Pathophysiology of anastomotic stricture following rectal anastomosis: Insights into mechanisms, risk factors, and preventive strategies

Abstract

Anastomotic stricture (AS) remains a significant complication following rectal anastomosis, with an incidence ranging from 5% to 30% depending on surgical technique, patient factors, and postoperative management. This review aims to elucidate the pathophysiology of AS, exploring the underlying mechanisms that contribute to its development, including ischemia, inflammation, fibrosis, and impaired healing. Key risk factors such as low anterior resection, preoperative radiotherapy, and anastomotic leakage are critically analyzed based on recent clinical and experimental evidence. The article synthesizes current insights into the molecular and cellular processes, such as excessive collagen deposition and myofibroblast activation, that drive stricture formation. Furthermore, preventive strategies, including optimized surgical techniques (e.g., tension-free anastomosis), enhanced perioperative care, and emerging therapeutic interventions (e.g., anti-fibrotic agents), are discussed with an emphasis on translating research into clinical practice. By integrating findings from preclinical studies, clinical trials, and meta-analyses, this review highlights gaps in current knowledge and proposes future directions for research, such as the role of personalized medicine and novel biomaterials in reducing AS incidence. This comprehensive analysis underscores the need for a multidisciplinary approach to mitigate this challenging postoperative complication.

Key Words: Anastomotic stricture; Rectal cancer; Fibrosis; Inflammation; Anastomotic leakage; Radiotherapy; Ischemia; Surgical technique

Core Tip: Anastomotic stricture following rectal anastomosis is a multifactorial complication driven by fibrosis, inflammation, anastomotic leakage, radiotherapy, and ischemia. This review highlights the pathophysiological mechanisms, including excessive collagen deposition and transforming growth factor-beta activation, and identifies key risk factors such as neoadjuvant radiotherapy and surgical technique. Preventive strategies, such as preserving blood supply and using standardized stapling techniques, are emphasized to improve patient outcomes and reduce stricture incidence.

INTRODUCTION

Anastomotic stricture (AS), or stenosis, is a significant complication following low anterior resection (LAR) for rectal cancer, with a reported incidence of 3%-20%[1,2]. This condition is characterized by luminal narrowing at the anastomotic site, leading to clinical symptoms such as bowel obstruction, pain, bloating, and impaired quality of life[3]. The development of AS is multifactorial, involving a complex interplay of fibrosis, inflammation, anastomotic leakage, radiotherapy, ischemia, and surgical techniques[1,2]. Understanding the pathophysiology of this complication is crucial for developing effective preventive strategies and improving patient outcomes. This Minireview explores the mechanisms underlying AS, identifies key risk factors, and discusses preventive approaches.

PATHOPHYSIOLOGICAL MECHANISMS

Fibrosis and scar formation

Fibrosis is the cornerstone of AS pathogenesis, driven by an imbalance between extracellular matrix (ECM) deposition and degradation. Following rectal anastomosis, the healing process involves the activation of fibroblasts, which differentiate into myofibroblasts under the influence of transforming growth factor-beta (TGF-β), a key fibrogenic cytokine[4]. TGF-β activates the Smad signaling pathway, upregulating the expression of collagen types I and III and other ECM components, such as fibronectin and laminin[4]. This leads to excessive ECM deposition, which, if uncontrolled, forms a dense, collagen-rich scar tissue that narrows the lumen[5,6]. The imbalance between matrix metalloproteinases and their inhibitors (tissue inhibitors of metalloproteinases) further exacerbates this process by impairing ECM turnover, resulting in a fibrotic, rigid anastomotic segment[7]. Studies have shown that in patients with a history of neoadjuvant therapy, the anastomotic site exhibits increased expression of collagen and reduced elastic fibers, leading to a loss of bowel wall compliance and subsequent stricture formation[8]. Additionally, the activation of the platelet-derived growth factor (PDGF) pathway contributes to fibroblast proliferation and migration, further amplifying the fibrotic response[9]. The chronicity of this fibrotic process is often perpetuated by hypoxia and oxidative stress at the anastomotic site, which sustain TGF-β signaling and collagen deposition[10]. Fibrosis, therefore, is the primary pathophysiological driver of AS, with its severity directly correlating with the degree of luminal narrowing[5].

Role of inflammation

Inflammation is a critical mediator in the pathogenesis of AS, acting as both a necessary component of healing and a driver of pathological fibrosis when dysregulated. The early postoperative inflammatory response involves the infiltration of neutrophils and macrophages, which release pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α)[4]. These cytokines stimulate fibroblast proliferation and collagen synthesis, initiating tissue repair[4]. However, chronic or excessive inflammation—often triggered by infection, anastomotic leakage, or radiation injury—leads to a sustained activation of myofibroblasts and overproduction of ECM components[7]. This chronic inflammatory state is characterized by the infiltration of lymphocytes and plasma cells, which perpetuate the release of fibrogenic mediators like TGF-β and connective tissue growth factor (CTGF)[11]. Histopathological analyses of ASs often reveal dense inflammatory infiltrates that drive fibrotic foci, with increased expression of nuclear factor-kappa B (NF-κB), a transcription factor that amplifies the inflammatory response[12]. Moreover, the presence of oxidative stress, marked by elevated levels of reactive oxygen species (ROS), further exacerbates inflammation by activating redox-sensitive pathways such as the mitogen-activated protein kinase (MAPK) pathway, which promotes fibroblast activation and collagen deposition[13]. Factors that prolong inflammation, such as radiation-induced tissue damage or localized infection, accelerate the injury-inflammation-fibrosis cycle, significantly contributing to stricture formation[7].

Anastomotic leakage

Anastomotic leakage is a pivotal risk factor for stricture development, acting as a trigger for both inflammation and fibrosis. Leakage occurs when the anastomotic suture line fails, allowing bowel contents to escape into the surrounding tissues, leading to localized infection, abscess formation, and a robust inflammatory response[2]. This inflammatory cascade involves the release of IL-1, IL-6, and TNF-α, which recruit immune cells and activate fibroblasts, promoting granulation tissue formation and excessive fibrosis[4]. The resulting fibrotic response creates a dense scar ring that narrows the lumen[2]. Studies have shown that anastomotic leakage significantly increases the risk of stricture, with one analysis reporting a 3.7-fold increased risk in patients with leakage[2]. The inflammatory environment created by leakage also upregulates TGF-β and CTGF, perpetuating the fibrotic process[11]. Furthermore, leakage-induced hypoxia at the anastomotic site activates hypoxia-inducible factor-1α (HIF-1α), which enhances the expression of vascular endothelial growth factor (VEGF) and other pro-fibrotic factors, further contributing to scar formation[14]. A post-hoc analysis of a randomized trial confirmed that clinical anastomotic leakage independently contributes to stricture development[15]. Thus, anastomotic leakage plays a dual role in stricture pathogenesis: It initiates inflammation and promotes scar formation, both of which contribute to luminal narrowing.

Impact of radiotherapy

Neoadjuvant radiotherapy, commonly used in rectal cancer treatment, significantly contributes to AS by inducing both acute and chronic tissue damage. Radiation causes microvascular injury, including endarteritis obliterans, which impairs blood flow to the anastomotic site and leads to tissue hypoxia[8]. This hypoxic environment triggers the release of ROS and pro-inflammatory cytokines, resulting in mucosal edema, ulceration, and chronic inflammation[8]. Over time, these subacute changes progress to fibrosis as fibroblasts are activated in response to tissue injury[8]. Radiation also upregulates TGF-β and PDGF, which promote collagen deposition and ECM remodeling[9]. Additionally, radiation-induced DNA damage in endothelial cells and fibroblasts leads to the activation of the p53 pathway, which further enhances fibrogenesis by upregulating pro-fibrotic genes[16]. Clinical studies have shown that preoperative radiotherapy increases the risk of AS, with a meta-analysis reporting a 2.3-fold higher likelihood in irradiated patients compared to non-irradiated patients[2]. Multivariate analyses indicate that radiotherapy contributes to stricture risk both directly, through its fibrogenic effects, and indirectly, by increasing the incidence of anastomotic leakage[15]. The chronic nature of radiation-induced damage, often manifesting months after treatment, underscores its role as a significant contributor to stricture pathophysiology.

Ischemic factors

Adequate blood supply is essential for anastomotic healing, and ischemia is a key contributor to stricture formation. Insufficient perfusion at the anastomotic site, often resulting from high ligation of the inferior mesenteric artery or excessive tension due to inadequate mobilization of the colon, leads to tissue hypoxia and necrosis[17]. Hypoxia activates HIF-1α, which upregulates pro-inflammatory and pro-fibrotic pathways, including the TGF-β/Smad signaling cascade and VEGF expression[14]. This results in impaired healing, with the anastomotic site undergoing a thin, fibrotic repair process that is prone to contraction[6]. Subclinical leaks may also develop in ischemic conditions, further promoting inflammation and fibrosis[6]. The ischemic environment also induces oxidative stress, with elevated ROS levels activating the MAPK and NF-κB pathways, which enhance fibroblast activation and collagen deposition[13]. A case series demonstrated that early subclinical ischemia following LAR can lead to long-segment fibrotic strictures months later[6]. Ischemia alone can initiate a cascade of inflammation and secondary fibrosis, significantly contributing to stricture formation[7]. The preservation of blood supply, such as maintaining the left colic artery when feasible, is therefore critical to preventing ischemic complications and subsequent stricture development[17].

Risk factors and surgical techniques

Several surgical and patient-related factors influence the risk of AS. The level of anastomosis is a critical determinant: Very low (rectoanal or intersphincteric) anastomoses are more prone to stricture than more proximal ones due to the narrower distal segment, limited vascularity, and frequent use of hand-sewn techniques[2]. Double-stapling techniques using mechanical staplers provide a standardized suture line and better luminal calibration, reducing stricture risk compared to hand-sewn anastomoses[2]. However, the impact of stapler diameter remains debated; a recent retrospective study found no significant difference in stricture incidence between 29 mm and 31 mm staplers[18]. Surgeon experience, technical errors (e.g., incomplete stapler closure or mucosal folds), and the presence of a diverting stoma also influence stricture risk. A meta-analysis reported a threefold increased risk of stricture in patients with a diverting stoma, likely due to the lack of luminal passage and the higher baseline risk in these patients[2]. Systemic factors such as male gender, advanced age, obesity, smoking, diabetes, and high body mass index further exacerbate stricture risk by impairing wound healing[2] (Table 1).

Table 1 Key pathophysiological mechanisms, risk factors, and preventive strategies for anastomotic stricture following rectal anastomosis.

Category	Details
Pathophysiological mechanisms
Fibrosis[4,5,7,9,11]	Excessive collagen deposition (types I and III) driven by TGF-β/Smad signaling, myofibroblast activation, and imbalance of MMPs/TIMPs. Leads to dense scar tissue and luminal narrowing
Inflammation[4,7,12,13]	Dysregulated inflammatory response with IL-1, IL-6, TNF-α, and NF-κB activation. Chronic inflammation promotes fibroblast proliferation and ECM overproduction
Anastomotic leakage[2,4,11,14,15]	Leakage triggers robust inflammation (IL-1, IL-6, TNF-α) and fibrosis via TGF-β/CTGF. Hypoxia activates HIF-1α, enhancing pro-fibrotic pathways
Radiotherapy[2,8,9,15,16]	Radiation-induced microvascular injury (endarteritis obliterans) causes hypoxia, ROS production, and TGF-β/PDGF upregulation, leading to chronic fibrosis
Ischemia[6,7,13,14,17]	Poor blood supply (e.g., due to high ligation of inferior mesenteric artery) causes hypoxia, activating HIF-1α and MAPK/NF-κB pathways, resulting in fibrotic repair
Risk factors
Surgical factors[2,18]	Low anastomosis level (rectoanal/intersphincteric), hand-sewn vs double-stapling techniques, diverting stoma, technical errors (e.g., incomplete stapler closure)
Patient-related factors[2]	Male gender, advanced age, obesity, smoking, diabetes, high BMI impair wound healing and increase stricture risk
Preventive strategies
Surgical techniques[2,17,18]	Preserve left colic artery, ensure tension-free anastomosis, use double-stapling techniques with appropriate stapler size to minimize ischemia and technical errors
Perioperative care[2]	Early detection of leakage, smoking cessation, glycemic control, weight management to optimize wound healing
Emerging therapies[5]	Anti-fibrotic agents (e.g., TGF-β inhibitors), novel biomaterials to modulate fibrotic response and enhance healing

TGF-β: Transforming growth factor-beta; MMPs: Matrix metalloproteinases; TIMPs: Tissue inhibitors of metalloproteinases; IL-1: Interleukin-1; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-alpha; NF-κB: Nuclear factor-kappa B; CTGF: Connective tissue growth factor; HIF-1α: Hypoxia-inducible factor-1α; PDGF: Platelet-derived growth factor; ROS: Reactive oxygen species; ECM: Extracellular matrix; BMI: Body mass index.

PREVENTIVE STRATEGIES

Preventing AS requires a multifaceted approach targeting the underlying mechanisms and risk factors. Optimizing surgical techniques is paramount: Ensuring adequate blood supply by preserving the left colic artery when possible and avoiding excessive tension at the anastomotic site can reduce ischemic complications[17]. The use of double-stapling techniques with appropriately sized staplers can minimize technical errors and ensure a uniform anastomosis[2]. Minimizing the use of neoadjuvant radiotherapy, or tailoring its application to high-risk cases, may reduce radiation-induced fibrosis and leakage[15]. Early detection and management of anastomotic leakage through vigilant postoperative monitoring can mitigate the inflammatory and fibrotic cascades[2]. Additionally, addressing patient-related risk factors—such as smoking cessation, glycemic control in diabetics, and weight management—can improve wound healing and reduce stricture risk[2]. Future research should explore novel therapeutic strategies, such as anti-fibrotic agents, to modulate the fibrotic response in anastomotic healing[5].

CONCLUSION

AS following rectal anastomosis is a complex, multifactorial complication driven by fibrosis, inflammation, anastomotic leakage, radiotherapy, and ischemia. Excessive collagen deposition, mediated by TGF-β, PDGF, and chronic inflammation, forms the pathological basis of luminal narrowing. Risk factors such as neoadjuvant radiotherapy, low anastomotic level, and poor surgical technique further increase stricture incidence. Preventive strategies, including optimized surgical techniques, preservation of blood supply, and careful use of radiotherapy, are essential to reducing stricture risk and improving patient outcomes. Future research should focus on novel therapeutic approaches to modulate fibrotic and inflammatory responses in anastomotic healing, as well as exploring personalized medicine and novel biomaterials to further mitigate AS incidence.