Cryoballoon treatment of endoscopically unresectable duodenal adenomas

Abstract

BACKGROUND

Snare polypectomy and endoscopic mucosal resection (EMR) are effective and widely utilized for treating duodenal adenomas. However, circumferential, recurrent and fibrotic adenomas can be challenging to treat with these techniques.

AIM

To develop a safe and effective treatment for these challenging lesions.

METHODS

Between 2022 and 2024, a retrospective review was performed for all patients treated with cryoballoon for duodenal adenomas at two institutions. Cryoballoon focal ablation was performed using nitrous oxide, in which a 1-second “pre-puff” of nitrous oxide was performed, followed by delivery for 10 seconds to 14 seconds. Repetition was performed as needed. Surveillance endoscopy was performed at 3 months to 12 months post-ablation to assess efficacy.

RESULTS

A total of ten individuals were treated, including six patients with recurrent adenomas following previous incomplete endoscopic resections, one patient with an extensive flat adenoma surrounding an ampullary polyp that could not be resected with a snare, and two patients with circumferential sessile duodenal adenomas longer than 5 cm that were considered unresectable by EMR. Follow-up endoscopy demonstrated no efficacy (< 20% improvement) in the two patients with circumferential sessile adenomas. Of the eight patients with non-circumferential adenomas, three had no residual adenoma. Five had significant improvement with < 40% of the adenoma remaining and were treated again with cryoballoon (3) or cold snare (2). Three of the five patients had no recurrence following the second treatment. The remainder are awaiting repeat endoscopy. Seven patients were treated as outpatients and had no adverse events. Two patients undergoing concomitant snare ampullectomy were hospitalized for observation; one developed mild pancreatitis and was discharged following a 48-hour admission, and the second patient was asymptomatic.

CONCLUSION

Cryoballoon treatment may be effective for non-circumferential flat duodenal adenomas that are not amenable to snare polypectomy or EMR, such as those with severe fibrosis from prior treatment. More than one treatment may be required. However, the treatments are safe and well-tolerated. Limited experience in two patients suggests that cryotherapy is not an effective treatment for bulky circumferential adenomas.

Key Words: Cryoballoon; Cryotherapy; Duodenal adenomas; Endoscopic mucosal resection; Endoscopic submucosal dissection

Core Tip: Conventional procedures for treating fibrotic, recurring, or widespread duodenal adenomas, such as snare polypectomy and endoscopic mucosal resection, may have limitations. This multicenter retrospective study examines cryoballoon ablation as a novel treatment for such complex lesions. The findings suggest that cryoballoon therapy is a safe and potentially successful treatment for non-circumferential flat adenomas, particularly those complicated by past resections and fibrosis. However, its effectiveness may be restricted in large circumferential lesions.

INTRODUCTION

Duodenal adenomas are identified in 0.1% to 0.4% of endoscopies[1]. Duodenal adenomas are precancerous lesions with potential for progression to duodenal adenocarcinoma. Risk of malignant transformation rises with larger lesion size, high-grade dysplasia, and villous histology[2]. As a result, early detection and removal are critical to preventing cancer development. Endoscopic mucosal resection (EMR) is presently the standard therapy for superficial duodenal adenomas[3]. However, given the thin wall and abundant vascular supply of the duodenum, EMR poses a significant risk. Delayed bleeding occurs in 15%-20% of patients, and perforation occurs in 4%-5%, making the surgery technically difficult and sometimes dangerous[4]. Furthermore, up to 25% of patients can have recurrence following EMR, particularly after piecemeal resections[5].

Another therapy for duodenal adenomas is endoscopic submucosal dissection (ESD). ESD has emerged as a promising technique for achieving en bloc resection with histologically clear margins. While ESD is well-established for gastric and esophageal lesions, its application in the duodenum remains limited due to technical challenges and a higher complication profile. In a prospective study by Honda, ESD was performed on patients with superficial duodenal neoplasms, achieving favorable resection outcomes such as 100% en bloc resection rate and a 77% R0 resection for superficial duodenal neoplasms; however, the procedure was associated with a perforation rate of 35%[6]. Similarly, Jung et al[7] examined the safety and efficacy of ESD for sessile, nonampullar duodenal adenomas. They reported en bloc resection in all cases but noted delayed perforation and bleeding as significant adverse events. These studies emphasize the importance of substantial endoscopic expertise in the adoption of ESD for duodenal lesions, which may not be suitable for all clinical scenarios, particularly in cases involving fibrotic or circumferential lesions. While alternative methods such underwater cold EMR, and device-assisted full-thickness resection are available for some lesions[8,9], their applicability may be limited in patients with extensive fibrosis or technically challenging anatomy. Cryoballoon ablation (CBA) provides a non-resection alternative that may reduce the risk of perforation and bleeding, particularly in duodenal lesions, where conventional endoscopic resection carries higher procedural risks.

Nitrous oxide CBA is a novel endoscopic technique that applies localized cryotherapy to ablate gastrointestinal mucosal lesions. Initially developed for the treatment of Barrett’s esophagus, CBA demonstrated high rates of dysplasia eradication while maintaining a favorable safety profile, making it a promising alternative to other ablative therapies in the esophagus[10]. The method involves placing a balloon catheter over the lesion, inflating it to flatten the mucosal folds, followed by the delivery of a rapid burst of nitrous oxide. This regulated freezing causes surface tissue necrosis while limiting damage to deeper layers, thereby reducing the likelihood of complications such as bleeding or perforation. More recently, the technique has been adapted for the treatment of duodenal adenomas. In a multicenter study by Dbouk, CBA was successfully used to treat non-polypoid duodenal adenomas. The procedure achieved a technical success rate of 100%, and over 70% of patients remained recurrence-free at follow-up. Importantly, no serious adverse events were reported, even among lesions exceeding 2 cm in size[11]. At our centers, we have reserved CBA for the treatment of duodenal adenomas that are not amenable to EMR, either due to fibrosis that impairs the ability to grasp the lesion with a snare or due to extensive circumferential extent, which would make snare resection too risky to perform and unlikely to succeed.

MATERIALS AND METHODS

Study design and patient selection

All patients who underwent duodenal CBA at Stanford University (Stanford, CA, United States) and the Veterans Affairs Palo Alto Health Care System (Palo Alto, CA, United States) between 2022 and 2024 were retrospectively reviewed. All procedures were performed by one endoscopist (Friedland S). This retrospective study was approved by the Ethics Committee of Stanford University Administrative Panel on Human Subjects in Medical Research. Duodenal adenomas that were deemed endoscopically unresectable due to fibrosis from prior incomplete treatment or extensive (> 3 cm) circumferential extent were included. Lesions with suspected invasive malignancy were excluded. Exclusion criteria included endoscopic features such as deep ulceration, non-lifting sign after submucosal injection, irregular or depressed morphology, or friability with spontaneous bleeding.

The CryoBalloon Focal Ablation System (CbFAS, Pentax Medical, GA, United States) was used in all procedures. Under monitored anesthesia care, the cryoballoon catheter was introduced via a high-definition therapeutic upper endoscope[10,12]. A 1-second “prepuff” of nitrous oxide was used to inflate the balloon and orient the diffuser against the lesion, followed by cryogen delivery for 10-14 seconds until an ice patch entirely covered the lesion. Applications were applied as needed until post-treatment erythema was observed over the entire lesion (Figure 1)[11,13]. Technical success was defined as accurate catheter positioning and the execution of at least one cryotherapy application. Surveillance endoscopy with biopsy was performed at 3 months to 12 months post-ablation to assess efficacy (≥ 50% lesion reduction and no recurrence) and to identify potential adverse events, such as perforation, bleeding, or stricture formation[11].

Figure 1 Successful endoscopic management of a refractory duodenal adenoma using cryoballoon ablation. A: Residual duodenal adenoma with high-grade dysplasia after piecemeal endoscopic mucosal resection and clipping outside the hospital. The clips were firmly attached, allowing the cryoballoon treatment to be performed without needing to remove them; B: Performing cryoballoon treatment; C: A 3-month follow-up demonstrated the spontaneous passage of clips and residual adenoma, which was treated with a repeat cryoballoon; D: At 6 months, repeat biopsies at the erythematous areas showed no residual adenoma. There was also no recurrence on subsequent follow-up endoscopy at 18 months.

Statistical analysis

For all analyses, all tests were 2-tailed. A P-value < 0.05 was considered statistically significant. Continuous variables were expressed as mean ± SD.

RESULTS

Between 2022 and 2024, ten patients underwent CBA of duodenal adenomas (Table 1; Figure 2). The study comprised of six patients with recurrent lesions after prior endoscopic resection and four individuals with previously untreated, unresectable lesions due to morphology or anatomical restrictions. The mean age of the patients was 66.7 years (standard deviation 12.1 years), and 60% were male. The lesions primarily involved D2, which affected 70% (7 of 10) of patients, while 30% (3 of 10) involved duodenal bulb, and 30% (3 out of 10) had involvement in horizontal duodenum; 3 of the lesions involved more than one segment. Average lesion size was 34.5 mm (standard deviation 26.9 mm). CBA was completed successfully in all patients, with no intra-procedural complications.

Figure 2 Flow diagram of patient outcomes.

Table 1 Baseline characteristics of patients undergoing cryoballoon ablation for duodenal adenomas.

Case	Age	Sex	Comorbidities	Location	Prior treatment	Size at first cryogenic (mm)	Morphology	Fibrosis	Pathology	Cryogenic performed	Adverse event	Follow-up outcome
1	73	Male	Cardiomyopathy, metastatic cancer	D3	Tattoo and biopsy	20 mm	Flat	Severe	Adenomas	12 seconds × 2 sites	None	Minimal residual adenoma at 4 months (5 mm, biopsied and repeat cryoballoon), no further surveillance due to severe comorbidities
2	55	Male		D2	Incomplete EMR	15 mm	Flat	Severe	Adenomas	10 seconds × 2 sites	None	Two 8 mm residual adenomas were ablated at 3 months, 3 mm residual adenomas at 8 months were ablated, and no residual adenomas were found at biopsy at 15 months
3	77	Male	FAP	D1, D3 (including periampullary)	Biopsy	100 mm	Circumferential sessile	None	Adenomas	12 seconds × 9 sites	None	< 20% improvement at 4 months, cryogenic repeated (12 seconds × 6 sites), no improvement at 9 months. Adenoma on biopsy
4	72	Male		D2	Incomplete EMR and Ovesco for bleeding	20 mm	Flat and Ovesco are attached	Severe	Adenomas	12 seconds × 3 sites	None	Ovesco was still attached at 6 months, removed by traction. 1/3 of adenoma remained, removed by cold snare. Awaiting repeat endoscopy
5	71	Male		D2, D3 (starting 1 cm distal to ampulla)	Biopsy	50 mm	Circumferential sessile	None	Adenomas	12 seconds × 12 sites	None	< 20% improvement at 2 months. Repeat biopsy of adenoma. Had surgical resection (adenoma)
6	70	Female	Cirrhosis with varices	D1	EMR/band	10 mm	Flat	Severe	HGD	10 seconds × 1 sites	None	No recurrence at 1 year (biopsy normal)
7	78	Female	Prior XRT for lymphoma	D2	PEMR with clip	15 mm	Flat with clip attached	Severe	HGD	10 seconds × 1 sites	None	2/3 gone at 3 months, repeat ablation 10 seconds × 3 sites, no recurrence on biopsy at 6 months or 18 months
8	78	Female		D2 (including ampulla)	None	50 mm	Flat, unable to grasp the snare	Mild	HGD	10 seconds × 5 sites	None	90% gone at 6 months, treated with cold snare. Recurrence at the ampulla treated with snare at 12 months. No recurrence on 18-month follow-up
9	41	Female	FAP	D1, D2 (including near the ampulla)	PEMR	20 mm	Flat	Severe	Adenomas	10 seconds × 4 sites	Admitted 48 hours for mild pancreatitis	No recurrence at 6 months
10	52	Male		D2	PEMR/tattoo	20 mm	Flat (IIa + IIc)	Severe	Foveolar metaplasia but only small piece so unclear	14 seconds × 3 sites	None	No recurrence at 6 months

FAP: Familial adenomatous polyposis; XRT: Radiation therapy; D3: Horizontal duodenum; D2: Distal duodenum; D1: Duodenal bulb; EMR: Endoscopic mucosal resection; PEMR: Piecemeal endoscopic mucosal resection; HGD: High-grade dysplasia.

Eight patients were treated on an outpatient basis and experienced no adverse events. Two patients underwent concurrent snare ampullectomy and were admitted for observation. One patient developed mild post-procedural pancreatitis, which resolved with supportive care during a 48-hour hospital stay. The second patient remained asymptomatic and was discharged without incident.

Treatment response varied by lesion morphology during follow-up endoscopy. Two patients with large circumferential sessile duodenal adenomas > 5 cm experienced a < 20% reduction in lesion size and were classified as non-responders. One of the patients subsequently received surgical resection. In contrast, among the eight patients with non-circumferential adenomas, three achieved complete eradication of the adenoma on the first follow-up endoscopy. Five patients experienced a significant improvement, with a reduction of ≥ 60% in adenoma burden. Of these, three underwent repeat CBA, while two were managed with cold snare resection. One patient achieved complete resolution after a second cryoablation session, and another remained recurrence-free following a third treatment. Another patient received two rounds of snare resection, with no recurrence at the third follow-up (18 months after the index treatment). The remaining two patients are pending repeat endoscopic assessment or were unable to do so due to severe comorbidities.

DISCUSSION

Current endoscopic management strategies for duodenal adenomas have primarily been limited to EMR and ESD. EMR is widely considered the preferred first-line therapy for non-ampullary duodenal adenomas; however, its efficacy diminishes in cases of fibrosis or lesion recurrence. In a multicenter, prospective study, EMR for duodenal adenomas ≥ 10 mm was associated with an overall adverse event rate of 22.2%, including 18.5% delayed bleeding and 4.2% perforation, with lesion recurrence observed in 23% of patients at follow-up[4]. ESD offers higher en bloc and R0 resection rates but carries a significantly greater risk of complications. Honda et al[6] reported a perforation rate of 35% in their experience with duodenal ESD, while Jung et al[7] observed delayed perforation and bleeding despite successful en bloc resection.

CBA has rapidly evolved from an experimental therapy to a practical option for duodenal adenomas, driven by three key reports that collectively define its scope and safety. In the multicenter series by Dbouk, flat (Paris 0-IIa) duodenal adenomas in over 30 patients were treated with cryoballoon therapy, achieving 100% technical success. Notably, 76.5% of lesions shrank by at least half after a median of two sessions. No serious adverse events were observed, underscoring the safety of CBA[11]. Raphael presented a single patient “rescue” case: After repeated EMR attempts failed to clear a 1.2 cm flat adenoma, a single nitrous oxide cryoballoon application resulted in complete endoscopic and histologic eradication, with no immediate or delayed complications[12]. Similarly, in our experience, cryoablation treatment demonstrated a high technical success rate, with all ten cases (100%) achieving successful deployment and delivery of cryogen to the intended location. Out of the 6 cases of non-circumferential adenomas with completed follow-up, all six were able to achieve complete eradication, though several repeat therapies were required in some instances. On the other hand, circumferential sessile adenomas were unsuccessfully treated by cryoballoon, with < 20% improvement. This suggests that cryoballoon may not be a feasible strategy for managing bulky circumferential lesions, but more data are needed at this time, given the limited number of cases.

Strengths of this study include its focus on real-world cases of duodenal adenomas considered unresectable by conventional methods, a uniform treatment approach, and detailed follow-up with both clinical and technical outcomes. All procedures being performed by a single expert operator increased procedural consistency. Limitations include retrospective design and small sample size, but our data and findings have been consistent with available literature. Variation in treatment parameters (e.g., cryogen application time 10-14 seconds, number of sites) may also reduce reproducibility but is an accepted approach in this technique[11,13].

CONCLUSION

While EMR and ESD are accepted therapies for duodenal adenomas, in our case series, we find that cryotherapy can also be an accepted approach for challenging lesions. While more than one therapy session may be required, the high safety profile of this procedure makes cryoballoon treatment an attractive approach. In our study, we find that cryoballoon treatment is effective in noncircumferential duodenal adenomas that cannot be treated with snare polypectomy or EMR due to significant fibrosis from previous treatments. However, cryoballoon therapy may be less effective for bulky circumferential adenomas. Further studies are needed to evaluate the application of cryotherapy in the management of duodenal lesions.