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Management of Undifferentiated Solitary Mucinous Cystic Lesion of the Pancreas: A Clinical Dilemma
Accepted Manuscript Management of Undifferentiated Solitary Mucinous Cystic Lesion of the Pancreas: A Clinical Dilemma Alexandra M. Roch, MD, MS, Katherine Bigelow, Christian M. Schmidt, II, Rosalie A. Carr, MD, Andrea L. Jester, MD, Eugene P. Ceppa, MD, FACS, Michael G. House, MD, FACS, Nicholas J. Zyromski, MD, FACS, Attila Nakeeb, MD, FACS, C Max Schmidt, MD, PhD, MBA PII:
S1072-7515(17)30066-2
DOI:
10.1016/j.jamcollsurg.2016.12.045
Reference:
ACS 8622
To appear in:
Journal of the American College of Surgeons
Received Date: 22 December 2016 Accepted Date: 22 December 2016
Please cite this article as: Roch AM, Bigelow K, Schmidt II CM, Carr RA, Jester AL, Ceppa EP, House MG, Zyromski NJ, Nakeeb A, Schmidt CM, Management of Undifferentiated Solitary Mucinous Cystic Lesion of the Pancreas: A Clinical Dilemma, Journal of the American College of Surgeons (2017), doi: 10.1016/j.jamcollsurg.2016.12.045. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Management of Undifferentiated Solitary Mucinous Cystic Lesion of the Pancreas: A Clinical Dilemma Alexandra M Roch, MD, MS1, Katherine Bigelow1, Christian M Schmidt II1, Rosalie A Carr, MD1, Andrea L Jester, MD1, Eugene P Ceppa, MD, FACS1, Michael G House, MD, FACS1, Nicholas J Zyromski, MD, FACS1, Attila Nakeeb, MD, FACS1, C Max Schmidt, MD, PhD, MBA1 Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
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Disclosure Information: Nothing to disclose.
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CE: Bigelow and Schmidt do not have degrees.
Presented at the Southern Surgical Association 128th Annual Meeting, Palm Beach, FL, December 2016.
Correspondence:
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C Max Schmidt, MD, PhD, MBA, FACS Vice Chairman of Surgery, Academic Affairs Chief of Surgery, IUH University Hospital Director, IUH Pancreatic Cyst and Cancer Early Detection Center Professor, Surgery, Biochemistry & Molecular Biology Indiana University School of Medicine 545 Barnhill Drive EH 129 Indianapolis, IN 46202 Phone: Office 317.948.8358 Email: [email protected]
Short title: Undifferentiated Solitary Mucinous Cysts
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ABSTRACT Background: Management of solitary mucinous cystic lesions of the pancreas (MCLs) relies on correct differentiation between branch-duct intraductal papillary mucinous neoplasm(BD-IPMN)
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and mucinous cystic neoplasm(MCN). Current international consensus guidelines recommend resection for MCN, whereas unifocal BD-IPMN may be followed in the absence of worrisome
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features/high-risk stigmata. We hypothesized that preoperative differentiation of solitary MCLs is suboptimal, and that all solitary MCLs should be treated similarly. Methods: A retrospective review of an institutional database (2003-2016) identified 711 patients who underwent resection for pancreatic cyst. Only lesions that met cytological and/or biochemical criteria for diagnosis of MCLs were included. MCN were defined by presence of
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ovarian stroma on pathology. Patients with formal preoperative diagnosis of BD-IPMN (multifocality, GNAS mutation) were excluded.
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Results: 180 solitary MCLs were identified on preoperative imaging (mean age 54 years, 24% men). On surgical pathology, 108 were MCN and 72 BD-IPMN. There was no difference in
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invasive rate (7/108=6.5% MCN vs. 4/72=5.6% BD-IPMN, p≈1). Pancreatic ductal connectivity was reported on imaging/endoscopy in 10/108(9%) MCN and 22/72(31%) BD-IPMN, representing a 67% accuracy in differentiating MCN from BD-IPMN. On multivariate analysis, typical risk factors failed to predict invasiveness in either MCN or BD-IPMN. When all undifferentiated solitary MCLs were analyzed together, older age(p=0.03) and cyst size (p=0.04) were associated with increased invasive rate in multivariate analysis.
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Conclusion: Unreliable differentiation and limited ability to predict invasiveness make solitary MCLs clinically challenging. With similar invasive rates, MCN and unifocal BD-IPMN should be merged into one new entity for management, the undifferentiated solitary mucinous cystic
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lesion (US-MCLs).
INTRODUCTION Solitary mucinous cystic lesions of the pancreas (MCLs) are well established
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precancerous pancreatic lesions that follow a stepwise malignant progression pattern similar to that of polyp in colonic cancer1,2. Solitary MCLs include mucinous cystic neoplasm (MCN) and
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unifocal branch-duct intraductal papillary mucinous neoplasm (BD-IPMN)3.
Lacking clear differentiation criteria, remote surgical series used to consider both MCN and BDIPMN under the vague term “mucinous cystadenoma”4. In 2000, the World Health Organization incorporated the presence of ovarian stroma on pathology in the definition of MCN5. As our knowledge of MCLs grew, MCN and BD-IPMN also appeared to be 2 distinct neoplasms based
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on demographic characteristics and biologic behavior2,6-9. MCN occur almost exclusively in the pancreatic body/tail of young women, whereas BD-IPMN is usually diagnosed in older patients,
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preferentially involving the head of the pancreas7,8. Although the true natural history of MCN and BD-IPMN remains uncertain due to only
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scarce surveillance studies, numerous surgical series have reported the rate of invasive carcinoma in resected specimens for both lesions. BD-IPMN and MCN are associated with invasive rates of 4-15%2 and 6-37%3,6,9-14, respectively. Despite comparable rates of malignancy in both lesions, the 2012 revised International Consensus Guidelines recommend resection for MCN in all patients fit to undergo surgery, whereas surveillance of BD-IPMN is recommended in the absence of worrisome features or high-risk stigmata2. This distinct management relies heavily on correct preoperative differentiation between MCN and BD-IPMN, but the 2000
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World Health Organization definition of both entities is based on the postoperative presence/absence of ovarian stroma on pathology5,13. As such, the 2012 revised International Consensus Guidelines recommends radiographic/endoscopic identification of a connection to the
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main pancreatic duct as the preoperative distinguishing feature of BD-IPMN2.
We hypothesized that preoperative differentiation of solitary MCLs is suboptimal and that all undifferentiated solitary MCLs should be treated similarly.
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PATIENTS AND METHODS Patients selection
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From 2003 to 2016, electronic medical records of all patients who underwent pancreatic surgical resection for a pancreatic cyst at Indiana University Hospital were retrospectively reviewed (n=711). Patients with IPMN were prospectively collected in a database. For the purpose of this study, the database was supplemented with patients operated on for MCN. Data were compiled and reported in strict compliance with patient confidentiality guidelines as
Exclusion criteria
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defined by the Indiana University Institutional Review Board.
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Patients with incomplete pathological data or a final pathological diagnosis consistent with a non-mucinous cyst were excluded from our study. Patients with a high preoperative
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probability or formal diagnosis of IPMN were also excluded. This category comprised patients with isolated cystic dilation of the main pancreatic duct on preoperative imaging (owing to the likely diagnosis of main duct IPMN), multifocal cystic lesions on imaging/endoscopic studies and/and GNAS mutation on cyst fluid analysis (owing to the likely diagnosis of BD-IPMN). Patients with main duct involved IPMN (main-duct and mixed-type) on review of final pathology of the surgical specimen were also excluded. Pathology
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All pathological specimens were reviewed by staff pathologists with expertise in pancreatology to confirm the diagnosis of BD-IPMN or MCN. Histology was consistent with BD-IPMN if it showed an intraductal proliferation of tall, columnar, mucin-producing cells,
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arising from the branch duct, with or without papillary projections, and without ovarian-type stroma1,2. Conversely, the presence of ovarian stroma on pathology was pathognomonic of
MCN5. Ovarian stroma formed a layer of variable thickness beneath the epithelial lining, with
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stromal cells characterized by oval nuclei and spindled cytoplasm and arranged in long fascicles. The presence of ovarian stroma was confirmed by immunohistochemical staining showing
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stromal cells positive for estrogen receptor. Malignant BD-IPMN or MCN were defined according to the WHO classification as invasive carcinoma in the surgical specimen2,15. Parameters assessed
Medical records of patients were reviewed to obtain demographic and clinical data,
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including gender, age, presence and type of signs/symptoms/conditions (abdominal/back pain, nausea/vomiting, acute pancreatitis, steatorrhea/diarrhea, diabetes, weight loss, jaundice), and family history of pancreatic cancer. Size, location, dilation of the main pancreatic duct, thickness
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of walls, presence of septations, mural nodule/solid component and main duct connectivity were assessed on preoperative cross sectional imaging studies (computed tomography or magnetic
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resonance imaging/ magnetic resonance cholangiopancreatography) or pancreatic-directed endoscopic studies (endoscopic ultrasound, endoscopic cholangiopancreatography). Statistical analysis
Data were recorded using Microsoft Excel 2014 (Microsoft, Inc., Redmond, WA, USA)
and analyzed with IBM SPSS statistics version 21.0® (Armonk, NY: IBM Corp). Descriptive statistics for continuous data included median, mean, range, and standard error. Categorical data
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were expressed as numbers and percentages. Categorical data were compared with Fisher’s exact test, whereas Student’s t test compared continuous variables. Independent predictors of malignant progression were determined with univariable and multivariable analyses using a
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logistic regression model. Criteria with p-value <0.1 in univariate analysis were subsequently entered in the multivariate model. P-value <0.05 was accepted as statistically significant.
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RESULTS Patients population (Figure 1.)
Of the 711 patients who underwent resection for pancreatic cyst during the study period,
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455 were excluded due to a known preoperative diagnosis of BD-IPMN or MCN. Of the remaining 256 patients, 76 were excluded post hoc due to a postoperative diagnosis of mixedtype IPMN on surgical pathology. That left us with 180 patients (25.3%) identified as undifferentiated solitary MCLs on preoperative work-up. Mean age at surgery was 54.1 year (+/15.4, range 21-86), with a gender ratio of 0.3 (43 men, 137 women). The main indication for
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surgery was symptoms in 94 patients (52.2%). Other indications included a large size or an increase in size (n=34, 18.9%), patient’s preference (n=12, 6.7%), preoperative diagnosis of
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mucinous cyst in itself (n=11, 6.1%), suspected malignancy on preoperative workup (n=10, 5.6%), main pancreatic duct dilation (n=9, 5%), presence of mural nodule or solid component
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(n=7, 3.9%), and a family history of pancreatic cancer (n=3, 1.7%). Pathology
Among the 180 patients with undifferentiated solitary MCLs, 108 (60%) and 72 (40%)
were classified on pathology as MCN and unifocal BD-IPMN, respectively. Of the 108 MCN, 100 (92.6%) were low to moderate dysplasia (former adenoma), 1 (0.9%) was high-grade dysplasia (former carcinoma in situ) and 7 (6.5%) were invasive carcinoma. Regarding unifocal BD-IPMN (n=72), 64 (88.8%) were low/moderate dysplasia, 4 (5.6%) were high-grade dysplasia
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and the remaining 4 (5.6%) invasive carcinoma. There was no difference in invasive rate between MCN and unifocal BD-IPMN (6.5% vs. 5.6%, p≈1). Main duct connection (Table 1)
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Main pancreatic duct connectivity was reported on imaging and/or endoscopic studies in 10 MCN (9.3%) and 22 unifocal BD-IPMN (30.6%). Using ductal connection to differentiate
(sensitivity=30.6% and specificity=90.7%). Predictors of pathology subtype (Table 2)
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Clinical characteristics
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between MCN and unifocal BD-IPMN was associated with an accuracy of 66.7%
Patients with MCN were more likely to be young (48 vs. 63.3 years, p<0.0001) and women (all but 8, p<0.0001). Patients with BD-IPMN were more likely to present with jaundice (27.3% vs. 1.2%, p=0.0016). Acute pancreatitis was more common in patients with BD-IPMN
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than patients with MCN (33.3% vs. 13.9%, p=0.003). However, on multivariable analysis, only age and gender were statistical independent predictors of BD-IPMN vs. MCN (p=0.01 and 0.002, respectively).
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Imaging/endoscopy characteristics
The median diameter of the neoplasm on imaging studies was 3.6 cm (mean 4.6 cm +/-
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3.5, range 0.5-21.1). MCN were more frequently located in the tail of the pancreas (n=105, 97.2%), whereas BD-IPMN were more likely to be in the head of the pancreas (n=52, 72.2%) (p<0.0001). One hundred and seventy-six patients (97.8%) underwent either an endoscopic ultrasound (EUS) or an endoscopic retrograde cholangiopancreatography (ERCP) as part of their workup, with 134 (74.4%) patients having a fine needle aspiration and/or brushing and cytological evaluation. Thick walls and septations were reported in 34 (18.9%) and 76 (42.2%)
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of all MCLs, respectively, and more commonly found in MCN compared to unifocal BD-IPMN (thick walls: 27.8% vs. 5.6%, p=0.0002; septations: 49.1% vs. 31.9%, p=0.03). On multivariable
cyst size (larger in MCN) were predictive of BD-IPMN vs. MCN. Predictive factors of invasiveness (Table 3)
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analysis, however, only location in the pancreas (head for BD-IPMN vs. body/tail for MCN) and
When analyzed separately in multivariate analysis, typical risk factors (age, cyst
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diameter, main pancreatic duct dilation>5mm, mural nodule, symptoms especially acute
pancreatitis) failed to predict invasiveness in either MCN or unifocal BD-IPMN. Only jaundice
head of the pancreas (p<0.0001).
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was associated with a higher rate of invasive BD-IPMN due to its preferential location in the
When all MCLs were analyzed together, however, an older age and a larger cyst diameter were independently associated with an increased risk of invasive lesion (p=0.02 and p=0.04,
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respectively). When cyst size was analyzed through Receiver Operator Curve, it was, alone, a poor predictor of invasiveness with an area under curve of only 0.67 (Figure 2.). The best cut-off was found at 2.95 cm with a sensitivity of 82%, but an associated low specificity of 38%.
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Interestingly, a main pancreatic duct dilation of 5mm or greater and a mural nodule/solid component, were not associated with a statistically significant risk of malignant progression
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(p=0.30 and p=0.33, respectively). Intention-to-treat analysis
Seventy-six undifferentiated solitary MCLs were excluded post hoc because they were
found to be mixed-type IPMN on surgical pathology. Of these, 15 (20%) were invasive carcinoma. If those patients were included in an intention-to-treat analysis, the overall rate of invasive undifferentiated solitary MCLs would be 10% (6.5% MCN vs. 13% BD-IPMN,
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p=0.14). In an intention-to-treat analysis, main duct dilation of 5mm or greater was a multivariable risk factor for invasive carcinoma. Older age and larger cyst size remained independent predictors of invasiveness in-intention-to treat analysis.
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DISCUSSION
In 1978, Compagno and Oertel made a distinction between serous and mucinous
cystadenomas emphasizing the benign course of serous and the malignant potential of mucinous
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cysts16. It was not until 2000 that the WHO classified BD-IPMN and MCN as distinct lesions based on the presence/absence of ovarian stroma3,5,7,8. BD-IPMN and MCN represent the most
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frequent cystic lesions of the pancreas (up to 40% and 20%, respectively)17-21. The 2012 International Consensus Guidelines recommend resection of all MCN in surgically fit patients and non-operative management of BD-IPMN in the absence of worrisome features or high-risk stigmata2.
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This retrospective review of all solitary pancreatic MCLs found no difference in invasive rate between BD-IPMN and MCN (6.5 vs. 5.6, p≈1). A review of the most important series of MCN from the literature shows a wide discrepancy in malignancy rate ranging from 6 to 36%3,4, . This may in part be explained by the lack of standardized pathology especially the
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6,10-14
requirement of ovarian stroma to define MCN 4,12-14. As a result, MCN series were likely
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confounded by the presence of mixed type IPMN, lesions that typically have a higher malignancy rate that MCN. In our series the prevalence of invasive carcinoma in MCN is in line with the series from Reddy et al. (7%)7. Preoperative differentiation between BD-IPMN and IPMN is necessary for optimal
management as per the 2012 International Consensus Guidelines2. In a study by Correa-Gallego, 4/30 (13.3%) preoperative MCN were BD-IPMN on pathology, and 1/50 (2%) preoperative BD-
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IPMN were MCN on final pathology22 . This degree of accuracy, however, is the exception. Multifocality is associated with BD-IPMN, but is not a reliable diagnostic feature in the setting of solitary cysts. There is currently no definite serum biomarker to distinguish MCN from BD-
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IPMN, but based on studies from a Lustgarten Foundation Consortium (Johns Hopkins, Indiana University and Memorial Sloan Kettering), GNAS mutations are found in IPMN and no other types of pancreatic cystic neoplasms. GNAS testing, however, is not widely used and is only
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present in 52/86 (61%) of IPMN 23,24. A core biopsy to rule in/out ovarian stroma can
distinguish IPMN from MCN but is rarely used owing to the perceived high procedural risk.
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In the present series, we analyzed main duct communication as a diagnostic criterion to differentiate between BD-IPMN and MCN as it is currently recommended by the International Consensus Guidelines. This feature was associated with a high specificity of 90.7%, but a low sensitivity of 30.6% and an associated accuracy of only 66.7%. The low reliability of main duct
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connectivity in distinguishing BD-IPMN from MCN has been described in a prior study by Zamboni et al.6 In this study, MCN from 48 patients had ovarian stroma on pathology. Eight additional patients (14%) were included as MCN based on the lack of main-duct connection
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although pathology did not show ovarian stroma. Patients without ovarian stroma on pathology were significantly older (63 vs. 46 years old, p=0.007) and had higher rate of invasive carcinoma
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(62.5% vs. 26.3%, p=0.01). It appears that the tumors without ovarian stroma had a distinctly different demographic profile compared to those with ovarian stroma and this MCN population may have been “contaminated” with mixed type IPMN patients. When BD-IPMN and MCN in our seriesa were analyzed separately to assess for
invasiveness risk factors, typical criteria failed to predict invasive carcinoma. When all MCL were analyzed together, however, older age (p=0.03) and cyst diameter (p=0.02) were associated
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with a higher rate of invasive lesions in multivariate analysis. Those 2 criteria have been previously described in the literature. In our study, patients with invasive MCLs were found to be 15 years older than those with non-invasive lesions (68 vs. 53 years old), suggesting a
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progression of benign MCLs to malignancy. Sarr et al.12 and Zamboni et al.6 have reported similar data regarding MCN, whereas Matthaei et al.25 described the same phenomenon in
IPMN. Similarly, previous studies have shown that invasive MCN were significantly larger than
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benign lesions. In a combined analysis, those studies represent a total of 385 patients and found a size cut-off at 3cm to predict invasive carcinoma3,6,7,11. This is similar to our result of a 2.95cm
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cut-off. Reddy et al.12, however, have set a cut-off for invasiveness and surgical resection at a larger diameter of 5cm.
Our study presents limitations. It has a selection bias as only surgically resected MCLs are included. Thus, the true natural history (and true rate of invasiveness) remains uncertain. It is
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possible that pathological misclassification may occur as ovarian stroma is not seen on every slide in MCN. In Reddy’s series7, ovarian stroma was only present in 76% of slides, suggesting that correct pathological distinction between BD-IPMN and MCN may require thin sectioning to
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obtain adequate sampling. Finally, main duct communication as a criterion to differentiate between BD-IPMN and MCN is often detected preoperatively on endoscopic ultrasound studies,
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an operator-dependent test.
Patients with MCLs are middle aged (median age 54 years old) with a long life
expectancy. Surveillance would require periodic cross-sectional imaging studies (computed tomography or magnetic resonance imaging/magnetic resonance cholangiopancreatography) and/or endoscopic studies (endoscopic ultrasound, endoscopic cholangiopancreatography) and long follow-up. The risk associated with pancreatic surgery (mortality 1%, morbidity 20-
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40%)26,27 needs to be weighed against the anxiety and the cost of a long-term follow-up protocol28. Although the cornerstone of management for pancreatic mucinous cystic neoplasm relies
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on a reliable differentiation between unifocal BD-IPMN and MCN, main duct communication reported on imaging/endoscopy has limited predictability. If present, it is very specific for BDIPMN, but it is only visualized in 31% of those lesions. In the present series, independent
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predictors of solitary MCN over solitary BD-IPMN included young age, female gender, body/tail location in the pancreas and larger cyst size. However, there is no failsafe combination of these
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criteria. In doubtful cases, it is better to classify these mucinous lesions as “undifferentiated” solitary MCLs rather than to include them with one entity or the other. Unifocal BD-IPMN and MCN have similar invasive rates, with only a size of 3cm or greater associated with invasive carcinoma. Due to the limited ability to correctly identify the pathological subtype preoperatively
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and to predict invasiveness, we believe that the International Consensus Guidelines could be
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improved if preoperative undifferentiated solitary MCLs were addressed as a new entity.
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16. Compagno J, Oertel JE. Mucinous cystic neoplasms of the pancreas with overt and latent malignancy (cystadenocarcinoma and cystadenoma). A clinicopathologic study of 41 cases. Am J Clin Pathol 1978;69:573–580.
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Table 1. Performance Characteristics of Main Duct Connection in Differentiating Branch-Duct Intraductal Papillary Mucinous Neoplasm from Mucinous Cystic Neoplasm MCN (n=108)
MPD connection
22 (TP)
10 (FP)
No MPD connection
50 (FN)
Sensitivity=30.6%; Specificity=90.7%; Accuracy=66.7%
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BD-IPMN (n=72)
Connection
98 (TN)
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BD-IPMN, branch-duct intraductal papillary mucinous neoplasm; MCN, mucinous cystic neoplasm; MPD: main pancreatic duct; TP, true positive; FP, false positive; FN, false negative; TN, true negative
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Table 2. Univariate and Multivariate Analysis for Predictors of Pathological Subtypes (BranchDuct Intraductal Papillary Mucinous Neoplasm vs. Mucinous Cystic Neoplasm) MCN (n=108)
Univariate p Value
63.3 35 (48.6)
48 8 (7.4)
<0.0001* <0.0001*
0.01† 0.002†
0.07*
0.96
Demographic Age, y, mean Sex, m, n (%) Family history of pancreatic cancer, n (%) Clinical, n (%) Symptoms Abdominal/back pain Nausea/vomiting
4 (3.7)
8 (11.1)
80 (74.1) 73 (67.6) 26 (24.1)
57 (79.2) 48 (66.7) 21 (29.2)
Acute pancreatitis
24 (33.3)
Steatorrhea/diarrhea Diabetes Weight loss Jaundice Imaging/endoscopy Location, head, n (%) Thick walls, n (%) Septations, n (%) MPD communication, n (%)
18 (16.7) 13 (12) 15 (13.9) 3 (27.3)
*
-
15 (13.9)
0.003*
0.54
17 (23.6) 13 (18.1) 17 (23.6) 2 (1.2)
0.26 0.28 0.11 0.0016*
0.16
52 (72.2) 4 (5.6) 23 (31.9)
3 (2.8) 30 (27.8) 53 (49.1)
<0.0001* 0.0002* 0.03*
<0.0001† 0.7 0.59
22 (30.6)
10 (9.3)
<0.0001*
0.59
5.8
<0.0001*
0.006†
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0.48 ≈1 0.49
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Cyst size, cm, mean
Multivariate p Value
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BD-IPMN (n=72)
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Variable
2.7
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Statistically significant p Value in univariate p Value Statistically significant p Value in multivariate p Value MCN, mucinous cystic neoplasm; BD-IPMN, branch-duct intraductal papillary mucinous neoplasm; MPD: main pancreatic duct
†
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Table 3. Univariate and Multivariate Analysis of All Undifferentiated Solitary Mucinous Cystic Lesions (N=180) for Independent Predictors of Invasiveness Non-invasive
Univariate
Multivariate
lesion (n=11)
lesion (n=169)
p Value
p Value
Age, y, mean
68.4
53.2
Sex, m, n (%)
5 (45.5)
38 (22.5)
Demographic
Clinical, n (%)
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Invasive
Variable
0.0014*
0.025†
0.14
-
≈1
-
0 (0)
12 (7.1)
7 (63.6)
130 (76.9)
0.3
-
Abdominal/ back pain
5 (45.5)
116 (68.6)
0.18
-
Nausea/vomiting
1 (9.1)
46 (27.2)
0.29
-
Acute pancreatitis
0 (0)
39 (23.1)
0.12
-
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Family history of pancreatic cancer Symptoms
2 (18.2)
33 (19.5)
≈1
-
Diabetes
2 (18.2)
24 (14.2)
0.66
-
Weight loss
2 (18.2)
30 (17.8)
≈1
-
Jaundice Imaging/endoscopy
3 (27.3)
2 (1.2)
0.0016*
0.99
4 (36.4)
51 (30.2)
0.74
-
Location, head, n (%)
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Steatorrhea/diarrhea
4.4
0.033
0.039†
3 (27.3)
15 (8.9)
0.08*
0.29
Thick walls, n (%)
1 (9.1)
33 (19.5)
0.69
-
Septations, n (%)
2 (18.2)
74 (43.8)
0.12
-
Mural nodule/solid 2 (18.2) component, n (%) * Significant p Value in univariate analysis
19 (11.2)
0.62
-
Cyst size, cm, mean
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(%)
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MPD dilation >5mm, n
†
6.7
*
Significant p Value in multivariate analysis
MPD, Main pancreatic duct
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Figure Legend Figure 1. Flow chart of patients who met inclusion/exclusion criteria for the study population
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MCN, Mucinous cystic neoplasm; BD-IPMN, branch-duct intraductal papillary mucinous neoplasm; MT-IPMN, Mixed-type intraductal papillary mucinous neoplasm; MCLs, Mucinous cystic lesions Figure 2. Receiver Operating Curve analyzing performance characteristics of cyst size in predicting invasiveness in undifferentiated solitary MCLs.
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MCLs, mucinous cystic lesions; Se, sensitivity; Sp, specificity, AUC, area under curve
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Precis Unreliable differentiation and limited ability to predict invasiveness make solitary pancreatic
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mucinous cysts clinically challenging. With similar invasive rates, mucinous cystic neoplasm and unifocal branch-duct intraductal papillary mucinous neoplasm should be merged into one
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new entity for management, the undifferentiated solitary mucinous cystic lesion.
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S1072-7515(17)30066-2
DOI:
10.1016/j.jamcollsurg.2016.12.045
Reference:
ACS 8622
To appear in:
Journal of the American College of Surgeons
Received Date: 22 December 2016 Accepted Date: 22 December 2016
Please cite this article as: Roch AM, Bigelow K, Schmidt II CM, Carr RA, Jester AL, Ceppa EP, House MG, Zyromski NJ, Nakeeb A, Schmidt CM, Management of Undifferentiated Solitary Mucinous Cystic Lesion of the Pancreas: A Clinical Dilemma, Journal of the American College of Surgeons (2017), doi: 10.1016/j.jamcollsurg.2016.12.045. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Management of Undifferentiated Solitary Mucinous Cystic Lesion of the Pancreas: A Clinical Dilemma Alexandra M Roch, MD, MS1, Katherine Bigelow1, Christian M Schmidt II1, Rosalie A Carr, MD1, Andrea L Jester, MD1, Eugene P Ceppa, MD, FACS1, Michael G House, MD, FACS1, Nicholas J Zyromski, MD, FACS1, Attila Nakeeb, MD, FACS1, C Max Schmidt, MD, PhD, MBA1 Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
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Disclosure Information: Nothing to disclose.
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CE: Bigelow and Schmidt do not have degrees.
Presented at the Southern Surgical Association 128th Annual Meeting, Palm Beach, FL, December 2016.
Correspondence:
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C Max Schmidt, MD, PhD, MBA, FACS Vice Chairman of Surgery, Academic Affairs Chief of Surgery, IUH University Hospital Director, IUH Pancreatic Cyst and Cancer Early Detection Center Professor, Surgery, Biochemistry & Molecular Biology Indiana University School of Medicine 545 Barnhill Drive EH 129 Indianapolis, IN 46202 Phone: Office 317.948.8358 Email: [email protected]
Short title: Undifferentiated Solitary Mucinous Cysts
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ABSTRACT Background: Management of solitary mucinous cystic lesions of the pancreas (MCLs) relies on correct differentiation between branch-duct intraductal papillary mucinous neoplasm(BD-IPMN)
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and mucinous cystic neoplasm(MCN). Current international consensus guidelines recommend resection for MCN, whereas unifocal BD-IPMN may be followed in the absence of worrisome
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features/high-risk stigmata. We hypothesized that preoperative differentiation of solitary MCLs is suboptimal, and that all solitary MCLs should be treated similarly. Methods: A retrospective review of an institutional database (2003-2016) identified 711 patients who underwent resection for pancreatic cyst. Only lesions that met cytological and/or biochemical criteria for diagnosis of MCLs were included. MCN were defined by presence of
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ovarian stroma on pathology. Patients with formal preoperative diagnosis of BD-IPMN (multifocality, GNAS mutation) were excluded.
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Results: 180 solitary MCLs were identified on preoperative imaging (mean age 54 years, 24% men). On surgical pathology, 108 were MCN and 72 BD-IPMN. There was no difference in
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invasive rate (7/108=6.5% MCN vs. 4/72=5.6% BD-IPMN, p≈1). Pancreatic ductal connectivity was reported on imaging/endoscopy in 10/108(9%) MCN and 22/72(31%) BD-IPMN, representing a 67% accuracy in differentiating MCN from BD-IPMN. On multivariate analysis, typical risk factors failed to predict invasiveness in either MCN or BD-IPMN. When all undifferentiated solitary MCLs were analyzed together, older age(p=0.03) and cyst size (p=0.04) were associated with increased invasive rate in multivariate analysis.
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Conclusion: Unreliable differentiation and limited ability to predict invasiveness make solitary MCLs clinically challenging. With similar invasive rates, MCN and unifocal BD-IPMN should be merged into one new entity for management, the undifferentiated solitary mucinous cystic
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lesion (US-MCLs).
INTRODUCTION Solitary mucinous cystic lesions of the pancreas (MCLs) are well established
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precancerous pancreatic lesions that follow a stepwise malignant progression pattern similar to that of polyp in colonic cancer1,2. Solitary MCLs include mucinous cystic neoplasm (MCN) and
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unifocal branch-duct intraductal papillary mucinous neoplasm (BD-IPMN)3.
Lacking clear differentiation criteria, remote surgical series used to consider both MCN and BDIPMN under the vague term “mucinous cystadenoma”4. In 2000, the World Health Organization incorporated the presence of ovarian stroma on pathology in the definition of MCN5. As our knowledge of MCLs grew, MCN and BD-IPMN also appeared to be 2 distinct neoplasms based
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on demographic characteristics and biologic behavior2,6-9. MCN occur almost exclusively in the pancreatic body/tail of young women, whereas BD-IPMN is usually diagnosed in older patients,
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preferentially involving the head of the pancreas7,8. Although the true natural history of MCN and BD-IPMN remains uncertain due to only
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scarce surveillance studies, numerous surgical series have reported the rate of invasive carcinoma in resected specimens for both lesions. BD-IPMN and MCN are associated with invasive rates of 4-15%2 and 6-37%3,6,9-14, respectively. Despite comparable rates of malignancy in both lesions, the 2012 revised International Consensus Guidelines recommend resection for MCN in all patients fit to undergo surgery, whereas surveillance of BD-IPMN is recommended in the absence of worrisome features or high-risk stigmata2. This distinct management relies heavily on correct preoperative differentiation between MCN and BD-IPMN, but the 2000
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World Health Organization definition of both entities is based on the postoperative presence/absence of ovarian stroma on pathology5,13. As such, the 2012 revised International Consensus Guidelines recommends radiographic/endoscopic identification of a connection to the
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main pancreatic duct as the preoperative distinguishing feature of BD-IPMN2.
We hypothesized that preoperative differentiation of solitary MCLs is suboptimal and that all undifferentiated solitary MCLs should be treated similarly.
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PATIENTS AND METHODS Patients selection
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From 2003 to 2016, electronic medical records of all patients who underwent pancreatic surgical resection for a pancreatic cyst at Indiana University Hospital were retrospectively reviewed (n=711). Patients with IPMN were prospectively collected in a database. For the purpose of this study, the database was supplemented with patients operated on for MCN. Data were compiled and reported in strict compliance with patient confidentiality guidelines as
Exclusion criteria
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defined by the Indiana University Institutional Review Board.
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Patients with incomplete pathological data or a final pathological diagnosis consistent with a non-mucinous cyst were excluded from our study. Patients with a high preoperative
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probability or formal diagnosis of IPMN were also excluded. This category comprised patients with isolated cystic dilation of the main pancreatic duct on preoperative imaging (owing to the likely diagnosis of main duct IPMN), multifocal cystic lesions on imaging/endoscopic studies and/and GNAS mutation on cyst fluid analysis (owing to the likely diagnosis of BD-IPMN). Patients with main duct involved IPMN (main-duct and mixed-type) on review of final pathology of the surgical specimen were also excluded. Pathology
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All pathological specimens were reviewed by staff pathologists with expertise in pancreatology to confirm the diagnosis of BD-IPMN or MCN. Histology was consistent with BD-IPMN if it showed an intraductal proliferation of tall, columnar, mucin-producing cells,
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arising from the branch duct, with or without papillary projections, and without ovarian-type stroma1,2. Conversely, the presence of ovarian stroma on pathology was pathognomonic of
MCN5. Ovarian stroma formed a layer of variable thickness beneath the epithelial lining, with
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stromal cells characterized by oval nuclei and spindled cytoplasm and arranged in long fascicles. The presence of ovarian stroma was confirmed by immunohistochemical staining showing
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stromal cells positive for estrogen receptor. Malignant BD-IPMN or MCN were defined according to the WHO classification as invasive carcinoma in the surgical specimen2,15. Parameters assessed
Medical records of patients were reviewed to obtain demographic and clinical data,
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including gender, age, presence and type of signs/symptoms/conditions (abdominal/back pain, nausea/vomiting, acute pancreatitis, steatorrhea/diarrhea, diabetes, weight loss, jaundice), and family history of pancreatic cancer. Size, location, dilation of the main pancreatic duct, thickness
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of walls, presence of septations, mural nodule/solid component and main duct connectivity were assessed on preoperative cross sectional imaging studies (computed tomography or magnetic
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resonance imaging/ magnetic resonance cholangiopancreatography) or pancreatic-directed endoscopic studies (endoscopic ultrasound, endoscopic cholangiopancreatography). Statistical analysis
Data were recorded using Microsoft Excel 2014 (Microsoft, Inc., Redmond, WA, USA)
and analyzed with IBM SPSS statistics version 21.0® (Armonk, NY: IBM Corp). Descriptive statistics for continuous data included median, mean, range, and standard error. Categorical data
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were expressed as numbers and percentages. Categorical data were compared with Fisher’s exact test, whereas Student’s t test compared continuous variables. Independent predictors of malignant progression were determined with univariable and multivariable analyses using a
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logistic regression model. Criteria with p-value <0.1 in univariate analysis were subsequently entered in the multivariate model. P-value <0.05 was accepted as statistically significant.
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RESULTS Patients population (Figure 1.)
Of the 711 patients who underwent resection for pancreatic cyst during the study period,
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455 were excluded due to a known preoperative diagnosis of BD-IPMN or MCN. Of the remaining 256 patients, 76 were excluded post hoc due to a postoperative diagnosis of mixedtype IPMN on surgical pathology. That left us with 180 patients (25.3%) identified as undifferentiated solitary MCLs on preoperative work-up. Mean age at surgery was 54.1 year (+/15.4, range 21-86), with a gender ratio of 0.3 (43 men, 137 women). The main indication for
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surgery was symptoms in 94 patients (52.2%). Other indications included a large size or an increase in size (n=34, 18.9%), patient’s preference (n=12, 6.7%), preoperative diagnosis of
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mucinous cyst in itself (n=11, 6.1%), suspected malignancy on preoperative workup (n=10, 5.6%), main pancreatic duct dilation (n=9, 5%), presence of mural nodule or solid component
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(n=7, 3.9%), and a family history of pancreatic cancer (n=3, 1.7%). Pathology
Among the 180 patients with undifferentiated solitary MCLs, 108 (60%) and 72 (40%)
were classified on pathology as MCN and unifocal BD-IPMN, respectively. Of the 108 MCN, 100 (92.6%) were low to moderate dysplasia (former adenoma), 1 (0.9%) was high-grade dysplasia (former carcinoma in situ) and 7 (6.5%) were invasive carcinoma. Regarding unifocal BD-IPMN (n=72), 64 (88.8%) were low/moderate dysplasia, 4 (5.6%) were high-grade dysplasia
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and the remaining 4 (5.6%) invasive carcinoma. There was no difference in invasive rate between MCN and unifocal BD-IPMN (6.5% vs. 5.6%, p≈1). Main duct connection (Table 1)
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Main pancreatic duct connectivity was reported on imaging and/or endoscopic studies in 10 MCN (9.3%) and 22 unifocal BD-IPMN (30.6%). Using ductal connection to differentiate
(sensitivity=30.6% and specificity=90.7%). Predictors of pathology subtype (Table 2)
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Clinical characteristics
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between MCN and unifocal BD-IPMN was associated with an accuracy of 66.7%
Patients with MCN were more likely to be young (48 vs. 63.3 years, p<0.0001) and women (all but 8, p<0.0001). Patients with BD-IPMN were more likely to present with jaundice (27.3% vs. 1.2%, p=0.0016). Acute pancreatitis was more common in patients with BD-IPMN
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than patients with MCN (33.3% vs. 13.9%, p=0.003). However, on multivariable analysis, only age and gender were statistical independent predictors of BD-IPMN vs. MCN (p=0.01 and 0.002, respectively).
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Imaging/endoscopy characteristics
The median diameter of the neoplasm on imaging studies was 3.6 cm (mean 4.6 cm +/-
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3.5, range 0.5-21.1). MCN were more frequently located in the tail of the pancreas (n=105, 97.2%), whereas BD-IPMN were more likely to be in the head of the pancreas (n=52, 72.2%) (p<0.0001). One hundred and seventy-six patients (97.8%) underwent either an endoscopic ultrasound (EUS) or an endoscopic retrograde cholangiopancreatography (ERCP) as part of their workup, with 134 (74.4%) patients having a fine needle aspiration and/or brushing and cytological evaluation. Thick walls and septations were reported in 34 (18.9%) and 76 (42.2%)
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of all MCLs, respectively, and more commonly found in MCN compared to unifocal BD-IPMN (thick walls: 27.8% vs. 5.6%, p=0.0002; septations: 49.1% vs. 31.9%, p=0.03). On multivariable
cyst size (larger in MCN) were predictive of BD-IPMN vs. MCN. Predictive factors of invasiveness (Table 3)
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analysis, however, only location in the pancreas (head for BD-IPMN vs. body/tail for MCN) and
When analyzed separately in multivariate analysis, typical risk factors (age, cyst
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diameter, main pancreatic duct dilation>5mm, mural nodule, symptoms especially acute
pancreatitis) failed to predict invasiveness in either MCN or unifocal BD-IPMN. Only jaundice
head of the pancreas (p<0.0001).
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was associated with a higher rate of invasive BD-IPMN due to its preferential location in the
When all MCLs were analyzed together, however, an older age and a larger cyst diameter were independently associated with an increased risk of invasive lesion (p=0.02 and p=0.04,
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respectively). When cyst size was analyzed through Receiver Operator Curve, it was, alone, a poor predictor of invasiveness with an area under curve of only 0.67 (Figure 2.). The best cut-off was found at 2.95 cm with a sensitivity of 82%, but an associated low specificity of 38%.
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Interestingly, a main pancreatic duct dilation of 5mm or greater and a mural nodule/solid component, were not associated with a statistically significant risk of malignant progression
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(p=0.30 and p=0.33, respectively). Intention-to-treat analysis
Seventy-six undifferentiated solitary MCLs were excluded post hoc because they were
found to be mixed-type IPMN on surgical pathology. Of these, 15 (20%) were invasive carcinoma. If those patients were included in an intention-to-treat analysis, the overall rate of invasive undifferentiated solitary MCLs would be 10% (6.5% MCN vs. 13% BD-IPMN,
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p=0.14). In an intention-to-treat analysis, main duct dilation of 5mm or greater was a multivariable risk factor for invasive carcinoma. Older age and larger cyst size remained independent predictors of invasiveness in-intention-to treat analysis.
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DISCUSSION
In 1978, Compagno and Oertel made a distinction between serous and mucinous
cystadenomas emphasizing the benign course of serous and the malignant potential of mucinous
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cysts16. It was not until 2000 that the WHO classified BD-IPMN and MCN as distinct lesions based on the presence/absence of ovarian stroma3,5,7,8. BD-IPMN and MCN represent the most
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frequent cystic lesions of the pancreas (up to 40% and 20%, respectively)17-21. The 2012 International Consensus Guidelines recommend resection of all MCN in surgically fit patients and non-operative management of BD-IPMN in the absence of worrisome features or high-risk stigmata2.
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This retrospective review of all solitary pancreatic MCLs found no difference in invasive rate between BD-IPMN and MCN (6.5 vs. 5.6, p≈1). A review of the most important series of MCN from the literature shows a wide discrepancy in malignancy rate ranging from 6 to 36%3,4, . This may in part be explained by the lack of standardized pathology especially the
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6,10-14
requirement of ovarian stroma to define MCN 4,12-14. As a result, MCN series were likely
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confounded by the presence of mixed type IPMN, lesions that typically have a higher malignancy rate that MCN. In our series the prevalence of invasive carcinoma in MCN is in line with the series from Reddy et al. (7%)7. Preoperative differentiation between BD-IPMN and IPMN is necessary for optimal
management as per the 2012 International Consensus Guidelines2. In a study by Correa-Gallego, 4/30 (13.3%) preoperative MCN were BD-IPMN on pathology, and 1/50 (2%) preoperative BD-
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IPMN were MCN on final pathology22 . This degree of accuracy, however, is the exception. Multifocality is associated with BD-IPMN, but is not a reliable diagnostic feature in the setting of solitary cysts. There is currently no definite serum biomarker to distinguish MCN from BD-
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IPMN, but based on studies from a Lustgarten Foundation Consortium (Johns Hopkins, Indiana University and Memorial Sloan Kettering), GNAS mutations are found in IPMN and no other types of pancreatic cystic neoplasms. GNAS testing, however, is not widely used and is only
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present in 52/86 (61%) of IPMN 23,24. A core biopsy to rule in/out ovarian stroma can
distinguish IPMN from MCN but is rarely used owing to the perceived high procedural risk.
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In the present series, we analyzed main duct communication as a diagnostic criterion to differentiate between BD-IPMN and MCN as it is currently recommended by the International Consensus Guidelines. This feature was associated with a high specificity of 90.7%, but a low sensitivity of 30.6% and an associated accuracy of only 66.7%. The low reliability of main duct
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connectivity in distinguishing BD-IPMN from MCN has been described in a prior study by Zamboni et al.6 In this study, MCN from 48 patients had ovarian stroma on pathology. Eight additional patients (14%) were included as MCN based on the lack of main-duct connection
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although pathology did not show ovarian stroma. Patients without ovarian stroma on pathology were significantly older (63 vs. 46 years old, p=0.007) and had higher rate of invasive carcinoma
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(62.5% vs. 26.3%, p=0.01). It appears that the tumors without ovarian stroma had a distinctly different demographic profile compared to those with ovarian stroma and this MCN population may have been “contaminated” with mixed type IPMN patients. When BD-IPMN and MCN in our seriesa were analyzed separately to assess for
invasiveness risk factors, typical criteria failed to predict invasive carcinoma. When all MCL were analyzed together, however, older age (p=0.03) and cyst diameter (p=0.02) were associated
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with a higher rate of invasive lesions in multivariate analysis. Those 2 criteria have been previously described in the literature. In our study, patients with invasive MCLs were found to be 15 years older than those with non-invasive lesions (68 vs. 53 years old), suggesting a
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progression of benign MCLs to malignancy. Sarr et al.12 and Zamboni et al.6 have reported similar data regarding MCN, whereas Matthaei et al.25 described the same phenomenon in
IPMN. Similarly, previous studies have shown that invasive MCN were significantly larger than
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benign lesions. In a combined analysis, those studies represent a total of 385 patients and found a size cut-off at 3cm to predict invasive carcinoma3,6,7,11. This is similar to our result of a 2.95cm
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cut-off. Reddy et al.12, however, have set a cut-off for invasiveness and surgical resection at a larger diameter of 5cm.
Our study presents limitations. It has a selection bias as only surgically resected MCLs are included. Thus, the true natural history (and true rate of invasiveness) remains uncertain. It is
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possible that pathological misclassification may occur as ovarian stroma is not seen on every slide in MCN. In Reddy’s series7, ovarian stroma was only present in 76% of slides, suggesting that correct pathological distinction between BD-IPMN and MCN may require thin sectioning to
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obtain adequate sampling. Finally, main duct communication as a criterion to differentiate between BD-IPMN and MCN is often detected preoperatively on endoscopic ultrasound studies,
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an operator-dependent test.
Patients with MCLs are middle aged (median age 54 years old) with a long life
expectancy. Surveillance would require periodic cross-sectional imaging studies (computed tomography or magnetic resonance imaging/magnetic resonance cholangiopancreatography) and/or endoscopic studies (endoscopic ultrasound, endoscopic cholangiopancreatography) and long follow-up. The risk associated with pancreatic surgery (mortality 1%, morbidity 20-
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40%)26,27 needs to be weighed against the anxiety and the cost of a long-term follow-up protocol28. Although the cornerstone of management for pancreatic mucinous cystic neoplasm relies
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on a reliable differentiation between unifocal BD-IPMN and MCN, main duct communication reported on imaging/endoscopy has limited predictability. If present, it is very specific for BDIPMN, but it is only visualized in 31% of those lesions. In the present series, independent
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predictors of solitary MCN over solitary BD-IPMN included young age, female gender, body/tail location in the pancreas and larger cyst size. However, there is no failsafe combination of these
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criteria. In doubtful cases, it is better to classify these mucinous lesions as “undifferentiated” solitary MCLs rather than to include them with one entity or the other. Unifocal BD-IPMN and MCN have similar invasive rates, with only a size of 3cm or greater associated with invasive carcinoma. Due to the limited ability to correctly identify the pathological subtype preoperatively
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and to predict invasiveness, we believe that the International Consensus Guidelines could be
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improved if preoperative undifferentiated solitary MCLs were addressed as a new entity.
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neoplasms revisited: Part II. Mucinous cystic neoplasms. Surg Oncol 2011;20:93–101. 20. Robinson SM, Scott J, Oppong KW, White SA. What to do for the incidental pancreatic cystic lesion? Surg Oncol 2014;23:117–25.
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23. Wu J, Matthaei H, Maitra A, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med. 2011;3:92ra66.
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pancreas. World J Gastroenterol 2010;16(45):5682-92.
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Table 1. Performance Characteristics of Main Duct Connection in Differentiating Branch-Duct Intraductal Papillary Mucinous Neoplasm from Mucinous Cystic Neoplasm MCN (n=108)
MPD connection
22 (TP)
10 (FP)
No MPD connection
50 (FN)
Sensitivity=30.6%; Specificity=90.7%; Accuracy=66.7%
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BD-IPMN (n=72)
Connection
98 (TN)
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BD-IPMN, branch-duct intraductal papillary mucinous neoplasm; MCN, mucinous cystic neoplasm; MPD: main pancreatic duct; TP, true positive; FP, false positive; FN, false negative; TN, true negative
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Table 2. Univariate and Multivariate Analysis for Predictors of Pathological Subtypes (BranchDuct Intraductal Papillary Mucinous Neoplasm vs. Mucinous Cystic Neoplasm) MCN (n=108)
Univariate p Value
63.3 35 (48.6)
48 8 (7.4)
<0.0001* <0.0001*
0.01† 0.002†
0.07*
0.96
Demographic Age, y, mean Sex, m, n (%) Family history of pancreatic cancer, n (%) Clinical, n (%) Symptoms Abdominal/back pain Nausea/vomiting
4 (3.7)
8 (11.1)
80 (74.1) 73 (67.6) 26 (24.1)
57 (79.2) 48 (66.7) 21 (29.2)
Acute pancreatitis
24 (33.3)
Steatorrhea/diarrhea Diabetes Weight loss Jaundice Imaging/endoscopy Location, head, n (%) Thick walls, n (%) Septations, n (%) MPD communication, n (%)
18 (16.7) 13 (12) 15 (13.9) 3 (27.3)
*
-
15 (13.9)
0.003*
0.54
17 (23.6) 13 (18.1) 17 (23.6) 2 (1.2)
0.26 0.28 0.11 0.0016*
0.16
52 (72.2) 4 (5.6) 23 (31.9)
3 (2.8) 30 (27.8) 53 (49.1)
<0.0001* 0.0002* 0.03*
<0.0001† 0.7 0.59
22 (30.6)
10 (9.3)
<0.0001*
0.59
5.8
<0.0001*
0.006†
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Cyst size, cm, mean
Multivariate p Value
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BD-IPMN (n=72)
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Variable
2.7
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Statistically significant p Value in univariate p Value Statistically significant p Value in multivariate p Value MCN, mucinous cystic neoplasm; BD-IPMN, branch-duct intraductal papillary mucinous neoplasm; MPD: main pancreatic duct
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Table 3. Univariate and Multivariate Analysis of All Undifferentiated Solitary Mucinous Cystic Lesions (N=180) for Independent Predictors of Invasiveness Non-invasive
Univariate
Multivariate
lesion (n=11)
lesion (n=169)
p Value
p Value
Age, y, mean
68.4
53.2
Sex, m, n (%)
5 (45.5)
38 (22.5)
Demographic
Clinical, n (%)
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Variable
0.0014*
0.025†
0.14
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≈1
-
0 (0)
12 (7.1)
7 (63.6)
130 (76.9)
0.3
-
Abdominal/ back pain
5 (45.5)
116 (68.6)
0.18
-
Nausea/vomiting
1 (9.1)
46 (27.2)
0.29
-
Acute pancreatitis
0 (0)
39 (23.1)
0.12
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2 (18.2)
33 (19.5)
≈1
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Diabetes
2 (18.2)
24 (14.2)
0.66
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Weight loss
2 (18.2)
30 (17.8)
≈1
-
Jaundice Imaging/endoscopy
3 (27.3)
2 (1.2)
0.0016*
0.99
4 (36.4)
51 (30.2)
0.74
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Location, head, n (%)
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Steatorrhea/diarrhea
4.4
0.033
0.039†
3 (27.3)
15 (8.9)
0.08*
0.29
Thick walls, n (%)
1 (9.1)
33 (19.5)
0.69
-
Septations, n (%)
2 (18.2)
74 (43.8)
0.12
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Mural nodule/solid 2 (18.2) component, n (%) * Significant p Value in univariate analysis
19 (11.2)
0.62
-
Cyst size, cm, mean
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MPD dilation >5mm, n
†
6.7
*
Significant p Value in multivariate analysis
MPD, Main pancreatic duct
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Figure Legend Figure 1. Flow chart of patients who met inclusion/exclusion criteria for the study population
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MCN, Mucinous cystic neoplasm; BD-IPMN, branch-duct intraductal papillary mucinous neoplasm; MT-IPMN, Mixed-type intraductal papillary mucinous neoplasm; MCLs, Mucinous cystic lesions Figure 2. Receiver Operating Curve analyzing performance characteristics of cyst size in predicting invasiveness in undifferentiated solitary MCLs.
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MCLs, mucinous cystic lesions; Se, sensitivity; Sp, specificity, AUC, area under curve
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Precis Unreliable differentiation and limited ability to predict invasiveness make solitary pancreatic
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mucinous cysts clinically challenging. With similar invasive rates, mucinous cystic neoplasm and unifocal branch-duct intraductal papillary mucinous neoplasm should be merged into one
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new entity for management, the undifferentiated solitary mucinous cystic lesion.
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