Expanding the therapeutic spectrum for duodenal adenomas: Cryoballoon ablation

Abstract

Duodenal adenomas are clinically significant premalignant lesions; however, their management is frequently challenging due to fibrosis, recurrence, and the procedural risks associated with resection-based techniques such as endoscopic mucosal resection and endoscopic submucosal dissection. Cryoballoon ablation (CBA) has recently emerged as a non-resection alternative that delivers controlled nitrous oxide-based cryotherapy while reducing the likelihood of deep mural injury. A recent two-center retrospective series by Modirian et al published in World Journal of Gastrointestinal Endoscopy involving ten patients demonstrated the high technical success and meaningful clinical efficacy of CBA for non-circumferential flat adenomas including lesions with severe fibrosis that precluded effective snare capture. Most patients achieved substantial lesion regression or complete eradication with an excellent safety profile, requiring only occasional repeat sessions. In contrast, bulky circumferential sessile lesions showed minimal or no response, underscoring an important limitation of this modality. Current evidence indicates that CBA represents a valuable therapeutic option for carefully selected complex duodenal adenomas; however, prospective studies are needed to clarify the long-term durability, recurrence rates, and optimal candidates for this approach.

Key Words: Cryoballoon ablation; Duodenum; Adenoma; Dysplasia; Endoscopy; Gastrointestinal

Core Tip: Cryoballoon ablation provides a selective, depth-limited injury that preserves the collagen matrix, making it a promising option for duodenal adenomas when conventional resection is unsafe. This technique is particularly useful for flat, fibrotic, or recurrent lesions for which endoscopic mucosal resection is difficult or hazardous and in which thermal ablation carries an increased perforation risk. This modality may fill an important therapeutic niche for patients with anatomically challenging or high-risk adenomas.

This editorial refers to “Cryoballoon treatment of endoscopically unresectable duodenal adenomas” by Modirian et al, 2026; https://doi.org/10.4253/wjge.v18.i1.112759.

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INTRODUCTION

Sporadic non-ampullary duodenal adenomas are relatively uncommon, with reported prevalence ranging from 0.3% to 1.5% in large upper endoscopy series[1-3]. In contrast to colorectal adenomas, these lesions represent a small fraction of gastrointestinal neoplasia encountered in routine practice. Nevertheless, their clinical significance is disproportionate to their frequency. Duodenal adenomas carry a well-recognized risk of malignant transformation, particularly in larger lesions or those with high-grade dysplasia, warranting endoscopic removal whenever feasible[4,5]. Moreover, in centers with established minimally invasive endoscopic resection programs, duodenal lesions constitute a high-risk subset of therapeutic procedures, consistently associated with higher rates of complications compared with gastric or colonic resections[6,7]. As a result, even though infrequent, these lesions continue to present a persistent technical and safety challenge in advanced endoscopic practice.

LIMITATIONS OF CONVENTIONAL APPROACHES

Endoscopic mucosal resection (EMR) remains the first-line therapy for most sporadic non-ampullary duodenal adenomas. However, its safety profile is constrained by the thin duodenal wall and rich vascular supply. In a recent cohort of 167 lesions, adverse events occurred in 22.2%, including delayed bleeding in 17.4% and perforation in 4.8%, with complication rates rising substantially for lesions larger than 20 mm[7]. Furthermore, piecemeal resection is frequently required for larger lesions, and recurrence rates ranging from 9% to 37% have been reported, often necessitating repeat endoscopic interventions. These limitations are particularly pronounced in fibrotic or non-lifting lesions, where adequate snare capture becomes technically challenging[1,8].

To mitigate the risk of deep thermal injury, cold snare resection (CSR) has recently emerged as an alternative technique for selected duodenal adenomas. By avoiding electrocautery, CSR may reduce transmural damage and perforation risk. In a multicenter study by Wang et al[9], CSR demonstrated a favorable safety profile with low perforation rates and acceptable recurrence outcomes, particularly for small-to-medium-sized non-fibrotic lesions. However, CSR remains limited in scarred, recurrent, or circumferential adenomas where tissue rigidity precludes effective cold snare capture.

Endoscopic submucosal dissection (ESD), although theoretically allowing en bloc resection with complete margin control, carries substantial risk in the duodenum. Reported perforation rates range from 20% to 45%, even in experienced centers, reflecting the anatomical vulnerability of the duodenal wall. For this reason, current guidelines restrict duodenal ESD to highly selected cases in expert hands[10-12]. Argon plasma coagulation (APC) offers superficial coagulation but lacks depth and is associated with higher recurrence rates[13,14]. These limitations highlight the persistent therapeutic gap in managing complex duodenal adenomas.

WHY CRYOTHERAPY IS APPEALING IN THE DUODENUM

Cryotherapy offers mechanistic advantages that are fundamentally distinct from resection or heat-based modalities. During rapid freeze-thaw cycling, intracellular and extracellular ice crystal formation, osmotic shifts, and microvascular stasis induce cell death through a combination of apoptosis and necrosis, while avoiding the deep coagulative necrosis characteristic of thermal ablation[15-17]. Importantly, experimental and clinical data suggest that collagen and other components of the extracellular matrix are relatively resistant to freezing injury, meaning that the epithelial layer is devitalized, but the underlying connective-tissue scaffold and muscularis propria are largely preserved[18,19]. In endoscopic applications, this translates into a depth-limited injury predominantly confined to the mucosa and superficial submucosa, with a lower likelihood of transmural weakening than radiofrequency ablation (RFA) or APC[20]. In contrast, thermal ablation modalities, such as APC, deliver high-temperature energy that causes non-selective destruction of both the epithelium and the underlying collagen matrix, producing deep coagulative necrosis that increases the risk of fibrosis, stricture formation, and even perforation, particularly in the thin duodenal wall[21,22]. RFA is designed to deliver a uniform depth of thermal injury through controlled radiofrequency energy; however, this uniformity does not prevent heat conduction into deeper mural layers. As a result, RFA has been associated with submucosal collagen denaturation, transmural extension of injury in thin-walled segments, and higher stricture rates in clinical series - especially when applied to irregular, scarred, or fibrotic mucosa[23,24]. These mechanistic differences have particular relevance in the duodenum, where the wall is exceptionally thin and the submucosal space is minimal, making the tissue especially susceptible to heat-related injury (Figure 1). Consequently, the unique combination of selective epithelial ablation and preservation of the collagen matrix provides a compelling biological rationale for cryoballoon ablation (CBA) as a potentially safer option for unresectable or high-risk duodenal adenomas.

Figure 1 Mechanistic comparison between thermal ablation and cryoablation in the duodenum. A: Thermal ablation (argon plasma coagulation/radiofrequency ablation): Heat energy causes non-selective destruction of both the epithelium and the underlying collagen matrix (red zone), increasing the risk of fibrosis, stricture, and perforation in the thin duodenal wall; B: Cryoablation: Rapid freezing creates intracellular ice crystals causing cell death (blue zone), but the collagenous extracellular matrix (scaffolding) remains intact. This preservation allows for healing with reduced risks of deep mural injury. APC: Argon plasma coagulation; RFA: Radiofrequency ablation.

EMERGING EVIDENCE FOR CBA IN THE DUODENUM

The initial clinical signal for nitrous oxide-based CBA in duodenal adenomas came from the report by Raphael et al[25] who successfully treated a recurrent, non-lifting fibrotic adenoma without the need for submucosal injection or snare capture. This early experience demonstrated that CBA could uniformly ablate fibrotic tissue - an important limitation of conventional EMR.

Dbouk et al[26] subsequently strengthened this evidence with a multicenter series of 17 lesions, showing high technical success (88%), a meaningful clinical response, and no intra- or postprocedural adverse events, even though 75% of the lesions represented recurrences or failures after prior EMR. Their results established CBA as a feasible and safe salvage option for challenging, fibrotic duodenal adenomas treated across multiple centers. In this cohort of 17 lesions (mean size 22.7 ± 14.3 mm), 76.5% represented recurrences or failures after prior EMR, and 71% (12/17) of patients achieved recurrence-free survival at a median follow-up of 15.5 months, underscoring the promising safety profile and early durability of CBA in this anatomically challenging region. These early studies established CBA as an attractive therapeutic strategy for recurrent or fibrotic duodenal adenomas for which conventional endoscopic resection is difficult and hazardous.

On this established foundation, the current study by Modirian et al[27] published in World Journal of Gastrointestinal Endoscopy provides the most clinically clarifying and practice-shaping contribution to date. Rather than demonstrating early feasibility, this study builds on the prior work by defining which lesions are appropriate candidates for CBA. By focusing on benign adenomas rendered unresectable due to severe fibrosis or unfavorable anatomy, the authors showed that CBA could be effective for flat, non-circumferential lesions, while bulky circumferential lesions (> 5 cm) showed a minimal response and should be considered poor candidates. In doing so, Modirian et al[27] meaningfully refine the evolving role of CBA by introducing selective indications and clear contraindications, moving the field beyond feasibility toward evidence-based clinical application. These emerging data collectively suggest that CBA may represent an attractive treatment or adjunctive strategy particularly for recurrent or fibrotic duodenal adenomas for which standard EMR is both difficult and risky.

FINDINGS FROM THE CURRENT STUDY

In this context, the study by Modirian et al[27] provides important clinical insight. The authors conducted a retrospective analysis of patients with benign duodenal adenomas deemed endoscopically unresectable due to severe fibrosis, non-lifting characteristics, or circumferential involvement. A total of 10 patients were treated with nitrous oxide-based CBA. Technical success was achieved in all cases. Importantly, no perforation or delayed bleeding was observed, supporting the procedural safety of CBA in this anatomically vulnerable segment.

The clinical response, however, varied according to lesion characteristics. Flat, non-circumferential fibrotic lesions demonstrated meaningful regression or complete eradication, whereas bulky circumferential lesions (> 5 cm) showed minimal response (< 20% reduction), ultimately requiring alternative management strategies. Several patients required more than one treatment session to achieve satisfactory lesion regression, highlighting that CBA may function as a staged ablation therapy rather than a single-session definitive treatment. At follow-up, the majority of appropriately selected lesions demonstrated durable local control without progression to invasive disease. These findings suggest that the efficacy of CBA is highly dependent on lesion morphology and extent, underscoring the importance of careful patient selection.

COMPARATIVE OVERVIEW OF AVAILABLE ENDOSCOPIC OPTIONS

The therapeutic landscape for sporadic non-ampullary duodenal adenomas encompasses a spectrum of endoscopic modalities, each with distinct advantages and limitations that influence their suitability for specific lesion types. EMR remains the most widely used first-line therapy due to its technical simplicity and broad availability (Table 1). However, its safety profile becomes progressively unfavorable in larger or fibrotic lesions, with real-world data demonstrating delayed bleeding rates of 17%-20% and perforation rates approaching 5%, particularly in lesions > 20 mm or those with non-lifting characteristics[6,7]. These physiological and technical limitations often necessitate piecemeal resection and increase the need for supplemental ablation or repeat procedures.

Table 1 Summarizes the relative advantages, limitations, and ideal indications for endoscopic mucosal resection, endoscopic submucosal dissection, argon plasma coagulation, and cryoballoon ablation, highlighting the therapeutic niche where cryoballoon ablation may offer benefit.

Treatment	Advantages	Limitations	Major risks	Best candidates
EMR[6,7]	Widely available; first-line therapy	Difficult in large or fibrotic lesions; non-lifting	Delayed bleeding (17%-20%); perforation (4%-5%)	≤ 20-30 mm, non-fibrotic lesions[6,7]
Cold snare resection[9]	Non-thermal; Lower perforation risk; technically simple	Limited in fibrotic or non-lifting lesions; piecemeal in larger lesions	Delayed bleeding (low); recurrence possible	Small-to-medium (≤ 15-20 mm), non-fibrotic lesions
ESD[12,28]	En bloc resection with clear margins	Technically demanding; limited working space in duodenum	Perforation (20%-45%) delayed bleeding	Highly selected lesions in expert centers
APC[12,30]	Simple; useful for small residual areas	Limited depth; higher recurrence	Rare delayed bleeding; thermal spread possible	Small residual adenoma within scar tissue
CBA[15,26]	Favorable safety profile; uniform, depth-limited injury	Superficial ablation only; may require repeat sessions; no histology	Mild pancreatitis; uneven balloon-mucosa contact; no perforations reported in published series	Flat, fibrotic, recurrent, non-circumferential lesions

EMR: Endoscopic mucosal resection; ESD: Endoscopic submucosal dissection; APC: Argon plasma coagulation; CBA: Cryoballoon ablation.

ESD offers the theoretical benefit of en bloc resection with complete margin control; however, application of this technique in the duodenum is severely restricted. The thin duodenal wall and constrained luminal anatomy contribute to reported perforation rates ranging between 20% and 45%, even in high-volume centers[12,28,29]. As a result, major guidelines recommend reserving duodenal ESD for highly selected lesions in expert hands, leaving many complex cases unsuitable for this approach.

APC has traditionally been employed as an adjunctive modality rather than a primary treatment. While APC is effective in ablating small residual foci after piecemeal EMR, its shallow depth of penetration often fails to eradicate deeper adenomatous glands, leading to recurrence rates as high as 40%-60% when used as monotherapy[12,30]. Thermal spread in the thin-walled duodenum can also result in delayed bleeding, deep ulceration, or, in rare cases, transmural injury. APC is accordingly best positioned as a supplemental technique in carefully selected residual or diminutive lesions rather than a definitive treatment strategy.

POTENTIAL ADVANTAGES AND APPROPRIATE INDICATIONS FOR CBA

CBA offers several mechanistic and procedural advantages that distinguish it from conventional thermal and resection-based strategies. By delivering a depth-limited and uniform cryogenic injury, CBA minimizes the risk of transmural damage in the thin-walled duodenum. Preservation of the submucosal collagen matrix further supports structural integrity and may reduce the likelihood of fibrosis or stricture formation. In addition, the non-thermal mechanism avoids coagulative necrosis, which is particularly relevant in fibrotic or previously manipulated lesions where heat conduction may be unpredictable. The balloon-based system also allows technically straightforward application, even in angulated or anatomically constrained segments.

Clinically, these characteristics position CBA as a potentially valuable option for benign non-ampullary duodenal adenomas, particularly flat (Paris 0-IIa/IIb), recurrent, or EMR-resistant fibrotic lesions. It may also be considered for residual adenoma within scar tissue or near previously placed clips, as well as in patients who are poor surgical candidates. These considerations collectively define a narrow but meaningful therapeutic niche for CBA in contemporary endoscopic practice. CBA is not recommended for bulky or circumferential lesions (> 5cm), as Modirian et al[27] demonstrated that such lesions showed a minimal response (< 20% reduction) and ultimately required surgery or alternative management (Table 2).

Table 2 Clinical advantages and appropriate indications of cryoballoon ablation.

Potential advantages	Appropriate indications	Lesions unsuitable for CBA
Depth-limited uniform injury (reduced perforation risk)	Benign non-ampullary duodenal adenomas (Paris 0-IIa/IIb)	Bulky circumferential lesions (> 5 cm)
Preservation of submucosal collagen matrix	Recurrent or fibrotic (non-lifting) lesions	Suspected deep submucosal invasion
Non-thermal mechanism avoiding coagulative necrosis	Residual adenoma within scar tissue or near clips	Lesions requiring histologic margin assessment
Technically simple balloon-based delivery system	Lesions in angulated or technically challenging locations

CBA: Cryoballoon ablation.

LIMITATIONS AND CURRENT CHALLENGES OF CBA

Important limitations remain. Cryotherapy creates superficial injury, limiting the effectiveness of this technique in deep or bulky lesions and preventing histologic margin assessment. Inconsistent balloon-mucosal contact in the duodenum may produce skipped areas. Many cases require repeat sessions, and long-term durability data are sparse. A small but notable risk of pancreatitis exists when treating periampullary lesions. Moreover, CBA therapy is new, and only a limited number of centers worldwide have substantial experience. This restricts standardization, slows evidence accumulation, and raises concerns about generalizability. Thus, CBA remains an adjunctive or investigational therapy at this stage.

CONCLUSION

CBA represents a promising but still developing modality for unresectable or high-risk duodenal adenomas. Supported by esophageal safety data and early duodenal experience, CBA may offer a safer option for flat, fibrotic, or recurrent lesions that are not amenable to EMR or ESD. However, the current evidence remains preliminary, and rigorous prospective studies with standardized protocols and long-term follow-up will be required to define its role more clearly. For now, CBA should be regarded as a cautious, adjunctive therapy and should be applied selectively within a narrow but clinically important therapeutic niche.