
==== Front
Dig Surg
Dig Surg
DSU
DSU
Digestive Surgery
0253-4886
1421-9883
S. Karger AG Basel, Switzerland

38981458
540181
10.1159/000540181
00000
Research Article
Lymphocyte-to-Monocyte Ratio Predicts Survival for Intraductal Papillary Mucinous Neoplasm with Associated Invasive Carcinoma of the Pancreas: Results from a High-Volume Center
LMR Predicts Prognosis for IPMN-INV
2747282
Cui Ming a
2747283
Hu Ya a
2747284
Zheng Bang b
2747285
Chen Tianqi c
2747286
Dai Menghua a
2747287
Guo Junchao a
2747288
Zhang Taiping a
2747289
Yu Jun d e
2747290
Liao Quan a
2747291
Zhao Yupei a
a Department of General Surgery, Key Laboratory of Research in Pancreatic Tumor, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
b Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
c Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Disease, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
d Department of Medicine, Oncology, and Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
e Pancreas Center of Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
Correspondence to: Quan Liao, liaoq@pumch.cn or Yupei Zhao, zhao8028@263.net
Ming Cui and Ya Hu contributed equally to this work.

18 7 2024
9 2024
41 3 111121
20 12 2023
26 6 2024
2024
© 2024 The Author(s). Published by S. Karger AG, Basel
2024
https://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.
Abstract

Introduction

Intraductal papillary mucinous neoplasm (IPMN) is an important precursor lesion of pancreatic cancer. Systemic inflammatory parameters are widely used in the prognosis prediction of cancer; however, their prognostic implications in IPMN with associated invasive carcinoma (IPMN-INV) are unclear. This study aims to explore the prognostic value of systemic inflammatory parameters in patients with IPMN-INV.

Methods

From 2015 to 2021, patients with pathologically confirmed IPMN who underwent surgical resection at Peking Union Medical College Hospital were enrolled. The clinical, radiological, and pathological data of the enrolled patients were collected and analyzed. Preoperative systemic inflammatory parameters were calculated as previously reported.

Results

Eighty-six patients with IPMN-INV met the inclusion criteria. The lymphocyte-to-monocyte ratio (LMR) was the only systemic inflammatory parameter independently associated with the cancer-specific survival (CSS). An LMR higher than 3.5 was significantly associated with a favorable CSS in univariate (hazard ratio [HR] 0.305, p = 0.003) and multivariate analyses (HR 0.221, p = 0.001). Other independently prognostic factors included the presence of clinical symptoms, cyst size, N stage, and tumor differentiation. Additionally, a model including LMR was established for the prognosis prediction of IPMN-INV and had a C-index of 0.809.

Conclusions

Preoperative LMR could serve as a feasible prognostic biomarker for IPMN-INV. A decreased LMR (cutoff value of 3.5) was an independent predictor of poor survival for IPMN-INV.

Keywords

Intraductal papillary mucinous neoplasm
Systemic inflammatory parameter
Lymphocyte-to-monocyte ratio
Survival
Prognosis
This work was supported by grants National High Level Hospital Clinical Research Funding (2022-PUMCH-D-001), Milstein Medical Asian American Partnership (MMAAP) foundation, National Natural Science Foundation of China (82302076), and Beijing Natural Science Foundation (7224340).
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pmcIntroduction

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has been identified as a radiographically identifiable precursor lesion of pancreatic cancer and the most common pancreatic cystic lesion [1]. Due to the increasing application of cross-sectional imaging, the incidence of IPMN continues to rise [2]. It is estimated that nearly 10% of pancreatic surgeries are performed for IPMN [3]. IPMN has a wide spectrum of malignant potential ranging from low-grade IPMN (LG-IPMN) to high-grade IPMN (HG-IPMN) to IPMN with associated invasive carcinoma (IPMN-INV), in which IPMN-INV is considered a subtype of pancreatic cancer and accounts for more than 20% of pancreatic cancer cases [4, 5].

Compared to noninvasive IPMNs (LG-IPMN and HG-IPMN) with 5-year survival rates of nearly 100%, IPMN-INV confers a significantly worse prognosis [6–8]. Due to the lack of prognostic studies, previously identified prognostic predictors of IPMN-INV were mainly restricted to traditional clinicopathological factors such as serum CA19-9 level, tumor stage, and pathological grade [9–11]. Therefore, more prognostic markers need to be explored to improve the prognostic assessment of IPMN-INV and deepen the understanding of this distinct subtype of pancreatic cancer.

Tumor-associated inflammation and immune escape play important roles in carcinogenesis [12]. Recently, several systemic inflammatory parameters, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammation response index (SIRI), systemic immune inflammation index (SII), and advanced lung cancer inflammation index (ALI), were found to be closely associated with the progression and prognosis of pancreatic cancer [13–18]. These newly proposed markers possess obvious advantages since they are calculated based on routinely checked laboratory data and can be achieved preoperatively. However, whether these systemic inflammatory parameters could serve as prognostic markers for IPMN-INV is unclear.

In the present study, we aimed to evaluate the prognostic significance of systemic inflammatory parameters in IPMN-INV, explore independent prognostic predictors for IPMN-INV, and further establish a comprehensive model for the prognosis prediction of IPMN-INV after surgical resection. To the best of our knowledge, this study is the first to comprehensively evaluate the prognostic value of systemic inflammatory parameters in patients with IPMN-INV.

Methods

Patients

From January 2015 to December 2021, 231 consecutive patients who underwent surgical resection of IPMN at Peking Union Medical College Hospital were identified using a prospectively maintained database. For the purpose of the study, the database was analyzed retrospectively and supplemented by a review of electronic medical records. The exclusion criteria included pancreatic ductal adenocarcinoma concomitant with IPMN, combination with other malignancies, infection or inflammation leading to abnormal preoperative routine blood counts, receiving neoadjuvant therapy, undergoing initial surgery at other hospitals, perioperative death, other causes of death, and lost to follow-up. The pathological diagnosis of IPMN was reviewed by pathologists and classified into three grades: LG-IPMN, HG-IPMN, and IPMN-INV, based on the Baltimore consensus [4]. The study was conducted in accordance with the Declaration of Helsinki and approved by the medical Ethics Committee at Peking Union Medical College Hospital (Approval No. JS-1893). All individual participants included in the study provided written informed consent for the subsequent use of their clinical data.

Data Collection

Demographic information and clinical and pathological data were collected and analyzed. Radiological features, such as IPMN type, lesion location, cyst size measured by its largest axis, main pancreatic duct (MPD) diameter, presence of solid portion, and distal atrophy of pancreas presented on CT or MRI at preoperative diagnosis, were collected and analyzed. The following laboratory data were routinely collected on any day from 1 week to 1 day before surgery: serum CA19-9 level, serum CEA level, absolute neutrophil count, absolute lymphocyte count, absolute platelet count, absolute monocyte count, and serum albumin level. Systemic inflammatory parameters, including NLR, PLR, LMR, SIRI, SII, and ALI, were calculated as previously reported (Table 1). The tumor staging of IPMN-INV was based on the eighth edition of the American Joint Committee on Cancer (AJCC) manual [19]. T stage was defined specifically as the solid component of the cystic tumor, excluding the cystic portion. The primary outcome of the study was cancer-specific survival (CSS), which was calculated from the date of pancreatic surgery to the date of death due to the relapse of IPMN-INV or the last follow-up. The secondary outcome was disease-free survival (DFS), which was calculated from the date of pancreatic surgery to the date of relapse of IPMN, death due to IPMN, or the last follow-up. Follow-up was conducted through electronic medical records and telephone interviews, persisting until loss of follow-up, death, or the last follow-up date of December 31, 2022. The minimum duration of follow-up was 3 months.

Table 1. Calculation formulas for systemic inflammatory parameters

Parameters	Calculation	
NLR	Neutrophil count	/	Lymphocyte count	
PLR	Platelet count	/	Lymphocyte count	
LMR	Lymphocyte count	/	Monocyte count	
SIRI	Neutrophil count × monocyte count	/	Lymphocyte count	
SII	Neutrophil count × platelet count	/	Lymphocyte count	
ALI	BMI, kg/m2 × albumin, g/dL	/	NLR	
BMI, body mass index; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; LMR, lymphocyte-to-monocyte ratio; SIRI, systemic inflammation response index; SII, systemic immune inflammation index; ALI, advanced lung cancer inflammation index.

Statistical Analysis

Statistical analyses were performed using IBM SPSS 26.0, GraphPad Prism 9, and R 4.2.2. Student’s t test was used to compare continuous variables, and the χ2 test was used to compare categorical variables. The optimal cutoff values of continuous variables for survival analysis were identified by X-tile plots using X-tile 3.6.1 (Yale University School of Medicine) based on the association with patients’ CSS [20]. Kaplan-Meier survival curves were generated and compared using the log-rank test. A Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Variables with significant prognostic value in univariate analysis were selected for inclusion in multivariate analysis. A multivariable Cox proportional hazards model with backward selection based on the likelihood ratio test was used to obtain independent predictors and generate a prediction model. The discrimination and calibration properties of the established prediction model were assessed with Harrell’s C-index, the area under the receiver operating characteristic curve (AUC), and calibration plots. The final prediction model was visually presented using a nomogram. A two-sided p < 0.05 was considered statistically significant.

Results

Patient Characteristics

From 2015 January to 2021 December, 231 patients pathologically diagnosed with IPMN underwent resection. After excluding patients meeting the exclusion criteria, 86 patients diagnosed with IPMN-INV were included in the study (shown in Fig. 1). The patients’ clinicopathologic characteristics are shown in Table 2. Overall, the mean age of the patients was 61.9 years, with an equal sex ratio. Fifty-seven patients (66.3%) had clinical symptoms, including 8 patients (9.3%) presenting jaundice and 16 patients experiencing pancreatitis (18.6%). The most common type of IPMN-INV was the mixed type (36.0%), followed by the main duct type (34.9%) and the branch duct type (29.1%). The lesions were most frequently located in the pancreatic head (57.0%). The mean size of cysts was 35 mm, and the mean diameter of MPDs was 8.5 mm. The solid portion was present in 77.9% of patients. Distal atrophy of the pancreas was found in 48.8% of patients. Serum CA19-9 and CEA were abnormally elevated in 37.2% and 14% of patients, respectively. Six preoperative systemic inflammatory parameters, including NLR, PLR, LMR, SIRI, SII, and ALI, were calculated as previously reported. During a median follow-up time of 25.2 months (3.4–91.0 months), the 1-, 3-, and 5-year CSS rates were 88.4%, 62.9%, and 46.4%, respectively.

Fig. 1. Flowchart of the patient cohort included in the present study.

Table 2. Clinicopathological characteristics of patients with INV-IPMN

Variables	n = 86	
Age (mean±SD), years	61.9±11.4	
Sex, n (%)	
 Male	43 (50.0)	
 Female	43 (50.0)	
BMI (mean±SD), kg/cm2	22.7±3.3	
Clinical, n (%)	
 Symptoms (general)	57 (66.3)	
 Jaundice	8 (9.3)	
 Pancreatitis	16 (18.6)	
 Preoperative diabetes	31 (36.0)	
 Weight loss	45 (52.3)	
IPMN type, n (%)	
 MD	30 (34.9)	
 BD	25 (29.1)	
 MT	31 (36.0)	
Lesion location, n (%)	
 Head	49 (57.0)	
 Body and tail	32 (37.2)	
 Diffuse	5 (5.8)	
Cyst size (mean±SD), mm	35.0±20.2	
MPD diameter (mean±SD), mm	8.5±5.5	
Presence of solid portion, n (%)	67 (77.9)	
Distal atrophy, n (%)	42 (48.8)	
CA19-9 (normal range, ≤34 U/mL), n (%)	
 ≤34 U/mL	54 (62.8)	
 >34 U/mL	32 (37.2)	
CEAa (normal range, ≤5 ng/mL), n (%)	
 ≤5 ng/mL	70 (81.4)	
 >5 ng/mL	12 (14.0)	
Systemic inflammatory parameter	
 NLR (mean±SD)	2.7±1.8	
 PLR (mean±SD)	151.6±85.8	
 LMR (mean±SD)	5.3±1.8	
 SIRI (mean±SD)	0.9±0.8 × 109/L	
 SII (mean±SD)	581.5±469.2 × 109/L	
 ALI (mean±SD)	46.4±23.7	
T stage, n (%)	
 T1	26 (30.2)	
 T2	44 (51.2)	
 T3	15 (17.4)	
 T4	1 (1.2)	
N stage, n (%)	
 N0	58 (67.4)	
 N1	17 (19.8)	
 N2	11 (12.8)	
TNM stage, n (%)	
 IA	18 (20.9)	
 IB	28 (32.6)	
 IIA	11 (12.8)	
 IIB	17 (19.8)	
 III	12 (14.0)	
Tumor differentiation, n (%)	
 Well	34 (39.5)	
 Moderate	32 (37.2)	
 Poor	20 (23.3)	
Adjuvant chemotherapy, n (%)	
 Yes	63 (73.3)	
 No	23 (26.7)	
SD, standard deviation; BMI, body mass index; IPMN, intraductal papillary mucinous neoplasm; MD, main duct; BD, branch duct; MT, mixed type; MPD, main pancreatic duct; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; LMR, lymphocyte-to-monocyte ratio; SIRI, systemic inflammation response index; SII, systemic immune inflammation index; ALI, advanced lung cancer inflammation index.

aThe CEA values of 4 patients were unavailable.

Prognostic Value of Systemic Inflammatory Parameters for IPMN-INV

The cutoff values for the systemic inflammatory parameters were determined using X-tile software as follows: NLR (3.7), PLR (96.6), LMR (3.5), SIRI (1 × 109/L), SII (650.7 × 109/L), and ALI (25.3). Survival curves of CSS and DFS were statistically analyzed by the log-rank test and are shown in Figure 2 and online supplementary S1 (for all online suppl. material, see https://doi.org/10.1159/000540181). LMR was found to be significantly associated with favorable CSS and DFS in patients with IPMN-INV (median CSS: 67.6 months [LMR high] vs. 23.5 months [LMR low], p = 0.002; median DFS: 56.4 months [LMR high] vs. 14.2 months [LMR low], p = 0.004). In addition, SIRI was found to be significantly associated with unfavorable CSS and DFS in patients with IPMN-INV (median CSS: 23.5 months [SIRI high] vs. 67.6 months [SIRI low], p = 0.012; median DFS: 20.2 months [SIRI high] vs. 58.1 months [SIRI low], p = 0.020). Other systemic inflammatory parameters, including NLR, PLR, SII, and ALI, were not significantly associated with CSS or DFS in patients with IPMN-INV. In addition, we compared six systemic inflammatory parameters among IPMN cohorts with different pathological grades (LG-IPMN, HG-IPMN, and IPMN-INV) and found that NLR and ALI exhibited significant variations between different groups (shown in online suppl. Fig. S2, S3).

Fig. 2. Prognostic value of neutrophil-to-lymphocyte ratio (NLR) (a), platelet-to-lymphocyte ratio (PLR) (b), lymphocyte-to-monocyte ratio (LMR) (c), systemic inflammation response index (SIRI) (d), systemic immune inflammation index (SII) (e), and advanced lung cancer inflammation index (ALI) (f) for the CSS of patients with IPMN-INV shown by Kaplan-Meier curves.

Univariate and Multivariate Analyses of Prognostic Factors for IPMN-INV

We further incorporated clinicopathological factors into the prognostic analysis. The cutoff values of body mass index, cyst size, and MPD diameter were determined by X-tile software. In univariate analysis, weight loss, cyst size, serum CA19-9 level, LMR, SIRI, N stage, and tumor differentiation were found to be significantly associated with the CSS and DFS of patients with IPMN-INV. The presence of clinical symptoms was significantly associated with an unfavorable CSS but not with DFS (Table 3). Other clinicopathological factors, such as age, sex, body mass index, presence of jaundice, pancreatitis, preoperative diabetes, IPMN type, lesion location, MPD diameter, presence of solid portion, distal atrophy of the pancreas, serum CEA level, NLR, PLR, SII, ALI, T stage, and receiving adjuvant chemotherapy, were not associated with the CSS or DFS of patients with IPMN-INV. In multivariate analysis, LMR was the only systemic inflammatory parameter independently associated with the CSS of patients with IPMN-INV (HR 0.221, 95% CI: 0.090–0.544, p = 0.001). Other prognostic factors independently associated with CSS included the presence of clinical symptoms (HR 3.263, 95% CI: 1.266–8.411, p = 0.014), cyst size (HR 0.215, 95% CI: 0.079–0.584, p = 0.003), N stage (HR 2.448, 95% CI: 1.196–5.009, p = 0.014), and tumor differentiation (poor vs. well: HR 8.038, 95% CI: 2.936–22.006, p = 0.001; moderate vs. well: HR 3.577, 95% CI: 1.288–9.930, p = 0.014). In addition, weight loss, SIRI, N stage, and tumor differentiation were independently associated with the DFS of patients with IPMN-INV (Table 4). For the aforementioned multivariate model, a collinearity diagnostic analysis was conducted, revealing no significant collinearity.

Table 3. Univariate analysis for CSS and DFS of patients with INV-IPMN

Variables	CSS	DFS	
p value	HR	95% CI	p value	HR	95% CI	
Age (>65 years vs. ≤65 years)	0.582	0.826	0.418–1.631	0.814	0.930	0.506–1.706	
Sex (male vs. female)	0.213	0.808	0.577–1.130	0.354	0.868	0.644–1.170	
BMI (>25.9 kg/cm2 vs. ≤25.9 kg/cm2)	0.188	1.749	0.760–4.021	0.280	1.567	0.694–3.542	
Symptoms (yes vs. no)	0.023	2.615	1.144–5.975	0.150	1.630	0.838–3.171	
Jaundice (yes vs. no)	0.305	1.724	0.609–4.885	0.478	1.452	0.518–4.070	
Pancreatitis (yes vs. no)	0.393	1.410	0.641–3.103	0.868	1.068	0.495–2.302	
Preoperative diabetes (yes vs. no)	0.961	1.018	0.500–2.073	0.734	1.114	0.597–2.082	
Weight loss (yes vs. no)	0.018	2.308	1.151–4.626	0.010	2.249	1.212–4.172	
IPMN type (BD)	0.860	Ref.		0.650	Ref.		
 MD	0.589	0.793	0.342–1.840	0.363	0.709	0.337–1.490	
 MT	0.861	0.933	0.431–2.022	0.543	0.803	0.397–1.626	
Lesion location (head)	0.474	Ref.		0.508	Ref.		
 Body and tail	0.287	0.682	0.337–1.380	0.421	0.774	0.415–1.445	
 Diffuse	0.441	0.563	0.131–2.424	0.336	0.492	0.116–2.084	
Cyst size (>39 mm vs. ≤39 mm)	0.024	0.384	0.167–0.884	0.019	0.412	0.196–0.865	
MPD diameter (>5.8 mm vs. ≤5.8 mm)	0.246	0.675	0.347–1.311	0.237	0.693	0.377–1.272	
Presence of solid portion (yes vs. no)	0.779	1.126	0.491–2.586	0.724	0.880	0.432–1.790	
Distal atrophy (yes vs. no)	0.260	0.684	0.353–1.324	0.720	0.897	0.495–1.626	
CA19-9 (>34 U/mL vs. ≤34 U/mL)	0.005	3.247	1.420–7.422	0.003	3.016	1.448–6.281	
CEA (>5 ng/mL vs. ≤5 ng/mL)	0.687	1.199	0.496–2.902	0.323	1.453	0.693–3.050	
NLR (>3.7 vs. ≤3.7)	0.101	1.997	0.874–4.565	0.165	1.723	0.799–3.718	
PLR (>96.6 vs. ≤96.6)	0.249	1.675	0.696–4.031	0.345	1.447	0.672–3.115	
LMR (>3.5 vs. ≤3.5)	0.003	0.305	0.140–0.664	0.006	0.359	0.174–0.742	
SIRI (>1 × 109/L vs. ≤1 × 109/L)	0.015	2.380	1.182–4.791	0.023	2.098	1.107–3.978	
SII (>650.7 × 109/L vs. ≤650.7 × 109/L)	0.075	1.905	0.936–3.877	0.096	1.735	0.907–3.319	
ALI (>25.3 vs. ≤25.3)	0.168	0.539	0.224–1.298	0.269	0.633	0.282–1.423	
T stage (T3-4 vs. T1-2)	0.644	0.822	0.359–1.884	0.797	0.908	0.436–1.893	
N stage (N1-2 vs. N0)	0.001	3.859	1.971–7.557	0.001	2.859	1.561–5.238	
Tumor differentiation (well)	0.001	Ref.		0.001	Ref.		
 Moderate	0.052	2.507	0.993–6.331	0.003	3.482	1.517–7.990	
 Poor	0.001	8.935	3.580–22.298	0.001	8.868	3.725–21.115	
Adjuvant chemotherapy (yes vs. no)	0.953	1.023	0.480–2.178	0.371	1.397	0.671–2.907	
HR, hazard ratio; CI, confidence interval; BMI, body mass index; IPMN, intraductal papillary mucinous neoplasm; BD, branch duct; MD, main duct; MT, mixed type; MPD, main pancreatic duct; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; LMR, lymphocyte-to-monocyte ratio; SIRI, systemic inflammation response index; SII, systemic immune inflammation index; ALI, advanced lung cancer inflammation index.

Table 4. Multivariate analysis for CSS and DFS of patients with INV-IPMN

Variables	CSS	DFS	
p value	HR	95% CI	p value	HR	95% CI	
Symptoms (yes vs. no)	0.014	3.263	1.266–8.411	–			
Weight loss (yes vs. no)	–			0.001	3.566	1.709–7.440	
Cyst size (>39 mm vs. ≤39 mm)	0.003	0.215	0.079–0.584	–			
CA19-9 (>34 U/mL vs. ≤34 U/mL)	–			–			
LMR (>3.5 vs. ≤3.5)	0.001	0.221	0.090–0.544	–			
SIRI (>1 × 109/L vs. ≤1 × 109/L)	–			0.001	3.282	1.623–6.638	
N stage (N1-2 vs. N0)	0.014	2.448	1.196–5.009	0.003	2.637	1.397–4.979	
Tumor differentiation (well)	0.001	Ref.		0.001			
 Moderate	0.014	3.577	1.288–9.930	0.001	6.206	2.442–15.773	
 Poor	0.001	8.038	2.936–22.006	0.001	7.712	3.121–19.055	
HR, hazard ratio; CI, confidence interval; CA19-9, carbohydrate antigen 19-9; LMR, lymphocyte-to-monocyte ratio; SIRI, systemic inflammation response index.

Establishment of a Prediction Model for the Survival of IPMN-INV

A prediction model for CSS was established with five independent prognostic factors, including the presence of clinical symptoms, cyst size, LMR, N stage, and tumor differentiation, which were derived from multivariable Cox models (Table 4). The discriminative accuracy as measured by Harrell’s C-index was 0.809 for the prediction model. Specifically, the AUCs for 1-year and 2-year CSS outcomes both showed good discriminative accuracy (1 year: AUC 0.813, 95% CI: 0.672–0.955; 2 years: AUC 0.883, 95% CI: 0.803–0.962) (shown in Fig. 3a, b). According to the calibration plots, the predicted 1-year and 2-year cancer-specific mortality risks conformed well to the observed cancer-specific mortality risks (shown in Fig. 3c, d). These results suggest optimal model performance when using information from these five factors. Furthermore, a nomogram predicting the CSS of patients with IPMN-INV was constructed based on the above five factors and age (shown in Fig. 3e). With this 6-predictor nomogram, the CSS of a given patient diagnosed with IPMN-INV could be visually predicted.

Fig. 3. Prognosis prediction of IPMN-INV. a, b ROC curves of the prediction model for 1-year (a) and 2-year (b) CSS. c, d Calibration plots of the prediction model for 1-year (c) and 2-year (d) CSS rates. e Nomogram for the CSS prediction of IPMN-INV.

Discussion

Tumor-promoting inflammation and dysfunctional immune responses are considered hallmarks of cancer [21]. Systemic inflammatory parameters are used as indicators for host systemic inflammation and are mainly based on routinely collected laboratory data. Studies have shown that systemic inflammatory parameters are closely correlated with the level of tumor-infiltrating immune cells and thus could reflect the status of the local tumor immune microenvironment [22, 23]. More importantly, several systemic inflammatory parameters have been proven to serve as strong predictors of prognosis in patients with cancer [14, 24, 25]. Considering their accessibility and convenience, systemic inflammatory parameters show promise in clinical applications as prognostic markers.

Previous studies have shown that inflammation is abnormally activated in IPMN-INV, and systemic inflammatory parameters could serve as diagnostic markers to distinguish IPMN-INV from noninvasive IPMN [26–29]. However, whether systemic inflammatory parameters could serve as independent prognostic markers for IPMN-INV is unknown. The present study is the first to identify LMR as an independent prognostic predictor for IPMN-INV. With a cutoff value of 3.5, the median CSS of patients with a high LMR was nearly 6 years, while that of patients with a low LMR was less than 2 years. Since the value of LMR can be obtained preoperatively, it can be applied as a promising predictor to evaluate the survival benefit of surgery and improve surgical decision-making for patients with IPMN-INV, especially for those with an advanced age or morbidities who are high-risk populations for surgery. The LMR is calculated based on the combination of the peripheral blood lymphocyte count and monocyte count. Decreased lymphocyte counts and increased monocyte counts are common phenomena in patients with cancer and are associated with an unfavorable prognosis [30]. Mechanistically, lymphocytes are the main subgroup of immune cells mediating the antitumor immune response, whereas monocytes are the precursor cells for tumor-associated macrophages that promote tumor immune escape in the tumor microenvironment [31]. The LMR can reflect the status of the antitumor immune response and is thus closely associated with the prognosis of patients with cancer. Other systemic inflammatory parameters, such as NLR, PLR, SIRI, SII, and ALI, were also examined in the present study. However, they were not independent prognostic predictors for IPMN-INV, as shown by multivariate analysis. This suggests that LMR may be a more sensitive indicator of the body’s antitumor immune response to IPMN-INV. Further experimental studies could provide valuable insights into the underlying mechanisms of lymphocyte and monocyte interactions within the tumor microenvironment of IPMN.

Based on the present study, we identified several independent prognostic predictors other than LMR for IPMN-INV, including the presence of clinical symptoms, cyst size, N stage, and tumor differentiation. The presence of clinical symptoms may reflect the invasiveness of the tumor and is thus associated with an unfavorable prognosis. The significant association between cyst size and the prognosis of IPMN-INV was first proposed by our study. Interestingly, the size of the pancreatic cyst is a protective factor for the CSS of IPMN-INV patients. It should be noted that cyst size is different from tumor size or T stage of the tumor; instead, it mainly reflects the mucin secretion ability of the tumor. Mass spectrometry-based proteomic studies showed that the molecular pathways related to pancreatic secretion were significantly downregulated with the malignant progression of IPMN [32]. Thus, we speculate that cyst size, representing mucin secretion ability, may be inversely correlated with the malignant behaviors of tumor cells in IPMN-INV. Pathological features, including N stage and tumor differentiation, were identified as prognostic predictors for IPMN-INV, which conforms with the findings of previous studies [9, 10]. Other radiological features, such as IPMN type, lesion location, MPD diameter, presence of solid portion, or distal atrophy of pancreas, did not present prognostic value for IPMN-INV.

In addition, we established a model to predict the CSS of patients with IPMN-INV after surgical resection. The model demonstrated satisfactory discrimination and calibration. Five independent prognostic factors identified by multivariate analysis and age, as a commonly used demographic factor, were selected to establish a predictive nomogram for survival. As a prognostic tool, the nomogram can predict individualized 1-year and 2-year CSS probabilities for a given IPMN-INV patient with high accuracy. It is expected that this practical nomogram will be prospectively applied and generalized to a broader population of patients with IPMN-INV.

Our study had certain limitations. First, it was a single-center retrospective study, potentially introducing selection bias. Future external validation is imperative to assess its applicability in broader clinical practice. Second, there is a possibility that some late-stage IPMN-INV cases may have been misclassified as conventional pancreatic cancer if the pathological appearances predominantly exhibited invasive cancer without classic IPMN lesions. This misclassification may lead to a more favorable prognosis for IPMN-INV. Moreover, 6 patients were lost to follow-up, likely due to death, which may further skew the prognostic outcomes in a favorable direction. Finally, more studies are warranted to elucidate the relationship and mechanisms underlying the association between LMR and the local tumor immune microenvironment of IPMN-INV.

Conclusion

The present study identified preoperative LMR as a feasible prognostic biomarker for patients with IPMN-INV. A decreased LMR with a cutoff value of 3.5 was an independent predictor for poor CSS in IPMN-INV. Other independently prognostic factors included the presence of clinical symptoms, cyst size, N stage, and tumor differentiation. With the six-predictor nomogram established in the study, the prognosis of IPMN-INV could be accurately predicted.

Statement of Ethics

The study was conducted in accordance with the Declaration of Helsinki and approved by the medical Ethics Committee at Peking Union Medical College Hospital (Approval No. JS-1893). All individual participants included in the study provided written informed consent.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This work was supported by grants National High Level Hospital Clinical Research Funding (2022-PUMCH-D-001), Milstein Medical Asian American Partnership (MMAAP) foundation, National Natural Science Foundation of China (82302076), and Beijing Natural Science Foundation (7224340).

Author Contributions

M.C., Y.H., Q.L., and Y.Z. contributed to the conception and design. T.C., M.D., J.G., T.Z., Q.L., and Y.Z. collected the data. M.C., Y.H., B.Z., and J.Y. analyzed and interpreted the data. M.C. and Y.H. drafted the manuscript. J.Y., Q.L., and Y.Z. revised the manuscript. All authors read and approved the final manuscript.

Data Availability Statement

All data analyzed during this study are included in this article. Further reasonable requests can be directed to the corresponding author.

Supplementary Material
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