Abstract
Solid pseudopapillary tumor of pancreas (SPT) is a rare neoplasm that occurs most often in young females with the two distinct features, the ‘solid-cystic’ gross appearance, and the ‘solid-pseudopapillary’ microscopic pattern. It has been reported that almost all SPT tumors contain a mutation in the β-catenin gene; however, the histogenetic origin of this tumor remains largely a mystery. E-cadherin is a cell adhesion molecule that links to catenins to form cell adhesion junctions, which is associated with the cytoskeleton formation. In this study, we examined the expression of E-cadherin and β-catenin from SPT in an attempt to determine the molecular basis for the unusual morphology of this tumor. Nine cases of SPT were retrieved from Surgical Pathologic Archives of three institutions, including one male and eight females. H&E slides of each case were reviewed to confirm the diagnosis. The β-catenin gene was sequenced in one case. E-cadherin and β-catenin immunostains, were performed on all nine cases. Sequencing analysis on one case showed a point mutation of the β-catenin gene, confirming previous findings that almost all SPT tumors contain mutation in the β-catenin gene. Immunostains showed that, in both solid and pseudopapillary areas, all the tumor cells lost expression of E-cadherin, and β-catenin nuclear expression was observed in all cases. Our findings suggest that loss of cytoplasmic β-catenin protein in the cell adhesion complex due to β-catenin gene mutation, results in instability of the complex, loss of E-cadherin in cell membrane, and eventually dissociation of the tumor cells to form the pseudopapillary pattern.
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Main
Solid pseudo-papillary tumor of the pancreas (SPT) is a rare tumor found predominantly in young females. As it was first described by Franz,1 numerous names have been suggested for this tumor, including Frantz's tumor; solid and papillary tumor; papillary cystic tumor; solid, cystic and papillary epithelial neoplasm; solid-cystic tumor; benign or malignant papillary tumor of the pancreas; papillary epithelial neoplasm of pancreas in a child and adenocarcinoma of the pancreas in childhood.1, 2, 3 These various names reflect the important features of this tumor, the ‘solid-cystic’ gross appearance and the ‘solid-pseudopapillary’ histopathological pattern. Microscopically, the tumor cells in ‘solid’ areas are uniform, arranged in sheets and cords around fibrovascular septa; whereas those in ‘pseudo-papillary’ areas show degenerative changes in the cells away from the vasculature.4, 5, 6, 7, 8 Despite its characteristic microscopic appearance and recent studies of this type of tumor for molecular changes,9 the immunophenotype of markers is not specific and does not define a line of differentiation corresponding to any normal pancreatic cell type.
The pathogenesis of such striking microscopic patterns has been studied extensively. Almost all SPTs harbor mutations in the β-catenin gene.10, 11 Diffuse cytoplasmic and nuclear localization for β-catenin is found in this type of tumor. The Wnt signaling pathway, in which β-catenin protein functions as a downstream transcriptional co-activator, is thought to play a major role in tumorigenesis of SPT. β-Catenin protein also functions as a submembranous component of cell adhesion. The cytoplasmic tail of E-cadherin molecule is linked to the cytoskeleton through β-catenin and other small proteins.12, 13 E-cadherin is a transmembrane protein that is present as a parallel dimer at the adhesion junction. The extracellular portion is involved in Ca2+-dependent, homotypic interactions with E-cadherin molecules on the surface of adjacent cells. The sequential binding of the catenin proteins (β-cat and α-cat) to the cytoplasmic tail of cadherin physically bridges the cadherin dimer with the actin cytoskeleton and actin-binding proteins. p120 catenin binds to the juxtamembrane region of the cytoplasmic tail of E-cadherin. The ability of the catenin proteins to interact with microtubule-plus-end-binding proteins might potentially link the adhesion junction to the microtubule network.
In this study, we studied the expression of E-cadherin and β-catenin proteins in nine cases of SPTs to examine, whether cell adhesion is altered in this type of tumor.
Materials and methods
Patients and Tissues
Paraffin blocks from nine cases of SPT specimens were obtained from Surgical Pathology Archives of the University of Texas Medical Branch (Galveston, TX, USA), Harbor-UCLA Medical Center (Torrance, CA, USA), and Methodist Hospital (Houston, TX, USA). Sections were stained with hematoxylin and eosin to confirm the presence of SPT on the paraffin blocks subjected to the study. These cases are listed in Table 1.
The patients' characteristics are as follows: median age 38 (range 10–49 years), both male and female, mean tumor size 5.9 cm (range 3.2–12.8 cm). The location of tumor in pancreas: three at head, one at body, and five at tail. Eight of the nine tumors are confined within pancreas. No lymph node involvement in any of the tumors.
Immunohistochemistry
Immunohistochemical stains with E-cadherin (Zymed, San Francisco, CA, USA; 1:200) and β-catenin (Dako, Glostrup, Denmark; 1:100) were performed in these nine cases. Count staining was performed using hematoxylin.
Genetic Analysis
SPT and surrounding normal pancreatic glandular tissue were first deparaffinized; DNA was then isolated by standard technique.14 β-Catenin-specific primers were used to amplify the β-catenin gene exon II. Primer sequences: forward 5′-AGC TGA TTT GAT GGA GTT GG-3′; reverse 5′-ACC AGC TAC TTG TTC TTG AG-3′. The PCR products were sequenced and compared with wild-type β-catenin gene in GenBank (AY081165).
Results
As shown in Figure 1, hematoxylin and eosin stained slides of all nine tumors show similar classic microscopic features of SPT: solid and pseudopapillary tumor pattern (Figure 1). The solid area was surrounded by pseudo-papillary area.
To test whether cell adhesion is altered in SPT, we examined expression of E-cadherin and β-catenin by immunohistochemistry. As shown in Figure 2, all the tumors, regardless of ‘solid’ or ‘pseudopapillary’ regions, were negative for E-cadherin staining; whereas the surrounding glandular cells are positive. In contrast, nuclear localization of β-catenin is detected in both ‘solid’ and ‘pseudo-papillary’ regions (Figure 3). Expression of these cell adhesion molecules is altered in SPT, which can be used to differentiate tumor tissues from the surrounding normal pancreas.
To test whether gene mutation of β-catenin is responsible for nuclear localization of the protein, we examined the exon III of the β-catenin gene from Case 2 SPT tumor cells. Sequencing the genomic DNAs extracted from deparaffinized tissue revealed a single base pair change (S33C), which is located in a GSK-3-β phosphorylation site (Figure 4).15, 16, 17 This finding is consistent with previous literature reports that β-catenin mutations occur commonly in this type of tumor.
These results indicate that loss of adhesion molecule complexes is an important feature of SPT, and may be useful for future clinical diagnosis of this tumor type.
Discussion
Since it was first described in 1959, the origin and pathogenesis of SPT have been controversial. Mutations of the β-catenin gene have been identified in most cases of SPTs.10 The mutations are mostly at or around the GSK-3-β phosphorylation sites. It has been postulated that these somatic mutations would interfere with normal phosphorylation by GSK-3-β and the subsequent ubiquitin-mediated degradation of the β-catenin protein. This is consistent with the fact that strong nuclear and cytoplasmic accumulation of β-catenin protein is present in nearly all SPTs, and that cyclin D1, a downstream transcriptional target of the nuclear β-catenin-Tcf/Lef complex, is overexpressed in SPTs. In our study, the β-catenin gene from SPT contains a somatic mutation, which changes from serine to cysteine. This S33C mutation has been identified in β-catenin genes of various tumors15, 18, 19, 20 and this serine has been shown to be mutated in other SPTs.10 On the basis of these findings, it is suggested that the Wnt signaling is associated with β-catenin mutations and may play an important role in tumorigenesis of SPT.10 However, this hypothesis fails to explain the characteristic microscopic ‘solid’ and ‘pseudopapillary’ features in SPT.
It has been well known that β-catenin protein is an important linking molecule between E-cadherin and the cytoskeleton. Our immunohistochemical staining of E-cadherin and β-catenin suggest that nuclear localization of β-catenin as well as E-cadherin loss are important changes in this type of tumor. Although it is known that β-catenin mutation can cause disorganization of E-cadherin, silencing of E-cadherin by a variety of factors has been reported in several types of tumors. On the basis of these data, we propose that disruption of adhesion junction is the major feature for SPT. Whereas nuclear translocation is caused by β-catenin mutation, loss of E-cadherin expression can result from promoter silencing, overexpression of transcription repressors such as Snail. As a result of adhesion junction disruption, the pseudopapillary portion of the tumor is formed with help of other factors, such as mechanic stress. Figure 5 shows our proposed model for morphological development of SPT.
In conclusion, our results suggest that loss of adhesion junction is a unique microscopic feature distinguishing the SPT tumor from the normal pancreas. Our findings suggest that loss of cytoplasmic β-catenin protein in the cell adhesion complex due to β-catenin gene mutation results in instability of the complex, loss of E-cadherin in cell membrane, and eventually dissociation of the tumor cells to form the pseudopapillary pattern.
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Acknowledgements
Grant numbers and sources of support: NCI R01-94160 (Xie, J), Sealy Center for Cancer Cell Biology Predoctoral fellowship (Stelter, AA) and NASA scholarship (Stelter, AA).
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Tang, W., Stelter, A., French, S. et al. Loss of cell-adhesion molecule complexes in solid pseudopapillary tumor of pancreas. Mod Pathol 20, 509–513 (2007). https://doi.org/10.1038/modpathol.3800764
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DOI: https://doi.org/10.1038/modpathol.3800764
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