Pancreatic tumors with cystic dilatation of the ducts: intraductal papillary mucinous neoplasms and intraductal oncocytic papillary neoplasms

Intraductal papillary mucinous neoplasms (IPMNs) and intraductal oncocytic papillary neoplasms (IOPNs) are the 2 types of intraductal neoplasms of the pancreas that may appear cystic because of dilatation of the ducts. Both are characterized by intraductal proliferation of mucinous cells usually arranged in papillary patterns. This proliferation is often associated with intraluminal mucin accumulation, which produces cystic dilatation of the ducts, mimicking mucinous cystic neoplasms. Endoscopic and radiologic studies and careful macroscopic examination are crucial for the correct diagnosis of IPMNs and IOPNs by showing the origin within the native ducts. Microscopically, these tumors display a spectrum of cytoarchitectural atypia that ranges from adenoma to borderline and to carcinoma-in-situ. Although they are defined as "intraductal tumors," IPMNs and IOPNs are associated with invasive carcinoma in about a third of the cases. It, therefore, appears that, like mucinous cystic neoplasms or pancreatic intraepithelial neoplasia involving the smaller ducts associated with ordinary ductal adenocarcinomas, these tumors are precursors of invasive carcinoma. Invasive carcinomas associated with IPMNs are of either tubular or colloid (mucinous noncystic) types, whereas those associated with IOPNs may be oncocytic. Even in the presence of invasive carcinoma, these tumors may follow a more protracted clinical course than ordinary ductal adenocarcinoma. On the other hand, rare examples of IPMNs after an aggressive clinical course despite the lack of any identifiable invasive carcinoma are on record. Therefore, IPMNs and IOPNs should be examined carefully and sampled extensively, first, to confirm that the main pathology is an intraductal process and, more importantly, to rule out the presence of an invasive carcinoma.     

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.     

胰腺黏液性非囊性腺癌

目的探讨胰腺黏液性非囊性腺癌的病理形态学特征和相关蛋白表达状态与生物学行为的关系。方法对249例胰腺外分泌癌中6例符合黏液性非囊性腺癌病例进行形态学观察,应用免疫组织化学EnVision法检测了p21^ras、p21^WAF1、p16、p33^ING1、p53、ATM、MDM2、增殖细胞核抗原(PCNA)和细胞周期蛋白(Cy)D1、D3、A、B和E的表达,AB-PAS染色观察细胞内外黏液分布,同时对6例进行生存期随访。结果6例全部位于胰头部位,4例有十二指肠浸润,2例肝转移,2例局部淋巴结转移,1例周围神经浸润,具有相似的组织学特征。免疫组织化学染色阳性为p21^ras 5例,p21^WAF1 3例,p16 1例,p33^ING1 4例,p53 2例,ATM 3例,MDM2 3例,PCNA 6例,CyA 3例,CyD1 3例,CyD3 4例,CyB 4例,CyE 6例。AB-PAS染色见细胞内、外黏液分布。随访结果2例死亡(分别为术后14、20个月),3例存活(分别为28、49、87个月),1例失访。结论胰腺黏液性非囊性腺癌具有一些独特的病理形态学特征和生物学行为,肿瘤细胞存在多种肿瘤相关蛋白的改变和细胞周期蛋白的过表达,显示较差的生物学行为和较强的侵袭能力,但预后可能比普通导管腺癌好。     

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.     

Pseudomyxoma peritonei (mucinous carcinoma peritonei) preceded by intraductal papillary neoplasm of the bile duct

Pseudomyxoma peritonei (mucinous carcinoma peritonei) is a rare clinical disease. Although most cases derive from appendiceal mucinous tumors, a few are associated with pancreatic intraductal papillary mucinous neoplasms. Intraductal papillary neoplasms of the bile duct share many similarities with pancreatic intraductal papillary mucinous neoplasms and are thought to be their biliary counterparts. We report a case of low-grade intraductal papillary neoplasm of the bile duct who developed pseudomyxoma peritonei 6 years after surgical treatment of the primary biliary tumor. To the best of our knowledge, this is the first case of pseudomyxoma peritonei associated with intraductal papillary neoplasm of the bile duct. The tumor recurrence in our case may be due to tumor spillage at the time of the first surgery, since there is no recurrent biliary tumor in the preserved liver lobe. Prevention of spillage of epithelial cell-containing mucin during surgical operations is important in treating intraductal papillary neoplasms of the bile duct.     

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.     

Mucinous (so-called colloid) carcinomas of lung.

We present 24 cases of primary mucinous (so-called colloid) carcinomas of the lung. The patients were between 33 and 81 yr old (median: 57 yr), including 15 men and nine women. The lesions were discovered incidentally on chest X-ray, where they presented in diverse forms. No predilection for a particular lobe or pulmonary segment was observed. The tumors varied from 0.5 to 10 cm in greatest diameter. Grossly, the tumors were poorly circumscribed, soft, tan-to-gray mucoid lesions. Microscopically, they showed intra-alveolar pools of mucin containing small clusters of atypical cells floating in the mucin, and foci of neoplastic columnar epithelium lining scattered alveoli. Seven cases showed areas of solid, well-differentiated malignant glands adjacent to pools of mucin. In two cases, lymph node metastases were found at surgery. Eleven (57%) of 19 patients were alive over a follow-up period ranging from 2 to 192 mo; one of them had metastases to bone and another had intrapulmonary recurrence. Eight patients died with/of their tumors, two of them with known metastases to bone and/or brain, and one with recurrence after 2 yr of initial diagnosis. No follow-up was obtained in five patients. Although the extent of clinical evaluation varied, no other primary neoplasms (i.e., breast, gastrointestinal tract, or other organs where primary mucinous carcinomas are known to occur) were observed. These tumors probably represent a variant of bronchioloalveolar carcinoma and share the prognosis of that neoplasm. However, because of their often bland cytologic features and paucity of malignant cells, they may be difficult to diagnose as neoplasms.     

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.     

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.     

Pancreatic neoplasms with abundant mucus production: emphasis on intraductal papillary-mucinous tumors and mucinous cystic tumors.

The clinicopathologic features and problems in classification and diagnosis of the pancreatic neoplasms with abundant mucus production are presented. In this article, the various reported concepts and terminology of these mucus-producing pancreatic tumors are summarized, and the differences between intraductal papillary-mucinous tumors and mucinous cystic tumors are specifically discussed. Intraductal papillary-mucinous tumors show diffuse or segmental dilatation of the pancreatic ducts with intraductal papillary growth. Mucinous cystic tumors are mucus-producing tumors showing cyst formation, which is often accompanied by intracystic papillary projections and "ovarian-type" stroma. Intraductal papillary-mucinous tumors occur most often in the pancreatic head of elderly men, whereas mucinous cystic tumors typically occur in the pancreatic tail or body of middle-aged women. Histologically, these tumors show a wide cytologic spectrum from benign to borderline to malignant. These tumors pursue an indolent clinical course compared with conventional ductal carcinoma of the pancreas. Mucinous cystadenocarcinomas have a higher malignant potential than intraductal papillary-mucinous adenocarcinomas, yet these tumors recur infrequently if they are excised completely. Because of the differences in clinicopathologic features, these tumors should be clearly separated from conventional ductal carcinoma of the pancreas.     

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.     

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.     

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.     

Pure mucinous (colloid) carcinoma of the male breast. An uncommon subtype

Pure mucinous (colloid, mucous) carcinoma of the male breast is an extremely rare neoplasm. We report the case of a 74-year-old male who displayed a rapidly growing retroareolar tumor of the left breast. The patient underwent modified radical mastectomy. The tumor was well demarcated, had a soft consistency with a glistening gelatinous appearance. Histologically, the neoplasm corresponded to a pure mucinous carcinoma which is one of the most unusual subtYpes, accounting for less than 2% of male breast carcinomas.