Abstract

BACKGROUND
The combined index of hemoglobin, albumin, lymphocyte, and platelet (HALP) can reflect systemic inflammation and nutritional status simultaneously, with some evidence revealing its prognostic value for some tumors. However, the effect of HALP on recurrence-free survival (RFS) in patients with gastrointestinal stromal tumors (GISTs) has not been reported.
AIM
To investigate the prognostic value of HALP in GIST patients.
METHODS
Data from 591 untreated patients who underwent R0 resection for primary and localized GISTs at West China Hospital between December 2008 and December 2016 were included. Clinicopathological data, preoperative albumin, blood routine information, postoperative treatment, and recurrence status were recorded. To eliminate baseline inequivalence, the propensity scores matching (PSM) method was introduced. Ultimately, the relationship between RFS and preoperative HALP was investigated.
RESULTS
The optimal cutoff value for HALP was determined to be 31.5 by X-tile analysis. HALP was significantly associated with tumor site, tumor size, mitosis, Ki67, National Institutes of Health (NIH) risk category, and adjuvant therapy (all P < 0.001). Before PSM, GIST patients with an increased HALP had a significantly poor RFS (P < 0.001), and low HALP was an independent risk factor for poor RFS (hazard ratio (HR): 0.506, 95% confidence interval (95%CI): 0.291-0.879, P = 0.016). In NIH high-risk GIST patients, GIST patients with low HALP had a worse RFS than patients with high HALP (P < 0.05). After PSM, 458 GIST patients were identified; those with an increased HALP still had significantly poor RFS after PSM (P < 0.001) and low HALP was still an independent risk factor for poor RFS (HR: 0.558, 95%CI: 0.319-0.976, P = 0.041).
CONCLUSION
HALP was significantly correlated with postoperative pathology and postoperative treatment. Furthermore, HALP showed a strong ability to predict RFS in GIST patients who underwent radical resection.
Key Words: Gastrointestinal stromal tumors, GISTs; Nutrition assessment; Immuno-inflammatory-based prognostic scores; Prognosis; Propensity score Core Tip: The combined index of hemoglobin, albumin, lymphocyte, and platelet (HALP) can reflect systemic inflammation and nutritional status simultaneously. We demonstrated that HALP also has a statistically significant correlation with postoperative pathology and postoperative treatment in patients with gastrointestinal stromal tumors (GISTs). Furthermore, we revealed that a low level of HALP was an independent risk factor for poor recurrence-free survival in GIST patients following radical resection before and after propensity scores matching.

INTRODUCTION

Gastrointestinal stromal tumors (GISTs), a rare type of tumor, are the most frequent mesenchymal tumors arising from the gastrointestinal tract[1]. GISTs may occur anywhere in the digestive tract and even occasionally outside the gastrointestinal tract, with the stomach accounting for 60% and the small intestine 30% of all GISTs[2]. The morphology, immunohistochemistry, and molecular markers are helpful to the diagnosis of GISTs. Surgical resection is the standard treatment for resectable GISTs[3]. Nowadays, novel small molecular tyrosine kinase inhibitors, such as imatinib and sunitinib, have revolutionized the integrated treatment of GISTs and greatly improved the long-term prognosis of patients[4].
Some GIST-specific parameters based on postoperative pathologies, such as tumor size, primary tumor location, mitotic index, and tumor rupture, have been used to stratify the risk of recurrence for GISTs[2, 5-7]. Meanwhile, a recent effort has shed light on the role of preoperative cancer-related inflammation and nutrition status in progression of various cancers, such as those of gastric[8], colorectal[9], non-small lung[10], and GIST[11-15]. Several preoperative immuno-inflammatory-based prognostic scores, such as the preoperative neutrophil-to-lymphocyte ratio (NLR), the lymphocyte-to-monocyte ratio (LMR), and the platelet-to-lymphocyte ratio (PLR), reflect the systematic inflammatory response, with some evidence supporting their prognostic ability for GISTs[13-17]. Furthermore, nutritional status, such as measured by the prognostic nutritional index (PNI), has also been shown to play an important role in GIST progression[10, 11].
Recent studies have proposed a new combined index of hemoglobin, albumin, lymphocyte, and platelet (HALP) which can reflect systemic inflammation and nutritional status simultaneously[18]. It has already been reported as related to the prognosis of patients with pancreatic cancer[19], renal cancer[20], gastric cancer[18], prostate cancer[21], bladder cancer[22], esophageal cancer[23], and small cell lung cancer[24]. However, there are no studies on the relationship between HALP and recurrence in GIST patients who undergo radical resection. Therefore, this study aimed to investigate the prognostic value of preoperative HALP in resected GIST patients.

METHOD

Patient population
A flow diagram of the patient selection process is shown in Figure 1. Data from consecutive, previously untreated patients who underwent R0 resection for primary, localized GISTs at West China Hospital between December 2008 and December 2016 were included in this study. Patients who were younger than 18 years in age, without complete preoperative blood routine information or medical history, or with infectious diseases, blood counts with white blood cells (WBCs) > 10 × 109/L, neutrophils > 8 × 109/L, or lymphocytes > 5 × 109/L, other tumors, severe liver, kidney or heart diseases, emergency surgery, or follow-up less than 6 mo were excluded. In total, 591 GIST patients were enrolled for the current analysis.
This study was reviewed and approved by the Ethics Committee of the West China Hospital of Sichuan University (Reference No. 1135(2019)) and adhered to the tenets of the Declaration of Helsinki. All patients provided written informed consent.
 
Definition
Recurrence-free survival (RFS) was defined as the time interval between the time of surgery and the time of the first documented appearance of tumor after complete resection. The HALP, PNI, NLR, PLR, and LMR were calculated using the following formulas: HALP = hemoglobin level (g/L) × albumin level (g/L) × lymphocyte count (/L) / platelet count (/L)[19]; PNI = albumin level (g/L) + 5 × lymphocyte count (n/mm3)[25]; NLR = neutrophil count (n/mm3) / lymphocyte count (n/mm3)[15, 16]; PLR = platelet count (n/mm3) / lymphocyte count (n/mm3)[14]; LMR = lymphocyte count (n/mm3) / monocyte count (n/mm3)[26].
 
Data collection
Clinicopathological data, postoperative treatment, and recurrence status were recorded. The following data of each patient were retrieved from the self-built GISTs database: demographic characteristics, tumor sites, tumor size, mitotic index (mitosis / 50 high-power field or mitosis / 50 mm2), morphology, immunohistochemistry, molecular markers, preoperative hemoglobin, albumin, WBC count, absolute neutrophil count, monocyte count, platelet count, and lymphocyte count. Tumor risk stratification was determined based on the modified National Institutes of Health (NIH) classification[27].
 
Perioperative evaluation and postoperative histopathological diagnosis
For all patients, the laboratory tests were evaluated within 1 wk before operation. Preoperative blood routine and blood biochemical examination were performed by the Laboratory Department of Sichuan University West China Hospital. The parameters included complete blood cell count and serum albumin. Histopathological diagnosis was performed by the Department of Pathology of Sichuan University West China Hospital; the postoperative pathological findings included data on gross appearance, tumor size, tumor site, resection margin status, tumor cell morphology, lymph node metastasis status, and immunohistochemical staining, etc.
 
Follow-up
Abdominal/pelvic computed tomography was performed every 3-6 mo in the first 3 years after operation, and then every 6-12 mo, until 5 years after the operation, and then once a year until recurrence. Recurrence status was ascertained up to December 2020.
 
Statistical analysis
The optimal cutoff values for the HALP, PNI, NLR, PLR, and LMR were determined to be 31.5, 48.6, 2.60, 134.8, and 4.0, respectively, by X-tile analysis[28]. Propensity scores matching (PSM) was performed as 1:1 matching with nearest neighbor matching and a 0.02 caliper based on the patient's age, tumor size, tumor site, mitosis, and adjuvant targeted therapy using nearest neighbor matching with the MatchIt R package (https://cran.r-project.org/web/packages/MatchIt/MatchIt.pdf). The categorical variables are reported as n (%) and quantitative variables are reported as mean ± standard deviation (SD) or median (range). Statistical significance of group comparisons was analyzed via parametric and nonparametric tests for continuous variables and via chi-square analysis or Fisher’s test for categorical variables. Survival curves of the RFS were calculated by the Kaplan-Meier methods and compared by log-rank tests. Hazard ratio (HR) for recurrence was calculated by Cox regression analysis. Sensitivity and specificity of HALP, PNI, NLR, LMR, and PLR were defined using time-dependent receiver operating characteristic (ROC) curves, and areas under the curve (AUCs) were detected utilizing survival ROC R package[29]. All statistical analyses were performed using SPSS Statistics version 21 (SPSS 21.0; IBM Corp., Armonk, NY, United States) and GraphPad Prism version 7.0 (GraphPad Software, La Jolla, CA, United States). Statistical significance was set at P < 0.05 as two-sided.