Long-chain fatty acyl CoA synthetase 4 expression in pancreatic cancer: a marker for malignant lesions and prognostic indicator for recurrence

Abstract

Background: Long-chain fatty acyl CoA synthetase 4 (ACSL4) is crucial for lipid metabolism, primarily catalyzing the formation of 12-20 carbon chain fatty acids. ACSL4 is upregulated in various cancers and linked to aggressive behavior and poor survival. A bioinformatics study showing ACSL4 upregulation in pancreatic cancer. However, utility for actual pathological diagnosis and clinical significance in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) are unexplored. This study aimed to investigate ACSL4 expression in PDAC and IPMN, and evaluate its clinical implications.

Methods: We examined ACSL4 expression using immunohistochemistry in 165 patients with PDAC and IPMN. Differences in ACSL4 expression between malignant and benign lesions were evaluated using the Pearson χ2 test. The association between ACSL4 expression, pathological parameters, and survival was assessed through Kaplan-Meier and Cox regression analyses in 96 patients with invasive cancer.

Results: Compared to normal pancreatic ducts, low-grade pancreatic intraepithelial neoplasm, and intraductal papillary mucinous adenoma (IPMA) (3.3%, 3.4%, and 2.7%, respectively), ACSL4 expression was significantly higher in invasive PDAC, noninvasive intraductal papillary mucinous carcinoma (IPMC), and invasive IPMC (77%, 86.7%, and 93.9%, respectively). In invasive cancers, low ACSL4 expression was associated with a higher frequency of lymphovascular invasion and recurrence and shorter disease-free survival (P = 0.006). Additionally, low ACSL4 expression was an independent prognostic factor for shorter disease-free survival in multivariable Cox regression analysis (HR = 2.409, 95% CI: 1.121-5.180, P = 0.024).

Conclusion: ACSL4 expression helps differentiate cancerous from precancerous lesions in pancreatic cancer, but low expression is linked to a higher frequency of lymphovascular invasion and shorter disease-free survival in invasive cases. Due to the limited sample size and broad confidence intervals, the findings of this study should be interpreted with caution and require validation in larger, independent cohorts.

Keywords: ACSL4; Diagnosis; Intraductal papillary mucinous neoplasm; Pancreatic ductal adenocarcinoma; Prognosis.

Fig. 1

Consort diagram of patients in this study showing analysis of ACSL4 immunohistochemistry differences between malignant, benign, and normal lesions

Fig. 2

ACSL4 expression via immunohistochemical staining (Magnification, x400. Normal pancreatic duct (A) and IPMA (B) show negative cytoplasmic ACSL4 expression (Grade 1). Low-grade PanIN (C) shows weak expression in 51–100% or strong expression in 0–50% of the cytoplasm (Grade 2). IPMC (D) and PDAC (E) show strong expression in 51–100% of the cytoplasm (Grade 3)

Fig. 3

ACSL4 expression in normal pancreatic ducts, low-grade PanIN, IPMA, invasive PDAC, noninvasive IPMC, and invasive IPMC. ACSL4 expression was significantly higher in malignant lesions compared to benign lesions (A). ACSL4 expression was significantly higher in invasive PDAC than in low-grade PanIN and normal pancreatic duct (P < 0.001, respectively). ACSL4 expression was significantly higher in invasive IPMC than in IPMA (P < 0.001). ACSL4 expression was significantly higher in noninvasive IPMC than in IPMA (P < 0.001). ACSL4 expression was higher in cases of well or moderately differentiated tumors compared to those of poorly differentiated tumors (B, P = 0.024)

Fig. 4

In this slide, both low-grade PanIN, and invasive ductal carcinoma are present in the context of pancreatic ductal carcinoma (A, H&E, magnification x100; B, ACSL4, magnification x100). The low-grade PanIN exhibits ACSL4 low expression, graded as 1 or 2 (C, H&E, magnification x400; D, ACSL4, magnification x400). In contrast, invasive ductal carcinoma exhibit high ACSL4 expression (E, H&E, magnification x400; F, ACSL4, magnification x400). Even when low-grade PanIN and invasive PDAC were found in the same specimen, staining differences were typically clear, with low-grade PanIN being negative and invasive PDAC being positive

Fig. 5

Kaplan-Meier curves showing overall survival (A) and disease-free survival (B) stratified by ACSL4 expression in patients with invasive PDAC/IPMC. The red lines represent low ACSL4 expression, the blue lines represent high ACSL4 expression. Low ACSL4 expression is associated with shorter disease-free survival (P = 0.006)