Diagnostic and therapeutic endoscopic approaches to intraductal papillary mucinous neoplasm

Pancreatic cystic lesions are increasingly identified on routine imaging. One specific lesion, known as intraductal papillary mucinous neoplasm (IPMN), is a mucinous, pancreatic lesion characterized by papillary cells projecting from the pancreatic ductal epithelium. The finding of mucin extruding from the ampulla is essentially pathognomonic for diagnosing these lesions. IPMNs are of particular interest due to their malignant potential. Lesions range from benign, adenomatous growths to high-grade dysplasia and invasive cancer. These mucinous lesions therefore require immediate attention to determine the probability of malignancy and whether observation or resection is the best management choice. Unresected lesions need long-term surveillance monitoring for malignant transformation. The accurate diagnosis of these lesions is particularly challenging due to the substantial similarities in morphology of pancreatic cystic lesions and limitations in current imaging technologies. Endoscopic evaluation of these lesions provides additional imaging, molecular, and histologic data to aid in the identification of IPMN and to determine treatment course. The aim of this article is to focus on the diagnostic and therapeutic endoscopic approaches to IPMN.     

Characterization of K-ras gene mutations in association with mucinous hypersecretion in intraductal papillary-mucinous neoplasms

Background/Purpose Intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas have a favorable prognosis. However, invasive ductal carcinomas of the pancreas show a rapid progression. The aim of this study was to investigate gene mutations in pure pancreatic juice from IPMN patients and to define these genetic mutations in relation to the histopathological and clinical features of IPMNs. Methods Twenty-two patients with IPMN, 21 patients with ductal carcinoma, and 20 patients with normal pancreas or chronic pancreatitis were recruited for this study. We measured the main pancreatic duct’s largest diameter and the maximum size of a dilated branch was assessed by ultrasonography or endoscopic ultrasonography. Pure pancreatic juice was collected and was investigated for K-ras, p16, and p53 mutations. Results Mutant K-ras gene was detected in 13 of the 22 patients (59.1%) with IPMNs. Different kinds of mutations were detected in the same patient in 4 cases. In the 13 patients with mutant K-ras gene, the diameter of the most dilated part of the main pancreatic duct was 2–8 mm (average, 4.5 mm) and in 7 patients with wild-type K-ras gene, the diameter was 2–5 mm (average, 2.7 mm). There was a significant difference in the diameter of the main pancreatic duct between patients with and without the mutant K-ras gene (P = 0.0323). Conclusions The incidence of K-ras mutation may be associated with the hypersecretion of mucin.     

An aggressive surgical approach is warranted in the management of cystic pancreatic neoplasms

BACKGROUND: Cystic pancreatic neoplasms encompass a range of benign to malignant disease. Recommendations for surgical management vary. METHODS: Records of patients with cystic pancreatic neoplasms from January 1996 through December 2005 were retrospectively reviewed. RESULTS: Sixty resections were performed for 16 serous cystic neoplasms, 7 mucinous cystic neoplasms (MCNs), and 37 intraductal papillary mucinous neoplasms (IPMNs). Twenty-five percent (15/60) of neoplasms contained invasive cancer. Patients with MCN or IPMN invasive neoplasms experienced significantly diminished overall 5-year survival compared to patients with IPMN carcinoma in situ neoplasms and to patients with MCN or IPMN adenoma/borderline neoplasms (22% vs. 73% vs. 94%, P = .004). CONCLUSIONS: Given the poor long-term survival of patients with cystic pancreatic neoplasms containing invasive cancer and the current difficulty to preoperatively distinguish among the various types of lesions in a reliable manner, our data support an aggressive surgical approach to the management of cystic pancreatic neoplasms.     

Pancreatobiliary fistula associated with an intraductal papillary-mucinous pancreatic neoplasm manifesting as obstructive jaundice: Report of a case

We report a pancreatobiliary fistula caused by an intraductal papillary-mucinous pancreatic neoplasm (IPMN), manifesting as obstructive jaundice. Computed tomography showed dilatation of the bile duct and main pancreatic duct, with multiple cystic masses in the head of the pancreas. Endoscopic retrograde pancreatocholangiography showed a patulous papilla with mucin secretion. Contrast enhancement outlined amorphous material obstructing the lower part of the common hepatic duct. Pancreatogram and magnetic resonance cholangiopancreatography showed diffuse dilatation of the main pancreatic duct and side branches without communication with the adjacent organs or duct. We performed pancreaticoduodenectomy for IPMN of the pancreatic head and a tumor-like lesion in the lower common bile duct (CBD). Macroscopically, impacted thick mucus protruded into the CBD from the pancreas via a pancreatobiliary fistula. Histologic examination revealed a pancreatobiliary fistula caused by intraductal papillary-mucinous carcinoma of the pancreas with mucin hypersecretion, an adenoma without interstitial infiltration, and isolated implantation of an IPMN in the bile duct mucosa around the fistula.     

Pylorus-preserving total pancreatectomy for an intraductal papillary-mucinous neoplasm of the pancreas

Background/Purpose Total pancreatectomy (TP) is rarely performed to treat invasive ductal carcinoma of the pancreas, due to the associated markedly impaired quality of life and poor prognosis after the resection. Intraductal papillary-mucinous neoplasm (IPMN) of the pancreas is characterized by extensive intraductal spread and a favorable outcome even when presenting at an invasive stage. We herein reappraise the role of pylorus-preserving total pancreatectomy (PPTP) as a viable alternative pancreatic resection modality for borderline and malignant IPMN. Methods A total of five patients with IPMN underwent PPTP and their clinical follow-up data were reviewed. Results TP was performed due to recurrent IPMN in the remnant pancreas after distal pancreatectomy in three patients and due to massive involvement of the entire pancreas in the others. All patients were treated by the pylorus-preserving method, while the spleen was also preserved in one patient. The surgical margins were negative and no metastasis to the resected lymph nodes was evident, based on histological examinations. One patient underwent a re-operation due to postoperative intraabdominal bleeding, while another patient required tubedrainage for left pleural effusion. Three of the four patients who underwent PPTP with a splenectomy experienced postoperative gastric ulcer, which were controlled by medication. One patient died due to suicide 16 months after the PPTP. All the others were doing well without recurrence at periods of 62 to 127 months after the PPTP. Conclusions PPTP is therefore considered to be indicated as an effective treatment for borderline or malignant IPMN with extensive involvement, when the patient's condition permits, in order to achieve complete resection of the IPMN.     

Intraductal papillary-mucinous adenocarcinoma in the remnant pancreas after pancreatoduodenectomy for cancer of Vater's papilla associated with intraductal papillary-mucinous adenoma

A 72-year-old woman, who had undergone pylorus-preserving pancreatoduodenectomy 3 years before for cancer of Vater's papilla associated with a branch-type intraductal papillary-mucinous adenoma (IPMA), developed dilatation of the main duct and a nodular lesion in the remnant pancreas. Total pancreatectomy was performed, which revealed that the lesion was intraductal papillary-mucinous adenocarcinoma (IPMC) with minimal invasion, suggesting the metachronous multicentric occurrence of this intraductal papillary-mucinous neoplasm (IPMN). Because there were no malignant cells at the pancreaticojejunostomy, and because the histological appearance of the main-duct IPMC was different from that of the IPMA in the primary specimen, the main-duct IPMC was thought to be of different origin from the IPMA. These findings suggest that careful surveillance of the gastrointestinal tract and careful follow up are necessary for IPMN, because an IPMN could be associated with other gastrointestinal tract malignancies.     

Magnetic resonance cholangiopancreatography for postoperative follow-up of intraductal papillary-mucinous tumors of the pancreas

BACKGROUND: After resection of an intraductal papillary-mucinous tumor (IPMT), benign tumors or portions of the resected tumor are sometimes left in place to avoid total pancreatectomy. We evaluated the role of magnetic resonance cholangiopancreatography (MRCP) in postoperative follow-up. METHODS: Twenty-two patients underwent MRCP 0.5 to 6.5 years after pancreatic resection for IPMT. RESULTS: Two patients with surgical margin involvement of the main pancreatic duct showed mildly enhanced ductal dilatation due to anastomotic stenosis. In 4 patients with residual IPMT of the branch ducts, postoperative MRCP demonstrated no changes. MRCP revealed new IPMT 1 year after surgery in 1 patient. No patients showed intraductal or intracystic mural nodules postoperatively. In 3 patients with postoperative pancreatitis or recurrent abdominal discomfort, MRCP demonstrated ductal dilatation and poor secretin-stimulated pancreatic secretion into the gastrointestinal tract, which suggested pancreatoenterostomic stenosis. CONCLUSIONS: MRCP is useful for postoperative follow-up of IPMT, in terms of investigating residual or recurrent IPMT and evaluating postpancreatectomy long-term complications.     

胰腺导管内乳头状黏液肿瘤的分子病理学研究进展

胰腺导管内乳头状黏液肿瘤(IPMN)是一种较少见的胰腺囊性肿瘤,具有恶变为胰腺导管腺癌的风险,且一旦发生恶变,预后较差。目前国内外针对IPMN的研究较少,因此,更好地理解其发生发展的分子病理学机制对于该疾病的诊断、治疗和预后改善具有重要意义。已发现多种癌基因、抑癌基因、信号通路等分子参与了IPMN的发生发展及恶变过程,笔者着重对IPMN的分子病理学研究进展进行综述。     

Differentiating intraductal papillary mucinous neoplasms from other pancreatic cystic lesions

Intraductal papillary mucinous neoplasms (IPMN) can be difficult to distinguish from other cystic lesions of the pancreas. To understand better and discuss the current knowledge on this topic, the literature and the institutional experience at a large pancreatic disease center have been reviewed. A combination of preoperative demographic, historical, radiographic, laboratory data, as well as postoperative pathologic analyses can often distinguish IPMN from other lesions in the differential diagnosis.     

Extrapancreatic malignancies and intraductal papillary mucinous neoplasms of the pancreas

Over the last two decades multiple studies have demonstrated an increased incidence of additional malignancies in patients with intraductal papillary mucinous neoplasms (IPMNs). Additional malignancies have been identified in 10%-52% of patients with IPMNs. The majority of these additional cancers occur before or concurrent with the diagnosis of IPMN. The gastrointestinal tract is most commonly involved in secondary malignancies, with benign colon polyps and colon cancer commonly seen in western countries and gastric cancer commonly seen in Asian countries. Other extrapancreatic malignancies associated with IPMNs include benign and malignant esophageal neoplasms, gastrointestinal stromal tumors, carcinoid tumors, hepatobiliary cancers, breast cancers, prostate cancers, and lung cancers. There is no clear etiology for the development of secondary malignancies in patients with IPMN. Although population-based studies have shown different results from single institution studies regarding the exact incidence of additional primary cancers in IPMN patients, both have reached the same conclusion: there is a higher incidence of extrapancreatic malignancies in patients with IPMNs than in the general population. This finding has significant clinical implications for both the initial evaluation and the subsequent long-term follow-up of patients with IPMNs. If a patient has not had recent colonoscopy, this should be performed during the evaluation of a newly diagnosed IPMN. Upper endoscopy should be performed in patients from Asian countries or for those who present with symptoms suggestive of upper gastrointestinal disease. Routine screening studies (breast and prostate) should be carried out as currently recommended for patient's age both before and after the diagnosis of IPMN.     

胰腺黏液性囊性肿瘤的CT、MR诊断

目的分析胰腺黏液性囊性肿瘤（MCN）的CT及MR影像特点。方法18例胰腺黏液性囊性肿瘤均经病理证实,其中囊腺瘤11例,交界性肿瘤4例,囊腺癌3例。患者均进行了CT和（或）MR检查,回顾性分析肿瘤的CT及MR影像表现。结果胰腺黏液性囊性肿瘤平均大小为6．7cm,11例位于胰体、尾：除2例囊腺瘤为单房性无间隔外,其余16例均为多房性。3例囊腺癌囊壁及间隔明显增厚或囊壁上见壁结节,其中2例的囊腔直径大于2．0cm;13例非恶性肿瘤的囊壁及小房间隔较薄且均匀,无壁结节,小房直径大于2．0cm。1例囊壁钙化,4例合并胰腺炎改变,1例合并有胆总管扩张,1例周围血管包绕。结论胰腺黏液性囊性肿瘤的CT及MR表现具有一定的特点,有助于黏液性囊性肿瘤的诊断及鉴别诊断。     

p16 and p53 gene alterations and accumulations in the malignant evolution of intraductal papillary-mucinous tumors of the pancreas

Abstract. Background/Purpose: In general, intraductal papillary-mucinous tumors of the pancreas have a favorable prognosis. However, some invasive carcinomas show a rapid progression and a poor prognosis, such as invasive ductal carcinomas of the pancreas. The aim of this study was to clarify the genetic backgrounds underlying the evolution necessary for these tumors to become invasive carcinomas. Methods: Twenty-three patients with intraductal papillary-mucinous tumors, including 9 adenomas, 5 borderline tumors, 3 noninvasive carcinomas, and 6 invasive carcinomas, along with 24 patients with invasive ductal carcinomas were studied. After microdissection, K-ras mutation and loss of heterozygosity (LOH) of the p16 and p53 genes were investigated. Results: In the intraductal papillary-mucinous tumors, K-ras mutations were frequently seen, without a relationship to histological grade. LOH of the p16 gene was observed increasingly with increasing degrees of histological atypia. LOH of the p53 gene was seen only in invasive carcinomas. The frequency of each genetic alteration in invasive carcinomas was the same as that in invasive ductal carcinomas. The accumulation of genetic alterations was as common in invasive carcinomas, as they were in invasive ductal carcinomas. Conclusions: The p16 and p53 gene alterations and accumulations observed are crucial events during the carcinogenesis and malignant progression of intraductal papillary-mucinous tumors of the pancreas. Received: October 4, 2001 / Accepted: November 16, 2001     

胰腺导管内乳头状黏液性肿瘤13例临床分析

目的总结胰腺导管内乳头状黏液性肿瘤(IPMT)的诊治经验,提高对该病治疗水平。方法自1985年5月至2004年3月共收治IPMT病人13例,男8例,女5例。所有病人均有不同程度的胰管扩张,8例进行了ERCP检查,发现胰管扩张,胰液溢出5例。结果除1人外,其他病人均接受了手术治疗,手术效果良好。术后病理诊断为胰头导管乳头状黏液性腺癌3例;胰头导管内乳头状黏液性腺瘤伴局部癌变2例;胰头导管内乳头状黏液性腺瘤伴不典型增生2例;胰头导管内乳头状黏液性腺瘤5例。结论IPMT与胰腺导管癌不同,ERCP有助于诊断本病,积极的手术治疗可获得良好的预后。     

Surgical treatment of intraductal papillary-mucinous tumor (IPMT) of the pancreas: operative indications based on surgico-pathologic study focusing on invasive carcinoma derived from IPMT

Background/Purpose. Between 1979 and 2000, 51 patients with intraductal papillary-mucinous tumor (IPMT) of the pancreas underwent surgical resection.Methods. The patients were reviewed to disclose the surgical pathology of invasive carcinoma derived from IPMT and to determine the surgical indications for IPMT on the basis of the pathologic findings.Results. The incidence of invasive carcinoma derived from IPMT according to the localization of the tumor was as follows: 4/9 (44%) in the main pancreatic duct (MPD type), 4/9 (44%) showing ductal spread from the MPD to branch ducts (mixed type), and 2/33 (6%) in the 2 branch duct (branch type). The maximal size of the intraductal spread of invasive carcinomas (8 of 18 cases in the MPD and mixed type together and 2 of 33 cases in the branch type) was as follows: 6/8 (75%) in the MPD and mixed type were over 6cm in size, and the 2-branch-type invasive carcinomas were within the 3-cm size range.Conclusions. We concluded that for both invasive and noninvasive IPMTs, surgical resection was necessary for any MPD or mixed-type IPMTs, and that surgical resection was appropriate for branch-type lesions larger than or equal to 3cm in diameter, or for lesions smaller than 3cm showing rapid growth on clinical images.     

Mucinous cystic tumors of the pancreas

Purpose: This study was conducted to clarify the clinicopathologic characteristics relevant to the specific diagnosis of mucinous cystic tumors of the pancreas. Methods: We retrospectively reviewed the clinical features and histopathologic findings of five patients who underwent curative resection for mucinous cystic tumors of the pancreas at our hospital between 1975 and 2000. Results: All five patients were women, ranging in age from 36 to 69 years, and the tumors were located in the pancreatic body and tail. Histopathologically, three tumors were mucinous cystadenomas and two were mucinous cystadenocarcinomas. All five tumors had ovarian-type stroma, and stromal luteinization was found in the three adenomas. These tumors were classified into two groups according to whether the epithelial lining was endocervical or intestinal. All tumors were spherical and multilocular with a fibrous pseudocapsule. On T1-weighted magnetic resonance images, mucinous cystadenomas with watery mucin showed low signal intensity, but mucinous cystadenocarcinomas with gelatinous mucin or hemorrhagic contents demonstrated high signal intensity. Conclusions: Signal intensity on T1-weighted magnetic resonance images provides highly useful diagnostic information on mucinous cystic tumors of the pancreas. Furthermore, tumors may be classified into two groups according to the type of epithelial lining. Received: December 19, 2001 / Accepted: May 7, 2002 Reprint requests to: T. Hara     

Prognosis of invasive intraductal papillary mucinous neoplasms of the pancreas

Intraductal papillary mucinous neoplasms (IPMN) are mucin producing cystic neoplasms of the pancreas histologically classified as having non-invasive and invasive components. The five-year survival rates for non-invasive and associated invasive carcinoma are 90% and 40%, respectively in resected IPMN lesions. Invasive carcinoma within IPMN lesions can be further classified by histological subtype into colloid carcinoma and tubular carcinoma. Estimated five-year survival rates following resection of colloid carcinoma range from 57%-83% and estimated five-year survival following resection of tubular carcinoma range from 24%-55%. The difference in survival outcome between invasive colloid and tubular IPMN appears to be a function of disease biology, as patients with the tubular subtype tend to have larger tumors with a propensity for metastasis to regional lymph nodes. When matched to resected conventional pancreatic adenocarcinoma lesions by the Memorial Sloan Kettering Cancer Center pancreatic adenocarcinoma nomogram, the colloid carcinoma histological subtype has an improved estimated five-year survival outcome compared to conventional pancreatic adenocarcinoma, 87% and 23% (P = 0.0001), respectively. Resected lesions with the tubular carcinoma subtype overall have a similar five-year survival outcome compared to conventional pancreatic adenocarcinoma. However, when these groups were stratified by regional lymph node status patients with negative regional lymph nodes and the tubular subtype experienced significantly better survival than patients with a similar nodal status and ductal adenocarcinoma with estimated five-year survival rates of 73% and 27% (P = 0.01), respectively.     

胰腺导管内乳头状黏液性肿瘤的诊断与治疗

目的提高对胰腺导管内乳头状黏液性肿瘤(IPMTs)的认识,以改善其诊治水平。方法对1993年5月至2003年12月收治的15例IPMTs病人的临床、影像学表现及病理资料作回顾性分析。结果15例中男性12例,女性3例。年龄33～76岁,平均58岁。上腹痛为最常见症状。B超和CT检查,均提示有不同程度的胰管扩张和囊实性占位。11例行ERCP检查,发现十二指肠乳头肿大和黏液溢出者7例。14例行手术治疗(胰十二指肠切除术12例,胰体尾切除1例,全胰切除1例)。术后病理诊断胰头导管内乳头状黏液性腺癌3例、导管内乳头状黏液性腺瘤伴局部癌变6例、胰头导管内乳头状黏液性腺瘤伴不典型增生3例、胰头导管内乳头状黏液性腺瘤2例,术后除1例因肝广泛转移而死亡外,其余病人均健在,存活期最长1例已13年。结论胰腺有囊实性占位伴胰管全程扩张的病人应考虑IPMTs,ERCP发现十二指肠乳头增大有黏液溢出者可确诊该疾病。手术切除是最有效的治疗,术后预后良好。     

76例胰腺导管内乳头状黏液性肿瘤的外科治疗及预后分析

目的 分析胰腺导管内乳头状黏液性肿瘤患者的临床特征及手术疗效.方法 收集1999年1月至2008年12月复旦大学附属中山医院手术切除的76例胰腺导管内乳头状黏液性肿瘤的病史资料,并进行随访,分析其临床特征及手术疗效.结果 76例患者中,男性49例,女性27例;肿瘤位于胰头者63例,胰体尾10例,全胰3例;32例为非浸润性肿瘤(腺瘤16例,交界性肿瘤6例,原位癌10例),44例为浸润癌,两者在发病年龄及黄疸、消瘦、无症状患者、CA199升高等方面差异有统计学意义(P＜0.05);胰十二指肠切除59例,联合门静脉切除重建4例,胰体尾切除6例,局部切除2例,节段性胰腺切除2例,全胰切除3例;总体并发症发生率为28.9%,无手术相关死亡病例;非浸润性及浸润性肿瘤患者5年生存率分别为100%及35%;非浸润性肿瘤患者7例切缘阳性,其中1例术后67个月复发转移;多因素分析显示肿瘤直径及淋巴结状况是影响浸润性癌患者预后的独立因素.结论 非浸润性胰腺导管内乳头状黏液性肿瘤手术疗效极佳,而浸润癌患者的预后较差;及早手术是防止病变进展及改善预后的关键;术后必须进行长期随访.

Abstract：

Objective To investigate the outcome of intraductual papillary mucious neoplasms (IPMN) of the pancreas after surgical resection. Method Clinical data of 76 patients with intraductal papillary neoplasms of the pancreas undergoing surgical resection at Zhongshan Hospital, Fudan University between January 1999 and December 2008 were retrospectively analyzed. Results Among the 76 patients,49 were male, 37 were female. 32 had noninvasive IPMNs, including adenomas( n = 16), borderline tumors (n =6 ), carcinomas in situ (n = 10 ). 44 had invasive IPMNs. Lesions were present in the head in 63 cases, in the body or tail in 10, in the whole pancreas in 3. There were significant difference in age,jaundice, weight loss, asymptomatic cases and CA199 value between noninvasive and invasive IPMNs.Three patients underwent total pancreatectomy, 59 patients underwent pancreaticoduodenectomy, 4 patients underwent pancreaticoduodenectomy with portal vein resection and reconstruction, six patients underwent distal pancreatectomy, two patients each underwent central pancreatectomy or enucleation. The overall postoperative morbidity rate were 28.9%, there was no operative mortality. Positive pancreatic margin was identified in seven patients of noninvasive neoplasms, among thoee one developed recurrence after 67 months. The five-year survival rate for patients with noninvasive and invasive neolpasms was 100% and 35% ,respectively. Size and lymph node metastasis were significant prognostic factors after surgical resection of the invasive IPMNs. Conclusions Surgical resection provides a favorable outcome for patients with noninvasive IPMNs. In contrast, invasive IPMNs was associated with a poor survival. Early resection is essential for improving survival. Long-term follow-up is necessary for all patients with IPMNs after resection.