Pancreatic cyst ablation: why are we not doing more of these procedures?

Pancreatic cysts are classified as: 1) those complicating acute or chronic pancreatitis (acute fluid collections and pseudocysts), or 2) cystic neoplasms (PCNs) lined by epithelium. Acute fluid collections and pseudocysts possess no lining epithelium and therefore harbor no malignant potential. Epithelium from PCNs may have negligible malignant potential (serous cysts [SCNs]) or represent either premalignant (intraductal papillary mucinous neoplasms [IPMNs] or mucinous cystic neoplasms [MCNs]) or malignant tumors [1]. These lesions present either incidentally on imaging studies [2] [3], or as potential culprit lesions during evaluation of symptoms such as abdominal pain, weight loss or jaundice.

“Pancreatic cyst ablation may become an acceptable alternative to observation or surgery in selected patients.”

A recent American Gastroenterology Association guideline on asymptomatic PCNs estimated that an incidental cyst noted on magnetic resonance imaging has only a 1.0 – 1.7 per 10 000 chance of representing malignancy, and that endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of these lesions should be restricted to those with at least two features associated with an increased risk of malignancy (size > 3 cm, dilated main pancreatic duct [MPD], or a solid component) [4]. These recommendations stand in contrast to the 2012 Fukuoka guidelines for symptomatic or asymptomatic mucinous pancreatic cysts, which recommend EUS for all patients with one or more worrisome features (cyst ≥ 3 cm, thickened enhanced cyst walls, abrupt MPD caliber change with distal atrophy or lymphadenopathy), and surgery when feasible for those with high-risk stigmata (jaundice, enhanced solid component, MPD ≥ 10 mm) [5].

Pancreatic cyst ablation (PCA) has recently been studied to perhaps provide an alternative option to surgery or observation for selected PCNs. In the current issue of Endoscopy, Choi et al. [6] present the largest series to date describing PCA with ethanol and paclitaxel in 164 asymptomatic patients (71 MCNs, 16 SCNs, 11 IPMNs, 3 pseudocysts, and 63 indeterminate cysts). The authors found that an image-defined complete response and partial response occurred in 72.2 % and 19.6 %, respectively, following ablation, with recurrence in only 1.7 % of the 114 patients followed for a median of 6 years. Adverse events occurred in 9.8 % of ablated cysts, and in multivariate analysis, unilocular cysts and those < 35 mm in diameter were predictors of a complete response.

It is important to consider the patients enrolled in this study, in light of both the published guidelines above and previous studies evaluating PCA. Choi et al. considered ablation in asymptomatic patients with ≤ 6 locules, growth during observation, or those with a clinically indeterminate diagnosis and thus requiring EUS sampling. Furthermore, ablation was not considered for cysts with MPD communication on endoscopic retrograde cholangiopancreatography (ERCP; in the earlier study period) or magnetic resonance cholangiopancreatography (MRCP; in the later study period). Whereas some previous trials enrolled patients with or without a previous EUS [7] [8], others have only enrolled patients after previous EUS-FNA and cyst fluid analysis, in order to ensure selection of mucinous tumors or symptomatic SCN [9]. Despite the use of established criteria for cyst fluid carcinoembryonic antigen (CEA) and amylase, Choi et al. found that 63 (38.4 %) of the cysts treated were diagnosed as “indeterminate” and 16 (9.8 %) were SCNs. Furthermore, if the American Gastroenterology Association guidelines for the treatment of PCNs [4] were applied to the current study, only eight patients potentially required EUS-FNA (namely those with mural nodules and possibly over 3 cm in size), much less ablation. In the current study, the size of the MPD was not stated as a requirement for exclusion, but it is assumed that those with dilation were excluded. Although this study found that PCA was safe and efficacious, it is concerning that both EUS and, in particular, ablation was performed in so many indeterminate cysts with a low malignant potential. A better approach may be to consider ablation only after aspiration for cytology, CEA, and genetic mutations [10] [11], in order to ensure a proper diagnosis and determination of malignant potential. Although consideration for ablation at index endoscopy may save patients a procedure, the high accuracy of clinical criteria plus analysis of pancreatic cyst fluid genetic mutations [11] provides patients and surgeons with valuable information from which to make an informed decision about whether ablation, surgery or observation alone is optimal.

The current study excluded patients with obvious duct communication by ERCP or MRCP (thus attempting to minimize treatment of branched IPMNs [BD-IPMNs]), a practice that has been similarly followed by other studies [8] in order to both minimize potential damage to the MPD and leakage of the injectate out of the treated cyst. However, as most PCNs are BD-IPMNs, it remains questionable whether it is prudent to eliminate these cysts from consideration, as other studies have shown that treatment of these lesions may be safe [9], and there are no data showing that treating these lesions is riskier than treating other PCNs. If BD-IPMNs were considered by the authors, then a far greater population would have been eligible for treatment than the 2.7 % of the 6167 patients evaluated during the study period.

It is now clear that lavage of pancreatic cysts with ethanol alone is suboptimal and inferior [8] [12] to combined treatment with ethanol and paclitaxel [6] [9]. The image-defined complete and partial response rates of 72.2 % and 19.6 % reported by Choi et al. with a nondiluted and nonviscous (6 mg/mL) formulation of paclitaxel (Genexol-PM) is superior to the response reported with diluted (2 mg/mL or 3 mg/mL) paclitaxel used in studies from Western countries [9] [13]. The formulation of paclitaxel reported in the current study is not available in the United States, and the viscous formulation that is available requires dilution for it to pass through a 19-gauge or 22-gauge needle. These differences may explain the variation in response rates between studies.

The current study provides the clearest evidence to date that PCA significantly decreases the size of the vast majority of treated cysts, and is fairly safe (adverse event rate of 10 % – 15 %) and durable (with recurrence in 2 % of treated cysts). The obvious questions, therefore, are: 1) who should receive ablation, 2) who should perform ablation, and 3) why are we not doing more procedures?

First, as ablation appears to produce a better response in unilocular cysts smaller than 35 mm and may possibly be safer in those without MPD communication, the ideal cyst for treatment with PCA would appear to be an MCN. However, these lesions are easily removed with laparoscopic distal pancreatectomy, with essentially no mortality, and the procedure requires only 2 – 3 days in hospital. Furthermore, there is no risk of recurrence after resection – a fact that may also explain the low recurrence in the current study. If BD-IPMNs can be shown to be safely treated, then morphologically plausible BD-IPMNs may be the more ideal cyst to treat, given the higher prevalence of these lesions. Patients with a) high surgical comorbidities or an aversion to surgery, b) previous EUS-FNA and cyst fluid analysis, and c) whose case is discussed at a multidisclipinary (surgery and gastroenterology) meeting, ideally represent the patients who should be treated with PCA. It is premature at this time to solely offer PCA (or for that matter surgery alone) to a patient with a suspected MCN of the pancreatic tail.

Second, ablation is a fairly easy procedure to perform, and theoretically anyone experienced in EUS-FNA (perhaps lifetime experience over 500 cases) should be able to perform this procedure after some mentoring and observation of an expert. The bigger hurdles to overcome, however, may be the acceptance of PCA by surgeons as an alternative to surgery, and for oncologists, institutions, and institutional review boards to permit gastroenterologists to use chemotherapy to treat these lesions [9] [10].

Finally, to understand why more of these lesions are not ablated, the comparison of PCNs with dysplastic Barrett’s esophagus is helpful. Prior to development of endoscopic mucosal resection and mucosal ablation, esophagectomy (an operation with high morbidity and rare mortality) was the treatment of choice for Barrett’s esophagus with high grade dysplasia or T1a cancers. Clinical experience and research [14] [15] [16] [17] have now demonstrated that endoscopic eradication therapy is preferred to surgical management for these patients. Pancreatic surgery (also a high-risk surgery) remains the treatment of choice for high-risk mucinous pancreatic cysts [4] [5]. However, as more clinical experience accumulates, improved preoperative diagnostic tools become available, and prospective randomized trials comparing surgery with PCA are performed, PCA may become an acceptable alternative to observation or surgery in selected patients. The current study by Choi et al. provides relevant data to spur the required prospective randomized trials to make this a reality.

• References

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