Abstract
Nonfunctioning islet cell tumors or pancreatic endocrine tumors are the most common type of malignant islet cell tumor. Although previously detected usually at an advanced stage because of mass effect, the early detection rate of small localized disease has been increasing. To date it has been difficult to predict the clinical behavior in localized regional nonfunctioning tumors. To investigate potential markers predicting malignancy and poor prognosis in nonfunctioning pancreatic endocrine tumors, we analyzed the expression of Ki-67, topoisomerase IIα (Topollα), and p27, as well as a variety of clinicopathologic parameters in 76 cases of nonfunctioning islet cell tumors (23 benign cases and 53 malignant cases). Ki-67, Topollα, and p27 labeling indices were significantly different between benign and malignant tumors. Expression of Ki-67, Topollα, and p27 were associated with survival in patients with a malignant tumor in a univariate setting. However, only p27 and Topollα were jointly associated with survival in multivariate analysis. Immunohistochemical staining for p27, Topollα, and Ki-67 can be helpful in the diagnosis of nonfunctioning pancreatic endocrine tumor. Analysis of p27 and Topollα may also have potential utility as prognostic factors for malignant tumors.
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References
Klöppel G, Heitz PU. Pancreatic endocrine tumors. Path Res Pract 183:155–68, 1988.
La Rosa S, Sessa F, Capella C, Riva C, Leone BE, Klersy C, Rindi G, Solcia E. Prognostic criteria in nonfunctioning pancreatic endocrine tumors. Virchows Arch 429:323–333, 1996.
Capella C, La Rosa S, Solcia E. Criteria for malignancy in pancreatic endocrine tumors. Endocr Pathol 8:87–90, 1997.
Eckhauser FE, Cheung PS, Vinik AI, Strodel WE, Lloyd RV, Thompson NW. Nonfunctioning malignant neuroendocrine tumors of the pancreas. Surgery 100:978–988, 1986.
Kent III RB, van Heerden JA, Weiland LH. Nonfunctioning islet cell tumors. Ann Surg 193:185–190, 1981.
Lo CH, van Heerden JA, Thompson GB, Grant CS, Soreide JA, Harmsen WS. Islet cell carcinoma of the pancreas. World J Surg 20:878–884, 1996.
Liu TT, Zhu Y, Cui QC, Cai LX, Ye SF, Zhong SX, Jia HP. Nonfunctioning pancreatic endocrine tumors. An immunohistochemical and electron microscopic analysis of 26 cases. Path Res Pract 188:191–198, 1992.
Furukawa H, Mukai K, Kosuge T, Kanai Y, Shimada K, Yamamoto J, Mizuguchi Y, Ushio K. Nonfunctioning islet cell tumors of the pancreas: clinical, imaging and pathological aspects of 16 patients. Jpn J Clin Oncol 28:255–261, 1998.
Thompson GB, van Heerden JA, Grant CS, Carney A, Ilstrup DM. Islet cell carcinomas of the pancreas: a twenty-year experience. Surgery 104:1011–1017, 1988.
Capella C, Heitz PU, Höfler H, Solcia E, Klöppel G. Revised classification of neuroendocrine tumors of the lung, pancreas and gut. Virchows Arch 425:547–560, 1995.
Erickson LA, Jin L, Wollan PC, Thompson GB, van Heerden JA, Lloyd RV. Expression of p27kip1 and Ki-67 in benign and malignant thyroid tumors. Mod Pathol 11:169–174, 1998.
Erickson LA, Jin L, Wollan PC, Thompson GB, van Heerden JA, Lloyd RV. Parathyroid hyperplasia, adenomas, and carcinomas. Differential expression of p27kip1 protein. Am J Surg Pathol 23:288–295, 1999.
Lloyd RV, Jin L, Qian X, Kulig E. Aberrant p27kip1 expression in endocrine and other tumors. Am J Pathol 150:401–407, 1997.
Lloyd RV, Erickson LA, Jin L, Kulig E, Qian X, Cheville JC, Scheithauer BW. p27kip1: a multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol 154:313–323, 1999.
Lloyd RV. Utility of Ki-67 as a prognostic marker in pancreatic endocrine neoplasms. Am J Clin Pathol 109:245–247, 1998.
Pelosi G, Bresaola E, Bogina G, Pasini F, Rodella S, Castelli P, Calogero I, Serio G, Zamboni G. Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: a comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables. Hum Pathol 27:1124–1134, 1996.
Perret AG, Mosnier JF, Buono JP, Berthelot P, Chipponi J, Balique JG, et al. The relationship between MIB-1 proliferation index and outcome in pancreatic neuroendocrine tumors. Am J Clin Pathol 109:286–293, 1998.
Gibbons D, Fogt F, Kasznica J, Holden J, Nikulasson S. Comparison of Topoisomerase IIa and MIB-1 expression in uterine cervical squamous lesions. Mod Pathol 10:409–413, 1997.
Oberg K. Neuroendocrine gastrointestinal tumors-a condensed overview of diagnosis and treatment. Ann Oncol 10:S3–8, 1999.
Soga J, Tazawa K. Pathologic analysis of carcinoids. Histologic revaluation of 62 cases. Cancer 28:990–998, 1971.
Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta G, Jessup M, Pagano M. Increased proteasome-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nature Med 3:231–234, 1997.
Newcomb EW, Sosnow M, Demopoulos RI, Zeleniuch-Jacquotte A, Sorich J, Speyer JL. Expression of the cell cycle inhibitor is a new prognostic marker associated with survival in epithelial ovarian tumors. Am J Pathol 154:119–125, 1999.
Del Pizzo JJ, Borkowski A, Jacobs SC, Kyprianou N. Loss of cell cycle regulators p27Kip1 and cyclin E in transitional cell carcinoma of the bladder correlates with tumor grade and patient survival. Am J Pathol 155:1129–1136, 1999.
Lu CD, Morita S, Ishibashi T, Hara H, Isozaki H, Tanigawa N. Loss of p27Kip1 expression independently predicts poor prognosis for patients with resectable pancreatic adenocarcinoma. Cancer 85:1250–1260, 1999.
Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature 54:535–540, 1994.
Sherr CJ. Cancer cell cycles. Science 274:1672–1677, 1996.
Vlach J, Hennecke S, Alevizopoulos K, Conti D, Amati B. Growth arrest by the cyclindependent kinase inhibitor p27Kip1 is abrogated by c-myc. EMBO J 15:6569–6604, 1996.
Beghelli S, Pelosi G, Zamboni G, Falconi M, Iacono C, Bordi C, Scarpa A. Pancreatic endocrine tumors: Evidence for a tumor suppressor pathogenesis and for a tumor suppressor gene on chromososme 17p. J Pathol 186:41–™50, 1998.
Chung DC, Smith AP, Louis DN, Graeme-Cook F, Warshaw AL, Arnold A. Analysis of the retinoblastoma tumor suppressor gene in pancreatic endocrine tumors. Clin Endocr 47:523–528, 1997.
Höfler H, Ruhri C, Putz B, Wirnsberger G, Hauser H. Oncogene expression in endocrine pancreatic tumors. Virchows Arch B Cell Pathol 1988;55:355–361.
Pavelic K, Hrascan R, Kapitanovic S, Vranes Z, Cabrizan T, Spaventi S, Molecular genetics of malignant insulinoma. Anticancer Res 16:1707–1718, 1996.
Masciullo V, Sgambato A, Pacilio C, Pucci B, Ferrandina G, Palazzo J, et al. Frequent loss of expression of the cyclin-dependent kinase inhibitor p27 in epithelial ovarian cancer. Cancer Res 59:3790–3794, 1999.
Baldassarre G, Belletti B, Bruni P, Boccia A, Trapasso F, Pentimalli F, et al. Overexpressed cyclin D3 contributes to retaining the growth inhibitor p27 in the cytoplasm of thyroid tumor cells. J Clin Invest 104:865–874, 1999.
Clarke MR, Baker EE, Weyant RJ, Hill L, Carty SE. Proliferative activity in pancreatic endocrine tumors: Association with function, metastases, and survival. Endocr Pathol 8:181–187, 1997.
Iino K, Sasano H, Yabuki N, Oki Y, Kikuchi A, Yoshimi T, Nagura H. DNA topoisomerase IIα and Ki-67 in human adrenocortical neoplasms: a possible marker of differentiation between adenomas and carcinomas. Mod Pathol 10:901–907, 1997.
Lynch BJ, Guinee DG, Holden JA. Human DNA topoisomerase II-alpha: a new marker of cell proliferation in invasive breast cancer. Hum Pathol 28:1180–1188, 1997.
Rudolph P, MacGrogan G, Bonichon F, Frahm SO, de Mascarel I, Trojani M, et al. Prognostic significance of Ki-67 and topoisomerase IIα expression in infiltrating ductal carcinoma of the breast. Breast Cancer Res Treat 55:61–71, 1999.
Tanoguchi K, Sasano H, Yabuki N, Kikuchi A, Ito K, Sato S, Yajima A. Immunohistochemical and two-parameter flow cytometric studies of DNA topoisomerase II α in human epithelial ovarian carcinoma and germ cell tumor. Mod Pathol 11:186–193, 1998.
Guinee Jr DG, Holden JA, Benfield JR, Woodward ML, Przygodzki RM, Fishback NF, Koss MN, Travis WD. Comparison of DNA topoisomerase IIα expression in small cell and nonsmall cell carcinoma of the lung. In search of a mechanism of chemotherapeutic response. Cancer 78:729–735, 1996.
Jarvinen TAH, Kononen J, Pelto-Huikko M, Isola J. Expression of topoisomerase II alpha is associated with rapid cell proliferation, aneuploidy, and c-erb B2 overexpression in breast cancer. Am J Pathol 148:2073–2082, 1996.
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Chang, H.J., Batts, K.P., Lloyd, R.V. et al. Prognostic significance of p27, Ki-67, and topoisomerase IIα expression in clinically nonfunctioning pancreatic endocrine tumors. Endocr Pathol 11, 229–241 (2000). https://doi.org/10.1385/EP:11:3:229
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DOI: https://doi.org/10.1385/EP:11:3:229