Beyond local injury: Sarcopenia as a systemic host-related determinant of esophageal stenosis after endoscopic submucosal dissection

Abstract

Esophageal stenosis remains a clinically significant complication after endoscopic submucosal dissection (ESD), traditionally attributed to local factors such as mucosal defect size, circumferential involvement, and postoperative inflammation. However, growing evidence suggests that patient-related systemic conditions may play an underappreciated role in post-ESD healing outcomes. Recent retrospective observational data identifying computed tomography-defined sarcopenia as an independent predictor of esophageal stenosis suggest a challenge to the lesion-centered paradigm that has dominated risk assessment strategies. By integrating sarcopenia into a postoperative risk prediction model, this review highlights the importance of body composition and nutritional reserve in modulating tissue repair and fibrosis following endoscopic intervention. From a gastroenterology perspective, these findings have important clinical implications. They suggest that the risk of post-ESD stenosis may be influenced not only by what is resected, but also by who the patient is at the time of intervention. Early identification of sarcopenia could enable preemptive nutritional optimization, closer surveillance, and individualized preventive strategies. Recognizing sarcopenia as a host-related determinant systemic determinant of endoscopic outcomes may refine peri-procedural risk stratification and represents a step toward more holistic management of patients undergoing therapeutic endoscopy.

Key Words: Sarcopenia; Endoscopic submucosal dissection; Esophageal stenosis; Body composition; Wound healing; Fibrosis; Nutritional status; Risk stratification

Core Tip: Esophageal stenosis after endoscopic submucosal dissection has traditionally been regarded as a consequence of local mucosal injury. Emerging evidence indicates that sarcopenia, a systemic condition reflecting impaired nutritional reserve, inflammation, and reduced regenerative capacity, is independently associated with adverse post-endoscopic submucosal dissection outcomes. Recognizing sarcopenia as a host-related determinant of esophageal healing shifts risk assessment beyond lesion characteristics alone and supports more holistic peri-procedural management strategies.

INTRODUCTION

Endoscopic submucosal dissection (ESD) has become an established curative treatment for early esophageal neoplasia, enabling en bloc resection while preserving organ integrity, and this review specifically focuses on esophageal ESD and post-ESD esophageal stenosis[1-3]. Despite its oncological efficacy, esophageal stenosis remains one of the most clinically significant complications following ESD, often leading to dysphagia, repeated endoscopic dilations, and impaired quality of life[4,5]. Previous studies have consistently attributed post-ESD stenosis to local factors, including circumferential extent of mucosal resection, depth of injury, thermal damage, and postoperative inflammation[6-8].

However, lesion-centered models alone fail to fully explain the substantial inter-individual variability in stenosis risk observed in clinical practice[9]. Patients with comparable mucosal defects often experience markedly different healing trajectories, suggesting that host-related systemic factors, as well as age, comorbidities, and baseline nutritional status, may play an underrecognized role. In parallel, sarcopenia-defined by loss of skeletal muscle mass and quality-has emerged as a powerful prognostic indicator across multiple oncological and surgical settings, including esophageal cancer management[10-12].

Recent retrospective analyses and observational studies reported in the literature have extended the relevance of sarcopenia beyond survival and pulmonary complications, identifying it as an independent predictor of esophageal stenosis after ESD, although the current evidence base remains predominantly retrospective and hypothesis-generating[13,14]. These findings challenge the prevailing paradigm that post-ESD complications, particularly esophageal stenosis after esophageal ESD, are determined primarily by procedural characteristics and highlight the importance of patient body composition and physiological reserve at the time of intervention (Table 1). This review synthesizes current evidence supporting sarcopenia as a systemic and independent host-related factor associated with post-ESD esophageal stenosis, while acknowledging that the available evidence is predominantly retrospective and hypothesis-generating, explores potential biological mechanisms, and discusses its implications for peri-procedural risk stratification and management (Figure 1). However, despite emerging evidence, the role of sarcopenia in post-ESD esophageal stenosis remains controversial, particularly regarding its independence from confounding factors such as age, comorbidity burden, and systemic inflammation.

Figure 1 Sarcopenia as a systemic host-related determinant of esophageal stenosis after endoscopic submucosal dissection. IMAC: Intramuscular adipose tissue content; ESD: Endoscopic submucosal dissection; SMI: Skeletal muscle index; PMI: Psoas muscle index; NLR: Neutrophil-to-lymphocyte ratio.

Table 1 Conceptual summary of factors linking sarcopenia to post-endoscopic submucosal dissection esophageal stenosis.

Domain	Key components	Mechanistic relevance	Clinical implications
Body composition	Reduced skeletal muscle mass; impaired muscle quality; increased intramuscular fat	Reflects decreased physiological reserve and impaired regenerative capacity	Identifies high-risk patients prior to ESD; supports pre-procedural risk stratification
Systemic inflammation	Chronic low-grade inflammation; cytokine imbalance; elevated inflammatory markers	Promotes profibrotic signaling and dysregulated wound healing	May justify closer monitoring and anti-inflammatory strategies
Nutritional status	Hypoalbuminemia; low prognostic nutritional index; malnutrition	Impairs collagen remodeling, epithelial repair, and tissue regeneration	Supports nutritional optimization before and after ESD
Myokine signaling	Reduced secretion of muscle-derived cytokines and growth factors	Alters angiogenesis, immune regulation, and fibrosis balance	Highlights systemic-muscle-organ crosstalk in mucosal healing
Fibrotic remodeling tendency	Excess extracellular matrix deposition; imbalance between regeneration and fibrosis	Favors stricture formation rather than adaptive healing	Explains increased susceptibility to esophageal stenosis
Interaction with procedural injury	Extensive mucosal defects; deep tissue injury; circumferential resection	Amplifies the impact of systemic frailty on local healing	Suggests combined evaluation of lesion and host factors
Aging and frailty overlap	Sarcopenia coexisting with age-related decline and comorbidities	Multifactorial impairment of healing pathways	Requires integrated geriatric and metabolic assessment
Predictive modeling potential	Integration of body composition with clinical variables	Improves discrimination beyond lesion-based models alone	Supports development of individualized risk prediction tools
Modifiability	Nutritional support; exercise-based prehabilitation; metabolic optimization	Potential to partially reverse sarcopenia-related vulnerability	Opens avenue for preventive intervention strategies
Clinical paradigm shift	From lesion-centered to patient-centered risk assessment	Emphasizes host-related determinants in endoscopic outcomes	Promotes personalized and holistic peri-procedural management

ESD: Endoscopic submucosal dissection.

SARCOPENIA AS A SYSTEMIC CONDITION RATHER THAN A LOCAL PHENOMENON

Sarcopenia is increasingly recognized as a systemic disorder characterized not only by reduced muscle mass, but also by impaired muscle quality, chronic inflammation, and metabolic dysregulation[15-17]. In clinical research, sarcopenia is commonly assessed using computed tomography (CT)-derived skeletal muscle index (SMI) or psoas muscle index (PMI), often interpreted in the context of established consensus frameworks such as the AWGS and EWGSOP criteria, although no unified thresholds exist for esophageal ESD populations[18]. In patients with esophageal disease, sarcopenia is highly prevalent, with reported rates varying widely depending on diagnostic criteria and population characteristics[10].

CT-derived indices such as SMI and PMI are most commonly used to quantify sarcopenia in clinical studies[19]. However, substantial methodological heterogeneity exists across studies, including variability in imaging protocols, measurement landmarks, and cutoff thresholds used to define sarcopenia, which may affect comparability and reproducibility of risk estimates[20-22]. Importantly, indices incorporating muscle quality, including intramuscular adipose tissue content, appear to provide more robust and clinically relevant prognostic discrimination compared with muscle mass alone[23-25]. These imaging biomarkers reflect a systemic decline in regenerative capacity that may directly influence postoperative tissue repair[26]. In addition, cutoff values for SMI and PMI differ considerably between Asian and Western populations and across consensus criteria (e.g., AWGS vs EWGSOP), further contributing to inconsistency in sarcopenia classification in esophageal ESD cohorts. Notably, no universally accepted diagnostic thresholds for sarcopenia have been established specifically for patients undergoing esophageal ESD, highlighting the need for standardized assessment frameworks in future prospective studies.

BIOLOGICAL LINKS BETWEEN SARCOPENIA AND ESOPHAGEAL HEALING

The biological plausibility of sarcopenia contributing to esophageal stenosis lies in its close association with impaired wound healing, dysregulated regenerative signaling, and a shift toward profibrotic remodeling[13]. Skeletal muscle functions as an endocrine organ, secreting myokines that regulate inflammation, angiogenesis, tissue regeneration, and fibrotic balance during mucosal repair[27,28]. Sarcopenia is accompanied by chronic low-grade inflammation and cytokine imbalance, which may favor profibrotic pathways and excessive extracellular matrix deposition rather than organized mucosal regeneration after ESD[29]. Furthermore, ESD-induced deep mucosal and potential muscularis propria injury may interact with systemic frailty in sarcopenic patients, impairing coordinated regeneration and predisposing to fibrotic stricture formation rather than adaptive tissue remodeling.

Furthermore, sarcopenia frequently coexists with malnutrition, as reflected by low prognostic nutritional index (PNI) and hypoalbuminemia[30-32]. Nutritional deficiency compromises collagen remodeling and epithelial restitution, potentially leading to aberrant healing characterized by excessive fibrosis and luminal narrowing, processes essential for esophageal mucosal healing[33]. Several studies have demonstrated that inflammatory and nutritional biomarkers such as neutrophil-to-lymphocyte ratio and PNI correlate with both sarcopenia severity and postoperative complications[34,35], supporting a mechanistic link between systemic frailty and local healing failure[36]. Taken together, these mechanisms suggest that sarcopenia may not merely delay healing but may specifically bias the repair process toward fibrotic stenosis following extensive esophageal mucosal injury.

CLINICAL EVIDENCE LINKING SARCOPENIA TO POST-ESD COMPLICATIONS

While early investigations focused on sarcopenia as a predictor of survival and pulmonary complications after esophagectomy, more recent studies have extended these observations to endoscopic interventions. Sarcopenia has been shown to increase the risk of postoperative pneumonia and prolonged hospitalization following ESD, particularly in elderly populations[37,38]. This observation is consistent with broader oncological literature indicating that impaired skeletal muscle status may more strongly influence postoperative complications and healing trajectories than short-term mortality outcomes[36,39].

Importantly, emerging retrospective data indicate that CT-defined sarcopenia independently predicts esophageal stenosis after ESD, even after adjustment for established local risk factors, but these findings are derived primarily from observational designs and do not establish causality[13]. These findings suggest that sarcopenia captures a dimension of vulnerability not reflected by lesion size or circumferential involvement alone[40]. Notably, current nomogram-based prediction models for post-ESD stricture primarily incorporate procedural and inflammatory variables[41,42], and sarcopenia has yet to be systematically integrated into these tools, despite growing evidence that host-related factors such as muscle mass and nutritional reserve may provide incremental prognostic value beyond lesion-specific parameters[13].

IMPLICATIONS FOR RISK STRATIFICATION AND PERI-PROCEDURAL MANAGEMENT

Recognizing sarcopenia as a systemic contributory determinant and host-related risk factor of post-ESD outcomes has several important clinical implications. First, routine assessment of body composition using pre-procedural CT imaging may allow early identification of high-risk patients[13]. Unlike many procedural factors, sarcopenia is potentially modifiable through targeted nutritional support and rehabilitation[43].

It is also important to recognize that sarcopenia frequently coexists with other clinically relevant confounders, including advanced age, diabetes mellitus, systemic inflammation, and overall frailty, all of which may independently influence post-ESD healing and stricture risk[13]. Aging-related physiological decline, metabolic comorbidities, and impaired nutritional status can overlap with sarcopenia and jointly contribute to delayed mucosal regeneration and exaggerated fibrotic repair[44-46]. Therefore, the observed association between sarcopenia and esophageal stenosis should be interpreted within a multifactorial risk context rather than as an isolated predictor.

Second, sarcopenia-informed risk stratification may justify intensified surveillance or prophylactic strategies in selected patients, complementing established approaches such as steroid therapy and submucosal injection techniques[7,47,48]. Finally, these findings align with broader trends toward personalized endoscopic care, in which treatment decisions consider not only lesion characteristics but also patient physiological resilience, and future predictive models should incorporate sarcopenia alongside age, comorbidities, and inflammatory-nutritional indices with appropriate multivariable adjustment[49-51].

CONTROVERSIES AND CURRENT LIMITATIONS

Despite increasing recognition of sarcopenia as a potential determinant of post-ESD esophageal stenosis, several important controversies remain. First, the majority of current evidence is derived from retrospective observational studies, which are inherently subject to selection bias and residual confounding[52,53]. Sarcopenia frequently coexists with advanced age, frailty, systemic inflammation, and metabolic disorders, making it challenging to disentangle its independent contribution to stenosis risk[54].

Second, there is substantial heterogeneity in the definition and assessment of sarcopenia across studies[55-57]. Variability in imaging landmarks, cutoff thresholds, and whether muscle quality is incorporated may influence reported associations and limit comparability between cohorts. Importantly, no standardized criteria have been established specifically for patients undergoing esophageal ESD.

Third, causality remains uncertain. While biological plausibility supports a role for sarcopenia in impaired mucosal healing and fibrotic remodeling, current data do not establish whether sarcopenia directly drives stenosis or serves as a surrogate marker of broader physiological vulnerability[58-60].

Finally, the clinical utility of incorporating sarcopenia into predictive models has not been prospectively validated. Whether sarcopenia-guided interventions, such as prehabilitation or nutritional optimization, can reduce the incidence of post-ESD stenosis remains an open question.

FUTURE DIRECTIONS

Future research should prioritize prospective, multicenter cohort studies with standardized sarcopenia assessment protocols to validate its independent predictive value. Integration of muscle quantity and quality metrics into unified diagnostic frameworks will be essential to improve reproducibility. In addition, interventional studies targeting sarcopenia, including nutritional supplementation and exercise-based prehabilitation, are needed to determine whether modifying host factors can translate into reduced stenosis risk. The incorporation of sarcopenia into multimodal predictive models alongside procedural and inflammatory variables may further enhance individualized risk stratification in endoscopic practice.

CONCLUSION

Esophageal stenosis after ESD has long been interpreted as a complication driven predominantly by local mucosal injury. Accumulating evidence, largely derived from retrospective studies, now supports sarcopenia as an independent, systemic and contributory determinant of post-ESD healing outcomes. By reflecting impaired nutritional reserve, chronic inflammation, and reduced regenerative capacity, sarcopenia provides a biologically plausible explanation for inter-individual variability in stenosis risk beyond lesion-specific factors.

Incorporating sarcopenia into peri-procedural assessment represents a conceptual shift from a lesion-centered to a patient-centered model of risk stratification. However, it should be explicitly acknowledged that the current body of evidence is predominantly retrospective, subject to residual confounding, particularly from age-related frailty and metabolic comorbidities, and limited by heterogeneity in sarcopenia assessment methods. Therefore, current conclusions should be interpreted within the context of associative rather than causal evidence. Future well-designed prospective cohort studies and interventional trials are needed to clarify causal mechanisms, validate the independent predictive role of sarcopenia, and determine whether targeted interventions addressing sarcopenia can meaningfully reduce post-ESD esophageal stenosis. Nonetheless, current data already suggest that understanding who the patient is may be as important as what is resected in determining endoscopic outcomes. Importantly, sarcopenia should not be interpreted as a sole causal or decisive determinant, but rather as a contributory host-related factor within a multifactorial risk framework, and prospective studies are required to validate causality.