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.     

Zystische Pankreastumoren und ihre Klassifikation

Cystic tumors and tumor-like lesions of the pancreas are rare, but have attracted a great deal of attention because they are easily recognized with new imaging methods and, in contrast to ductal adenocarcinoma, they can usually be cured surgically. The increasing resection rate in recent years has also increased our knowledge of cystic pancreatic tumors by conspicuously enlarging their morphological spectrum. Known entities have been better characterized (i.e. solid pseudopapillary neoplasm, intraductal papillary mucinous neoplasm) and new ones described (serous oligocystic adenoma, mucinous non-neoplastic cyst, acinar cell cystadenoma and cystic hamartoma). This review discusses the most important cystic tumors and tumor-like lesions, presents a new classification, and summarizes the immunohistochemical differential diagnosis.     

Histologic characteristics of pancreatic intraepithelial neoplasia associated with different pancreatic lesions

Pancreatic intraepithelial neoplasia (PanIN) has been found in association with pancreatic ductal adenocarcinoma, intraductal papillary-mucinous neoplasm (IPMN), mucinous cystic neoplasm, and other pancreatic lesions, but the characteristics of PanINs associated with these lesions are not well characterized. In this study, 185 partial or total pancreatectomy specimens were collected, and 173 had complete slides for reviewed, which included 74 pancreatic ductal adenocarcinomas, 28 IPMNs, 7 mucinous cystic neoplasms, 44 other nonductal tumors, and 20 nontumorous lesions. Differences in grade, extent, and duct involvement among PanINs associated with different lesions were analyzed. Patients with PanINs were older than those without, regardless of associated tumor or lesions. No sex predilection was noted. PanINs were found in 89%, 96%, 86%, 64%, and 55% pancreata with ductal adenocarcinomas, IPMNs, mucinous cystic neoplasm, other nonductal tumors, and nontumorous lesions, respectively. PanIN 1 and 2 were commonly associated with all types of lesions, but high-grade PanIN 3 was more frequently associated with ductal adenocarcinomas. Ductal involvement of PanINs was more extensive in association with ductal adenocarcinomas than in any other types of pancreatic tumors or lesions. PanINs associated with pancreatic ductal adenocarcinomas affected both the main and branched ducts, whereas PanINs associated with other types of pancreatic tumors or lesions were mainly present in the branch ducts. No statistical differences were observed in distribution, extent, and grade of PanINs among IPMNs, mucinous cystic neoplasms, other nonductal tumors, and nontumorous lesions. Our study demonstrated a high concurrence between PanINs and other precancerous lesions and histologic features of PanINs associated with different pancreatic diseases.     

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.     

胰腺囊性肿瘤92例临床病理分析

目的探讨胰腺囊性肿瘤的临床病理特征及免疫组织化学特点,以期提高对胰腺囊性肿瘤的认识。方法复习复旦大学附属中山医院1999—2005年间手术切除的92例胰腺囊性肿瘤的临床病理资料和影像资料,根据2002年WHO胰腺肿瘤分类标准将其分类。并采用免疫组织化学EnVision法,借助-组抗体进行鉴别诊断。结果在92例囊性肿瘤中,发病年龄16～80岁,男33例,女59例。其中,浆液性肿瘤18例,黏液性肿瘤14例,导管内乳头状黏液性肿瘤36例,实性假乳头状肿瘤18例,导管腺癌囊性变4例,胰腺内分泌肿瘤囊性变2例。免疫组织化学检测无特异性标记物可以完全区分各类型,常有交叉和重叠。浆液性囊腺瘤表达MUC-1,黏液性囊性肿瘤表达MUC-5AC为主,实性假乳头状肿瘤表达d-抗胰蛋白酶、d-抗胰糜蛋白酶、波形蛋白及孕激素受体,导管内乳头状黏液性腺瘤表达MUC-2,囊性恶性肿瘤主要表达MUC-1。结论胰腺各类囊性肿瘤在临床症状、影像学表现、组织形态及免疫表型上均有一定特征,但均无特异性,需结合起来综合判断,才能做出正确诊断,以指导临床治疗和预后判断。     

Pancreatic ductal adenocarcinomas with cystic features: neither rare nor uniform.

Cystic tumors of the pancreas are uncommon but important because of their diverse pathology and biology. Their wide spectrum also includes cystic variants of otherwise solid tumors, such as cystic endocrine tumors, cystic acinar cell carcinomas and ductal adenocarcinomas with cystic changes. In this study, we screened pancreatic ductal adenocarcinomas and their variants for macrocystic changes and determined the nature of the cysts (neoplastic vs non-neoplastic). Of 483 tumors 38 (8%) had cystic features. The largest group consisted of 24 pancreatic ductal adenocarcinomas showing a large-gland pattern with small cysts whose diameter varied between 0.5 and 1.8 cm. The epithelial lining of these cysts was generally positive for CEA (83%) and/or MUC1 (71%) and MUC5AC (74%). p53 was positive in 57% of the cases. The second group of cystic tumors (8/483) showed degenerative cystic cavities with diameters ranging between 1 and 6 cm. This group consisted of poorly differentiated pancreatic ductal adenocarcinomas, undifferentiated carcinomas with or without osteoclast-like giant cells and one adenosquamous carcinoma. In the third group of cystic tumors there were four pancreatic ductal adenocarcinomas containing tumor-related retention cysts. Their epithelial cells were positive for MUC5AC, but negative for CEA, MUC1 and p53. The fourth group consisted of two pancreatic ductal adenocarcinomas showing closely attached pseudocysts caused by tumor-associated pancreatitis. The results indicate that a considerable number of pancreatic ductal adenocarcinomas and their variants display cystic features and must therefore be considered in the differential diagnosis of cystic neoplasms of the pancreas. Moreover, not all of the cystic structures we observed were neoplastic in nature. They may also represent non-neoplastic changes, such as retention cysts and inflammatory pseudocysts.     

Undifferenzierte Pankreaskarzinome

Undifferentiated pancreatic carcinomas are rare anaplastic variants of ductal adenocarcinoma of the pancreas. They have to be distinguished immunohistochemically from metastases of malignant melanoma or an infiltrating sarcoma. An uncommon variant is undifferentiated pancreatic carcinoma with osteoclast-like giant cells. This variant can be associated with mucinous cystic neoplasms and is characterized by abundant non-neoplastic osteoclast-like giant cells.     

Immunohistochemical studies on cystic pancreatic neoplasms

For the treatment of cystic changes of the pancreas, it is essential to distinguish cysts and pseudocysts from neoplasm. Since clinical parameters are usually not characteristic, only histologic and cytologic analyses will prove a diagnosis. The immunohistochemical characteristics of microcystic adenoma, mucinous cystic neoplasia in comparison to solid cystic pancreatic tumor, ductal carcinomas, and endocrine tumors, are studied with a panel of markers as well as enzyme, epithelial, neuroendocrine and pancreatic hormonal markers. The immunohistochemical results with diffuse cytoplasmatic expression of CEA and epithelial markers may be helpful in the exploration of carcinomatous transformed tissue parts within mucinous cystic pancreatic neoplasias, and are therefore of significance for surgical therapy.     

Large duct type invasive adenocarcinoma of the pancreas with microcystic and papillary patterns: a potential microscopic mimic of non-invasive ductal neoplasia

A morphological variant of pancreatic ductal adenocarcinoma forming large ductal elements, large duct type ductal adenocarcinoma, is documented and its clinicopathological features are studied. These tumors may have microcystic and papillary growth patterns that closely mimic the non-invasive cystic and papillary pancreatic tumors such as: intraductal papillary-mucinous neoplasia, including the oncocytic variant, mucinous cystic neoplasms, and ducts involved by pancreatic intraepithelial neoplasia. In a review of 230 pancreatectomy specimens with ductal adenocarcinoma, 28 (8%) cases of large duct type ductal adenocarcinomas were identified according to following criteria: more than 50% of the tumor sections available for examination contained infiltrative ducts with a diameter larger than 0.5?mm or had a macroscopically identifiable microcystic pattern. Overall characteristics of large duct type ductal adenocarcinomas were not too different than those of conventional ductal adenocarcinomas, except that there was a slight female predominance in the former (F/M=2.3). The mean age was 67 (vs 63 in conventional ductal adenocarcinomas; P=0.015), and occurrence in the tail was slightly more common (40% vs 18% in conventional ductal adenocarcinomas; P=0.006). Grossly, cysts measuring up to 1?cm was noted in 10 cases. Microscopically, large duct type adenocarcinomas were characterized by irregularly distributed large ducts with jagged edges, lined by columnar mucinous cells often having deceptively bland cytological features and variable degrees of papillomatosis. Stromal desmoplasia had a hypercellular quality (morphologically distinct from ovarian-like stroma) in four cases, and had a myxoid quality in others. KRAS oncogene mutation was identified in 9 out of 11 cases. Median, 1-year and 2-year survival rates were 16 months, 77% and 30%, respectively, as opposed to 12 months, 52% and 30%, respectively, in conventional ductal adenocarcinoma. In conclusion, it should be recognized that, some (8%) pancreatic ductal adenocarcinomas exhibit a large duct pattern that may microscopically mimic non-invasive pancreatic tumors characterized by cystic and papillary patterns. They may be distinguished by the relatively smaller size of the cysts, irregularity of the duct contours, clustering of the ducts, presence of intraluminal neutrophils and granular debris, degree of cytological pleomorphism, and myxoid quality of the stroma. Clinical behavior appears to be slightly better than that of conventional ductal adenocarcinoma, which may be accounted by the well-differentiated nature of these tumors.     

The clinical and morphological characteristics of mucinous cystic tumors of the pancreas

The authors present the data available in the literature and the results of their studies of intraoperative specimens from 24 patients with mucinous cystic tumors of the pancreas. The latter are a special group of neoplasms that are unrelated to the gland's ducts and consist of the mucin-producing epithelium with underlying ovarian-like stroma. Mucinous cystadenocarcinoma are detectable in older women (mean age 54.8 years), they are large and multicompartmental in nature. Microscopic study has indicated that all types of mucinous cystic tumors are characterized by ovarian-like stroma, the cells of which show a positive reaction to progesterone receptor antibodies. More significant ovarian-like stroma is typical of mucinous cystadenoma. The high (more than 30%) proliferative activity of epithelial lining cells is suggestive of the malignant nature of the process.     

Invasive ductal carcinoma of the pancreas tail with noninvasive growth through the nondilated main pancreatic duct and macroscopically cystic invasive carcinomatous glands

Noninvasive growth forming macroscopically dilated cystic pancreatic ducts is a fundamental feature of intraductal papillary mucinous neoplasm (IPMN), from which invasive carcinomas can arise. However, some invasive ductal carcinomas of the pancreas also show a macroscopically cystic feature. We experienced 2 cases of invasive ductal carcinoma of the pancreas tail with noninvasive growth through the main pancreatic duct without dilation at the body side, and with collection of macroscopically cystic carcinomatous glands infiltrating at the spleen side, which resembled some IPMNs and/or IPMN-derived invasive carcinomas. These cases were different from IPMN in that they lacked macroscopic dilatation of the pancreatic ducts, and the macroscopically dilated cystic carcinomatous glands were invasive but not intraductal. The intraductal component of the carcinomas showed papillary growth of neoplastic epithelia with atypia consistent with PanIN-3. Both intraductal and invasive components predominantly showed gastric mucin phenotype (MUC5AC+, MUC6 focally +, MUC2− or MUC2+ in scattered small number of cells). Recognition of these pancreatic carcinoma cases is important in the following 2 points: (1) The presence of such cases should always be kept in mind as differential diagnosis of IPMN or IPMN-derived invasive carcinoma in imaging and pathologic diagnoses. (2) The histogenesis of these cases might be placed in the intermediate between 2 major histogenetic pathways of pancreatic carcinoma, that is, one from microscopic precursors called PanIN and the other from macroscopic precursors of IPMN. These cases can be regarded as invasive carcinomas derived from semimacroscopic extension of the intraductal lesion of the main pancreatic duct.     

Biliary tumors with pancreatic counterparts

Some biliary diseases mimic pancreatic diseases pathologically as well as pathogenetically. Such diseases can be called “biliary diseases with pancreatic counterparts”. Biliary intraepithelial neoplasm (BilIN), intraductal papillary neoplasm of bile ducts (IPNB), hepatobiliary mucinous cystic neoplasm (hMCN), and IgG4-inflammatory pseudotumor represent the biliary counterparts of pancreatic intraepithelial neoplasm (PanIN), intraductal papillary mucinous neoplasm of pancreas (IPMN), pancreatic MCN, and mass forming type 1 autoimmune pancreatitis (AIP), respectively. BilIN and PanIN represent pre-invasive intraepithelial stages of nodular sclerosing cholangiocarcinoma and pancreatic ductal adenocarcinoma, respectively. IPNB and IPMN are grossly visible, predominant papillary, intraductal neoplasms that may progress to invasive carcinoma. Morphologically similar MCNs with subepithelial ovarian-like stroma occur in both the hepatobiliary system as well as the pancreas. IgG4-inflammatory pseudotumor, usually of the lymphoplasmacytic type, and mass forming type 1 AIP represent IgG4-related disease in the biliary tree and pancreas respectively. The biliary tract, which is associated with the peribiliary glands, including the pancreatic acini, can be regarded as an incomplete pancreas, so several diseases mimicking pancreatic diseases may be expected to occur in the biliary tract (biliary diseases with pancreatic counterparts).     

Accessory spleen presenting as a mass in the tail of the pancreas

In this case report, we describe an accessory spleen that presented as a mass in the tail of the pancreas and mimicked a neoplasm. Intrapancreatic accessory spleen have a relatively high prevalence and can be mistaken for tumors. We present a case of intrapancreatic accessory spleen in a 40-year-old man, which was discovered incidentally during a workup for an aortic dissection. Computerized axial tomography and magnetic resonance imaging scans demonstrated a hypervascular mass in the tail of the pancreas. The clinical and radiological differential diagnosis included pancreatic mucinous cystic neoplasm, pancreatic endocrine neoplasm, solid pseudopapillary tumor, ductal adenocarcinoma, and metastasis. After a distal pancreatectomy was completed, microscopic examination revealed heterotopic splenic tissue.     

Marked diffuse dilations of the biliary tree associated with intrahepatic calculi,biliary sludges and a mucinous cyst of the pancreatic head in a 99-year-old woman

A 99-year-old woman was admitted to Shizuoka Shimizu Municipal Hospital because of fever and anasarca. Imaging and laboratory tests showed pneumonia, urinary tract infection, and cardiac failure. The patient died 20 days after admission. An autopsy revealed marked diffuse dilations of the biliary tree ranging from the lower common bile duct to intrahepatic bile ducts. Intrahepatic calcium bilirubinate stones and biliary sludges were recognized within the dilated bile ducts. A unilocular cyst (2 cm in diameter) was present in the pancreatic head adjacent to the lower common bile duct, and it appeared to compress the common bile duct. Histologically, the walls of the dilated biliary tree showed proliferation of peribiliary glands, fibrosis, and infiltration of lymphocytes and neutrophils (cholangitis). The lumens of the dilated biliary ducts contained neutral and acidic mucins, fibrinous materials, bacteria, neutrophils, and Aspergillus fungi, in addition to the calculi and sludges. The background liver showed atrophy (400 g). The pancreatic unilocular cyst was composed of mucous columnar cells with a few infoldings, and the pancreas also showed foci of mucinous duct hyperplasia and ectasia; the pathological diagnosis of the cyst was cystic dilations of a pancreatic duct branch (mucinous ductal ectasia or mucinous cyst). Other lesions included aspiration pneumonia, emaciation, atrophy of systemic organs, gastric leiomyoma, serous cystadenoma of the right ovary, and arteriosclerotic nephrosclerosis. The present case suggests that a mucinous cyst of the pancreas may compress the biliary tree and lead to marked diffuse dilations of the biliary tree. Alternatively, the dilations of the bile ducts may be associated with aging or may be of congenital origin. The dilated bile ducts may, in turn, give rise to bacterial and fungal cholangitis and formation of biliary sludges and intrahepatic calcium bilirubinate stones.     

Serous cystic neoplasms of the pancreas: Clinicopathologic and molecular characteristics

We herein summarize the pathology and most recent advances in the molecular genetics of serous cystic neoplasms of the pancreas. They typically present as relatively large, well-demarcated tumors (mean size, 6 cm), predominantly occurring in females. Pre-operative diagnosis remains challenging; imaging findings and cyst fluid analysis often prove non-specific and fine-needle aspiration often does not yield diagnostic cells. Pathologically, they are characterized by a distinctive cytology referred to as “serous.” Although they have ductal differentiation, they distinctly lack the mucin production that characterizes most other pancreatic ductal tumors, including ductal adenocarcinoma and its variants, intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). They instead produce abundant glycogen (glycogen-rich adenoma). Serous cystadenomas also lack the molecular alterations that characterize ductal neoplasms, such as mutation of KRAS (high prevalence in most mucinous ductal neoplasms), inactivation of SMAD4 (seen in ductal adenocarcinomas), and mutations in GNAS (seen in some IPMNs) and RNF43 (detected in MCNs and IPMNs). Instead, new molecular and immunohistochemical observations place serous pancreatic tumors closer to “clear cell neoplasms” seen in various other organs that are associated with the von Hippel–Lindau (VHL) pathway, such as clear cell renal cell carcinomas and capillary hemangioblastomas. Patients with VHL syndrome have an increased risk of developing serous pancreatic tumors and somatic mutations of the VHL gene are common in these tumors along with modification of its downstream effectors including hypoxia-inducible factor (HIF1), glucose uptake and transporter-1 (GLUT-1), a common factor in clear cell (glycogen-rich) tumors, as well as expression of vascular endothelial growth factor (VEGF), thought to be a factor in the striking capillarization of serous cystadenomas and other non-pancreatic clear cell tumors. VEGF may prove to be of significant diagnostic value since its elevation in cyst fluid has recently been found highly sensitive and specific for serous neoplasms. These molecular alterations establish serous tumors as prototypes of clear cell tumorigenesis and angiogenesis and may prove helpful both as diagnostic and non-surgical therapeutic targets.