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.     

Cystic neoplasms of the exocrine pancreas

The increasing use of radiological imaging has led to greater detection of small and asymptomatic cystic lesions of the pancreas. Most are resectable, but not all are neoplastic. This review provides an update on the histopathology, immunohistochemistry, molecular biology, pathogenesis and management of cystic neoplasms of the exocrine pancreas. These include the serous, the mucinous cystic, the intraductal papillary mucinous and the solid pseudopapillary neoplasms. Recently reported variants are described and very rare cystic variants of other pancreatic epithelial and mesenchymal neoplasms are briefly mentioned.     

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。     

The morphofunctional diagnostics principles of pancreatic cystic tumors differentiation

The algorithm of morphological diagnostics of pancreatic cystic formation including true cystic tumors, solid neoplasm with secondary cystic formation, nonneoplastic true cysts and pseudocysts are submitted. The determination of epithelial lining type specific for different neoplasms is a crucial factor. Tumors with border-line metastatic potential and carcinomas has been diagnosing in the detection of dysplasia and cell atopy features. On a number of occasions it's necessary to carry out an immunohistochemical investigation facilitating the differential diagnostics of neoplasms and determined the type of epithelium in intraductal papillary-mucinous tumors.     

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.     

Cyst fluid analysis for the differential diagnosis of pancreatic cysts

Pancreatic cystic neoplasms comprise a pathologically heterogeneous group with many shared clinical features. We assessed the reliability of cyst fluid analysis for the differential diagnosis of pancreatic cysts. Cyst fluid was obtained by fine-needle aspiration from 78 pancreatic cysts. The lesions studied consisted of 17 mucinous cystic tumors (MCTs), 13 serous cystadenomas (SCAs), 5 solid pseudopapillary tumors (SPTs), 8 intraductal papillary mucinous tumors (IPMTs), 6 ductal adenocarcinomas (ACAs) with cystic degeneration, and 29 pseudocysts (PCs). Epithelial cells were observed in 27 (81%) of 33 successful aspirates of cystic neoplasms. Cytologic diagnosis was possible in 5 (31%) out of 16 MCTs. Mucicarmine staining was positive in five out of nine MCTs, one out of one ACA, and one out of two IPMTs, but in none of the SCAs, SPTs, or PCs. Cyst fluid carcinoembryonic antigen (CEA) levels of more than 467 ng/mL had a 87% sensitivity and a 98% specificity for detecting MCTs, and amylase levels of more than 479 U/L had a 73% sensitivity and a 90% specificity for detecting PCs. In conclusion, cyst fluid analysis for cytology, mucin staining, CEA, and amylase levels are useful in the differential diagnosis of pancreatic cysts.     

The use of fine needle aspiration cytology for the distinction of pancreatic mucinous neoplasia

Cytology frequently has some role in preoperatively distinguishing pancreatic mucus-producing neoplasia (intraductal papillary mucinous neoplasms [IPMNs] and mucinous cystic neoplasms [MCNs]) from other pancreatic cysts. We evaluated all cytologic specimens at our institutions from resected pancreatic cystic lesions for lesional extracellular and cellular material. Lesional extracellular material was identified in 32 of 38 of the cytologic samples from cystic pancreatic mucus-producing neoplasms (28 of 31 IPMNs and 4 of 7 MCNs). Lesional cellular material was seen in 22 of 38 cases (17 of 31 IPMNs and 5 of 7 MCNs). Lesional material was more commonly identified in higher grade and invasive lesions. Lesional extracellular material was seen in 3 of 14 samples of other pancreatic cysts, and lesional cellular material was seen in 6 of 14 cases.     

Pancreatic intraductal papillary-mucinous neoplasms: a new and evolving entity

For a long time, intraductal tumors of the pancreas were neglected because they were misdiagnosed as mucinous cystadenocarcinoma, ordinary ductal adenocarcinoma, or chronic pancreatitis. Only in recent years have they been recognized as clinical and pathological entities. Most common are the intraductal papillary-mucinous neoplasms. Although they show an adenoma-carcinoma sequence, they have proved to have a more favorable prognosis than ductal adenocarcinoma, when resected in a preinvasive state. Recently, it has become clear that they constitute a heterogeneous group with at least four subtypes. Their stratification reveals that the various intraductal papillary-mucinous neoplasm subtypes have different biological properties with different prognostic implications.     

Pitfalls in endoscopic ultrasound-guided fine-needle aspiration and how to avoid them

Although a broad range of pancreatic, gastrointestinal, thoracic, and abdominal pathology may be sampled by endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA), certain difficulties tend to recur because of the frequency of certain sample types and because of the nature of their individual cytomorphologic profiles. With this in mind, we review certain pitfalls that may befall cytopathologists with EUS-guided FNA. We discuss the diagnosis of pancreatic ductal adenocarcinoma and of other pancreatic epithelioid tumors including pancreatic endocrine neoplasms, solid pseudopapillary tumors, and acinar cell carcinomas. We also discuss the diagnosis of pancreatic cystic neoplasia including intraductal papillary mucinous neoplasms and mucinous cystic neoplasms and the diagnosis of gastrointestinal mesenchymal neoplasia with particular attention to gastrointestinal stromal tumors. Finally, we discuss the interpretation of lymph node aspirates.     

Reporting precursors to invasive pancreatic cancer: pancreatic intraepithelial neoplasia,intraductal neoplasms and mucinous cystic neoplasm

Invasive ductal adenocarcinoma of the pancreas remains an almost universally lethal disease. Despite strenuous research efforts, the prognosis of the disease has not improved in the past decades. However, knowledge of pancreatic tumorigenesis and the identification and characterization of the precursor lesions that give rise to invasive pancreatic cancer have dramatically improved. This, coupled with the finding that it takes almost two decades for a pancreatic cell with an initial mutation to develop into a metastatic pancreatic cancer provides hope for the early detection of curable pancreatic neoplasms. We present a review of established precursor lesions of pancreatic cancer, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms (including intraductal oncocytic papillary neoplasm and intraductal tubulopapillary neoplasm), and mucinous cystic neoplasm.     

Distinct progression pathways involving the dysfunction of DUSP6/MKP-3 in pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms of the pancreas.

DUSP6/MKP-3 is identified as a candidate tumor suppressor gene for pancreatic cancer. The aim of this study was to elucidate the roles of DUSP6 in the pancreatic carcinogenesis through the pancreatic intraepithelial neoplasia and/or intraductal papillary-mucinous neoplasms, both of which are considered to be precursor lesions of invasive carcinoma of the pancreas, by comparing with involvements of other major tumor suppressive pathways. Expressions of DUSP6, CDKN2A, TP53, and SMAD4 were investigated by immunohistochemistry in a total of 206 lesions of dysplastic ductal precursors and carcinomas retrieved from 52 pancreata with invasive ductal carcinomas and 51 of those with intraductal papillary-mucinous neoplasms. The intensity of staining was evaluated in lesions at different atypical grades and statistically compared among them. Mutations of KRAS2 were analyzed by methods of the allele-specific oligonucleotide hybridization and nucleotide sequencing. In pancreata with invasive ductal carcinomas, expressions of DUSP6 were abrogated exclusively in the invasive carcinoma cells in contrast to its fairly preserved expressions in pancreatic intraepithelial neoplasia. In pancreata with intraductal papillary-mucinous neoplasms, abrogated expressions of DUSP6 were observed in a relatively small fraction of intraductal adenoma/borderlines and intraductal carcinomas. Most of the intraductal adenoma/borderline lesions with abrogation of DUSP6 harbored mutations of KRAS2. None of the molecules was associated with each other in any grade of lesions. Morphological variations of papillae of the intraductal papillary-mucinous neoplasms were evaluated and analyzed for their associations with abrogations of the molecules, which resulted in finding of no significant associations. Our results suggest that the abrogation of DUSP6 is associated exclusively with progression from pancreatic intraepithelial neoplasia to the invasive ductal carcinoma while it is potentially associated with initiation of intraductal papillary-mucinous neoplasms with mutated KRAS2, which is independent of other major tumor suppressive pathways in both types of neoplasms.     

Expression of von Hippel-Lindau gene product (pVHL) and S100P in cystic neoplasms of the pancreas--with an implication for their roles in tumorigenesis

Our recent study demonstrated the inverse correlation of expression of S100P and von Hippel-Lindau gene product (pVHL) in pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDA). This study investigates whether there is a correlation of expression of these two markers in common cystic neoplasms of the pancreas. Immunohistochemical stains for S100P and pVHL were performed on 97 cystic neoplasms of the pancreas, including 23 mucinous cystic neoplasms (MCNs), 39 intraductal papillary mucinous neoplasms (IPMNs), 12 solid pseudopapillary tumors (SPTs), and 23 serous microcystic adenomas (SMAs). The results demonstrated a nuclear and cytoplasmic staining pattern of S100P in 91.3% of MCNs and 100% of IPMNs. In contrast, none of the SPTs or SMAs was positive for S100P. All IPMNs and SPTs, and all S100P-expressing MCNs were negative for pVHL, including 20 MCNs and 20 IPMNs with low-grade dysplasia. All cases of SMA were positive for pVHL. Our data suggest 1) the inverse correlation of expression of S100P and pVHL in MCN and IPMN is similar to that in PanIN and PDA, suggesting a role of these two proteins in early tumorigenesis; 2) the loss of pVHL expression in MCN and IPMN supports the recent recategorization of these neoplasms without any cytological atypia as low-grade dysplasia instead of adenoma; 3) the loss of expression of pVHL in SPT supports the concept of an uncertain malignant potential of this entity; and 4) the lack of expression of S100P and expression of pVHL in SMA supports the benign nature of this entity.     

Pseudointraductal papillary mucinous neoplasia caused by microscopic periductal endocrine tumors of the pancreas: a report of 3 cases

Intraductal papillary mucinous neoplasms constitute histologically distinctive pancreatic tumors characterized by cystically dilated pancreatic ducts lined by papillary epithelium, often with extensive mucin production. With increasing awareness of and vigilance for these tumors, there has been a surge in the incidence of intraductal papillary mucinous neoplasms in the last few decades. However, resections of presumed intraductal papillary mucinous neoplasms sometimes reveal other types of cystic lesions. Here we describe 3 cases of small, incidentally identified pancreatic endocrine tumors that focally compressed the main pancreatic duct and presented clinically, radiologically, and grossly as intraductal papillary mucinous neoplasm. The histology of the dilated ducts in all cases lacked convincing features of intraductal papillary mucinous neoplasm, prompting more careful examination of the specimens and eventual identification of small well-differentiated endocrine neoplasms. The constellation of findings represented by pancreatic endocrine neoplasm-associated duct stricture and dilatation can mimic intraductal papillary mucinous neoplasm clinically and pathologically. Awareness of this phenomenon can potentially avoid misdiagnosis of intraductal papillary mucinous neoplasm in such cases.     

A clinicopathologic and immunohistochemical study of 22 intraductal papillary mucinous neoplasms of the pancreas, with a review of the literature.

Intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas are rare lesions. We undertook this study to analyze these tumors by focusing on the diagnostic criteria and correlating the histologic features with clinical prognosis. Twenty-two cases of IPMN were retrieved from the Endocrine Tumor Registry of the Armed Forces Institute of Pathology. Blocks or unstained slides were available for histochemical and immunohistochemical studies (including proliferative markers and cell cycle regulators) and K-ras oncogene mutations in 15 cases. Patient follow-up was obtained in all of the cases. IPMN occurs in both genders with a slight male predominance, with a mean age at presentation of 64.4 years (range, 48-85 yr). The patients presented with abdominal pain. The neoplasms were radiologically and grossly cystic, usually (18 cases of 22) located in the head of the pancreas. Histologically, the tumors consisted of intraductal papillary proliferations protruding into and expanding the pancreatic ducts. Invasion into the surrounding pancreatic parenchyma was detected in 15 cases. Chronic pancreatitis was present in all of the cases. p27 immunoreactivity always exceeded the immunoreactivity of cyclin E. K-ras oncogene mutations were detected in two cases. Patients were treated with a complete surgical resection (n = 7) or a Whipple procedure (n = 13). Only 2 of 22 patients died of disease (3 died immediately postoperatively and 3 died of unrelated causes), whereas the remaining 14 patients were alive at last follow-up, without evidence of disease, an average of 58.2 months after initial presentation. IPMNs are rare, distinctive neoplasms, with complex intraductal papillae, that can be easily separated from in situ ductal adenocarcinoma and mucinous cystic neoplasms. The high ratio of p27 protein to cyclin E supports the excellent prognosis of these neoplasms, despite the presence of invasion and K-ras oncogene mutation.     

BCL10 as a useful marker for pancreatic acinar cell carcinoma,especially using endoscopic ultrasound cytology specimens

Acinar cell carcinomas (ACCs) of the pancreas are characterized by the histological and immunohistochemical features of acinar cell differentiation. Recently, BCL10, originally identified as a recurrent t(1;14)(p22;q32) translocation in MALT B‐cell lymphoma, was found to be immunohistochemically positive in some solid tumors, including ACC. To evaluate its diagnostic efficacy, we performed BCL10 immunohistochemistry and evaluated molecular markers correlated to pancreatic tumor lineages (neuroendocrine markers and a mutation analysis of KRAS and GNAS) using samples from 126 pancreatic tumors (17 ACCs, 24 pancreatic ductal adenocarcinomas, 4 adenosquamous carcinomas, 9 intraductal papillary mucinous neoplasms, 10 mucinous cystic neoplasms, 44 neuroendocrine tumors, 9 serous cystic tumors and 10 solid‐pseudopapillary neoplasms). BCL10 was exclusively expressed in normal acini. In pancreatic tumors, 14 of 17 (82%) ACCs and 2 of 4 (50%) adenosquamous carcinomas were positive, while the other subtypes were almost negative. We subsequently examined the diagnostic utility of BCL10 in endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) specimens using 57 pancreatic tumors. BLC10 correctly identified ACCs (9/13) and adenosquamous carcinomas (2/4) but none of the other subtypes (n = 41). Therefore, we suggested that BCL10 expression is a useful marker for acinar cell differentiation, particularly in the diagnosis of EUS‐FNA specimens.     

Inhibin expression in ovarian-type stroma in mucinous cystic neoplasms of the pancreas.

Mucinous cystic neoplasms (MCNs) of the pancreas are typically found in middle-aged to elderly women and contain ovarian-type stroma in the cyst wall. Whether the resemblance of this stroma to ovarian stroma is only morphologic or has more functional similarity is still unclear. Estrogen receptors (ER) and progesterone receptors (PR) have been shown to be expressed in a wide variety of tissues and tumors, including the ovarian-type stroma of MCN. Inhibin, on the other hand, has been shown to have a more restricted expression, limited to ovarian sex cord-stromal components and placental cells, and has recently been shown to be expressed in pancreatic MCNs. However, it is still unclear whether this expression is limited to MCNs of the pancreas and whether it has any diagnostic role. Seven cases of MCN (4 mucinous cystadenoma, 2 borderline MCN, and 1 mucinous cystadenocarcinoma with microinvasion), 6 cases of intraductal papillary mucinous tumor, 1 of mucinous cystic tumor of uncertain classification, 2 of mucinous noncystic adenocarcinoma, 4 of serous cystadenoma, and 4 solid pseudopapillary neoplasms were selected for this study. Five cases with normal pancreatic tissue were included as controls. Immunohistochemical stains for alpha-inhibin, ER, and PR were performed on a representative section from each case on formalin-fixed, paraffin-embedded tissue sections using a standard indirect immunoperoxidase method. All cases of MCN were in female patients with an average age of 55.3 years, showing ovarian-type stroma and clusters of alpha-inhibin-positive luteinized theca-like cells. In all these cases, moderate to strong PR positivity was also noted in the ovarian-type stroma, including many of the alpha-inhibin-positive luteinized theca-like cells. ER was expressed in 2 cases. The epithelial cells of MCNs were all negative for ER, PR, and alpha-inhibin staining. Of the other tumors, 4 solid pseudopapillary neoplasms showed positivity for only PR in the tumor cells. The remaining tumors were negative for all markers. In conclusion, the finding of alpha-inhibin positivity in MCN with ovarian-type stroma further supports its similarity to true ovarian stromal tissue and may suggest a role of complex hormonal interaction in the pathogenesis. In addition, its limited expression in MCNs of the pancreas may be diagnostically useful in difficult cases.     

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.     

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.     

Intraductal tubular neoplasms of the pancreas: an overview

Intraductal lesions of the pancreas are an uncommon but increasingly recognized group of entities mainly because of advances in imaging technology. In the past, precise categorization and understanding of true pancreatic intraduct neoplasms were hampered not only by their relative rarity but also because of the plethora of terminology and criteria used in nomenclature and diagnosis. Although significant progress has been made in the characterization of some of these lesions, as exemplified by intraductal papillary mucinous neoplasms, understanding of the rare intraductal tubular adenoma (ITA) and intraduct tubular carcinoma (ITC) continues to evolve. By definition, these are a group of intraductal, radiologically detectable neoplasms that can progress to or be associated with invasive adenocarcinoma and, as such, are precursor lesions to pancreatic ductal adenocarcinoma. Their often shared clinical and radiological features make precise histological diagnosis essential for appropriate management and optimal outcome. We provide an overview of these neoplasms and highlight recent developments in the understanding of ITA and ITC which have led to ITA being considered a variant of gastric-type intraductal papillary mucinous neoplasms and ITC being encompassed within the intraductal tubulopapillary neoplasm category. We also emphasize the distinguishing histological features to aid diagnosis of these rare lesions.