Diagnosis and management of intraductal papillary mucinous neoplasia

Intraductal papillary mucinous neoplasia (IPMN) encompasses a spectrum of neoplastic change in the epithelial lining of the pancreatic duct. As such, it is difficult to predict the presence of malignancy, and pancreatic resection is established as the only effective treatment for IPMN. There is controversy about the natural history, evaluation, surgical management and surveillance of IPMN; as IPMN is being increasingly recognized, this controversy is being brought to the forefront of clinical practice. This review presents pooled surgical data, future directions and a proposed algorithm for the management of patients with IPMN.     

Management of intraductal papillary mucinous neoplasm of the pancreas

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a distinct entity characterized by papillary proliferations of mucin-producing epithelial cells with excessive mucus production and cystic dilatation of the pancreatic ducts. IPMNs have malignant potential and exhibit a broad histologic spectrum, ranging from adenoma to invasive carcinoma. IPMNs are classified into main duct and branch duct types, based on the site of tumor involvement. IPMN patients have a favorable prognosis if appropriately treated. The postoperative 5-year survival rate is nearly 100% for benign tumors and noninvasive carcinoma, and approximately 60% for invasive carcinoma. A main duct type IPMN should be resected. Surgical treatment is indicated for a branch duct IPMN with suspected malignancy (tumor diameter ≥ 30 mm, mural nodules, dilated main pancreatic duct, or positive cytology) or positive symptoms. Malignant IPMNs necessitate lymph node dissection (D1). IPMNs are associated with a high incidence of extrapancreatic malignancies and pancreatic ductal carcinoma.     

Management of intraductal papillary-mucinous neoplasm of the pancreas: treatment strategy based on morphologic classification

GOALS: The aim of this study was to examine and clarify the preoperative markers that are useful for differentiating between benign and malignant lesions of intraductal papillary-mucinous neoplasms (IPMN) of the pancreas, grouped according to morphologic classification. BACKGROUND: There are various stages of pathology in IPMN, ranging from benign to malignant lesions. Although the determination of appropriate treatment guidelines to deal with IPMN is a critical issue, no such guidelines have been established. PATIENTS AND METHODS: One hundred twenty cases of IPMN were classified morphologically into either main or branch duct types. We compared the morphologic classification with histopathologic diagnosis using indicators of malignancy detected by imaging such as main duct diameter, the number and diameter of cysts, and the presence or absence of mural nodules. We also examined the usefulness of pancreatic juice cytology and measurement of telomerase activity as indicators of malignancy. Finally, we performed a survival analysis on the basis of morphologic classification to determine prognosis of IPMN. RESULTS: Whereas a high incidence (64%) of malignant lesions was seen in main duct type IPMN, benign lesions were dominant (80.5%) in branch duct type IPMN. Survival analysis showed that the prognosis was significantly worse in main duct type than in branch duct type IPMN. The lesions were aggravated in all patients with main duct type who did not undergo resection, resulting in death due to progression of the pancreatic lesion. The incidence of mural nodules was a useful indicator in main duct type, whereas main duct diameter and incidence of mural nodules were useful indicators in branch duct type. Although pancreatic juice cytology showed a high accuracy rate with low sensitivity for determining malignancy, measurement of telomerase activity in this juice was very effective for differentiating between benign and malignant lesions. CONCLUSIONS: The incidence of malignant lesions was extremely high in main duct type IPMN, indicating that surgery is required in all these patients. However, to determine whether surgery is indicated in branch duct type IPMN it is necessary to obtain an appropriate image diagnosis focusing on main duct diameter and mural nodules and also to carry out cytology and measurement of telomerase activity in samples of pancreatic juice.     

Clinical fate of branch duct and mixed forms of intraductal papillary mucinous neoplasia of the pancreas

Aims:  The aim of the present study was to assess the clinical fate of, and to gain new insights into, branch duct and mixed (predominantly main duct type) forms of intraductal papillary mucinous neoplasia of the pancreas (IPMN).
Methods:  During a 17-year period, 99 successive IPMN patients (52 men, 47 women; mean age, 64 years) were included and divided into two groups for further comparison: one group had branch duct IPMN, whereas the other had mixed IPMN.
Results:  Patients from the mixed IPMN group ( n  = 52) displayed a greater rate of symptoms (83% vs 55%, P  = 0.004), pancreatic resection (67% vs 38%, P  = 0.007), malignancy (35% vs 13%, P  = 0.017) and death (15% vs 4%, P  = 0.09) than those from the branch duct IPMN group. A 38-month follow up of non-operated, symptom-free patients confirmed that more than 85% of branch duct IPMN patients were asymptomatic without evidence of malignancy. Borderline lesions and carcinoma are found in up to 50% of symptomatic resected branch duct IPMN cases.
Conclusion:  Patients with the mixed form of IPMN as well as with symptomatic branch duct IPMN should require pancreatic resection because of symptoms and the risk for malignancy. In silent branch duct IPMN without radiological signs of malignancy, a non-operative watch-and-wait strategy can be discussed.     

Intraductal papillary mucinous neoplasm and acute pancreatitis

Intraductal papillary mucinous neoplasms (IPMNs) are cystic pancreatic tumors that arise from the pancreatic ducts and are increasingly reported worldwide. Both benign and malignant tumors of the pancreas are thought to contribute to recurrent pancreatitis possibly by pancreatic duct obstruction, and IPMNs contribute to a major share of this burden. The rate of acute pancreatitis (AP) in IPMN patients in the largest published surgical series has varied from 12% to 67%. IPMN may be categorized into 3 forms on the basis of the areas of involvement: main pancreatic duct (MD-IPMN), side branch (SB-IPMN), or combined. Both MD-IPMN and SB-IPMN may be the cause of pancreatitis. The risk of AP seems to be similar with both main duct IPMN and SB-IPMN, although data are controversial. AP in IPMN patients is not severe and often recurs without treatment. The rate of AP does not seem to differ among benign and malignant IPMNs, and the correlation between the malignant potential and the occurrence of AP is ill defined. AP seems to occur more often in patients with IPMN that in those with usual pancreatic adenocarcinoma possibly because of obstruction of the main duct by thick, abundant mucus secretion. Although the Sendai guidelines recommend surgical resection in patients with SB-IPMN with AP, data are controversial. Moreover, in patients with an episode of pancreatitis, the finding of pancreatic cysts is often attributed to pseudocysts or fluid collections that make the diagnosis of IPMN less suspicious. Future longitudinal and prospective studies to understand the natural history of AP in patients with IPMN are required to better manage patients with recurrent AP in the setting of IPMN.     

Pancreatic juice cytology in IPMN of the pancreas.

BACKGROUND: Intraductal papillary-mucinous neoplasm (IPMN) of the pancreas is a disease ranging from adenoma to borderline (with moderate dysplasia) and further to carcinoma (noninvasive and invasive) and surgical strategy is different by the grades of dysplasia. METHODS: Preoperative pancreatic juice cytology in IPMN was reviewed in 71 patients with IPMN who underwent surgical resection. RESULTS: The IPMN was adenoma in 48 patients, borderline in 13 and carcinoma (invasive) in 10. The sensitivity of pancreatic juice cytology in malignant IPMN was 40% (4/10). In 4 patients with the 48 IPM adenomas, diagnosis of pancreatic juice cytology was class IV or V. One of the 4 cases was considered to be an overdiagnosis of cytology, but the other 3 cases were considered to be a consequence of accompanying carcinoma in situ (or PanIN-3) (2 patients) or invasive ductal adenocarcinoma (1 patient) apart from IPMN. Sensitivity of pancreatic juice cytology was higher in IPMN of the main duct type with mucin hypersecretion and with mural nodules. CONCLUSIONS: These findings suggest that pancreatic juice cytology in IPMN is useful especially in the main duct type with mucin hypersecretion and mural nodules. When the diagnosis of pancreatic juice cytology is malignant in otherwise benign-looking IPMNs, coexistence of pancreatic carcinoma should be suspected.     

Imaging IPMN: take home messages and news

IPMN is a frequent disease involving pancreatic duct. This disease could be malignant (parenchymal invasive adenocarcinoma), particularly if the main pancreatic duct is involved (this involvement is considered present if > 6 mm), if this enlargement reaches 10 mm or more, and if the pathological phenotype is biliopancreatic or intestinal (malignancy is less frequent if gastric one). Invasiveness is suspected if hypodense parenchymal lesion is present, particularly near a cystical lesion or MPD, a mural nodule of the wall, or if MPD wall has got a contrast uptake. Mural nodules inside cystic branch duct are associated with in situ grade 3 malignancies. MPD IPMN must be resected to prevent malignancy. The follow-up of isolated branch duct cysts relies upon MDCT and MRI, every two years if lesion is less than 1cm. Every one year if bigger, particularly if more than to 3 cm.     

胰腺导管内乳头状黏液瘤

胰腺导管内乳头状黏液瘤（IPMN）是由胰腺导管内产生黏液的上皮细胞呈乳头状增殖形成的肿瘤。与经典的胰腺癌相比,IPMN具有低度恶性、生长缓慢、少有侵犯周围组织、淋巴结转移率和再发率低的特点。IPMN根据肿瘤累及的部位可分为主胰管型、分支胰管型和混合型,病理组织特征涵盖从单纯腺瘤到浸润癌等多个亚型,临床表现多样,多种影像学检查手段可显示弥漫性或节段性扩张的主胰管和囊状扩张的分支胰管,ERCP经扩大的乳头获取黏液和胰液,取胰腺导管内皮组织和壁结节供活检均有助于诊断。IPMN确诊后应积极手术,手术切除率高,术后5年生存率高于一般的胰腺癌。本文就其临床表现、分类、病理特征、影像学诊断和治疗等方面做一综述。     

Outcomes of nonresected main-duct intraductal papillary mucinous neoplasms of the pancreas

AIM:To compare characteristics and outcomes of resected and nonresected main-duct and mixed intraductal papillary mucinous neoplasms of the pancreas(IPMN).METHODS:Over a 14-year period,50 patients who did not undergo surgery for resectable main-duct or mixed IPMN,for reasons of precluding comorbidities,age and/or refusal,were compared with 74 patients who underwent resection to assess differences in rates of survival,recurrence/occurrence of malignancy,and prognostic factors.All study participants had dilatation of the main pancreatic duct by ≥ 5 mm,with or without dilatation of the branch ducts.Some of the nonsurgical patients showed evidence of mucus upon perendoscopic retrograde cholangiopancreatography or endoscopic ultrasound and/or after fine needle aspiration.For the surgical patients,pathologic analysis of resected specimens confirmed a diagnosis of IPMN with involvement of the main pancreatic duct or of both branch ducts as well as the main pancreatic duct.Clinical and biologic follow-ups were conducted for all patients at least annually,through hospitalization or consultation every six months during the first year of follow-up,together with abdominal imaging analysis(magnetic resonance cholangiopancreatography or computed tomography) and,if necessary,endoscopic ultrasound with or without fine needle aspiration.RESULTS:The overall five-year survival rate of patients who underwent resection was significantly greater than that for the nonsurgical patients(74% vs 58%; P =0.019).The parameters of age(< 70 years) and absence of a nodule were associated with better survival(P < 0.05); however,the parameters of main pancreatic duct diameter > 10 mm,branch ductdiameter > 30 mm,or presence of extra pancreatic cancers did not significantly influence the prognosis.In the nonsurgical patients,pancreatic malignancy occurred in 36% of cases within a mean time of 33 mo(median:29 mo; range:8-141 mo).Comparison of the nonsurgical patients who experienced disease progression with those who did not progress showed no significant differences in age,sex,symptoms,subtype of IPMN,or follow-up period; only the size of the main pancreatic duct was significantly different between these two sub-groups,with the nonsurgical patients who experienced progression showing a greater diameter at the time of diagnosis(> 10 mm).CONCLUSION:Patients unfit for surgery have a 36% greater risk of developing pancreatic malignancy of the main-duct or mixed IPMN within a median of 2.5 years.     

Clinical aspects of intraductal papillary mucinous neoplasm of the pancreas

Intraductal papillary mucinous neoplasm (IPMN) is a spectrum of neoplasia in the pancreatic duct epithelium characterized by cystic dilation of the main and/or branch pancreatic duct. According to the site of involvement IPMNs are classified into three categories, i.e., main duct type, branch duct type, and combined type. Most branch duct IPMNs are benign, whereas the other two types are often malignant. A large size of branch duct IPMN and marked dilation of the main pancreatic duct indicate the presence of adenoma at least. The additional existence of large mural nodules increases the possibility of malignancy in all types. Of recent interest is the relatively high prevalence of synchronous and/or metachronous malignancy in various organs, including the pancreas. The prognosis is favorable after complete resection of benign and noninvasive malignant IPMNs. Malignant IPMNs acquiring aggressiveness after parenchymal invasion necessitate adequate lymph node dissection. On the other hand, asymptomatic branch duct IPMNs without mural nodules can be observed without resection for a considerably long time. This review addresses available data, current understanding, controversy, and future directions.     

Intraductal papillary mucinous neoplasm of the pancreas: diagnosis and treatment

Intraductal papillary mucinous neoplasm (IPMN) is characterized by cystic dilatation of the main and/or branch pancreatic duct. Only one-third of all patients are symptomatic, and others are diagnosed by chance. IPMNs are classified into 3 types: main duct, branch duct, and mixed IPMN. Most branch-type IPMNs are benign, while the other 2 types are frequently malignant. The presence of large mural nodules increases the possibility of malignancy in all types. Presence of a large branch-type IPMN and marked dilatation of the main duct indicate, at the very least, the existence of adenoma. Ultrasonography, endosonography, and intraductal ultrasonography clearly demonstrate ductal dilatation and mural nodules, and magnetic resonance pancreatography best visualizes the entire outline of IPMN. Not infrequently, synchronous or metachronous malignancy develops in various organs, including the pancreas. Prognosis is excellent after complete resection of benign and noninvasive malignant IPMNs. Asymptomatic branch-type IPMNs without mural nodules may be followed up without resection. Malignant IPMNs displaying acquired aggressiveness after parenchymal invasion require adequate lymph node dissection. Total pancreatectomy is needed for some IPMNs; its benefits, however, must be balanced against operative and postoperative risks because most IPMNs are slow growing and affect elderly people, and prognosis is favorable for IPMN patients with even malignant neoplasms.     

Intraductal papillary mucinous neoplasms of the pancreas: clinical surveillance and malignant progression, multifocality and implications of a field-defect

Intraductal papillary mucinous neoplasms (IPMNs) are a heterogeneous group of mucin producing cystic tumors that involve the main pancreatic duct and/or branch ducts and may be associated with invasive carcinoma. Predicting the risk of malignant transformation of an IPMN lesion can be challenging. The Sendai criteria, based in large part on radiographic imaging features, help guide surgical intervention based on the stratification of cysts into high and low risk lesions for malignancy. Invasive carcinoma may develop in the index IPMN lesion or in a separate site within the pancreas, supporting the concept of a field defect in IPMN tumorigenesis. This stresses the importance of evaluation of the entire pancreas upon diagnosis of IPMN and continued surveillance of the residual pancreas following resection. Herein, the authors summarize the data presented at the 2012 ASCO Gastrointestinal Cancers Symposium regarding prevalence and site of invasive carcinoma detected in patients undergoing surveillance for IPMN (Abstract #152).     

Current roles of endoscopy in the management of intraductal papillary mucinous neoplasm of the pancreas

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is characterized by intraductal papillary proliferation of mucin‐producing epithelial cells that exhibit various degrees of dysplasia. IPMN is classified into four histological subtypes (gastric, intestinal, pancreatobiliary, and oncocytic) according to its histomorphological and immunohistochemical characteristics. Endoscopic retrograde cholangiopancreatography plays a crucial role in the evaluation of these features of IPMN. Endoscopic ultrasonography (EUS) has proven to be more sensitive than computed tomography or magnetic resonance imaging for early detection of malignancy. The present review addresses the current roles of endoscopy and related techniques in the management of IPMN. The particular focus is on diagnosing IPMN and malignancy within IPMN, detecting pancreatic cancer concomitant with IPMN, differentiating the epithelial subtypes of IPMN, determining the optimal strategy for the management of branch duct IPMN, and discussing innovative endoscopic technology related to IPMN. The disadvantages of endoscopic examinations of IPMN and different attitudes toward EUS‐guided fine‐needle aspiration for IPMN between Japan (negative) and other countries (active) are also discussed.     

胰管内乳头状黏液性肿瘤的术前良、恶性与浸润性预测因子

目的 分析术前预测胰管内乳头状黏液性肿瘤(IPMN)良、恶性与浸润性的因子,及不同病理类型IPMN的手术后生存率.方法 回顾性分析长海医院1993年1月至2009年9月间手术切除的78例IPMN病例资料,采用单因素与多因素分析的方法分析病史、临床表现、肝功能、CEA、CA19-9、影像学征象等在术前判断IPMN良、恶性与浸润性的价值,分析患者术后生存率.结果 单因素分析结果显示,黄疸、急性胰腺炎、血CA19-9>37 U/ml、AKP、肿块边界不清为恶性及浸润性预测因子;主胰管扩张、分支胰管直径>30 mm、出现壁节结等为恶性预测因子;CEA>6 ng/ml为浸润性预测因子.多因素分析显示,肿块边界不清为恶性及浸润性预测因子;急性胰腺炎为浸润性预测因子.良性IPMN患者的5年生存率为100%;恶性IPMN的2年生存率为78.9%、5年生存率为68.5%,其中浸润性IPMN的2年生存率为64.6%、5年生存率为43.1%.结论 肿块边界不清为IPMN恶性预测因子,急性胰腺炎、肿块边界不清是IPMN的浸润性预测因子.     

The distance of tumor spread in the main pancreatic duct of an intraductal papillary-mucinous neoplasm: where to resect and how to predict it

Background

The surgical decision regarding where to resect the pancreas is an important judgement that is directly linked to the surgical procedure. An appropriate surgical margin to resect intraductal papillary-mucinous neoplasm (IPMN) of the pancreas based on the distance of tumor spread (DTS) in the main pancreatic duct has not been adequately documented. We analyzed the appropriate surgical margin based on the DTS in the main pancreatic duct of IPMN and the positive rate at the pancreatic cut end margin.

Methods

Forty patients with main duct- or mixed-type IPMN diagnosed histopathologically who underwent surgery at Tokai University Hospital between 1991 and 2008 were retrospectively analyzed. The resection line was determined to achieve a 2-cm surgical margin in patients with main duct- or mixed-type IPMN and as limited a resection as possible to remove the dilated branch duct in patients with branch duct-type IPMN according to macroscopic type. The dysplastic state of the epithelium was judged as positive for carcinoma in situ (high-grade dysplasia) or adenoma (very low to moderate dysplasia) and judged as negative for hyperplasia or normal.

Results

The mean DTS in the main pancreatic duct was 41.6 ± 30.0 mm, and that of the distance of tumor absence was 13.6 ± 12.4 mm. The positive rate at the pancreatic cut end margin in frozen sections was 29.7%. The final positive rate at the pancreatic cut end margin was 26.2%. There has been no evidence of local recurrence in the remnant pancreas. DTS in the main pancreatic duct of IPMN was correlated with the maximum diameter of the duct (R = 0.678).

Conclusion

Distance of tumor spread offered important insights about the appropriate site to resect the pancreas and the positive rate at the cut end margin in IPMN.     

Surgical Management of Pancreatic Cysts: A Shifting Paradigm Toward Selective Resection

Due to the widespread use of high-quality cross-sectional imaging, pancreatic cystic neoplasms are being diagnosed with increasing frequency. Clinicians are therefore asked to counsel a growing number of patients with pancreatic cysts diagnosed incidentally at an early, asymptomatic stage. Over the last two decades, accumulating knowledge on the biologic behavior of these neoplasms along with improved diagnostics through imaging and endoscopic cyst fluid analysis have allowed for a selective therapeutic approach toward these neoplasms. On one end of the management spectrum, observation is recommended for typically benign lesions (serous cystadenoma), and on the other end, upfront resection is recommended for likely malignant lesions (main duct IPMN, mucinous cystadenoma, solid pseudopapillary tumor, and cystic pancreatic neuroendocrine tumors). In between, management of premalignant lesions (branch duct IPMN) is dictated by the presence of high-risk features. In general, resection should be considered whenever the risk of malignancy is higher than the risk of the operation. This review aims to describe the evolution and current status of evidence guiding the selection of patients with pancreatic cystic neoplasms for surgical resection, along with a specific discussion on the type of resection required and expected outcomes.     

Prevalence,Diagnosis and Management of Pancreatic Cystic Neoplasms: Current Status and Future Directions

Cystic neoplasms of the pancreas are found with increasing prevalence, especially in elderly asymptomatic individuals. Although the overall risk of malignancy is very low, the presence of these pancreatic cysts is associated with a large degree of anxiety and further medical investigation due to concerns about malignancy. This review discusses the different cystic neoplasms of the pancreas and reports diagnostic strategies based on clinical features and imaging data. Surgical and nonsurgical management of the most common cystic neoplasms, based on the recently revised Sendai guidelines, is also discussed, with special reference to intraductal papillary mucinous neoplasm (IPMN; particularly the branch duct variant), which is the lesion most frequently identified incidentally. IPMN pathology, its risk for development into pancreatic ductal adenocarcinoma, the pros and cons of current guidelines for management, and the potential role of endoscopic ultrasound in determining cancer risk are discussed. Finally, surgical treatment, strategies for surveillance of pancreatic cysts, and possible future directions are discussed.     

A case of mixed adenoneuroendocrine carcinoma of the pancreas mimicking intraductal papillary mucinous carcinoma

A previously healthy 52-year-old man was referred to our hospital for further evaluation of main pancreatic duct dilatation. The preoperative work-up was consistent with intraductal papillary mucinous carcinoma (IPMC) derived from a mixed type intraductal papillary mucinous neoplasm (IPMN), because multilocular cysts with enhancing thickened pancreatic head walls and dilated pancreatic ducts lined with dysplastic mucinous epithelium, with papillary proliferation from the pancreatic body to the tail, were observed; in addition, the pancreatic juice cytology was class V, which is suggestive of adenocarcinoma. Total pancreatectomy was performed because a definite mass was not found before surgical resection and the tumors could have spread to the tail. The pathological diagnosis was mixed adenoneuroendocrine carcinoma of the pancreatic head. IPMN with high- or low-grade dysplasia was not observed anywhere in the pancreatic duct. The pancreatic ductal adenocarcinoma consisted of large caliber malignant glands with intraluminal flat or papillary structures; therefore, we were unable to recognize a definite pancreatic mass before surgical resection, and suspected an IPMC derived from a mixed type IPMN.     

MANAGEMENT STRATEGIES FOR BRANCH DUCT INTRADUCTAL PAPILLARY‐MUCINOUS NEOPLASMS

Management strategies for branch duct intraductal papillary‐mucinous neoplasms (IPMN) have been discussed. The authors’ clinical criteria with special attention to the size of cystic lesion, the diameter of main pancreatic duct, and the size of mural nodule established in 2001 is useful for managing branch duct IPMN. A total of 55 of 60 cases with branch duct IPMN had no radiologic progression during an average follow up of 701 days. In addition, no case out of 27 cases with branch duct IPMN followed up for 3 years changed to positive in cytological examination using pancreatic juice. There were four cases of branch type IPMN with some changes in their image findings. There were two cases of branch type IPMN with pancreatic symptoms. A total of three out of these five cases were surgically resected. The ordinary‐type ductal carcinoma was detected in two cases with branch duct IPMN at 3 or 4 years later. These results suggest that a long‐term careful follow‐up study by computed tomography or ultrasonography at every 6 months would be needed in the management of branch duct IPMN. Further studies will be needed to dissolve this problem in the future.     

COMPARISON OF THE HEIGHT OF PAPILLARY TUMOR IN INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM OF THE PANCREAS BETWEEN MEASURED PREOPERATIVE IMAGES AND RESECTED MATERIAL

The height of the mural nodules and papillary tumors in main pancreatic duct or dilated branch duct is the most important factor for diagnosis of intraductal papillary mucinous neoplasm (IPMN). In this study, the authors compared the height of the papillary lesions and mural nodules between the height of resected tissues and the height detected by the preoperative imaging tools (endoscopic ultrasonography [EUS] and intraductal ultrasonography [IDUS]) in 38 patients with IPMN. In 21 out of 23 cases of adenoma, and in cases with the non‐invasive cancer, the difference of the height of operative and preoperative analysis measured by EUS and IDUS was within 1–2 mm. EUS and IDUS are useful for diagnosis of degree of malignancy in IPMN.