Denuding epithelium from pancreatic cysts: the bare essentials.

Abstract

In the current issue of Gastrointestinal Endoscopy, Gómez et al1Gómez V. Majumder S. Smyrk T.C. et al.Pancreatic cyst epithelial denudation: a natural phenomenon in the absence of treatment.Gastrointest Endosc. 2016; 84: 788-793Google Scholar present a single-center retrospective evaluation of the extent of histologic epithelial denudation in 140 patients with treatment-naïve pancreatic cystic neoplasms who underwent EUS-guided FNA (EUS-FNA) followed by surgery. Pathologic processing of the resected specimens was performed in a standardized fashion and reviewed by a single experienced GI pathologist, who reported the histologic findings and percentage of observed denuded epithelium. The authors identified 164 patients with completed preoperative imaging, EUS, and surgery and had “sufficiently intact and appropriately preserved” specimens to evaluate. Of those, 24 patients with pseudocysts and endocrine tumors were excluded. Of the 140 remaining patients, 61% of cysts were incidental findings that suggested that cyst size, duct diameter, or enhancing nodules on cross-sectional imaging prompted referral to endoscopy and thus to surgery. The authors report that all patients underwent EUS-FNA, but the results of cytologic examination and imaging are not given; thus, it is unclear why this frequency of incidentally discovered cysts was referred to surgery. It is also not stated which databases were used to identify these patients and how many patients were excluded without either (1) EUS or CT/magnetic resonance imaging or (2) fragmented or unpreserved pathologic specimens. Nevertheless, the authors are to be commended for this first large description of this phenomenon. This study resulted in 4 important findings. First, 80% of the cysts evaluated had some degree of epithelial cell loss, reflecting that this occurrence is the norm rather than the exception for these tumors. Pathologists and surgeons have long recognized the entity of denuding of pancreatic cyst epithelium,2Warshaw A.L. Compton C.C. Lewandrowski K. et al.Cystic tumors of the pancreas: new clinical, radiologic, and pathologic observations in 67 patients.Ann Surg. 1990; 212 (discussion 444-5): 432-443Crossref PubMed Scopus (620) Google Scholar, 3Yamada Y. Mori H. Hijiya N. et al.Intraductal papillary mucinous neoplasms of the pancreas complicated with intraductal hemorrhage, perforation, and fistula formation: CT and MR imaging findings with pathologic correlation.Abdom Imaging. 2012; 37: 100-109Crossref PubMed Scopus (13) Google Scholar, 4Adsay N.V. Cystic lesions of the pancreas.Mod Pathol. 2007; 20: S71-S93Crossref PubMed Scopus (148) Google Scholar but to date the frequency and description of any associated clinical features have not been described. The authors postulate that denudation occurs in vivo rather than surgical manipulation or EUS-FNA, given that histologically several cysts had areas of denudation replaced with fibrin and other inflammatory debris. Another plausible explanation is that pathologic processing of these surgical specimens may lead to denudation or that various subtypes of cystic neoplasms are more prone to denudation during processing than others. The second finding the authors noted was a greater degree of denudation (45%) for mucinous cystic neoplasms (MCNs) compared with that seen with serous cystadenomas (SCAs) or intraductal papillary mucinous neoplasms (IPMNs), which was present in 22% and 11% of patients, respectively. This finding is not surprising because MCNs histologically are known to be associated with inflammation and denuding.4Adsay N.V. Cystic lesions of the pancreas.Mod Pathol. 2007; 20: S71-S93Crossref PubMed Scopus (148) Google Scholar, 5Maire F. Hammel P. Terris B. et al.Benign inflammatory pancreatic mucinous cystadenomas mimicking locally advanced cystadenocarcinomas: presentation of 3 cases.Pancreatology. 2002; 2: 74-78Abstract Full Text PDF PubMed Scopus (5) Google Scholar The denuding of MCNs may histologically appear similar to a pseudocyst, and the associated inflammation may mistakenly raise suspicion of malignancy.5Maire F. Hammel P. Terris B. et al.Benign inflammatory pancreatic mucinous cystadenomas mimicking locally advanced cystadenocarcinomas: presentation of 3 cases.Pancreatology. 2002; 2: 74-78Abstract Full Text PDF PubMed Scopus (5) Google Scholar Furthermore, MCNs typically occur in middle-aged women and are lined by epithelium resembling endocervical epithelium. They are most importantly associated with ovarian stroma that routinely express progesterone and estrogen receptors.6Basturk O. Coban I. Adsay N.V. Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications.Arch Pathol Lab Med. 2009; 133: 423-438PubMed Google Scholar Thus, it is reasonable to postulate a hormonal influence on the neoplastic potential and, perhaps, observed denuding of its epithelium. Personally, observation of MCNs in vivo by needle-based confocal endomicroscopy may show inflammatory cells and few-to-absent epithelial cells, suggesting ongoing epithelial turnover and inflammation. Third, the authors found an inverse relationship between the degree of dysplasia for all mucinous cysts and the extent of denuded epithelium. Specifically, the mean percentages of denuded epithelium for low-grade, moderate-grade, and high-grade dysplasia were 23.3%, 4.5%, and 1.2%, respectively (P = .02). Unfortunately, the authors did not separate these findings for both MCN and IPMN or report other possible variables such as cyst size, histologic type of IPMN, or presence of high-risk stigmata, and worrisome features that may have also had an impact on the degree of observed dysplasia.7Tanaka M. Fernández-del Castillo C. Adsay V. et al.International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas.Pancreatology. 2012; 12: 183-197Abstract Full Text Full Text PDF PubMed Scopus (1691) Google Scholar Curiously, no patients with invasive malignancy were reported in this study, inasmuch as only the degree of dysplasia was recorded. Therefore, one has to wonder whether these patients were excluded from this study and not reported or whether patients with high-grade dysplasia and malignancy were considered as 1 group, as has been reported in previous surgical series on pancreatic cystic neoplasms. However, if this observation is correct, this is likely the most significant observation from this study and suggests that immature neoplastic cells may be more prone to turnover/denuding or to the ex vivo effects of histologic processing. Perhaps cyst wall epithelial turnover naturally selects epithelium more resistant to future denuding, which can thus progress later toward dysplasia. The fourth significant finding is that cystic neoplasms resected from the neck, body, and tail of the pancreas were associated with a greater extent of mean percentage of denuded epithelium than were those resected from the head and uncinate of the pancreas (23.9% vs 13.4%; P = .035). Although the study had nearly 3 times the number of IPMNs (85) as MCNs (33), it is likely that the reported relationship between denuding and tumor location is reflective of the statistically higher degree of observed denuding present in MCNs (which occur almost exclusively in the body and tail) compared with other neoplasms such as IPMNs (which are predominately located in the head and uncinate). The authors did not report the location of mucinous tumors in the current study. On the basis of the finding of variable denuding of treatment-naïve pancreatic cystic neoplasms, the authors suggest that the use of histologic examination of the ablated cyst epithelium after injection of ethanol or chemotherapy to evaluate the efficacy of therapy must be interpreted with caution. However, the low frequency of denuding reported by Gómez et al1Gómez V. Majumder S. Smyrk T.C. et al.Pancreatic cyst epithelial denudation: a natural phenomenon in the absence of treatment.Gastrointest Endosc. 2016; 84: 788-793Google Scholar for IPMNs (10.8% ± 21.0%) suggests that ablation rates higher than 50% for branched-duct IPMNs is probably reflective of ablation rather than of denuding. Because of the higher reported denuding rates for MCNs, interpreting the results of ablation of these tumors is likely more difficult. Published series to date8Gan S.I. Thompson C.C. Lauwers G.Y. et al.Ethanol lavage of pancreatic cystic lesions: initial pilot study.Gastrointest Endosc. 2005; 61: 746-752Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 9DeWitt J. McGreevy K. Schmidt C.M. et al.EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized, double-blind study.Gastrointest Endosc. 2009; 70: 710-723Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 10Oh H.C. Seo D.W. Song T.J. et al.Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts.Gastroenterology. 2011; 140: 172-179Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 11DeWitt J.M. Al-Haddad M. Sherman S. et al.Alterations in cyst fluid genetics following endoscopic ultrasound-guided pancreatic cyst ablation with ethanol and paclitaxel.Endoscopy. 2014; 46: 457-464Crossref PubMed Scopus (52) Google Scholar, 12Gómez V. Takahashi N. Levy M.J. et al.EUS-guided ethanol lavage does not reliably ablate pancreatic cystic neoplasms (with video).Gastrointest Endosc. 2016; 83: 914-920Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 13Moyer M.T. Dye C.E. Sharzehi S. et al.Is alcohol required for effective pancreatic cyst ablation? The prospective randomized CHARM trial pilot study.Endosc Int Open. 2016; 4: E603-E607Crossref Google Scholar, 14Park J.K. Song B.J. Ryu J.K. et al.Clinical outcomes of endoscopic ultrasonography-guided pancreatic cyst ablation.Pancreas. 2016; 45: 889-894Crossref Scopus (36) Google Scholar of histologic examination after surgical resection in patients undergoing EUS-guided pancreatic cyst ablation show that only 19 of 255 (7.5%) enrolled patients have undergone resection (Table 1). This low frequency of operative intervention after ablation principally reflects that most patients undergoing therapy with ethanol and chemotherapy have a complete or partial image-defined response to treatment,10Oh H.C. Seo D.W. Song T.J. et al.Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts.Gastroenterology. 2011; 140: 172-179Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 11DeWitt J.M. Al-Haddad M. Sherman S. et al.Alterations in cyst fluid genetics following endoscopic ultrasound-guided pancreatic cyst ablation with ethanol and paclitaxel.Endoscopy. 2014; 46: 457-464Crossref PubMed Scopus (52) Google Scholar, 13Moyer M.T. Dye C.E. Sharzehi S. et al.Is alcohol required for effective pancreatic cyst ablation? The prospective randomized CHARM trial pilot study.Endosc Int Open. 2016; 4: E603-E607Crossref Google Scholar whereas surgery is reserved for those with persistent cysts, rapid enlargement, or atypical cytologic features. Reported histologic ablation rates after endoscopic therapy range from 0% to 100% but are not reliably reported in 2 trials.8Gan S.I. Thompson C.C. Lauwers G.Y. et al.Ethanol lavage of pancreatic cystic lesions: initial pilot study.Gastrointest Endosc. 2005; 61: 746-752Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 14Park J.K. Song B.J. Ryu J.K. et al.Clinical outcomes of endoscopic ultrasonography-guided pancreatic cyst ablation.Pancreas. 2016; 45: 889-894Crossref Scopus (36) Google Scholar It is likely that if all patients (including those with complete or partial resolution) were to undergo surgery after therapy, these ablation rates would be much higher. Evidence of epithelial destruction after cyst ablation is measured not only histologically (as epithelial loss) or radiographically (as size change) but on a molecular, cytologic, and sonographic level. Therapy may eliminate genetic mutations present in cyst fluid, thus reflecting removal of the neoplastic tissue.11DeWitt J.M. Al-Haddad M. Sherman S. et al.Alterations in cyst fluid genetics following endoscopic ultrasound-guided pancreatic cyst ablation with ethanol and paclitaxel.Endoscopy. 2014; 46: 457-464Crossref PubMed Scopus (52) Google Scholar Furthermore, follow-up EUS and FNA cytologic analysis after ablation shows that compared with baseline measurements, cyst wall diameter increases in 68% of patients, and cyst fluid shows an increased amount of cells with acute and chronic inflammation.15Kim K.H. McGreevy K.A. La Fortune K. et al.Sonographic and cyst fluid cytological changes following the endoscopic ultrasound-guided pancreatic cyst ablation.Gastrointest Endosc. 2016; 83 ([abstract]): AB332-AB333Abstract Full Text Full Text PDF Google Scholar These findings likely reflect epithelial cell destruction, postablation inflammatory reaction, and replacement of the cyst lining with fibrosis similar to that observed in reported series.9DeWitt J. McGreevy K. Schmidt C.M. et al.EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized, double-blind study.Gastrointest Endosc. 2009; 70: 710-723Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 10Oh H.C. Seo D.W. Song T.J. et al.Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts.Gastroenterology. 2011; 140: 172-179Abstract Full Text Full Text PDF PubMed Scopus (165) Google ScholarTable 1Histologic results after surgical resection in patients undergoing EUS-guided pancreatic cyst ablationStudy (year)No. enrolledNo. to surgeryLavage agent(s)Clinical diagnosisEpithelial ablation (%)Associated histologic findingsGan et al (2005)8Gan S.I. Thompson C.C. Lauwers G.Y. et al.Ethanol lavage of pancreatic cystic lesions: initial pilot study.Gastrointest Endosc. 2005; 61: 746-752Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar255Increasing concentrations of ethanolMCN in all 5Variable, but up to 100No adjacent pancreatitisDeWitt et al (2009)9DeWitt J. McGreevy K. Schmidt C.M. et al.EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized, double-blind study.Gastrointest Endosc. 2009; 70: 710-723Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar424Saline solutionEthanolEthanolSaline solution + ethanolIPMNIPMNIPMNMCN050-7550-75100Rare pericystic chronic pancreatitisOh et al (2011)10Oh H.C. Seo D.W. Song T.J. et al.Endoscopic ultrasonography-guided ethanol lavage with paclitaxel injection treats patients with pancreatic cysts.Gastroenterology. 2011; 140: 172-179Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar524Ethanol + paclitaxelMCNMCNSCAPET25401000Variable denuded epithelium replaced with fibrosisDeWitt et al (2014)11DeWitt J.M. Al-Haddad M. Sherman S. et al.Alterations in cyst fluid genetics following endoscopic ultrasound-guided pancreatic cyst ablation with ethanol and paclitaxel.Endoscopy. 2014; 46: 457-464Crossref PubMed Scopus (52) Google Scholar223Ethanol + paclitaxelSCAMCNSCA0100100Not reportedGómez et al (2016)12Gómez V. Takahashi N. Levy M.J. et al.EUS-guided ethanol lavage does not reliably ablate pancreatic cystic neoplasms (with video).Gastrointest Endosc. 2016; 83: 914-920Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar230EthanolNANANAMoyer et al (2016)13Moyer M.T. Dye C.E. Sharzehi S. et al.Is alcohol required for effective pancreatic cyst ablation? The prospective randomized CHARM trial pilot study.Endosc Int Open. 2016; 4: E603-E607Crossref Google Scholar100Ethanol or saline solution, then gemcitabine and paclitaxelNANANAPark et al (2016)14Park J.K. Song B.J. Ryu J.K. et al.Clinical outcomes of endoscopic ultrasonography-guided pancreatic cyst ablation.Pancreas. 2016; 45: 889-894Crossref Scopus (36) Google Scholar913EthanolIPMNMCNMCNNot reportedNot reportedTotal25519MCN (11)IPMN (4)SCA (3)PET (1)IPMN, Intraductal papillary mucinous neoplasm; MCN, mucinous cystic neoplasm; NA, not applicable; PET, pancreatic endocrine tumor; SCA, serous cystadenoma. Open table in a new tab IPMN, Intraductal papillary mucinous neoplasm; MCN, mucinous cystic neoplasm; NA, not applicable; PET, pancreatic endocrine tumor; SCA, serous cystadenoma. In conclusion, the current study quantifies for the first time a long-observed phenomenon of histologic epithelial denudation of pancreatic cystic neoplasms. The data suggest that the frequency of denuding may vary by type of neoplasm, and location within the pancreas may inversely correlate with observed dysplasia. Prospective trials of patients proceeding to surgery without having undergone any endoscopy are ideally needed to replicate these findings. The author disclosed no financial relationships relevant to this publication. Pancreatic cyst epithelial denudation: a natural phenomenon in the absence of treatmentGastrointestinal EndoscopyVol. 84Issue 5PreviewThe presence and significance of epithelial denudation among treatment-naïve pancreatic cystic lesions (PCLs) remain undetermined. The aims of this study were to determine the prevalence, extent, and predictors of epithelial denudation in treatment-naïve PCLs. Full-Text PDF