Markus Kosmahl

Solid–pseudopapillary tumor of the pancreas: its origin revisited

Abstract Solid–pseudopapillary tumor of the pancreas (SPT) has distinctive morphologic and biologic features but an unclear origin. It is classified among the pancreatic epithelial tumors, though many are reported to be negative for cytokeratin. Also unclear are its neuroendocrine differentiation, its capability to express alpha-1-antitrypsin (AAT) and, in view of the tumor’s striking prevalence in women, its relationship with the female genital tract. To clarify these issues, the immunoprofiles of 59 SPTs were defined by applying a battery of antibodies against cytokeratin, vimentin, neuron-specific enolase (NSE), synaptophysin, chromogranin A, tyrosine hydroxylase (TH), AAT, LeuM1, Ki-M1P, smooth-muscle actin, CD34, alpha-inhibin, calretinin, placental alkaline phosphatase (PLAP), and progesterone and estrogen receptors. The most consistent markers with the strongest immunoreactivity were vimentin, AAT, NSE, and the progesterone receptor, which were each found in more than 90% of the tumors. Using immunocytochemical methods involving antigen retrieval, cytokeratin was demonstrated in almost 70% of the cases. Synaptophysin was found in 22% of the tumors, while chromogranin was absent and tyrosine hydroxylase was only present in a few tumors. None of the other markers tested were expressed by SPTs. This staining pattern fails to reveal a clear phenotypic relationship with any of the defined cell lineages of the pancreas. In view of the striking female preponderance of SPTs and the known close approximation of the genital ridges to the pancreatic anlage during embryogenesis, it is, however, hypothesized that SPTs might derive from genital ridge/ovarian anlage-related cells, which were attached to the pancreatic tissue during early embryogenesis.

Serous cystic neoplasms of the pancreas: an immunohistochemical analysis revealing alpha-inhibin, neuron-specific enolase, and MUC6 as new markers.

Serous cystic neoplasms (SCNs) of the pancreas include serous microcystic adenoma (SMA), serous oligocystic ill-demarcated adenoma (SOIA), solid serous adenoma (SSA), von Hippel-Lindau-associated cystic neoplasm (VHL-CN), and serous cystadenocarcinoma (SCC). These neoplasms are histologically similar but differ in their localization, gross appearance, gender distribution, and biology. A centroacinar origin is assumed but has not been proven. To clarify whether the various subtypes of SCN may be distinguished from each other by marker profiles that might also provide evidence of their origin, the immunoprofiles of 38 SCNs (21 SMAs, 13 SOIAs, 2 VHL-CNs, 1 SSA, and 1 SCC) were defined by applying antibodies against cytoskeletal, neuroendocrine, hormone receptor, and mucin markers. In addition, we examined the expression of calretinin and alpha-inhibin. The various types of SCN showed a very similar immunoprofile, characterized by positivity for cytokeratins and neuron-specific enolase and negativity for vimentin and synaptophysin. Further markers that were commonly expressed in SCNs were alpha-inhibin (SMAs: 76%, SOIAs: 92%, VHL-CNs: 100%), MUC6 (SMAs: 60%, SOIAs: 85%, VHL-CNs: 100%), and MUC1 (SMAs: 24%, SOIAs: 38%, VHL-CNs: 50%). Western blot analysis in one SMA revealed a distinct band that stained with neuron-specific enolase antiserum. Alpha-inhibin was only expressed in 4 of 11 acinar cell carcinomas and not in five ductal adenocarcinomas, five neuroendocrine tumors, one mixed ductal-endocrine carcinoma, and one acinar cell cystadenoma of the pancreas. These results suggest that, despite their biologic differences, the various types of SCNs are composed of the same (or a very similar) cell type and may therefore have a common direction of differentiation. This notion is further supported by the finding that neuron-specific enolase, alpha-inhibin, and MUC6, which may be regarded as new markers for this pancreatic tumor type, were also expressed in most SCNs. Because a number of SCNs share MUC1 and MUC6 expression with the pancreatic centroacinar cells, the possibility of a histogenetic relationship has to be considered.

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.

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.

Acinar cell cystadenoma of the pancreas: a new entity?

This report describes a newly observed cystic lesion of the pancreas showing acinar cell differentiation. The patients affected by this lesion included seven women and three men (age range 16–66 years). In six patients, all of whom were female and all but one of whom suffered from abdominal pain, the cystic lesions (diameters, 4–15 cm) were detected by imaging techniques and subsequently removed. In four patients the cystic lesions were incidental findings. Eight lesions occurred as unifocal, unilocular or multilocular cysts in the head (n = 6) or tail (n = 2) of the pancreas. One lesion was bifocal (head and tail) and another involved the entire pancreas. The cysts were only rarely connected with the pancreatic duct system, but with acinar structures. Their lining cells expressed pancreatic enzymes and lacked any cellular atypia or proliferative activity (Ki67 index <1%). For a follow-up period of 6–84 months all patients remained alive and well. Although a nonneoplastic nature cannot be fully excluded, we propose that this lesion, composed of well-differentiated acinar cells, may represent the benign counterpart of the well-recognized acinar cystadenocarcinoma. We therefore suggest the term acinar cell cystadenoma.

Mucinous Nonneoplastic Cyst of the Pancreas: A Novel Nonneoplastic Cystic Change?

Cystic lesions and neoplasms of the pancreas are uncommon, but they are of special interest because they can usually be cured by resection. During the last decade, the spectrum of these tumors has increased considerably. We present a series of five cystic lesions of the pancreas that differ from all categories described so far. The patients affected by these tumors were three men and two women (mean age, 57 y). Four lesions were unifocal and involved the head of the pancreas; one was multifocal and involved the pancreatic head and tail. Grossly, these tumors presented as unilocular or multilocular thin-walled cysts that contained turbid fluid, or, in two cases, blood, and lacked any communication with the duct system. Microscopically, the cysts were lined by cuboidal to columnar mucin-producing cells, supported by a small band of dense fibrous stroma. Immunocytochemically, the epithelial cells were positive for cytokeratins 7, 8, 18, 19, and 20 (except one), and Ca 19-9 but were negative for trypsin, CEA, synaptophysin, chromogranin A, calretinin, and α-inhibin. In four of the five lesions, the epithelial cells expressed MUC5AC, and in one of the five, MUC1. MUC2 and MUC6 were not expressed in any of the lesions. The stromal cells lacked the nuclear progesterone positivity that is typical of mucinous cystic neoplasms. During a mean follow-up period of 2 years, there were no recurrences or cases of malignant transformation after resection. The results suggest that these cystic lesions are distinct from mucinous cystic neoplasms, the most important entity in the differential diagnosis. Because they may represent a nonneoplastic cystic change of the pancreas, we propose the descriptive term mucinous nonneoplastic cyst for these tumors of unknown pathogenesis.

Pancreatic solid and cystic hamartoma in adults: characterization of a new tumorous lesion.

Nonneoplastic tumor-like lesions (“pseudotumors”) of the pancreas include cystic and noncystic varieties. We report on a solid and cystic tumor-like lesion of the pancreas that occurred in 2 adult patients. The lesions, located in the head and neck of the gland, respectively, were well demarcated and composed of cystic ductal structures embedded in focally inflamed stromal tissue. In addition, one of the lesions showed irregularly arranged but well-differentiated acini and small intralobular and interlobular ducts embedded in hypocellular, fibrotic tissue. Discrete islets were lacking, but immunohistochemical staining for chromogranin A revealed individual scattered endocrine cells evenly distributed between acinar and ductal cells. The surrounding pancreatic parenchyma did not show significant chronic pancreatitis. After tumor removal, the follow-up of the patients was uneventful. Because of the irregular arrangement of otherwise mature tissue components of the pancreas, the lesions were considered solid and cystic hamartomas. Their pathogenesis is so far unknown.

Solid pseudopapillary neoplasms of the pancreas show an interruption of the Wnt-signaling pathway and express gene products of 11q.

Solid pseudopapillary neoplasms of the pancreas almost consistently show a β-catenin mutation activating the Wnt-signaling pathway, resulting in overexpression of cyclin D1, but not in overt malignancy of this tumor. Besides cyclin D1, a set of markers (ie FLI-1, CD56 and progesterone receptor), whose genes map to chromosome 11q, are frequently expressed in solid pseudopapillary neoplasms. Chromosome 11q is a region that is also often affected in pancreatic neuroendocrine tumors. This immunohistochemical study was undertaken to gain insights into the downstream regulation of the Wnt-signaling pathway and the significance of overexpressed gene products belonging to chromosome 11q for the tumorigenesis in solid pseudopapillary neoplasms. Fourteen solid pseudopapillary neoplasms were analyzed for the expression of cyclin-dependent kinase inhibitors p21, p27, p16 and hyperphosphorylated retinoblastoma (pRb) proteins. In an extended series of 93 solid pseudopapillary neoplasms, β-catenin, cyclin D1, FLI-1 and CD56 expression was examined and compared with that in 22 pancreatic neuroendocrine tumors. Solid pseudopapillary neoplasms (98%) showed aberrant expression of β-catenin with a concomitant cyclin D1 expression in 69% of the cases, but no expression of pRb (0%) was found. p27 and p21 were expressed in 100% (14/14) and 86% (12/14) of the cases, but only 2/14 (14%) were positive for p16. FLI-1 was expressed in 63% of solid pseudopapillary neoplasms, but only in 1/22 pancreatic neuroendocrine tumors (5%), cyclin D1 expression was present in 14% of the latter. We conclude that in solid pseudopapillary neoplasms the activated Wnt-signaling pathway is disrupted, and that p21 and p27 are contributing to this fact by blocking of the hyperphosphorylation of the Rb protein, thus causing the very low proliferation rate characterizing the solid pseudopapillary neoplasms. The accumulation of high expression of proteins whose genes are located on chromosome 11q is characteristic of solid pseudopapillary neoplasms, but not of pancreatic neuroendocrine tumors.

[Cystic pancreas tumors and their classification: features old and new].

ZusammenfassungZystische Tumoren and tumorartige Läsionen des Pankreas sind selten. Trotzdem haben sie erhebliche Bedeutung erlangt, da sie mit den neuen radiologischen Verfahren leicht zu entdecken sind und im Gegensatz zum duktalen Adenokarzinom zumeist kurativ reseziert werden können. Durch die zunehmende Resektionsquote hat sich in den letzten Jahrzehnten auch die Kenntnis von den zystischen Pankreastumoren und ihr morphologisches Spektrum enorm erweitert. Bekannte Entitäten wurden besser charakterisiert (solid-pseudopapilläre Neoplasien, intraduktal-papillär-muzinöse Neoplasien) und neue Entitäten beschrieben (seröses oligozystisches Adenom, muzinöse nichtneoplastische Zyste, Azinuszellzystadenom und zystisches Hamartom). Diese Übersicht präsentiert die wichtigsten zystischen Tumoren und Läsionen des Pankreas, stellt eine neue Klassifikation vor und fasst die immunhistochemische Differenzialdiagnose zusammen.AbstractCystic 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.

Solid pseudopapillary neoplasms of the pancreas are associated with FLI-1 expression, but not with EWS/FLI-1 translocation.

Solid pseudopapillary neoplasms of the pancreas are rare pancreatic tumors with mostly benign behavior, affecting almost exclusively women. Their histogenetic origin is still unsolved, but a recently reported EWS/FLI-1 translocation t(11;22)(q24;q21) and the consistent expression of CD56 and the progesterone receptor, both genes located on the long arm of chromosome 11, point to chromosome 11q as a potential locus of gene aberration in solid pseudopapillary neoplasms. To further elucidate this issue, we studied 30 cases of solid pseudopapillary neoplasms by comparative genomic hybridization (CGH), fluorescent in situ hybridization (FISH) and immunohistochemistry. Immunohistochemically, 38% showed nuclear expression of FLI-1 and all cases revealed positivity for CD56 and the progesterone receptor, whereas no solid pseudopapillary neoplasm expressed CD34. No translocation of the EWS gene was found by FISH and no gross chromosomal gain or loss was detected by CGH. It is concluded that FLI-1 expression in solid pseudopapillary neoplasms is not associated with an EWS/FLI-1 translocation. In addition, there are no chromosomal gains or losses, especially on chromosome 11, where the FLI-1 gene is located adjacent to the gene for CD56 (NCAM). These data add another feature to the complex phenotypic appearance of solid pseudopapillary neoplasms.