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.     

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.     

Differential expression of MUC1, MUC2, and MUC5AC in carcinomas of various sites: an immunohistochemical study

We studied immunohistochemical expression of MUC1, MUC2, and MUC5AC in 194 carcinomas of different primary sites to determine whether differential expression patterns could be used to distinguish different carcinomas. MUC1 was expressed by most (except adrenocortical and hepatocellular carcinomas). MUC2 was expressed infrequently (positive immunoreactivity primarily in tumors of gastrointestinal origin). MUC5AC was expressed by most pancreatic ductal and endocervical adenocarcinomas and a variable number of tumors of the gastrointestinal tract. A MUC1+/MUC2-/MUC5AC- immunophenotype was observed in most breast, lung, kidney, bladder, endometrial, and ovarian carcinomas; MUC1+/MUC2-/MUC5AC+ was characteristic of pancreatic ductal adenocarcinomas and cholangiocarcinomas. Adrenocortical and hepatocellular carcinomas were negative for all mucins. Carcinomas of gastrointestinal origin exhibited variable expression of each mucin examined and no consistent immunoreactivity pattern. Many carcinomas can exhibit distinct MUC1, MUC2, and MUC5AC expression patterns, which might be valuable diagnostically in specific settings (eg, distinguishing cholangiocarcinoma from hepatocellular carcinoma or renal from adrenocortical carcinoma). However the overlapping and heterogeneous patterns of MUC1, MUC2, and MUC5AC expression observed in many tumors, particularly those of gastrointestinal origin, preclude use of these markers in the routine immunohistochemical assessment of carcinomas of an unknown primary site.     

Diagnosis of cystic lesions of the pancreas: a biochemical and cytologic analysis of material obtained utilizing radiographic or intraoperative technique

The widespread use of imaging modalities may detect clinically unsuspected "pancreatic cysts" in which the differential diagnoses include pseudocysts, cystic neoplasms, necrotic carcinomas, abscesses, and, uncommonly, islet cell tumors. Accurate preoperative diagnosis requires clinical, radiologic, microbiologic, cytologic, and biochemical studies. Material obtained by fine-needle aspiration from cysts can be triaged for cytology, amylase, and carcinoembryonic antigen (CEA) studies. The four cases described suggest that an elevated fluid CEA is specific for carcinoma, and an elevated amylase and negative CEA suggests pseudocysts, while both amylase and CEA are negative in abscesses. Thus, "cystic lesions of pancreas" can be accurately diagnosed in cases in which radiologic and cytologic studies are inconclusive. The routine inclusion of these tests with cytologic study should be encouraged to obviate unnecessary surgery for diagnostic purposes.     

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.     

Differential expression of MUC2 and MUC5AC in benign and malignant glandular lesions of the cervix uteri

The expression of mucin genes in the normal glandular epithelium of the endocervix has been well characterized. However, mucin gene expression in neoplastic or particular non-neoplastic glandular cervical lesions has not been addressed. This immunohistochemical study was carried out to analyze the expression of MUC2 and MUC5AC in neoplastic and non-neoplastic glandular lesions of the cervix. Monoclonal antibodies were used on paraffin-embedded sections from 41 adenocarcinomas, 2 adenosquamous carcinomas, 13 adenocarcinomas in situ (ACIS), 3 glandular dysplasias, 8 endometrioses, 5 tubal metaplasias, 17 squamous metaplasias, 3 microglandular hyperplasias and normal tissue of the endocervix, endometrium and fallopian tube. The patterns of expression of MUC2 and MUC5AC were different and in principle contrary. Focal MUC2 expression was observed almost exclusively in neoplastic lesions (36%) and not in normal epithelia and non-neoplastic lesions, the one notable exception being immature metaplasia. In contrast, strong expression of MUC5AC was observed in both normal endocervical epithelium (100%) and neoplastic lesions (73%). The expression of MUC5AC, however, was diminished in most neoplastic glandular lesions. Co-expression of MUC2 and MUC5AC was consistently documented in the lesions with intestinal differentiation. In contrast, cases of tubal metaplasia and endometriosis were negative for MUC2 and MUC5AC. These results indicate that discrimination of mucin gene expression may be helpful in discriminating lesions of the cervix. Received: 20 March 2000 / Accepted: 31 May 2000     

Mucin gene expression in intraductal papillary-mucinous pancreatic tumours and related lesions

Intraductal papillary-mucinous tumours (IPMTs) of the pancreas are heterogeneous proliferations characterized by a malignant potential. The molecular mechanisms underlying the tumourigenesis process are not well understood. Recently, it has been shown that IPMTs secreting the mucin antigen MUC2 have a better prognosis, but the complete pattern of MUC gene expression has not yet been established. The aims of this study were to evaluate the mucin gene expression in 57 IPMTs and eight related lesions surgically resected and to relate MUC gene expression to the histological diagnosis. In situ hybridization (ISH) was performed in 28 cases with probes specific for the MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC5B, MUC6, and MUC7 genes. An immunohistochemical analysis was carried in all 65 cases and in 90 conventional ductal adenocarcinomas of the pancreas using MUC1, MUC2, and MUC5AC antibodies. IPMTs of adenoma (dysplasia) type exhibited high expression of MUC2 (93%), MUC5AC (97%), and, to a lesser extent, of MUC4 (71%), all of which were also observed in colloid carcinomas associated with IPMTs. In contrast, IPMTs with simple hyperplasia, intraductal oncocytic papillary neoplasms, and pyloric glandular adenomas exhibited little or no expression of MUC2. The mucin expression profile supports the existence of two types of invasive tumour associated with IPMTs: a colloid and an ordinary form. The latter shows a pattern similar to the conventional ductal adenocarcinomas with a loss of MUC2 and a gain of MUC1 and has a greater tendency to metastasize. In conclusion, the altered expression of mucin, characteristic of IPMT of adenoma type and of colloid carcinomas, may contribute to the better clinical outcome of these neoplasms, compared to conventional pancreatic ductal adenocarcinomas.     

Das duktale Pankreaskarzinom und seine Vorläufer

Pancreatic ductal adenocarcinoma is the most frequent malignant pancreatic tumor. It is one of the tumors that has a particularly poor prognosis. Its morphological characteristics are: preferential localization in the head of the pancreas, ductal-glandular tumor structures combined with marked desmoplasia and CEA and MUC1 positivity. Variants of this carcinoma include adenosquamous carcinomas, undifferentiated pleomorphic carcinomas and mixed ductal-endocrine tumors. With the definition of ductal lesions as pancreatic intraepithelial neoplasia, a progression model for pancreatic ductal carcinoma has been developed and corresponding gene alterations have been detected.     

Cystic neoplasms of the pancreas and tumor-like lesions with cystic features: a review of 418 cases and a classification proposal

Although cystic neoplasms and lesions of the pancreas are rare, they have attracted a great deal of attention because of their potential curability. Since, in recent years, several new entities have been identified, the relative frequency of the tumors and their classification need to be reevaluated. In a series of 1454 tumorous lesions of the pancreas collected between 1971 and 2003 in our surgical pathology files and consultation files, all cystic pancreatic neoplasms and tumor-like lesions were identified and typed both histologically and immunohistochemically. There were 418 cases (29%) showing cysts with a diameter ranging between 0.5 cm and 27 cm. Most common were solid pseudopapillary neoplasms (21%) and intraductal papillary-mucinous neoplasms (18%). When only the cystic neoplasms and lesions that had been resected in a single institution were considered, intraductal papillary mucinous neoplasms were the most frequent cystic neoplasms, while solid pseudopapillary neoplasms took fifth place behind ductal adenocarcinomas with cystic features, serous cystic neoplasms and mucinous cystic neoplasms. The most frequent cystic tumor-like lesions were pancreatitis-associated pseudocysts. New and rare entities that have recently been identified are mucinous nonneoplastic cysts, acinar cell cystadenomas and cystic hamartomas. Bearing in mind that figures from referral centers such as ours may be biased regarding the relative frequency of lesions, we concluded from our data that intraductal papillary-mucinous neoplasms are the most frequently occurring pancreatic cystic neoplasms, rather than solid pseudopapillary neoplasms. It was possible to classify all cystic lesions encountered in our files or described in the literature in a new system that distinguishes between neoplastic and nonneoplastic lesions, with further subdivisions into epithelial (adenomas, borderline neoplasms and carcinomas) and nonepithelial tumors. This classification is easy to handle and enables a distinction on the basis of clinical behavior and prognosis.     

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 study of endocrine cells in ductal adenocarcinoma of the pancreas

To clarify whether scattered endocrine cells in pancreatic ductal adenocarcinoma are neoplastic or not, we immunohistochemically studied 29 cases of invasive pancreatic ductal adenocarcinomas, 17 with metastases, for chromogranin A, insulin, glucagon, pancreatic polypeptide, serotonin, gastrin, laminin, and Ki-67. Endocrine cells were found in primary sites in 24 cases (82.3%), where endocrine cells showed at least a visibly close location to adjacent islet cells. Although endocrine cells in neoplastic glands were within the neoplastic basement membrane, endocrine cells were not seen in invasive sites beyond the pancreas where islets were not present. Endocrine cells in neoplastic glands were reactive for two or three of the islet hormones in all cases, and different types of hormonal reactivity was recognized in the same neoplastic gland or the same cluster of neoplastic glands in 22 (91.7%) cases, thus suggesting a close relation with islets. Ki-67 did not stain any endocrine cells in ten of the adenocarcinomas studied. In three (10.3%) cases, endocrine cells were found in the intraductal extensions. They may have pre-existed in non-neoplastic ducts. In 17 cases with metastatic sites, all but one had no endocrine cells in the metastases. Serotonin-positive cells were found in one metastatic lymph node in one case. We concluded that most endocrine cells seen in ductal adenocarcinomas of the pancreas are non-neoplastic and are derived from the surrounding islets. Some neoplastic endocrine cells may exist, though their frequency is low.     

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。     

Intraductal tubulopapillary neoplasm of the bile duct: potential origin from peribiliary cysts

We report two patients with unique biliary tumors histologically similar to pancreatic intraductal tubulopapillary neoplasm (ITPN). One patient underwent right hepatectomy for a partly cystic mass in the hepatic hilum. The other patient had liver transplantation for cryptogenic cirrhosis and multiple hilar cysts detected in the explanted liver, some obliterated by papillary nodules. Histologically both tumors consisted of intracystic non-invasive and well differentiated adenocarcinoma with a papillary and tubular architecture. Associated cysts were peribiliary cysts partly lined by carcinoma cells that were continuous with the intracystic papillotubular masses. Both tumors shared the same immunophenotype: K7(+)/K20(-)/MUC1(+)/MUC2(-)/MUC5AC(-)/MUC6(+). Genetic analysis of KRAS and BRAF revealed wild type genotypes. These pathological and genetic features are similar to those of pancreatic ITPNs. This report suggested that ITPNs may rarely develop in the bile duct seemingly in association with peribiliary cysts.     

The dichotomy in the preinvasive neoplasia to invasive carcinoma sequence in the pancreas: differential expression of MUC1 and MUC2 supports the existence of two separate pathways of carcinogenesis.

Emerging evidence suggests a dichotomy in the dysplasia-CIS-invasive carcinoma sequence in the pancreas. Pancreatic intraepithelial neoplasms (PanINs; small, incidental duct lesions) progress to invasive ductal adenocarcinomas (5-y survival of < 15%), whereas intraductal papillary mucinous neoplasms (large, intraductal tumors with ductal dilatation) are often associated with colloid carcinoma (5-y survival of > 55%). We explored the relationship of these lesions by examining the expression of MUC1 and MUC2, glycoproteins reportedly reflecting "aggressive" and "indolent" phenotypes in pancreas cancer, respectively. Immunohistochemical labeling with MUC1 (clone Ma695) and MUC2 (clone Ccp58) antibodies was performed on PanINs (n = 43), intraductal papillary mucinous neoplasms (n = 74), ductal adenocarcinomas (n = 136), and colloid carcinomas (n = 15). Fifty-four percent of the intraductal papillary mucinous neoplasms expressed MUC2, whereas none of the PanINs did. In contrast, PanINs, especially higher grade lesions, were often positive for MUC1 (61% of PanIN 3), whereas the expression of this glycoprotein was infrequent in intraductal papillary mucinous neoplasms (20%). This dichotomy was further accentuated in the invasive carcinomas with which these two preinvasive pathways are respectively associated: all colloid carcinomas were MUC2+ (100%) and MUC1- (0%), whereas the labeling pattern was the reverse for ductal adenocarcinomas: 63% were MUC1+ and only 1% were MUC2+. These results support a dichotomy in the dysplasia-CIS sequence in the pancreas. Because these two pathways often lead to different types of invasive carcinomas, this is an invaluable model for the study of carcinogenesis. The findings here also support the previous impression that MUC2 (the mucin associated with gel formation) is a marker of the "indolent" pathway (intraductal papillary mucinous neoplasm and colloid carcinoma), whereas MUC1 (the glycoprotein known to have an inhibitory role in cell-cell and cell-stroma interactions as well as in immunoresistance of tumor cells) is a marker of the "aggressive" pathway (PanIN to ductal adenocarcinoma).     

Intestinal type adenocarcinoma: a previously unrecognized histologic variant of ductal carcinoma of the pancreas

Adenocarcinomas with intestinal differentiation have been described in a wide variety of anatomical sites. To our knowledge, however, ductal adenocarcinomas with intestinal phenotype have not been described in the pancreas. We report here 11 ductal carcinomas of the pancreas that were morphologically similar to colonic adenocarcinomas. These pancreatic carcinomas of intestinal type represented 10% of 110 consecutively removed ductal carcinomas of the pancreas. All intestinal type carcinomas expressed cytokeratin 7, carcinoembryonic antigen, CDX2, and MUC2. The pattern of reactivity of cytokeratin 7 and carcinoembryonic antigen was diffuse, whereas that of mucin 2 staining and CDX2 nuclear labeling was focal and confined predominantly to goblet cells and less frequently to columnar cells. Six carcinomas contained collections of endocrine cells admixed with the columnar and goblet cells. Five carcinomas were associated with high-grade pancreatic intraepithelial neoplasia of intestinal type. Six patients were female and 5 were male. Their ages ranged from 52 to 76 years (mean age, 61 years). The clinical presentation did not differ from that of the conventional ductal carcinomas. All carcinomas originated in the head of the pancreas, and 5 had metastasized to the regional lymph nodes at the time of surgical resection. Only 1 patient survived 5 years. Three patients are disease free from 2.8 to 8.9 months after surgery. Six patients died as a direct result of the carcinomas, and 1 was lost to follow-up. More studies are needed to determine the biologic behavior of this distinctive histologic variant of ductal adenocarcinoma of the pancreas.     

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.     

胰腺胶样癌四例临床病理学分析

目的 探讨胰腺胶样癌的临床病理学特征、诊断、鉴别诊断及分子生物学特点.方法 分析4例胰腺胶样癌的临床特点,对标本进行病理形态学观察、免疫组织化学EnVision法和K-ras基因突变检测.结果 4例胶样癌中3例发生在胰头部,患者均为男性;另1例在胰体尾部,为女性;平均发病年龄为56.5岁.其中2例首发症状为腹痛,1例为尿糖增高,1例为查体发现.3例大体形态为囊实性结节,囊内含黏液,1例大体呈实性.低倍镜下,纤维及胰腺组织中可见边界清楚的黏液结节,大的黏液湖中可见纤细的纤维结缔组织间隔成多个小黏液湖;肿瘤细胞漂浮在黏液湖中,呈小巢或条索状,或腺管状,也可看到印戒细胞漂浮其中.3例癌周可见肠型胰腺导管内乳头状黏液性肿瘤(IPMN),仅例1伴发胰胆管型IPMN.免疫组织化学染色3例MUC2细胞膜阳性,1例MUC1阳性.3例中例1和例3发现K-ras基因突变,突变位点均位于12密码子Gly12Asp(GGT＞GAT)和Gly12Arg( GGT＞ CGT).结论 胰腺胶样癌是少见的胰腺导管腺癌亚型,经常伴发于IPMN和胰腺黏液性囊性肿瘤,应与普通胰腺导管腺癌、印戒细胞癌及假性囊肿等病变相鉴别.免疫组织化学MUC2多阳性表达,MUC1多为阴性,K-ras基因突变率较低.