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Repeated pancreatic cyst sampling for carcinoembryonic antigen analysis: Is it worth another poke?
EDITORIAL
Repeated pancreatic cyst sampling for carcinoembryonic antigen analysis: Is it worth another poke? With the rising diagnosis of asymptomatic pancreatic cysts comes the burden of triaging patients to the most appropriate management. Pancreatic cysts belong to diverse pathologic groups, many of which can be indistinguishable from one another on the basis of clinical and radiographic grounds. The management of any pancreatic cyst usually starts with a simple question: is this a mucinous or a nonmucinous lesion? Because of their malignant potential, mucinous lesions like intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms require imaging surveillance or surgical resection depending on their malignancy risk at the time of the diagnosis. By contrast, serous cysts have virtually no malignant potential and therefore require no further interventions unless they are symptomatic. Nowadays, incidental side-branch IPMNs are the most commonly encountered pancreatic cysts in our practices. They encompass a heterogeneous group of lesions with variable characteristics including size, location, multiplicity, and epithelial origin among many; most important is their ability to progress to malignancy, starting with high-grade dysplasia and ending with invasive disease. The widespread use of EUS-guided FNA (EUS-FNA) in pancreatic diseases has been accompanied by the emergence of various cyst-fluid biochemical and molecular markers. Although far from perfect, such markers like carcinoembryonic antigen (CEA) and K-ras mutations have made distinguishing mucinous from nonmucinous cysts feasible even when a very small amount of cyst fluid is available. However, the real challenge in managing mucinous cysts resides in our inability to accurately predict early malignancy (advanced dysplasia or minimally invasive cancer) in a lesion at the time they are detected. This represents the optimal stage at which to detect and resect a mucinous lesion before gross invasion ensues and has a negative impact on a patient’s survival. But if the cyst is not currently malignant (to the best of our knowledge), is it capable of aggressive biologic behavior in the future? To date, no single characteristic or a combination of imaging characteristics or cyst-fluid markers can answer this question with certainty. Therefore, our management of pancreatic cysts continues to rely on a
presumptive rather than a definitive knowledge of their future behavior in most patients. The management of asymptomatic pancreatic cysts has evolved as we have come to learn more about their natural history in the past few decades, as reflected in the multiple clinical practice and consensus guidelines.1-4 Initially, many patients were referred for surgical resection on the basis of a mere suspicion of a mucinous pathologic state. This later gave way to regular imaging surveillance for all cysts regardless of specific morphologic or clinical factors. We then realized that some cysts with certain features (like
The question remains: when should we undertake the extra risk and repeat FNA? Is change in cyst size alone sufficient? Should the development of new high-risk features on EUS trigger repeated sampling?
Copyright ª 2016 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2016.05.044
mural nodules, main duct involvement) possess a higher risk of malignancy and would benefit from more intensive management, whether close imaging surveillance or surgical resection. More recently, our community of practitioners has grown more permissive by adopting more relaxed imaging surveillance intervals or even discontinuing surveillance altogetherdin some cases after years of stability, as per the recent American Gastroenterological Association guidelines.2 Despite this rapid pace of evolution, our algorithms remain challenged by the imperfect surgical selection of patients, leading to many unnecessary pancreas resections known to be associated with high morbidity and mortality. Since its identification as the cyst-fluid tumor marker of choice to identify mucinous cysts more than a decade ago, CEA remains the most widely used assay to date. A level of 192 ng/mL provides a diagnostic accuracy of approximately 80% for a mucinous pathologic state.5 However, its role in the management of pancreatic cysts is limited to identifying mucinous lesions without being predictive of histologic grade or the presence of invasive malignancy. Therefore, its impact on decisions concerning surgical resection remains unclear, particularly in asymptomatic lesions or those lacking high-risk features. Finally, little is
www.giejournal.org
Volume 84, No. 5 : 2016 GASTROINTESTINAL ENDOSCOPY 785
Editorial
Al-Haddad
known about what factors affect the micromilieu within mucinous cysts that could lead to changes in CEA levels; even less known is whether this change in level represents a sign of disease progression to malignancy. In this issue of Gastrointestinal Endoscopy, Nakai et al6 present a single-center experience with the outcomes of repeated pancreas cyst-fluid analysis for CEA. Of 400 patients with pancreatic cysts aspirated during the span of the study, 87 underwent at least 2 or more separate EUSFNAs with cyst-fluid analysis included. Patients with repeated cyst sampling were more likely to have multifocal or multiloculated lesions or lesions that communicated with the pancreatic duct. In addition, this cohort had significantly higher initial CEA values (94.8 vs 25.6 ng/mL, P Z .003) despite the lack of any significant differences in EUS or cyst-fluid analysis between the index FNA and the prior one. Cyst-fluid CEA classification (using a cutoff value of 192 ng/mL or higher for mucinous lesion) changed in 17 patients (20%) based on CEA level changes between examinations without being associated with any other changes on EUS. After repeated EUS-FNA, surgical resection was performed in 3 patients, all found to have nonmalignant disease on pathologic examination. None of the 3 patients had a CEA change in category or new EUS findings of concern on the most recent EUS examination. Fourteen patients had at least 3 serial CEA levels available to study, but no specific trend or pattern of fluctuations was observed in this group. The investigators are commended for shedding light on a highly variable part of our EUS practices: resampling of pancreatic cysts during surveillance examinations. As it stands, several deficiencies weaken the conclusions of the study and remain to be fully elucidated by future research. First, the retrospective design of the study lends itself to potential selection bias in the cohort that underwent repeated sampling. This is further confounded by the lack of predefined criteria for repeated FNA, which was left to the discretion of the endosonographer. It is interesting that the investigators chose to reaspirate many lesions with previously established CEA levels and no new morphologic changes on EUS that aroused concern. Second, the clinical relevance of CEA fluctuations remains unclear in the absence of solid outcomes, either pathologic examination of surgically resected tissue or extended clinical and radiologic follow-up. Needless to say, extended follow-up would have provided serial data on more patients over time, allowing potential associations between CEA trends and clinical or radiologic outcomes. Finally, as practical as using a specific CEA cutoff might seem for classifying a mucinous cyst, minor oscillations above and below this cutoff point will change cyst classification and might dictate new management strategies in a lesion that has remained otherwise unchanged. We should nevertheless not dismiss the substantial value in documenting that the majority of patients would retain their initial cyst designation as mucinous or nonmucinous on the basis of CEA, which has not previously been reported.
The study likely reflects how the majority of endosonographers approach pancreatic cysts during surveillance and confirms that we continue to sample many lesions with prior CEA levels that are satisfactory for mucinous classification, and in the absence of EUS changes. Despite being overall a safe intervention, FNA is not entirely benign and could result in adverse events, including pancreatitis and infection in as many as 2% of patients, in addition to the need for prophylactic antibiotic coverage as routinely performed after cyst FNA. The question remains: when should we undertake the extra risk and repeat FNA? Is change in cyst size alone sufficient? Should the development of new high-risk features on EUS trigger repeated sampling? Some answers can be extracted from the current study by Nakai et al.6 At one end of the spectrum, the detection of new changes that arouse concern, like main duct involvement and definite mural nodules, that would justify surgical resection regardless of FNA outcomes, clearly obviates the need for repeated sampling. At the other end, a lesion lacking high-risk features with prior CEA clearly falling in the mucinous range (or the serous range, for that matter) likely requires no repeated sampling either. What is left is an infinite number of potential scenarios in which clinical judgment continues to direct our decisions. It is fair to state that repeated sampling is justifiable if no previous determination was reached regarding pathologic classification (ie, mucinous vs nonmucinous) caused by inconclusive cytology results, insufficient fluid for CEA or K-ras determinations, or CEA levels not conclusive for a mucinous diagnosis. It is also clear that fluctuations in CEA alone should not drive new management decisions, particularly referral to surgery. So where is the future of pancreatic cyst-fluid analysis taking us? In addition to tumor markers like CEA, cyst fluid remains a very rich medium for a variety of molecular assays. Mutations in oncogenes like K-ras and GNAS have shown promise in differentiating mucinous from nonmucinous lesions, but they remain unreliable predictors of advanced dysplasia or invasive cancer.7 MicroRNAs are currently under intensive study as potential differentiators between low-grade and high-grade dysplasia in mucinous cysts, but they remain investigational at this stage pending further prospective validation studies. Many believe that it is a matter of time before highly accurate biomarkers that both classify cysts and predict their biologic behavior are discovered. Until then, CEA will continue to serve as our rather inexpensive, widely available first-line cyst-fluid marker.
786 GASTROINTESTINAL ENDOSCOPY Volume 84, No. 5 : 2016
www.giejournal.org
DISCLOSURE Dr Al-Haddad is a consultant for Boston Scientific and disclosed no other financial relationships relevant to this publication.
Al-Haddad
Mohammad Al-Haddad, MD, MSc, FASGE, FACG, AGAF Department of Gastroenterology and Hepatology Digestive Disease Institute Cleveland Clinic Abu Dhabi Abu Dhabi, United Arab Emirates
Editorial
3.
4.
neoplastic pancreatic cysts. Gastroenterology 2015;148:819-22; quiz e12-3. Sahani DV, Kambadakone A, Macari M, et al. Diagnosis and management of cystic pancreatic lesions. AJR Am J Roentgenol 2013;200: 343-54. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006;6: 17-32. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004;126:1330-6. Nakai Y, Iwashita T, Shinoura S, et al. Role of serial EUS-guided FNA on pancreatic cystic neoplasms: a retrospective analysis of repeat carcinoembryonic antigen measurements. Gastrointest Endosc 2016;84: 780-4. Kadayifci A, Al-Haddad M, Atar M, et al. The value of KRAS mutation testing with CEA for the diagnosis of pancreatic mucinous cysts. Endoscopy Int Open 2016;4:e391-6.
Abbreviations: EUS-FNA, endoscopic ultrasound fine needle aspiration; CEA, carcinoembryonic antigen; IPMN, intraductal papillary mucinous neoplasm.
5.
REFERENCES
6.
1. Tanaka M, Fernandez-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183-97. 2. Vege SS, Ziring B, Jain R, et al. American Gastroenterological Association Institute guideline on the diagnosis and management of asymptomatic
7.
www.giejournal.org
Volume 84, No. 5 : 2016 GASTROINTESTINAL ENDOSCOPY 787
Repeated pancreatic cyst sampling for carcinoembryonic antigen analysis: Is it worth another poke? With the rising diagnosis of asymptomatic pancreatic cysts comes the burden of triaging patients to the most appropriate management. Pancreatic cysts belong to diverse pathologic groups, many of which can be indistinguishable from one another on the basis of clinical and radiographic grounds. The management of any pancreatic cyst usually starts with a simple question: is this a mucinous or a nonmucinous lesion? Because of their malignant potential, mucinous lesions like intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms require imaging surveillance or surgical resection depending on their malignancy risk at the time of the diagnosis. By contrast, serous cysts have virtually no malignant potential and therefore require no further interventions unless they are symptomatic. Nowadays, incidental side-branch IPMNs are the most commonly encountered pancreatic cysts in our practices. They encompass a heterogeneous group of lesions with variable characteristics including size, location, multiplicity, and epithelial origin among many; most important is their ability to progress to malignancy, starting with high-grade dysplasia and ending with invasive disease. The widespread use of EUS-guided FNA (EUS-FNA) in pancreatic diseases has been accompanied by the emergence of various cyst-fluid biochemical and molecular markers. Although far from perfect, such markers like carcinoembryonic antigen (CEA) and K-ras mutations have made distinguishing mucinous from nonmucinous cysts feasible even when a very small amount of cyst fluid is available. However, the real challenge in managing mucinous cysts resides in our inability to accurately predict early malignancy (advanced dysplasia or minimally invasive cancer) in a lesion at the time they are detected. This represents the optimal stage at which to detect and resect a mucinous lesion before gross invasion ensues and has a negative impact on a patient’s survival. But if the cyst is not currently malignant (to the best of our knowledge), is it capable of aggressive biologic behavior in the future? To date, no single characteristic or a combination of imaging characteristics or cyst-fluid markers can answer this question with certainty. Therefore, our management of pancreatic cysts continues to rely on a
presumptive rather than a definitive knowledge of their future behavior in most patients. The management of asymptomatic pancreatic cysts has evolved as we have come to learn more about their natural history in the past few decades, as reflected in the multiple clinical practice and consensus guidelines.1-4 Initially, many patients were referred for surgical resection on the basis of a mere suspicion of a mucinous pathologic state. This later gave way to regular imaging surveillance for all cysts regardless of specific morphologic or clinical factors. We then realized that some cysts with certain features (like
The question remains: when should we undertake the extra risk and repeat FNA? Is change in cyst size alone sufficient? Should the development of new high-risk features on EUS trigger repeated sampling?
Copyright ª 2016 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2016.05.044
mural nodules, main duct involvement) possess a higher risk of malignancy and would benefit from more intensive management, whether close imaging surveillance or surgical resection. More recently, our community of practitioners has grown more permissive by adopting more relaxed imaging surveillance intervals or even discontinuing surveillance altogetherdin some cases after years of stability, as per the recent American Gastroenterological Association guidelines.2 Despite this rapid pace of evolution, our algorithms remain challenged by the imperfect surgical selection of patients, leading to many unnecessary pancreas resections known to be associated with high morbidity and mortality. Since its identification as the cyst-fluid tumor marker of choice to identify mucinous cysts more than a decade ago, CEA remains the most widely used assay to date. A level of 192 ng/mL provides a diagnostic accuracy of approximately 80% for a mucinous pathologic state.5 However, its role in the management of pancreatic cysts is limited to identifying mucinous lesions without being predictive of histologic grade or the presence of invasive malignancy. Therefore, its impact on decisions concerning surgical resection remains unclear, particularly in asymptomatic lesions or those lacking high-risk features. Finally, little is
www.giejournal.org
Volume 84, No. 5 : 2016 GASTROINTESTINAL ENDOSCOPY 785
Editorial
Al-Haddad
known about what factors affect the micromilieu within mucinous cysts that could lead to changes in CEA levels; even less known is whether this change in level represents a sign of disease progression to malignancy. In this issue of Gastrointestinal Endoscopy, Nakai et al6 present a single-center experience with the outcomes of repeated pancreas cyst-fluid analysis for CEA. Of 400 patients with pancreatic cysts aspirated during the span of the study, 87 underwent at least 2 or more separate EUSFNAs with cyst-fluid analysis included. Patients with repeated cyst sampling were more likely to have multifocal or multiloculated lesions or lesions that communicated with the pancreatic duct. In addition, this cohort had significantly higher initial CEA values (94.8 vs 25.6 ng/mL, P Z .003) despite the lack of any significant differences in EUS or cyst-fluid analysis between the index FNA and the prior one. Cyst-fluid CEA classification (using a cutoff value of 192 ng/mL or higher for mucinous lesion) changed in 17 patients (20%) based on CEA level changes between examinations without being associated with any other changes on EUS. After repeated EUS-FNA, surgical resection was performed in 3 patients, all found to have nonmalignant disease on pathologic examination. None of the 3 patients had a CEA change in category or new EUS findings of concern on the most recent EUS examination. Fourteen patients had at least 3 serial CEA levels available to study, but no specific trend or pattern of fluctuations was observed in this group. The investigators are commended for shedding light on a highly variable part of our EUS practices: resampling of pancreatic cysts during surveillance examinations. As it stands, several deficiencies weaken the conclusions of the study and remain to be fully elucidated by future research. First, the retrospective design of the study lends itself to potential selection bias in the cohort that underwent repeated sampling. This is further confounded by the lack of predefined criteria for repeated FNA, which was left to the discretion of the endosonographer. It is interesting that the investigators chose to reaspirate many lesions with previously established CEA levels and no new morphologic changes on EUS that aroused concern. Second, the clinical relevance of CEA fluctuations remains unclear in the absence of solid outcomes, either pathologic examination of surgically resected tissue or extended clinical and radiologic follow-up. Needless to say, extended follow-up would have provided serial data on more patients over time, allowing potential associations between CEA trends and clinical or radiologic outcomes. Finally, as practical as using a specific CEA cutoff might seem for classifying a mucinous cyst, minor oscillations above and below this cutoff point will change cyst classification and might dictate new management strategies in a lesion that has remained otherwise unchanged. We should nevertheless not dismiss the substantial value in documenting that the majority of patients would retain their initial cyst designation as mucinous or nonmucinous on the basis of CEA, which has not previously been reported.
The study likely reflects how the majority of endosonographers approach pancreatic cysts during surveillance and confirms that we continue to sample many lesions with prior CEA levels that are satisfactory for mucinous classification, and in the absence of EUS changes. Despite being overall a safe intervention, FNA is not entirely benign and could result in adverse events, including pancreatitis and infection in as many as 2% of patients, in addition to the need for prophylactic antibiotic coverage as routinely performed after cyst FNA. The question remains: when should we undertake the extra risk and repeat FNA? Is change in cyst size alone sufficient? Should the development of new high-risk features on EUS trigger repeated sampling? Some answers can be extracted from the current study by Nakai et al.6 At one end of the spectrum, the detection of new changes that arouse concern, like main duct involvement and definite mural nodules, that would justify surgical resection regardless of FNA outcomes, clearly obviates the need for repeated sampling. At the other end, a lesion lacking high-risk features with prior CEA clearly falling in the mucinous range (or the serous range, for that matter) likely requires no repeated sampling either. What is left is an infinite number of potential scenarios in which clinical judgment continues to direct our decisions. It is fair to state that repeated sampling is justifiable if no previous determination was reached regarding pathologic classification (ie, mucinous vs nonmucinous) caused by inconclusive cytology results, insufficient fluid for CEA or K-ras determinations, or CEA levels not conclusive for a mucinous diagnosis. It is also clear that fluctuations in CEA alone should not drive new management decisions, particularly referral to surgery. So where is the future of pancreatic cyst-fluid analysis taking us? In addition to tumor markers like CEA, cyst fluid remains a very rich medium for a variety of molecular assays. Mutations in oncogenes like K-ras and GNAS have shown promise in differentiating mucinous from nonmucinous lesions, but they remain unreliable predictors of advanced dysplasia or invasive cancer.7 MicroRNAs are currently under intensive study as potential differentiators between low-grade and high-grade dysplasia in mucinous cysts, but they remain investigational at this stage pending further prospective validation studies. Many believe that it is a matter of time before highly accurate biomarkers that both classify cysts and predict their biologic behavior are discovered. Until then, CEA will continue to serve as our rather inexpensive, widely available first-line cyst-fluid marker.
786 GASTROINTESTINAL ENDOSCOPY Volume 84, No. 5 : 2016
www.giejournal.org
DISCLOSURE Dr Al-Haddad is a consultant for Boston Scientific and disclosed no other financial relationships relevant to this publication.
Al-Haddad
Mohammad Al-Haddad, MD, MSc, FASGE, FACG, AGAF Department of Gastroenterology and Hepatology Digestive Disease Institute Cleveland Clinic Abu Dhabi Abu Dhabi, United Arab Emirates
Editorial
3.
4.
neoplastic pancreatic cysts. Gastroenterology 2015;148:819-22; quiz e12-3. Sahani DV, Kambadakone A, Macari M, et al. Diagnosis and management of cystic pancreatic lesions. AJR Am J Roentgenol 2013;200: 343-54. Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006;6: 17-32. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004;126:1330-6. Nakai Y, Iwashita T, Shinoura S, et al. Role of serial EUS-guided FNA on pancreatic cystic neoplasms: a retrospective analysis of repeat carcinoembryonic antigen measurements. Gastrointest Endosc 2016;84: 780-4. Kadayifci A, Al-Haddad M, Atar M, et al. The value of KRAS mutation testing with CEA for the diagnosis of pancreatic mucinous cysts. Endoscopy Int Open 2016;4:e391-6.
Abbreviations: EUS-FNA, endoscopic ultrasound fine needle aspiration; CEA, carcinoembryonic antigen; IPMN, intraductal papillary mucinous neoplasm.
5.
REFERENCES
6.
1. Tanaka M, Fernandez-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183-97. 2. Vege SS, Ziring B, Jain R, et al. American Gastroenterological Association Institute guideline on the diagnosis and management of asymptomatic
7.
www.giejournal.org
Volume 84, No. 5 : 2016 GASTROINTESTINAL ENDOSCOPY 787