generalized linear mixed model outcomes delineated clear subtype-dependent relationships connecting inflammatory markers, clinical interventions, and depressive outcomes. Across the entire cohort of 164 patients, elevated log-transformed C-reactive protein levels and the absence of surgical resection were independently associated with clinically significant depression. Within the intrahepatic cholangiocarcinoma subgroup of 97 patients, these exact factors maintained statistical significance, confirming that higher C-reactive protein concentrations and non-surgical status independently correlated with depressive symptoms. Conversely, analysis of the 67 extrahepatic cholangiocarcinoma patients identified a divergent pattern: receipt of radiation therapy was positively and independently associated with depression, while lower serum albumin concentrations were independently linked to increased depression risk. Crucially, direct comparison between treatment modalities revealed that surgical patients maintained significantly more favorable inflammatory profiles than non-surgical patients across both tumor subtypes, characterized by higher serum albumin and reduced inflammatory markers.
The observed correlation between elevated C-reactive protein and depressive symptoms is supported by documented neurobiological mechanisms. Elevated C-reactive protein reflects increased upstream signaling by interleukin-1, interleukin-6, and tumor necrosis factor-alpha, cytokines that disrupt blood-brain barrier integrity, stimulate microglial activation, and promote neuroinflammation. These inflammatory cytokines activate the kynurenine metabolic pathway through induction of indoleamine 2,3-dioxygenase, depleting tryptophan and reducing central serotonin availability. Furthermore, cytokine activity stimulates cyclooxygenase-2 expression, accelerating prostaglandin synthesis and intensifying central neuroinflammatory cascades. Although the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios showed univariate associations with depression, their lack of persistence after adjusting for C-reactive protein reflects susceptibility to physiological confounders such as age, hydration status, and acute stress. In contrast, serum albumin functions as an antioxidant and tryptophan transporter; chronic inflammation suppresses albumin synthesis and accelerates oxidative degradation, which compromises neurotransmitter production and elevates depression risk in extrahepatic disease.
The distinct effects observed between surgical intervention and radiation therapy highlight complex interactions between oncological treatments and psychological outcomes. Surgical candidates exhibited superior physiological reserve, marked by higher baseline albumin and attenuated inflammation, whereas non-surgical patients carried greater systemic inflammatory burdens that contributed both to surgical ineligibility and heightened affective vulnerability. These findings parallel observations across pancreatic cancer, where pre-existing depression correlates with lower resection rates, breast cancer, where reconstructive surgery alleviates depressive symptoms, and lung cancer, where surgery demonstrates bidirectional psychological links. In extrahepatic cholangiocarcinoma, radiation therapy was independently linked to increased depression risk, likely reflecting sustained reactive oxygen species generation, cytokine cascades, and treatment distress that further suppress albumin synthesis amid obstructive cholestasis. To address these vulnerabilities, the researchers noted that nutritional optimization and anti-inflammatory strategies, including selective cyclooxygenase-2 inhibitors or corticosteroid regimens, could help mitigate physical complications and psychological burden.
Several methodological limitations characterize the study. The observational prospective design precludes inferring causal relationships between inflammatory biomarkers, oncological therapies, and depressive outcomes. Somatic items within the Patient Health Questionnaire-9 may overlap with cancer-related physical manifestations, although multivariate adjustments confirmed persistent biomarker associations. In addition, patient attrition reached 51.2 percent over twelve months, and only 18.3 percent of the cohort underwent surgical resection, limiting statistical power. Markedly disparate baseline stage IV proportions between intrahepatic and extrahepatic cases may have further influenced findings, warranting larger prospective trials to confirm these associations.
Subject of Research: Systemic inflammatory markers and treatment-related factors associated with depression in cholangiocarcinoma
Article Title: Inflammation-associated depression in cholangiocarcinoma: impacts of surgical resection and radiotherapy
Article References: Sung, T.-H., Shen, Y.-C., Yen, C.-J., Shan, Y.-S., & Chen, P. S. (2026). Inflammation-associated depression in cholangiocarcinoma: impacts of surgical resection and radiotherapy. BioPsychoSocial Medicine, 20(1), Article 3. https://doi.org/10.1186/s13030-026-00350-6
Image Credits: AI Generated
DOI: 10.1186/s13030-026-00350-6
Keywords: cholangiocarcinoma, systemic inflammation, depression, C-reactive protein, surgical resection, radiotherapy, albumin, psycho-oncology, Inflammation-associated, impacts, surgical, resection
