Intraductal tubular adenoma (pyloric gland-type) of the pancreas: a reappraisal and possible relationship with gastric-type intraductal papillary mucinous neoplasm

Aims:  Intraductal tubular adenoma (ITA) is an uncommon intraluminal polypoid lesion that occurs in the main pancreatic duct and involves the main pancreatic duct in the region of head or body. Three cases of ITA are presented, the literature reviewed and their association with intraductal papillary mucinous neoplasm (IPMN) is postulated.
Methods and results:  ITA is composed of tightly packed tubular structures with focal cystic dilation and papillary areas lined by gastric/pyloric epithelium showing minimal to mild cytological atypia. Pancreatic intraepithelial neoplasia (PanIN) 1A and B was present in smaller ducts of all cases. In addition, in the cases in this report and 50% of cases reported in the literature, an associated gastric-type IPMN was present in the same duct as the ITA or in adjacent ducts. The coexistence of ITA and IPMN and the similarities of their epithelial lining (gastric/pyloric mucosa) suggest a possible pathogenic link.
Conclusions:  ITA can occur without (type A) or with (type B) an associated gastric-type IPMN. ITA could represent a localized, polypoid form of gastric-type IPMN.It is a benign lesion with no evidence of invasion and no direct tumour-related deaths. Its relationship to intraductal tubular carcinoma remains to be elucidated.     

Cystic lesion mimicking intraductal papillary mucinous tumor arising in heterotopic pancreas of the stomach and synchronous intraductal papillary mucinous adenocarcinoma of the pancreas

This article presents the study of a 66-year-old man with an asymptomatic pancreatic mass detected incidentally 4 months earlier. A magnetic resonance imaging scan revealed 2 distinct cystic masses in the pancreas and the gastric antrum. Microscopically, the pancreatic lesion showed dilated cysts containing papillary structures lined by mucinous epithelium, which showed a loss of polarity, an increased nucleus-to-cytoplasm ratio, a prominent nucleolus, and high proliferation on immunostaining for Ki-67. The gastric lesion was composed of heterotopic pancreatic tissue surrounding a large dilated cyst that was lined with mucinous epithelium and contained a few intraluminal papillae.     

Senescence in intraductal papillary mucinous neoplasm of the pancreas

Intraductal papillary mucinous neoplasm of the pancreas is attracting attention as a precursor lesion of the invasive ductal adenocarcinoma, whereas it has been reported that some intraductal papillary mucinous neoplasms do not display progression to malignancy and remain almost unchanged in size and morphology. Recent studies have reported that oncogene-induced senescence has been observed in neoplasms, especially in premalignant lesions, and that it can play an important role in preventing malignant progression. To clarify the presence of senescence in intraductal papillary mucinous neoplasms, we analyzed the expression of several markers of senescence. The intraductal papillary mucinous neoplasms evaluated in this study were classified into 4 groups according to the degree of dysplasia. Senescence-associated β-galactosidase activity and senescence-associated heterochromatin foci formation were investigated in 33 cases of intraductal papillary mucinous neoplasms and 6 normal controls. Immunohistochemical analysis of p16(INK4a) and p15(INK4b) was performed in 158 cases of intraductal papillary mucinous neoplasms and 10 normal controls. In the normal controls, neither senescence-associated β-galactosidase activity nor senescence-associated heterochromatin foci formation was observed. Most of the normal epithelia were negative for either p16(INK4a) or p15(INK4b). For all 4 markers, the percentages of positive cases reached a peak in intraductal papillary mucinous neoplasm with low-grade dysplasia and showed significant decreasing trends in the transition from intraductal papillary mucinous neoplasm with low-grade dysplasia to intraductal papillary mucinous neoplasm with an associated invasive carcinoma. Our results indicate that senescence is induced in the early stage of intraductal papillary mucinous neoplasm and gradually attenuated according to the progression. It is suggested that senescence plays a role in preventing malignant progression of intraductal papillary mucinous neoplasm.     

Clonality and K-ras mutation analyses of epithelia in intraductal papillary mucinous tumor and mucinous cystic tumor of the pancreas

Histological criteria for subclassification of intraductal papillary mucinous tumor (IPMT) and mucinous cystic tumor (MCT) of the pancreas remain ambiguous in the absence of apparent invasion or metastasis. To elucidate this issue, we evaluated clonality and K- ras mutations in 11 cystic tumors of the pancreas from female patients, including 7 IPMTs and 4 MCTs. The analyses were performed on DNA from laser microdissected epithelia showing different degrees of atypia as well as normal-appearing epithelia (NAE) in the individual tumors. The grades of atypia were classified into three groups on conventional hematoxylin-eosin staining. Clonality was assessed using the methylation-induced polymorphic inactivation of the X-linked phosphoglycerate kinase gene. The incidence of monoclonality increased with the grades of atypia: 27% for NAE, 43% for grade 1, and 100% for grades 2 and 3. In three of four MCTs, foci of NAE were polyclonal, while monoclonality was seen in each one of grades 1 and 2. The frequency of K- ras mutation depended on the grades of atypia: 0% for NAE, 29% for grade 1, 50% for grade 2, and 75% for grade 3. Polyclonal epithelia were devoid of K- ras mutation in 92% of sites, while monoclonality was associated with both wild and mutational types in an approximately equal ratio. Both IPMT and MCT seem to arise from polyclonal epithelia and to be replaced by monoclonal neoplastic cells as they undergo dysplastic changes and K- ras mutation. These data suggest that the monoclonal expansion precedes K- ras mutation.     

Immunohistochemical expression of Sonic hedgehog in intraductal papillary mucinous tumor of the pancreas.

Aberrant expression of Sonic hedgehog (Shh) has been reported in many human cancers including ductal carcinoma of the pancreas. The intraductal papillary mucinous tumor (IPMT) has been considered as one of the precursor lesions of invasive ductal carcinoma of the pancreas. Shh expression in pancreatic IPMT has not been reported. We investigated an immunohistochemical (IHC) expression of Shh in 55 cases of pancreatic IPMT. We analyzed the IHC expression of Shh in the following histologic grades of tumor: adenoma (AD), moderate dysplasia (MD), noninvasive carcinoma (NIC), and invasive carcinoma (IC), and with the following histologic subtype classification: intestinal, pancreatobiliary, null, and unclassifiable type. IHC Shh expression was noted in 6 (46.2%) of 13 AD, 5 (35.7%) of 14 MD, 12 (80%) of 15 NIC, and 11 (84.6%) of 13 IC. Shh expression was significantly increased in malignant IPMT (NIC+IC) compared with nonmalignant IPMT (AD+MD) (82.1% vs. 40.7%, P=0.0005). IHC Shh expression was found in 11 (68.8%) of 16 intestinal types, 13 (92.8%) of 14 pancreatobiliary types, 8 (38.1%) of 21 null types, and 2 (50%) of 4 unclassifiable types. Intestinal and pancreatobiliary subtypes showed a high expression of Shh compared with the null and unclassifiable type of IPMT. All 3 cases of node metastasis showed IHC Shh expression in tumor cells of metastatic lymph nodes. Therefore, Shh expression may have a critical role in the late stage of carcinogenesis of IPMT, and may impact metastatic progression to the lymph nodes in malignant IPMT.     

A case of minute intraductal papillary mucinous tumor of the pancreas presenting with recurrent acute pancreatitis

Intraductal papillary mucinous tumor (IPMT) of the pancreas, a lesion consisting of mucin-producing cells with neoplastic potential, is characterized by duct ectasia, mucin hypersecretion, often extensive papillary intraductal growth, varying degrees of cytologic atypia, and relatively indolent growth. The clinical presentation of IPMT of the pancreas is characterized by chronic or recurrent attacks of abdominal discomfort often in association with low level pancreatic enzyme elevations. Less commonly these lesions may be detected as asymptomatic radiographic abnormalities. Interestingly, a case of a minute IPMT (2 mm in height and 7 mm in length, adenoma) in the main pancreatic duct presenting with acute pancreatitis in a 55 year-old man has been reported in the Japanese literature. Recently, we also experienced a case of a minute IPMT in a branch pancreatic duct causing repeated bouts of acute pancreatitis in a 75 year-old man. A filling defect at the neck of the main pancreatic duct seen on an endoscopic retrograde pancreatogram performed after recovery of the second attack of acute pancreatitis led the patient to undergo an exploratory laparotomy. After a near-total pancreatectomy was carried out, a minute (3 x 7 mm) IPMT of borderline malignancy was discovered in a branch duct at the head portion near the pancreatic neck without any lesions in the main pancreatic duct. Surprisingly, despite the resective surgery the patient died of carcinomatosis 8.5 months after the operation. We herein report a case of a minute but aggressive IPMT of the pancreas with a review of the literature.     

胰腺导管内乳头状黏液性肿瘤的诊断和鉴别诊断

目的探讨胰腺导管内乳头状黏液性肿瘤的临床病理学特征及其与黏液囊性肿瘤的鉴别诊断要点。方法复习17例导管内乳头状黏液性肿瘤的临床病理学特征,与13例黏液囊性肿瘤对照;行HE染色及免疫组织化学EnVision法染色,检测肿瘤内黏液素MUC（1、2、5AC）的表达。结果17例导管内乳头状黏液性肿瘤中10例发生在男性;13例位于胰头。大体切面可观察到15例肿瘤与胰腺主导管相通。镜下可见到胰腺导管增生呈乳头状,并有上皮轻至重度不典型增生的改变。无卵巢样间质,肿瘤内交错出现萎缩或正常的胰腺腺泡和胰岛。9例主要表达MUC2,4例主要表达MUC5AC,4例伴有浸润癌者主要表达MUC1。13例黏液囊性肿瘤中11例发生于中老年女性;胰尾部10例,胰头1例,全胰腺2例;肿瘤与主导管不相通。组织学特征是含有卵巢样间质。肿瘤细胞主要表达MUC5AC,不表达MUC2,伴有浸润癌的2例,癌组织也表达MUC1。结论导管内乳头状黏液性肿瘤预后较好,患者性别、年龄、肿瘤部位、卵巢样间质、与主胰管是否相通及表达MUC2和（或）MUC1检测均可帮助诊断,并与黏液囊性肿瘤鉴别。后者主要表达MUC5AC。MUC1阳性提示侵袭性生物学行为。     

Nesidioblastosis coexisting with islet cell tumor and intraductal papillary mucinous hyperplasia

A coexisting of intraductal papillary mucinous hyperplasia (IPMH) and islet cell tumor with nesidioblastosis of the pancreas in a 51-year-old man is reported. All of the clinical data indicated an insulinoma. A distal pancreatectomy was performed. A discrete mass measuring 1.9 x 2.0 cm was grossly identified in the tail of the pancreas. There were no other gross lesions. An islet cell tumor with nesidioblastosis was confirmed by immunostains and ultrastructural study. In addition, an IPMH was found that involved mainly branches of the pancreatic duct. The islet cell tumor and IPMH were topographically separated; however, there was a histologically intimate relationship between the nesidioblastosis and the IPMH. These findings indicate that the IPMH may have derived from autocrine and paracrine influences on the existing duct epithelial cells. To the best of our knowledge, this is the first report of nesidioblastosis coexisting with islet cell tumor and IPMH.     

MUC-1 mucin expression in invasive areas of intraductal papillary mucinous tumors of the pancreas

The expression of MUC-1 mucin (membrane-associated mucin) and MUG2 much (secretory mucin) were immunohistochemically examined in 46 invasive ductal carcinomas (IDC) and 16 intraductal papillary mucinous tumors (IPMT) of the pancreas. lntraductal papillary mucinous tumors usually reveal expansive growth. However, of the 16 IPMT examined in the present study, three showed an invasive growth pattern, which was similar to 'mucinous carcinoma', around the non-invasive growth areas. Of 46 IDC, MUCl much detected by monoclonal antibodies, DF3 and MY.1E12, was expressed in 44 cases (96%) and in 45 cases (98%), respectively, whereas MUC-2 mucin detected by polyclonal antibody, anti-MRP, was not expressed in any of the cases (0%). In contrast, in the non-invasive growth areas of the 16 IPMT, MUG1 much detected by DF3 and MY.1 E12 was expressed in four cases (25%) and in six cases (38%), respectively, whereas MUG2 mucin detected by anti-MRP was expressed in 13 cases (81%). The invasive growth areas of the three IPMT showed positive expression of MUG-1 mucins detected by DF3 and MY.1E12, although the non-invasive growth areas showed negative expression of MUG1 muclns, except for their focal positive expression in one of the three cases. These findings indicate that the invasive growth areas of IPMT acquire a characteristic of MUC-1 much expression that is usually seen In IDC.     

Expression and intracellular localization of matrix metalloproteinases in intraductal papillary mucinous neoplasms of the pancreas

To analyze the expression of matrix metalloproteinases (MMPs) and their relationships with the histological grades of the intraductal papillary mucinous neoplasm (IPMN) of the pancreas, we examined the frequency of expression and intracellular localization of MMP1, MMP2, MMP3, MMP7, and MMP9 in IPMN by immunohistochemistry. A total of 45 IPMN lesions (14 adenomas, 17 borderline lesions, nine noninvasive carcinomas, and five invasive lesions) from 21 patients were examined. MMP1, MMP2, MMP7, and MMP9 were expressed in tumor cells. Frequency of tumor cells expressing MMP7 was low in adenomas (median, 5.0%), higher in borderline lesions (median, 30.0%), in noninvasive carcinomas (median, 50.0%), and in invasive lesions (median, 80.0%), with a significant trend (P < 0.0001). Such a trend was also observed when the lesions were classified into gastric and intestinal subtypes (P < 0.0001 and P = 0.011, respectively). Basolateral expression of MMP7 in tumor cells was more prominent in lesions with higher histological grades (P < 0.0001). The frequency and the localization of MMP1, MMP2, and MMP9 did not correlate to the histological grades. MMP7 may contribute to the process by which IPMN advances from adenoma to carcinoma and to subsequent invasion of tumor cells in IPMN.     

Cystic, mucin-producing neoplasms of the pancreas: the distinguishing features of mucinous cystic neoplasms and intraductal papillary mucinous neoplasms

Perhaps due to the increasing use of sensitive cross-sectional imaging of the abdomen, cystic lesions of the pancreas are being increasingly recognized. In many such cases, biopsy or resection reveals a multilocular cyst lined by columnar mucinous epithelium. Over the past two to three decades, there have been many advances in our understanding of the clinical, pathological, and molecular features of cystic mucin-producing pancreatic neoplasms, most of which are now broadly classified as either mucinous cystic neoplasms (MCNs) or intraductal papillary mucinous neoplasms (IPMNs). Although both share certain histological features and both are regarded to represent preinvasive neoplasms with the potential to progress to invasive carcinoma, there are many significant differences in their pathology and clinical management. The purpose of this review is to highlight the clinical and pathological characteristics of MCNs and IPMNs, with an emphasis of the features that distinguish them and allow proper pathological subclassification.     

K-Ras and microsatellite marker analysis of fine-needle aspirates from intraductal papillary mucinous neoplasms of the pancreas

Preoperative diagnosis of pancreatic cystic lesions is difficult despite the combination of cytomorphology, radiographic imaging characteristics, and fluid tumor markers such as carcinoembryonic antigen. Intraductal papillary mucinous neoplasms (IPMNs) represent a subset of preinvasive pancreatic cystic neoplasms and are associated with accumulated genetic mutations, especially K-ras and tumor suppressor genes such as p53. Application of molecular techniques to cyst fluid obtained by endoscopic ultrasound guided fine-needle aspiration (EUSFNA) may contribute to preoperative assessment.Sixteen patients with pancreatic cystic lesions had cyst fluid obtained by preoperative pancreatic EUSFNA or intraoperative aspiration. All patients subsequently underwent surgical resection of the pancreas and IPMN was documented in all (6 adenomas, 6 borderline tumors, and 4 carcinomas). DNA was extracted from the cyst fluids and mutational analysis for K-ras point mutations and loss of heterozygosity (LOH) analysis using a preselected panel of genomic loci were performed. LOH was observed in 3 of 4 carcinomas as compared to 4 of 11 adenomas and borderline lesions (1 was QNS). LOH and K-ras mutations were both acquired in 2 of 4 carcinomas and in 1 of 12 adenoma/borderline lesions.Although the study is small, molecular analysis for LOH and K-ras mutations is useful in the preoperative evaluation of cystic pancreatic lesions. Increasing degree of neoplasia appears to correlate with increased genetic abnormality using a panel of selected genomic markers.