Introduction

Cholangiocarcinoma (CCA) accounts for about 3% of all gastrointestinal cancers, and intrahepatic CCA is the second most common primary malignant liver tumour after hepatocellular carcinoma (HCC) [1–4]. Cholangiocarcinoma comproses a heterogeneous group of neoplasms arising from biliary epithelium or periductal glands, divided into intrahepatic, perihilar, and extrahepatic subtypes depending on their anatomical localisation [1, 5]. Perihilar CCA constitutes the largest part (50–60%) of biliary cancers, followed by extrahepatic (20–30%) and intrahepatic tumours (10–20%) [1–3]. Except for the above-mentioned location, specific variants of CCA are gallbladder cancer (gCA) and carcinoma of the papilla of Vater (pVCA).

The epidemiological account of CCA is complicated by the fact that most cancer registries combine CCA with other hepatobiliary malignancies [6, 7]. The average age of CCA patients is 70 years, and the male-to-female sex ratio is 1.2–1.5 [8, 9]. Over the last decades, the incidence and mortality rates of CCA have increased worldwide; however, estimates vary greatly by geographical region. In Western European countries CCA incidence ranges 0.3–6.0 cases per 100,000 inhabitants [1, 10]. Due to its early asymptomatic and aggressive growth, CCA is usually diagnosed in advanced stages, resulting in very limited therapeutic options [10, 11].

Gallbladder cancer represents almost 50% of all biliary cancers [12, 13]. Late clinical presentation and unfavourable anatomic site determine poor prognosis [12]. Ampullary cancer accounts only 0.2% of gastrointestinal cancers [14, 15]. Early detection of papillary tumour at the adenoma stage is associated with good prognosis [16, 17].

The neutrophil percentage-to-albumin ratio (NPAR) is a cost-effective, readily available biomarker of systemic inflammation used to assess cardiovascular disease prognosis, acute kidney injury, liver disease prognosis, and cancer prognosis. The neutro- phil percentage-to-albumin ratio uses neutrophil counts and albumin values. A similar biomarker, the neutrophil-to-lymphocyte ratio (NLR), is an indicator of acute and chronic inflammation (cardiac ischaemia, shock, cancers, liver fibrosis), using two values – neutrophil and lymphocyte counts – which are easily obtained from routine blood tests [18–23].

The purpose of this study was to observe and evaluate the role of new, readily available markers NPAR and NLR in adults patients with CCA, especially with administration any cancer-specific therapy, including chemotherapy and mortality.

Material and methods

Patients

In retrospective, single-centre study patients with CCA hospitalised in the gastroenterology unit of third degree of reference, specialised in endoscopic treatment of cholestatic jaundice, from July 2018 to June 2023, were analysed according to final clinical diagnosis. Only adult patients (104) with histologically confirmed biliary cancer (several CCA subtypes) were enrolled in the study. The exclusion criteria were as follows: other neoplasms, concurrent extrabiliary neoplasm, acute and chronic circulatory failure, kidney failure, acute surgical problem, and pregnancy. Clinical and demographic data derived from medical documentation were collected.

The patients were allocated into one of three groups: without jaundice and strictures of bile ducts and not demanding decompressing of bile duct (I), with strictures, jaundice, and demanding decompressing procedures internal or external (II), and with strictures, jaundice, fever, and demanding decompressing procedures (installing introducing prothesis or external drainage) (III).

The three groups mentioned above consisted of patients with the following final histopathological diagnosis: intrahepatic cholangiocarcinoma (iCCA), perihilar biliary cancer (pCCA), extrahepatic cholangiocarcinoma (eCCA), gCA, and pVCA. Patients with iCCA (66.7%) and gCA (33.3%) were in group I. Group II consisted of patients with pCCA (27.1%), eCCA (29.2%), gCA (10.4%), and pVCA (33.3%). Group III consisted of patients with pCCA (25%), eCCA (25%), gCA (28.2%), and pVCA (21.8%). The patient follow-up was completed three years after histopathological diagnosis.

Data collection

Data derived from the hospital electronic records included medical interview, physical examination, laboratory results, reports of pharmacological or endoscopic therapy, and decisions of local Oncology Councils on further management. The severity of pain assessment ranged from 0 (no pain) to 10 (strong pain) according to the numerical ratio scale (NRS). The general physical condition and quality of life was assessed by the Zubrod scale [24] modified in 1982 by the Eastern Cooperative Oncology Group (ECOG).

The neutrophil percentage-to-albumin ratio was calculated using the same blood sample and the following formula: neutrophil percentage (in total white blood count)  100/albumin (g/dl). The neutrophil- to-lymphocyte ratio was determined as a quotient of the total absolute neutrophil count and the total absolute lymphocyte count.

Imaging data (ultrasound, computed tomography, magnetic resonance, endoscopic retrograde cholangiopancreatography – ERCP) included the anatomical site of cancer, size of the tumour, presence of ascites, infiltration of large vessels, and the presence of liver or peritoneal metastases. The perihilar CCA was specified by Bismuth-Corlette classification [25]. Histological reports provided information on cancer grading, infiltration, invasion of lymph nodes, and metastases.

Statistical analysis

Baseline demographics and risk factors were summarised using descriptive statistics. The qualitative variables were presented as n (%). For variables showing normal distribution, the means and standard deviations were calculated, and for variables deviating from normal distribution, the median values were chosen. The distribution of quantitative variables was tested using the Shapiro-Wilk test. One-way ANOVA (one-way analysis of variance) was applied to check the differences between means of the studied groups. In the case of variables that did not meet the required assumptions, the Kruskal-Wallis one-way ANOVA was used. The area under the curve was used to compare treatments. Kaplan-Meier curves show the probability of survival in the study groups.

The p level less than 0.05 was considered statistically significant. All statistical analyses were performed with TIBCO Software Inc. (2017) Statistica (data analysis software system), version 13 (http://statistica.io).

Results

General characteristics of patients

The characteristics of 104 patients aged 36–89 years (mean 68.8 ±10.8 years) enrolled to the study are shown in Table 1.

The most common symptoms in group I were pain (58.3%) and loss of weight (58.3%). Patients in this group were without jaundice or fever. The mean pain measured by the NRS score was 4.0 ±2.8, and the mean loss of weight was 9.0 ±6.4 kg per 6 months. The most common symptom in group II was jaundice (79.2%). Pain was observed in 47.9% of patients and loss of weight in 45.8%. Patients in this group were without fever. Mean pain measured by the NRS score was 5.1 ±2.3, and mean loss of weight was 8.9 ±4.2 kg per 6 months. In group III the most common symptoms were jaundice (100.0%) and fever (100.0%). Pain was observed in 39.5% of patients and loss of weight in 50.0%. Mean pain measured by the NRS score was 3.8 ±2.1, and the mean loss of weight was 11.7 ±9.3 kg per 6 months. No patient showed signs of circulatory or respiratory failure during hospitalisation.

Comorbidities and oncological history

The main comorbidities are presented in Table 2.

Laboratory data

The basic laboratory data of the study groups of patients with biliary cancer are presented in Table 3. In group I the value of NPAR was higher than in group II – 29.0 ±27.9 and 23.3 ±9.4, respectively. In group III this value was the highest, at 35.4 ±23.5. Results of NPAR in median are presented in Figure 1. A statistically significant difference of NPAR was observed in the study groups (p = 0.03).

The indicator NLR was higher in group I than in group II (6.5 ±8.4 and 5.2 ±5.5, respectively), and in group III it was the highest, at 11.4 ±13.2. Median values of NLR are presented in Figure 2. No significant difference in NLR was observed in the study groups (p = 0.22).

Advancement of neoplastic disease, choice of treatment, and survival time

Invasion of hepatic hilar or periportal lymph nodes was found in 79.1% of patients of group I. Meta- stases to peritoneum were reported in 16.6% of patients. Palliative care was offered to 50.0% of patients, and 50.0% of them were treated with chemotherapy. No patients underwent resection. 58.3% of patients died before the end of observation, and the mean survival time in this group was 3.2 ±1.7 months.

Hepatic hilar lymph nodes were affected in 50.0% of patients in group II. Metastases to peritoneum were found in 8.3% of cases. According to the Bismuth- Corlette classification, 7 patients were staged as I, 3 patients as II, 1 patient as IIIa, 2 patients as IIIb, and 4 patients as IV. In all patients ERCP was performed, with successful biliary stenting in 95.8% of cases, and percutaneous drainage was done in 2 patients. Only 6.3% of patients were eligible for radiotherapy, surgical resection was done in 16.6% of patients, 27.1% were treated with chemotherapy, and only palliative care was applied in 50.0% of patients. Similarly to group I, in group II the majority of patients (58.3%) died before the end of observation, and the mean survival time was 5.1 ±2.7 months.

Hepatic hilar lymph nodes were affected in 65.6% of patients in group III. Metastases to peritoneum were found in 9.4% of cases. According to the Bismuth- Corlette classification, 2 patients were staged as I, 1 patient as II, 2 patients as IIIa, 1 patient as IIIb, and 2 patients as IV. In all patients ERCP was performed, with successful biliary stenting in 90.6% of cases, and percutaneous drainage was done in 3 patients. Only 6.3% of patients were eligible for radiotherapy, surgical resection was done in 9.4% of patients, 12.5% were treated with chemotherapy, and only palliative care was applied in 71.9% of patients. The majority of patients (81.3%) died before the end of observation, and the mean survival time was 4.5 ±3.1 months.

A comparison of survival times in the study groups is presented by Kaplan-Meier curves (Figure 3). The survival probability at 12 months in group I was 38.0%, and in group II and III it was 31.4% and 14.4%, respectively (p = 0.09). The difference between group II and III was statistically significant (p = 0.03).

The comparison of sensitivity and specificity of NLR and NPAR between any cancer treatment vs. only palliative care is presented as a receiver operator characteristic graph. A non-significant tendency for chance of treatment other than palliative (p = 0.08) was observed with a cut-off point of 7.079 (Figure 4). Above this point patients were classified only for palliative care. It is not statistical importance of NPAR marker – the cut-off point was 23.527 (Figure 5).

Discussion

This study analysed the significance of NPAR and NLR markers in patients with CCA.

Statistically significant differences in NPAR values ​​were observed between the study groups (p = 0.03). The highest values ​​of this indicator were observed in group III, in patients with jaundice and fever, which may indicate an advanced form of the disease and a stronger inflammatory response. The increased NPAR level results from both components: an increased percentage of neutrophils (p < 0.05 between in study groups), which are markers of inflammation, and a reduced level of albumin (p < 0.001 between study groups), which indicates the body’s poor state. Previous studies confirm that high NPAR values ​​may be associated with a worse prognosis in neoplastic diseases, especially in digestive system cancers [26, 27].

The stricture of bile ducts with jaundice, high intraductal pressure, and stasis may have importance in the development of inflammation.

The neutrophil-to-lymphocyte ratio marker was also used to assess prognosis in other cancers [28, 29]. Although NLR had the highest value in group III, it did not reach statistical difference compared to other groups (p = 0.22). This suggests that although NLR reflects inflammation and immunosuppression, its reflection of the course of the disease was less pronounced in the analysed groups of patients (statistically significant increased percentage of neutrophils and non-significant increased percentage of lymphocytes – components of NLR). Nevertheless, numerous previous studies suggest that high NLR is a negative prognostic factor in many cancers, indicating a weakened immune response of the organism and a higher risk of disease progression [30].

In the studied group of patients with CCA, high NPAR values ​​correlated with reduced albumin levels, which may indicate advanced cancer stage, cachexia, and malnutrition. Patients with the highest NPAR values ​​also had the highest C-reactive protein (CRP) levels, confirming the strong association of this indicator with the inflammatory response (cholangitis). Similar relationships were observed in studies on other gastrointestinal cancers, where high CRP and low albumin levels were independent predictors of poorer prognosis [31, 32].

A similar mechanism can be observed in relation to the NLR marker, the increased value of which indicates the predominance of the inflammatory response over the lymphocytic immune response. There is evidence in the literature that a high NLR is associated with a worse prognosis in patients with hepatobiliary cancer, which suggests that it may be a useful clinical tool [33]. However, in the studied group of patients, these differences did not reach statistical significance, which may be related to the limited sample size or the heterogeneity of the studied groups.

The survival analysis showed that patients in group III, in whom the NPAR and NLR values ​​were the highest, had the highest mortality – 81.3% of them died before the end of the observation period, and the mean survival time was 4.5 ±3.1 months. In the remaining groups (I and II) the mortality rate was similar – about 58%, but lower than in group III. These results confirm that higher values ​​of inflammatory markers may be associated with a more aggressive course of the disease and limited therapeutic options. The relatively short survival time of patients from group III was due to the advanced stage of neoplasm disease and the resulting observation of small group of patients during the assumed period. Short survival time was also seen in group I (patients without jaundice). This group consisted of patients with iCCA and gCA – cancers with worse prognosis than the other CCA. However, 12-month survival in group I was higher (38%) than in the other groups.

It is worth noting that in group III specific oncologic treatment was frequently not applied, but palliative care was used (71.9%), while in groups I and II specific and systemic treatment, including chemotherapy, was more frequent. Patients in group III were generally in worse condition, with higher results in ECOG. The general condition in patients with cholangitis had not improved or the bilirubin level had not reached a satisfactory level over a longer period. Therefore, specialist oncological treatment was postponed or disqualified by decision of the Oncology Council. This suggests that patients with high NPAR and NLR values above > 7.08 are in a worse general condition and are less likely to qualify for causal therapy. More of them have symptomatic and hospice treatment.

Overweight and obesity are also worldwide clinical problems. In group I more patients had high body mass index – p < 0.05. This group consisted mainly of patients with iCCA. Overweight and obesity are risk factors of iCCA [34].

The obtained results are consistent with previous reports on the role of inflammatory markers in gastrointestinal cancers. Studies on HCC and pancreatic cancer have shown that high NPAR and NLR are correlated with more advanced disease and poorer survival [35, 36]. Similar relationships have also been observed in other cancers, such as gastric and colon cancer [37, 38]. However, studies on their role in CCA are limited, and the available literature is ambiguous. Some studies suggest that NPAR may be a better marker than NLR, because it takes into account both the inflammatory process and the patient’s nutritional status, which are of significant prognostic importance. The results of this study support this hypothesis, indicating significant differences in NPAR values ​​between groups but no significant differences in NLR.

Due to its asymptomatic, aggressive early and fast growth, the prognosis of CCA is still poor, resulting in very limited therapeutic options [39].

Actually, for diagnostic methods detecting early stages neoplasm, certain early symptoms and simple, cost-effective, not time-consuming prognostic and predictive markers are needed. We observed that the simple and easily markable indicators NPAR and NLR could initially be used in this regard.

Despite the important observations, this study has some limitations. First, it was a retrospective analysis, which limits the ability to fully control for confounding variables, including jeopardised analyses due to lack of stratification according to advancement of cancer and imprecise criteria of denying chemotherapy. The sample size was relatively small, which could have contributed to the lack of statistical significance in the case of NLR. Due to the groups including others types of cancers, heterogeneity in cancer type could have affected survival time and treatment methods. The influence of other factors, such as genetic mutations, which may have prognostic significance in CCA, was not analysed. However, the study seems be valuable due to practical and clinical aspects.

Conclusions

Patients with CCA and high NPAR values are in worse general condition and have higher mortality rates. High NLR values are related with less chance of receiving any cancer-specific therapy. These patients more often require palliative care. Markers may be helpful to assess the patient’s chances for oncological treatment. The neutrophil percentage-to-albumin ratio may be more useful than NLR because it takes into account both the inflammation and nutritional status of the patient. Neutrophil percentage-to-albumin ratio and NLR are the examples of new, simple markers that reflect advanced stage of the disease. Both markers require special attention and further clinical research in larger groups, also with other designs, and with analysis of the impact of other prognostic factors.

Disclosures

1. Institutional review board statement: Not applicable.

2. Assistance with the article: None.

3. Financial support and sponsorship: None.

4. Conflicts of interest: None.

References