COMMENTARIES Managing Pancreatic Cysts: Less Is More? See related Commentaries on pages 685 and 692; Guideline, Clinical Decision Tool, and Technical Review (pages 819824); and related Commentary by RP Harris in the April issue of Annals of Internal Medicine.
T
he management of patients with an incidentally detected pancreatic cyst is a significant clinical challenge. The US Centers for Disease Control and Prevention reported a rising trend from 1996 to 2007 in the number of advanced imaging tests (MRI, CT, and positron emission tomography [PET]) ordered or provided in American hospital outpatient departments from 30 per 100 persons per year (Figure 1). Indeed, 15.8% of ambulatory visits in the United States were associated with an MRI or CT, compared with 4.4% 10 years before.1 With the increased use of MRI and CT, we are faced with the growing need to decide which of the thousands of detected cysts are innocuous and which are potentially deadly. To help clinicians manage patients with suspected mucin-producing cysts (branch duct intraductal papillary mucinous neoplasms [BD-IPMNs], and mucinous cystic neoplasms [MCNs]), an international multidisciplinary group proposed in 2006 consensus guidelines for management of these neoplastic cysts.2 These “Sendai guidelines” proposed repeat imaging annually for cysts 3 cm in size or for any cysts with associated symptoms or high-risk stigmata (enhancing mural nodules, dilated main pancreatic duct), or positive cyst fluid cytology. These 2006 Sendai guidelines were subsequently validated in a number of studies3–10 using retrospectively and prospectively collected data, and they proved to be highly sensitive in Gastroenterology 2015;148:688–691
identifying malignant, mucin-producing cysts. However, these guidelines were imperfect. For example, Pelaez–Luna et al6 reported that the use of the 2006 Sendai guidelines led to unnecessary surgery for some patients with benign low-risk cysts >3 cm, while missing 20% of cysts with high-grade dysplasia or an associated invasive cancer. The Sendai guidelines were therefore revised in 2012.11 With cyst size still a major driver of the recommendations, the newer guidelines sought to minimize operations on low-risk larger cysts and decrease the frequency of imaging (to every 2–3 years) for cysts 0.01% or 1 in 10,000 based on an analysis of Surveillance Epidemiology and End Results (SEER16) data in which the numerator includes “cystadenocarcinomas” or “mucinous pancreatic adenocarcinomas” and the denominator of all cysts is considered. This contrasts with the much higher prevalence of invasive malignancy (15%) and high-grade dysplasia (17%) in resected pancreatic cysts (predominantly BD-IPMNs) that physicians quote to patients. However, the use of SEER data in the technical review15 and the cited analysis by Gardner et al17 to estimate the prevalence of malignant cysts is a serious methodologic flaw. First, the term “cystadenocarcinoma” was historically used in a nonspecific manner to denote an invasive carcinoma arising in association with a mucinous cystic neoplasm (with ovarian stroma) or a carcinoma arising in either and MCN or an IPMN. Second, the term “cystadenocarcinoma” is no longer accepted by the World Health Organization18 or by the American Registry of Pathology.16 It should not be surprising that the SEER prevalence of “cystadenocarcinomas” is low if the term is no longer employed by most pathology practices. Hence, the estimated risk of malignancy in pancreatic cysts used in the review15 may be inaccurate owing to underreporting of malignant cysts. It is not impossible to provide an estimate of the prevalent or incident cancer risk in all asymptomatic pancreatic cysts because most cysts are not detected and most are not surgically removed.
COMMENTARIES
Figure 1.Ambulatory care visits with MRI/CT/PET scans ordered or provided. ED, emergency department; OPD, hospital outpatient department. (Reprinted from CDC/NCHS, Health, United States, 2009, Figure 25. Data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey.)
Given the limitations of the data, the technical review does provide us for the first time with pooled point estimates of cancer risk in pancreatic cysts. Based on imaging features of all resected cysts (data from retrospective cohorts, possibly with referral and selection bias), the prevalent risk of malignancy in cysts >3 cm compared with those 3 cm (pooled specificity, 49%; range, 44%54%) and dilated pancreatic duct (specificity, 80%; range, 75%-84%).15 We would want to know the pooled specificity and negative predictive value of MRI if 2 of the 3 concerning features (high-risk stigmata by Sendai guidelines11) were absent, because these test characteristics are used to support AGA guidelines 3, 4, and 5. The technical review also quantifies the estimated incident risk of malignancy
in uncharacterized cysts detected by imaging in from all over the world (22 case series, 42 invasive cancers in 6,240 patients during 18,079 patientyears of follow-up) to be 0.24% per year.15 Furthermore, in 37 case series involving 112 invasive cancers in 3,980 patients over 14,830 patient-years of follow up), the pooled incidence of malignancy in suspected BD-IPMN (nearly all retrospective) was 0.72% per year or only 2.8% overall (95% CI, 1.8%–4%).15 In contrast, 1 singlecenter, prospective study of 642 patients with suspected BD-IPMNs followed for median 4.8 years reported a standardized incidence rate of 10.7 (95% CI, 6.2–17.1).19 There were also no invasive cancers in 75 years of age (available from: http:// www.uspreventiveservicestaskforce.org/ uspstf/uspscolo.htm ). Another key principle of the AGA guidelines is to risk stratify cysts; the guidelines consider EUS-FNA only in selected MRI-detected cysts that have 2 positive high-risk stigmata (>3 cm, dilated duct, solid component), or if further characterization would change management. This would potentially eliminate a number of EUS procedures performed on low-risk cysts. The AGA guidelines rely on MRI for detection of cysts and risk stratification. The reliance on MRI and elimination of EUSFNA at baseline is problematic. First, the interobserver agreement between MRI and EUS in the evaluation of pancreatic cysts can be poor,4 and the misdiagnosis rate of the etiology of cysts on cross-sectional imaging can be high.4,20 Second, EUS-FNA improves diagnosis21 and risk stratification because of its higher resolution and the opportunity to biopsy the lesion and aspirate fluid for cytology.3,21 Cyst fluid cytology can detect more cancers in small cysts than high-risk stigmata3 or symptoms,22 and can diagnose malignancy in cancers without any high-risk imaging features.3,9 In addition, if EUS and cyst fluid sampling are not performed routinely in the absence of concerning features by MRI, how can we then accurately and confidently discriminate between neoplastic (the main target of the AGA guidelines) and non-neoplastic cysts? How can we exclude solid pseudopapillary neoplasms, cystic neuroendocrine tumors, cystic degeneration of pancreatic ductal adenocarcinomas, and main duct IPMNs, without adding cytology and tumor markers to the proposed algorithm? Finally, the value of obtaining cyst fluid will only grow as new molecular markers are developed that can type and grade cysts based on the mutational profile of the cyst fluid.23 We need clarification on how a clinician might confidently discharge a patient from a surveillance program based on MRI alone. We agree that high specificity is more important than high sensitivity in a low prevalence disease (malignant cysts), but more studies using the latest MRI technologies are 690
needed before we are comfortable with discontinuing follow-up and abandoning EUS-FNA as an adjunctive tool for baseline and follow-up diagnostic test. AGA guidelines 7 and 8 address the selection of patients for potentially preventative or curative (less likely) surgery for asymptomatic cysts only when both a solid component and/or a dilated main pancreatic duct are seen by MRI and preferably confirmed by EUS-FNA. It is unclear if this recommendation is independent of size. The AGA guidelines underscore the risk versus benefit of surgery versus do nothing. We strongly agree that referral to a center with expertise in pancreatic surgery and individualized decision making, ideally with a multidisciplinary approach,24 should be performed whenever operative treatment is considered. We should keep in mind that the decision to operate on an asymptomatic patient with advanced age and/or medical comorbidities is influenced by the prevalent risk of pancreatic malignancy, whereas the incident risk of cancer in young, surgically fit patient is what matters. Two unique, albeit unsupported, approaches of the AGA guidelines are the postoperative surveillance recommendations. Guideline 9 suggests we should continue postoperative surveillance in patients who had a pancreatic cyst with high-grade dysplasia or an associated invasive carcinoma every 2 years. Surveillance for a metachronous cancer makes sense, particularly if the patient is disease free from cancer. However, the choice of MRI and the selection of a 2-year interval both need to be supported. Short interval CT surveillance might be preferable owing to the lower spatial resolution of MRI. Invasive carcinomas have also been reported in patients
T
he management of patients with an incidentally detected pancreatic cyst is a significant clinical challenge. The US Centers for Disease Control and Prevention reported a rising trend from 1996 to 2007 in the number of advanced imaging tests (MRI, CT, and positron emission tomography [PET]) ordered or provided in American hospital outpatient departments from 30 per 100 persons per year (Figure 1). Indeed, 15.8% of ambulatory visits in the United States were associated with an MRI or CT, compared with 4.4% 10 years before.1 With the increased use of MRI and CT, we are faced with the growing need to decide which of the thousands of detected cysts are innocuous and which are potentially deadly. To help clinicians manage patients with suspected mucin-producing cysts (branch duct intraductal papillary mucinous neoplasms [BD-IPMNs], and mucinous cystic neoplasms [MCNs]), an international multidisciplinary group proposed in 2006 consensus guidelines for management of these neoplastic cysts.2 These “Sendai guidelines” proposed repeat imaging annually for cysts 3 cm in size or for any cysts with associated symptoms or high-risk stigmata (enhancing mural nodules, dilated main pancreatic duct), or positive cyst fluid cytology. These 2006 Sendai guidelines were subsequently validated in a number of studies3–10 using retrospectively and prospectively collected data, and they proved to be highly sensitive in Gastroenterology 2015;148:688–691
identifying malignant, mucin-producing cysts. However, these guidelines were imperfect. For example, Pelaez–Luna et al6 reported that the use of the 2006 Sendai guidelines led to unnecessary surgery for some patients with benign low-risk cysts >3 cm, while missing 20% of cysts with high-grade dysplasia or an associated invasive cancer. The Sendai guidelines were therefore revised in 2012.11 With cyst size still a major driver of the recommendations, the newer guidelines sought to minimize operations on low-risk larger cysts and decrease the frequency of imaging (to every 2–3 years) for cysts 0.01% or 1 in 10,000 based on an analysis of Surveillance Epidemiology and End Results (SEER16) data in which the numerator includes “cystadenocarcinomas” or “mucinous pancreatic adenocarcinomas” and the denominator of all cysts is considered. This contrasts with the much higher prevalence of invasive malignancy (15%) and high-grade dysplasia (17%) in resected pancreatic cysts (predominantly BD-IPMNs) that physicians quote to patients. However, the use of SEER data in the technical review15 and the cited analysis by Gardner et al17 to estimate the prevalence of malignant cysts is a serious methodologic flaw. First, the term “cystadenocarcinoma” was historically used in a nonspecific manner to denote an invasive carcinoma arising in association with a mucinous cystic neoplasm (with ovarian stroma) or a carcinoma arising in either and MCN or an IPMN. Second, the term “cystadenocarcinoma” is no longer accepted by the World Health Organization18 or by the American Registry of Pathology.16 It should not be surprising that the SEER prevalence of “cystadenocarcinomas” is low if the term is no longer employed by most pathology practices. Hence, the estimated risk of malignancy in pancreatic cysts used in the review15 may be inaccurate owing to underreporting of malignant cysts. It is not impossible to provide an estimate of the prevalent or incident cancer risk in all asymptomatic pancreatic cysts because most cysts are not detected and most are not surgically removed.
COMMENTARIES
Figure 1.Ambulatory care visits with MRI/CT/PET scans ordered or provided. ED, emergency department; OPD, hospital outpatient department. (Reprinted from CDC/NCHS, Health, United States, 2009, Figure 25. Data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey.)
Given the limitations of the data, the technical review does provide us for the first time with pooled point estimates of cancer risk in pancreatic cysts. Based on imaging features of all resected cysts (data from retrospective cohorts, possibly with referral and selection bias), the prevalent risk of malignancy in cysts >3 cm compared with those 3 cm (pooled specificity, 49%; range, 44%54%) and dilated pancreatic duct (specificity, 80%; range, 75%-84%).15 We would want to know the pooled specificity and negative predictive value of MRI if 2 of the 3 concerning features (high-risk stigmata by Sendai guidelines11) were absent, because these test characteristics are used to support AGA guidelines 3, 4, and 5. The technical review also quantifies the estimated incident risk of malignancy
in uncharacterized cysts detected by imaging in from all over the world (22 case series, 42 invasive cancers in 6,240 patients during 18,079 patientyears of follow-up) to be 0.24% per year.15 Furthermore, in 37 case series involving 112 invasive cancers in 3,980 patients over 14,830 patient-years of follow up), the pooled incidence of malignancy in suspected BD-IPMN (nearly all retrospective) was 0.72% per year or only 2.8% overall (95% CI, 1.8%–4%).15 In contrast, 1 singlecenter, prospective study of 642 patients with suspected BD-IPMNs followed for median 4.8 years reported a standardized incidence rate of 10.7 (95% CI, 6.2–17.1).19 There were also no invasive cancers in 75 years of age (available from: http:// www.uspreventiveservicestaskforce.org/ uspstf/uspscolo.htm ). Another key principle of the AGA guidelines is to risk stratify cysts; the guidelines consider EUS-FNA only in selected MRI-detected cysts that have 2 positive high-risk stigmata (>3 cm, dilated duct, solid component), or if further characterization would change management. This would potentially eliminate a number of EUS procedures performed on low-risk cysts. The AGA guidelines rely on MRI for detection of cysts and risk stratification. The reliance on MRI and elimination of EUSFNA at baseline is problematic. First, the interobserver agreement between MRI and EUS in the evaluation of pancreatic cysts can be poor,4 and the misdiagnosis rate of the etiology of cysts on cross-sectional imaging can be high.4,20 Second, EUS-FNA improves diagnosis21 and risk stratification because of its higher resolution and the opportunity to biopsy the lesion and aspirate fluid for cytology.3,21 Cyst fluid cytology can detect more cancers in small cysts than high-risk stigmata3 or symptoms,22 and can diagnose malignancy in cancers without any high-risk imaging features.3,9 In addition, if EUS and cyst fluid sampling are not performed routinely in the absence of concerning features by MRI, how can we then accurately and confidently discriminate between neoplastic (the main target of the AGA guidelines) and non-neoplastic cysts? How can we exclude solid pseudopapillary neoplasms, cystic neuroendocrine tumors, cystic degeneration of pancreatic ductal adenocarcinomas, and main duct IPMNs, without adding cytology and tumor markers to the proposed algorithm? Finally, the value of obtaining cyst fluid will only grow as new molecular markers are developed that can type and grade cysts based on the mutational profile of the cyst fluid.23 We need clarification on how a clinician might confidently discharge a patient from a surveillance program based on MRI alone. We agree that high specificity is more important than high sensitivity in a low prevalence disease (malignant cysts), but more studies using the latest MRI technologies are 690
needed before we are comfortable with discontinuing follow-up and abandoning EUS-FNA as an adjunctive tool for baseline and follow-up diagnostic test. AGA guidelines 7 and 8 address the selection of patients for potentially preventative or curative (less likely) surgery for asymptomatic cysts only when both a solid component and/or a dilated main pancreatic duct are seen by MRI and preferably confirmed by EUS-FNA. It is unclear if this recommendation is independent of size. The AGA guidelines underscore the risk versus benefit of surgery versus do nothing. We strongly agree that referral to a center with expertise in pancreatic surgery and individualized decision making, ideally with a multidisciplinary approach,24 should be performed whenever operative treatment is considered. We should keep in mind that the decision to operate on an asymptomatic patient with advanced age and/or medical comorbidities is influenced by the prevalent risk of pancreatic malignancy, whereas the incident risk of cancer in young, surgically fit patient is what matters. Two unique, albeit unsupported, approaches of the AGA guidelines are the postoperative surveillance recommendations. Guideline 9 suggests we should continue postoperative surveillance in patients who had a pancreatic cyst with high-grade dysplasia or an associated invasive carcinoma every 2 years. Surveillance for a metachronous cancer makes sense, particularly if the patient is disease free from cancer. However, the choice of MRI and the selection of a 2-year interval both need to be supported. Short interval CT surveillance might be preferable owing to the lower spatial resolution of MRI. Invasive carcinomas have also been reported in patients
