Positive immunohistochemical staining of KIT in solid-pseudopapillary neoplasms of the pancreas is not associated with KIT/PDGFRA mutations

Abstract

Solid-pseudopapillary neoplasms of the pancreas are uncommon neoplasms of low malignant potential and of uncertain histogenesis. A small percentage of patients develop metastatic disease and some succumb to disease. The management of patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates is problematic. Novel therapy targets are needed. Successful treatment of metastatic and unresectable gastrointestinal stromal tumors with KIT kinase inhibitor, imatinib mesylate (Gleevec), makes it intriguing to look at the status of KIT in solid-pseudopapillary neoplasms of the pancreas. In this study, we investigated KIT expression in 50 solid-pseudopapillary neoplasms by immunohistochemical staining. Of the 50 (50%) solid-pseudopapillary neoplasms, 25 showed diffuse expression (in 450% neoplastic cells) of KIT and additional five (10%) cases showed focal staining (in 10-50% neoplastic cells). Expression of KIT was not associated with tumor behavior and prognosis. A subset of 11 cases showing diffuse KIT expression detected by immunohistochemical staining were further evaluated for the presence of activating mutations in KIT exons 9, 11, 13 and 17, and PDGFRA exons 12 and 18 using PCR amplification followed by direct sequencing. However, no KIT or PDGFRA mutations were identified in any of these 11 cases tested, suggesting that the overexpression of KIT is probably not due to activating mutations in KIT or PDGFRA. The exact mechanism of KIT overexpression in solid-pseudopapillary neoplasms remains to be elucidated. One possible mechanism is gene dose effect (increased copies of KIT gene). Experience in gastrointestinal stromal tumors and other tumors have shown that mutation-mediated activation of KIT or PDGFRA is a prerequisite for clinical response with imatinib mesylate. Thus, lack of mutations in KIT or PDGFRA in solid-pseudopapillary neoplasms suggests that imatinib mesylate is less likely to be effective in the treatment for patients with metastatic disease or unresectable tumor, and patients who are just not good surgical candidates.

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

“…7,8 Recently, we showed that solid pseudopapillary neoplasms express FLI-1, which has also been demonstrated in neuroendocrine tumors of the skin (so-called Merkel cell carcinomas). 9 Finally, a non-mutation-mediated activation of c-kit was demonstrated in about 50% of solid pseudopapillary neoplasms, 10 a finding similar to that seen in neuroendocrine small cell carcinomas of the lung. 11,12 When the genes encoding for the above mentioned markers are localized, it is striking that many of them reside on chromosome 11q, a chromosomal area that also is involved in the genetics of pancreatic neuroendocrine tumors because it harbors the MEN1 gene.…”

Characterization of gene expression and activated signaling pathways in solid-pseudopapillary neoplasm of pancreas

“…23 Also, studies have reported that B50% of solid-pseudopapillary neoplasms express KIT, a well-known stem cell marker. 24 Interestingly, examination of stem cell marker expression in our microarray data did not reveal any significant changes in these markers in solid-pseudopapillary neoplasms (Supplementary Table 2). Instead, the expression of genes associated with epithelial-mesenchymal transition changed dramatically in solid-pseudopapillary neoplasms.…”

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

“…34 We conclude from our data that in Merkel cell carcinoma, expression of KIT and occurrences of activating mutations in the receptor may be unrelated events. This is true in other tumors as well, such as solid psuedopapillary neoplasms of the pancreas, 35 melanomas, 36,37 pulmonary small cell carcinomas 38,39 and breast carcinomas. 40 Cytogenetic studies revealed frequent genetic abnormalities in Merkel cell carcinoma, 5 but no alterations were observed in chromosome 4q12, the area to which KIT and PDGFRA are mapped.…”