Deregulated Expression of Cell Cycle–Associated Proteins in Solid Pseudopapillary Tumor of the Pancreas

Abstract

Solid pseudopapillary tumor of the pancreas was studied in a 20-year-old woman and a 54-year-old woman. In the younger patient, the tumor had metastasized to the liver 8 years after distal pancreatectomy. In both neoplasms, the distinct histologic pattern of solid, pseudopapillary, and degenerative cystic areas was present. Analysis by means of immunohistochemistry revealed a diffuse expression for vimentin, neuron-specific enolase, and a focal positivity for ␣1-antitrypsin, whereas epithelial markers were negative in the tumor of the older patient and only focally expressed in the tumor of the younger patient. Immunohistochemical analysis of cell cycle-associated proteins provided an overexpression of cyclin D1 and cyclin D3 in both tumors, although to varying degrees. In addition, the cyclin-dependent kinase inhibitors p21, and to a lesser extent p27, were up-regulated just as mdm2. There was no accumulation of p53 protein, and Ki67-positive cells were extremely scarce. Analysis of the liver metastases showed an immunoreactive profile similar to that of the primary tumor. The results show a deregulation of the cell cycle with overexpression of cell cycle-activating proteins D1 and D3 and a probably counterbalancing upregulation of the cyclin-dependent kinase inhibitors p21 and p27. The findings may explain the low pool of Ki67-reactive tumor cells and the generally good clinical outcome of these tumors. Whether a more profound dysbalance of the cell cycle regulation is responsible for the development of metastatic disease remains to be clarified.

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

“…15 This results in cyclin D1 overexpression in 70-100% of solid pseudopapillary neoplasms, as has been demonstrated in this and several other studies. 1,2,16 One aim of our study was to clarify why the overexpression of the cell cycle-associated cyclin D1 in solid pseudopapillary neoplasms fails to increase their proliferative activity as it does in so many other neoplasms [17][18][19] but instead results in a low growth rate.…”

“…20 In two solid pseudopapillary neoplasms, p21 and to a lesser extent p27 were shown to be upregulated. 16 We investigated a subset of 14 tumors in our solid pseudopapillary neoplasms series and also found overexpression of p21 and p27 in all but two (for p21) solid pseudopapillary neoplasms. In the same subset of solid pseudopapillary neoplasms, which includes one metastasizing and one grossly invasive solid pseudopapillary neoplasm, we were, however, unable to detect hyperphosphorylated Rb using an antibody recognizing the (hyper) phosphorylated Rb protein.…”

“…An altered p53 which commonly accounts for p21 and p27 overexpression can be ruled out, since p53 inactivation is an exceptional finding in solid pseudopapillary neoplasms. 2,16 In solid pseudopapillary neoplasms, p21 and p27 are, therefore, to be upregulated by factors that so far are not known. In particular, there is no indication that the p21 and p27 overexpression is linked to the genetic alterations, which, in addition to the b-catenin mutation, are most conspicuous in the molecular profile of solid pseudo- Solid pseudopapillary neoplasm and Wnt pathway K Tiemann et al papillary neoplasms.…”

Nonductal neoplasms of the pancreas

“…Immunolabeling for b-catenin demonstrates abnormal nuclear labeling in 490% of the tumors, 83,182,189 and 75% also express cyclin D1. 83,190 The pattern of staining is not typical for any normal epithelial cells of the pancreas. There is certainly no evidence for acinar or ductal differentiation, and although the positivity for CD56 and synaptophysin might suggest an endocrine phenotype, the most specific endocrine marker (chromogranin) is always negative.…”

“…82 Solid-pseudopapillary neoplasms lack the genetic alterations of infiltrating ductal adenocarcinomas (KRAS, p16, DPC4, and p53 genes). 53,83,186,190,[196][197][198] Almost all, however, have somatic point mutations in exon 3 of the b-catenin gene, 83,189 implicating the same genetic pathway that is abnormal in acinar neoplasms (acinar cell carcinoma and pancreatoblastoma). As expected in the presence of b-catenin activation, solid-pseudopapillary neoplasms typically have cyclin D1 overexpression.…”