Differentiating large-duct pancreatic ductal adenocarcinoma from malignant intraductal papillary mucinous neoplasm: MRI characteristics and diagnostic implications.

Evaluation of the Guidelines for Management of Pancreatic Branch-Duct Intraductal Papillary Mucinous Neoplasm

Role of Endoscopic Ultrasound in the Diagnosis of Intraductal Papillary Mucinous Neoplasms: Correlation With Surgical Histopathology

Epithelial-to-mesenchymal transition (EMT) is generally associated with increased tumor aggressiveness and poor prognosis. We evaluated EMT characteristics in intraductal papillary mucinous neoplasm (IPMN) tumor specimens and their potential role as biomarkers for malignancy, metastasis, and adverse patient outcomes. IPMN surgical specimens were identified and reviewed by two gastrointestinal pathologists. Immunohistochemical analysis of E-cadherin, vimentin, and ZEB-1 was performed. Samples were linked to clinicopathologic and outcome data for these patients. Western blot test was used to evaluate ZEB-1 expression in IPMN samples; 846 human miRNAs were profiled, and EMT-related differentially expressed miRNAs were validated using quantitative real-time polymerase chain reaction. Fifty-eight IPMN specimens and five normal pancreatic tissue samples were immunohistochemically stained and scored. E-cadherin expression was significantly lower in malignant versus low-grade IPMN (p < 0.05). Vimentin expression was increased in malignant IPMN tumor samples (p < 0.05). EMT was associated with increased lymph node metastasis and decreased survival of malignant IPMN patients (p < 0.05). ZEB-1, an imperative EMT regulator, was exclusively expressed by malignant IPMN tumors. miRNA hierarchical clustering demonstrated grouping of two main IPMN subgroups: low-grade IPMN versus high-grade IPMN and carcinoma. Twenty-four miRNAs were differentially expressed (14 up-regulated, 10 down-regulated). The EMT-regulatory miRNAs, miR-200c and miR-141, were down-regulated (twofold and 1.8-fold decrease, respectively) in malignant versus low-grade IPMN (p < 0.05). EMT may play a role in IPMN tumorigenesis and metastasis. EMT molecular deregulations could be utilized as potential novel biomarkers for the identification of high-risk IPMN patients.

Diagnostic yield of EUS-FNA-based cytology distinguishing malignant and benign IPMNs: A systematic review and meta-analysis

Peroral pancreatoscopy and intraductal ultrasound for diagnosis of intraductal papillary mucinous tumors of the pancreas 1,2

Intraductal papillary mucinous tumor (IPMT) of the pancreas is a rare disease. Preoperative determination of the nature (benign or malignant IPMT) and extent of the disease may be challenging. Experience in this regard is still limited. Hara et al. performed a retrospective review of their extended experience in evaluating patients with IPMT by means of peroral pancreatoscopy (POPS) and intraductal ultrasound (IDUS) over a 13-yr period. Sixty consecutive IPMT patients were included in this study (POPS performed in all and IDUS performed in 40 patients). The authors assessed tumor type (elevated vs excavated), tumor morphology as per POPS (type I: granular; type II: fish-egg like without vascular images; type III: fish-egg like with vascular images; type IV: villous type; and type V: vegetative type), maximum tumor height as determined by IDUS, and tumor extent (head vs body vs tail; main pancreatic duct vs side branches). Results obtained with POPS and IDUS were correlated and compared with surgical pathology serving as the gold standard. The ability of CT, endoscopic ultrasound, and K-ras point mutations in pancreatic juice to distinguish benign (hyperplasia or adenoma) from malignant (carcinoma in situ or invasive carcinoma) IPMT were also studied. Relapse-free and overall survival of this retrospective cohort of patients in whom treatment was guided by POPS and IDUS findings were assessed. Forty of the 60 patients evaluated had protruding lesions (67%). Among them, most malignant tumors had a POPS morphology type III, IV, or V (P < 0.0001), with a reported sensitivity, specificity, and accuracy of 68%, 87%, and 75% for differentiating benign (hyperplasia or adenoma) from malignant (carcinoma in situ or invasive carcinoma) IPMT. Maximum tumor height as measured by IDUS (2.27 ± 1.5 mm in the benign group, and 5.96 ± 4.03 in the malignant group) was able to discriminate benign from malignant tumors (p < 0.001). Lesions protruding 4 mm or more on IDUS were malignant in 88% of cases, and the sensitivity, specificity, and accuracy of IDUS at that cutoff was 68%, 89%, and 78%, respectively. CT and endoscopic ultrasound had a sensitivity and accuracy ranging from 32% to 65%. When positive K-ras point mutation was considered as a malignant finding, sensitivity, specificity, and accuracy reached 87%, 15%, and 61%, respectively. Only one of the 60 patients resected (1.6%) had positive margins on surgical resection after POPS and IDUS had been performed. The 3-yr relapse-free and overall survival was 93% and 95%, respectively. Based on these results, Hara et al. concluded POPS and IDUS can reliably distinguish benign from malignant IPMT, determine tumor extent, and guide therapy. These new techniques may contribute to improvement in postoperative results.

Evaluation of computed tomography (CT) and magnetic resonance imaging (MRI) for differentiation of pancreatic intraductal papillary mucinous neoplasm (IPMN) subtypes based on objective imaging criteria. Fifty-eight patients with 60 histologically confirmed IPMNs were included in this retrospective study. Eighty-three imaging studies (CT,n = 42; MRI,n = 41) were analysed by three independent blinded observers (O1-O3), using established imaging criteria to assess likelihood of malignancy (-5, very likely benign; 5, very likely malignant) and histological subtype (i.e., low-grade (LGD), moderate-grade (MGD), high-grade dysplasia (HGD), early invasive carcinoma (IPMC), solid carcinoma (CA) arising from IPMN). Forty-one benign (LGD IPMN,n = 20; MGD IPMN,n = 21) and 19 malignant (HGD IPMN,n = 3; IPMC,n = 6; solid CA,n = 10) IPMNs located in the main duct (n = 6), branch duct (n = 37), or both (n = 17) were evaluated. Overall accuracy of differentiation between benign and malignant IPMNs was 86/92 % (CT/MRI). Exclusion of overtly malignant cases (solid CA) resulted in overall accuracy of 83/90 % (CT/MRI). The presence of mural nodules and ductal lesion size ≥30 mm were significant indicators of malignancy (p = 0.02 and p < 0.001, respectively). Invasive IPMN can be identified with high confidence and sensitivity using CT and MRI. The diagnostic problem that remains is the accurate radiological differentiation of premalignant and non-invasive subtypes. • CT and MRI can differentiate benign from malignant forms of IPMN. • Identifying (pre)malignant histological IPMN subtypes by CT and MRI is difficult. • Overall, diagnostic performance with MRI was slightly (not significantly) superior to CT.

The value of 18F-FDG positron emission tomography to differentiate benign from malignant intraductal papillary mucinous neoplasms: A prospective multicenter study

Intraductal Papillary Mucinous Tumor of the Pancreas: Computerized Tomography and Magnetic Resonance Imaging Features

This study aimed at determining the additional value of FDG PET/CT to contrast-enhanced CT in the differentiation between benign and malignant intraductal papillary mucinous neoplasms (IPMNs) of the pancreas with mural nodules. This retrospective review of medical records was approved by our institutional review board. The preoperative PET/CT images of 16 non-diabetic patients with surgically proven IPMN, where mural nodules of 3mm or larger were shown by preoperative contrast-enhanced CT, were retrospectively evaluated. The 16 patients were divided into two groups: 7 patients with benign IPMN [adenoma (n=1) and borderline tumor (n=6)] and 9 patients with malignant IPMN [carcinoma in situ (CIS) (n=8) and invasive carcinoma (n=1)]. Nuclear medicine physician blinded to the pathologic assessment of malignancy of IPMN set a spherical volume of interest (VOI) over the mural nodules on PET/CT images and recorded the peak standardized uptake value (SUV(max)) in the VOI, referring the contrast-enhanced CT images. Statistical differences in the size of mural nodule, the diameter of main pancreatic duct (MPD), and SUV(max) of the tumors between benign IPMNs and malignant IPMNs were compared using the Mann-Whitney U test. Statistical significance was set at p<0.05. Additionally, the diagnostic accuracy of FDG PET for the detection of malignancy was calculated. The SUV(max) of the malignant IPMNs with mural nodules of 3mm or larger was higher than that of benign IPMNs (2.7±0.6 vs. 1.9±0.3, p<0.01). Meanwhile, there was no significant difference in mural nodule diameter and MPD diameter between the two groups. FDG PET/CT showed an excellent diagnostic accuracy for the differentiation between malignant and benign IPMNs with mural nodules: the sensitivity, specificity, PPV, NPV, and accuracy in malignant IPMN with mural nodule of FDG PET/CT were 77.8, 100, 100, 77.8, and 87.5 for the cutoff value of 2.3; and 100, 57.1, 75.0, 100, and 81.3 for the cutoff value of 2.0, respectively. The result of this study indicates that FDG PET/CT can provide additional information for the differentiation between benign and malignant IPMNs of the pancreas with mural nodules.

To retrospectively determine the accuracy of magnetic resonance (MR) imaging combined with MR cholangiopancreatography (CP) in differentiating benign from malignant intraductal papillary mucinous neoplasms (IPMNs) involving the main pancreatic duct (MPD), with histopathologic analysis as the reference standard. The informed consent requirement was waived for this institutional review board-approved study. A total of 51 patients with histopathologically proved IPMNs (MPD IPMN, n = 29; mixed type IPMN, n = 22), underwent MR imaging, MR CP, and surgery, with a mean interval of 2.6 months between MR examination and surgery. Qualitative image analysis included assessment of the site of MPD dilatation (head of the pancreas, body and/or tail of the pancreas, or diffuse), presence or absence of duct wall nodules, and contrast enhancement of the MPD walls. Quantitative image analysis included measurement of the maximum diameter of the MPD. A comparison of adenomas and borderline IPMNs with cancerous IPMNs was performed with the Student t test or the Mann-Whitney U test for continuous variables. At histopathologic analysis, 27 IPMNs were classified as carcinomas; 13, as borderline tumors; and 11, as adenomas. MPD wall nodules were observed in 16 carcinomas involving the MPD and one adenoma or borderline neoplasm (P < .00001). Duct wall enhancement was observed in 20 MPD or mixed type carcinomas and five adenomas or borderline neoplasms (P = .0001). The median maximal diameter of the MPD was 18 mm in malignant MPD or mixed type IPMNs and 11 mm in benign borderline IPMNs (P = .038). No significant difference in the overall 5-year survival rate of patients with MPD IPMNs and those with mixed type IPMNs was observed (P = .813). Duct wall nodules and enhancement of the MPD walls are signs of malignant MPD or mixed type IPMNs. http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.2531080604/-/DC1.

Published studies have revealed the diagnostic yield of cytology obtained from endoscopic retrograde cholangiopancreatography (ERCP) in distinguishing malignant and benign intraductal papillary mucinous neoplasm (IPMN). However as a result of small sample sizes, the overall magnitude of benefit is unknown. Additionally, the optimal endoscopic procedure for cytology acquisition is also unclear. The aim of the present study was to evaluate the diagnostic yield of ERCP-based cytology in patients with IPMN and clarify the optimal sampling technique. Relevant studies with a reference standard of definitive surgical histology were identified via MEDLINE and SCOPUS. Malignant IPMN included invasive adenocarcinoma, carcinoma in situ, and high-grade dysplasia. For ERCP, studies using aspiration, brush, and lavage cytology were included. The main objective was the diagnostic yield (pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio) of cytology obtained from ERCP to distinguish malignant and benign IPMN. Meta-analysis of 13 international studies with 483 IPMN patients was conducted. Pooled sensitivity was 35.1%, specificity 97.2%, and accuracy 92.9%. Among the three ERCP techniques, lavage cytology showed the best diagnostic ability (sensitivity 45.8%, specificity 97.9%). Malignant IPMN were observed in 45.1% (218/483) of patients in ERCP studies. Cytology from ERCP has good specificity but poor sensitivity in distinguishing benign from malignant IPMN. Newer techniques or markers are needed to improve diagnostic yield.

Utility of EUS-FNA and Cyst Fluid Analysis in the Diagnosis of Intraductal Papillary Mucinous Tumors: Correlation with Histopathology in 74 Patients

Objective To investigate the clinical features and surgical indications of subtypes of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, and analyze its malignant risk factors. Methods The retrospective case-control study was conducted. The clinicopathological data of 77 patients with IPMN of the pancreas who were admitted to the First Hospital of Peking University from January 2008 to December 2016 were collected. The subtypes of IPMN of the pancreas detected by preoperative imaging examination included main-duct type (MD-IPMN) in 46 patients, branch-duct type (BD-IPMN) in 12 patients, mixed type (MT-IPMN) in 19 patients. The surgical indications were consulted from the Guideline for the diagnosis and treatment of pancreatic cystic lesions composed by the Pancreatic Surgery Group of Surgery Branch of China Medical Association. Surgical procedure was selected according to the location and size of the IPMN. Four to 6 cycles of chemotherapy with S-1 and/or Gemcitabine were conducted for patients with malignant IPMN according to the tolerance and baseline characteristics. Observation indicators included: (1) comparison of the clinical features MD-IPMN, MT-IPMN and BD-IPMN; (2) surgical and postoperative conditions; (3) results of postoperative pathological examination and malignant risk factors analysis; (4) accuracy evaluation of Sendai and Fukuoka guidelines for the diagnosis of malignant IPMN of the pancreas; (5) follow-up results and survival. Patients were followed up by outpatient examination and telephone interview till December 2016. The postoperative adjuvant therapy, tumor recurrence and metastasis of malignant IPMN patients and postoperative survival condition of all the patients were collected. Measurement data with normal distribution were expressed as ±s or average (range), and pairwise comparison was analyzed by t test. Measurement data with skewed distribution were expressed by median (range). Comparison between count data and univariate analysis were done by chi-square test. Multiple factors analysis was done by Logistic regression model. The survival curve was drawn and the survival rate were calculated by Kaplan-Meier method. The comparison of survival was done by Log-rank test. Results (1) Comparison of clinical features between MD-IPMN, MT-IPMN and BD-IPMN: The numbers of patients with symptoms, jaundice, those complicated with diabetes and elevated CA19-9 were 55, 20, 43 and 28 in MD-IPMN and MT-IPMN, and 6 , 0, 3 and 1 in BD-IPMN, with statistically significant difference (χ2=5.421, 3.516, 5.525, 3.834, P 0.05), while significant difference in the specificity between the 2 guidelines were detected (χ2=12.500, P<0.05). (5) Follow-up and survival: Seventy of 77 patients were followed up, including 42 with benign IPMN and 28 with malignant IPMN. The median survival time was 35.0 months (range, 6.0-94.0 months). All the malignant IPMN patients received adjuvant therapy. The 1-, 3-, 5-year overall survival rates of 47 patient with benign IPMN were 100.0%, 96.2% and 96.2%, respectively, and 1 patient died of cardiac infarction. The 1-, 3-, 5-year overall survival rates of 30 patients with malignant IPMN were 96.6%, 81.8%, 38.6%, respectively, and 11 patients died of tumor recurrence or metastasis with median time of tumor recurrence or metastasis of 20.5 months (6.0-61.6 months). The 1-, 3-, 5-year overall survival rates of 17 patients with negative lymph node metastasis were 100.0%, 100.0% and 60.0%, respectively, and the 1-, 3-, 5-year overall survival rates of 13 patients with positive lymph node metastasis were 91.7%, 57.1% and 0, respectively. There was statistically significant difference between patients with benign and malignant IPMN (χ2=12.530, P<0.05). There was statistically significant difference between patients with negative lymph node metastasis and those with positive lymph node metastasis (χ2=16.977, P<0.05). Conclusions Patients with MD-IPMN or MT-IPMN are more vulnerable to be complicated with diabetes, jaundice, elevated CA19-9 and high malignancy, and thus surgery is recommended. Jaundice, elevated CEA and CA19-9, tumor diameter≥3.0 cm, MD-IPMN are the independent risk factors influencing the malignancy of IPMN. Key words: Intraductal papillary mucinous neoplasms of the pancreas; Classification; Surgical procedures, operative; Prognosis

BackgroundSerum ferritin levels are elevated in many malignancies. In this study, we showed the performance of serum ferritin in identifying malignant intraductal papillary mucinous neoplasms (IPMNs).MethodsA total of 151 patients with pathologically confirmed IPMNs were enrolled. Serum tumor biomarker (carbohydrate antigen 19–9 (CA19–9) and carcinoembryonic antigen (CEA)) levels and serum ferritin levels were recorded. Lesion location, tumor size, diameter of the main pancreatic duct (MPD), mural nodule, and IPMN type, were collected from imaging examinations. IPMNs with high grade dysplasia and associated invasive carcinoma were considered malignant IPMNs.ResultsSerum ferritin levels in patients with malignant IPMNs were higher than those in patients with nonmalignant IPMNs (p < 0.05). Serum ferritin was an independent factor for the occurrence of malignant IPMNs (odds ratio (OR) = 1.18, 95% confidence interval (CI):1.01–1.39). A similar trend was found between high serum ferritin (> 149 ng/ml) and malignant IPMNs (OR = 5.64, 95% CI:1.78–17.92). The area under the curve (AUC) of serum ferritin was higher than that of CEA and CA19–9 in identifying malignant IPMNs (AUC = 0.67 vs. AUC = 0.58, 0.65). The combination of serum ferritin with IPMN type showed a similar performance to MPD diameter and the combination of serum CA19–9 with IPMN types in identifying malignant IPMNs (AUC = 0.78 vs. AUC = 0.79, 0.77) and invasive carcinoma (AUC = 0.77 vs. AUC = 0.79, 0.79).ConclusionsElevated serum ferritin is a factor associated with malignant IPMNs. Serum ferritin may be a useful marker for identifying malignancy in IPMNs.