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Solid pseudopapillary tumors (SPT) are uncommon tumors, constituting 1–2% of all pancreatic exocrine tumors and 5% of cystic pancreatic tumors.1 First described by Franz in 1959,2 several large series have recently been presented in the literature, which perhaps indicates the increased awareness and ability to characterize this tumor. The classic scenario is of a young woman presenting with non-specific symptoms. The tumors, though dramatically large on presentation, are indolent with low-grade malignant potential and with excellent response to surgical resection.3

Imaging and histology are the two keystones on which the diagnosis rests. Despite progress in imaging, SPT have to be differentiated from cystic neoplasms and the intraductal papillary mucinous neoplasms of the pancreas. On the other hand, although the microscopic appearance of SPT is characteristic, it is a challenge to differentiate these tumors from pancreatic neuroendocrine tumors, acinar cell carcinoma, metastatic renal cell carcinoma and metastatic melanoma, especially in the limited material available by way of needle biopsy (percutaneous or endoscopic ultrasound-guided).

The definitive diagnosis of SPT, especially in limited material as in needle biopsies is based on characteristic immunohistochemistry findings. A typical SPT demonstrates CD10 (neural endopeptidase) immunoexpression in 80% of cases, progesterone receptor positivity, focal synaptophysin staining, beta-catenin and E-cadherin expression. The beta-catenin expression is 100% in SPT with cytoplasmic and nuclear staining. As regards E-cadherin, there is loss of membrane staining with the antibody to the extracellular domain whereas there is nuclear staining with the antibody to the cytoplasmic domain.3,4 In contrast, in pancreatic neuroendocrine tumors, there is characteristic membrane staining of E-cadherin with absent nuclear staining of beta-catenin, which differentiates these tumors from SPT.4

E-cadherin and beta-catenin are important molecules in the Wnt signaling pathway and the distinct over-expression profile of beta-catenin seen provides irrefutable evidence of this pathway in the tumorigenesis of SPT. Moreover, mutations of the beta-catenin gene have been identified in most SPT. These mutations are at or around the GSK-3 beta phosphorylation sites, which abrogate subsequent ubiquitin-mediated degradation of beta-catenin protein; this allows for cytosolic accumulation with consequent nuclear shift and an increase in transcriptional activity.5,6

The question is whether this key information is limited for use in diagnosis alone, or whether we can move further to explain and understand the tumor phenotype and behavior, or even to develop and evaluate targeted therapy for this tumor. Beta-catenin protein is an important linking molecule between E-cadherin and cytoskeleton. Thus, mutation of beta-catenin and loss of membrane E-cadherin leads to disruption of adhesion junctions and eventual disorganized growth that forms the characteristic pseudopapillary pattern of SPT.7

Based on this molecular profiling and characterization, it would be beneficial as a next step to identify candidate molecularly targeted therapies for SPT. A novel methodology is to create a virtual prototype tumor cell using all the known signal pathways. This biological system would then enable virtual screening of molecularly targeted drugs alone or in combination, coupled to the capability to predict quantitatively cellular pathways and markers like apoptosis, survival, angiogenesis, metastasis and tumor metabolism.8,9

Using the knowledge about beta-catenin over-expression and activity as being the key differentiator for SPT, one can create a virtual customized tumor profile of SPT, where beta-catenin is functionally over-expressed tenfold. On this virtual platform, the SPT cell dynamically exhibited trends like increase in proliferation markers, such as cyclin D1 and c-myc; reduction in membrane E-cadherin as a consequence; increased expression of cell cycle inhibitors p21 and p27; slight increase in vimentin expression and others. These same characteristics have been observed and corroborated from clinical specimens thus indicating that the virtual platform closely represents the tumor cell.

Besides the Wnt-beta-catenin pathway that can be targeted for SPT based on its distinct molecular profile, additional pathways intervening the growth factor signaling, key kinases and inherent converging points in the signaling machinery can also be targeted (Figure 1).10 Growth factor receptor inhibitors, such as epidermal growth factor receptor inhibitors (erlotinib that is used to treat non-small-cell lung cancer, pancreatic, colorectal and many other cancer types; iressa, cetuximab and other antibody drugs in this class), platelet-derived growth factor receptor subtype A (PDGFRA) inhibitors (such as imatinib [Gleevec] used to treat chronic myelogenous leukemia and gastrointestinal stromal tumor), could also be tested. Additionally kinase inhibitors are in clinical trials for various cancer types, including lung, colorectal, gliomas, pancreatic cancers and target key kinases, including phosphoinositide-3-kinase (PI3K) inhibitor (XL147). Protein kinase B inhibitor (perifosine) and mitogen-activated protein kinase kinase kinase inhibitor (AZD6244) would probably also be worth looking into. Other commonly used drugs, such as celecoxib (a cyclooxygenase 2 inhibitor that also has an impact on transcription factor nuclear factor kappa B), and Torisel (the mammalian target of rapamycin inhibitor) could be clinically tested in combination with the above-mentioned molecularly targeted drugs. When these molecular targets are tested on the SPT virtual tumor profile, the sensitivity versus resistance to these therapies can be assessed based on the impact on two key cancer phenotypes of proliferation and cell viability. The predictive analysis gives insight into the shortlist of sensitive therapies that can be possibly clinically tested in SPT (Table 1).

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Figure 1. The schematic shows the Wnt signaling pathway and also highlights different drugs that can be targeted at specific molecular targets to intervene and disrupt the tumor pathways. The key drugs indicated here with their respective targets in brackets are: XL147 (phosphoinositide-3-kinase [PI3K] inhibitor); AZD6244 (mitogen-activated protein kinase kinase kinase [MEKK] inhibitor); Torisel (mammalian target of rapamycin [mTOR] inhibitor); CGP049090 (beta catenin inhibitor); Perifosine (protein kinase B [AKT] inhibitor); Erlotinib (epidermal growth factor receptor [EGFR] inhibitor); Gleevec (platelet-derived growth factor receptor [PDGFR] inhibitor) and Celecoxib (cyclooxygenase 2 [COX2] inhibitor and has indirect inhibition of nuclear factor kappa B [NFkB] through phosphoinositide-dependent kinase 1 [PDPK1]). E-Cdh, E-cadherin.

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Table 1.  The results tabulated here indicate the molecularly targeted drugs tested on a beta-catenin over-expressed solid pseudopapillary tumor (SPT)-like tumor profile that are classified as either: “Extremely Sensitive”, “Partially Sensitive” and “Resistant” based on their impact on the two key cancer phenotypes of proliferation and cell viability that account for a ratio of markers linked to survival and apoptosis. Extremely Sensitive classification is based on the therapy having a positive impact on both phenotypes, Partially Sensitive indicates that despite a reduction in proliferation, it is not reducing cell viability and the resistant category indicates that the therapy is not having any impact on the particular tumor profile
Tumor ProfileExtremely SensitivePartially SensitiveResistant
Proliferation [DOWNWARDS ARROW]Proliferation [DOWNWARDS ARROW]Proliferation –
Cell Viability [DOWNWARDS ARROW]Cell Viability –Cell Viability –
  1. AKT, protein kinase B; EGFR, epidermal growth factor receptor; MEKK, mitogen-activated kinase kinase kinase; mTOR, mammalian target of rapamycin; PDGFRA, platelet-derived growth factor subtype A; PI3K, phosphoinosited-3-kinase; PPARg, peroxisome proliferator activated receptor gamma.

SPT (beta-catenin)PI3K inhibitor, EGFR inhibitor, MEKK inhibitor, Beta-catenin inhibitorPPARg agonist, Gamma secretase inhibitormTOR inhibitor, AKT inhibitor, PDGFRA inhibitor, Celecoxib

Advances in diagnosis based on the molecular pathways involved in tumorigenesis provide critical insights not only into the phenotypic behavior of the tumor, but also into identifying specific molecular targets that could be an important adjunct in the treatment of these tumors. Considering the fact that these tumors are uncommon and indolent, use of the virtual platforms and the predictive analysis may help select therapies, which may be more specific and effective.

References

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