Abstract
A series of 26 malignant peripheral nerve sheath tumours (MPNST) and 24 benign peripheral nerve sheath tumours (BPNST) were analysed immunocytochemically for p53 expression and the cell proliferation markers proliferating cell nuclear antigen (PCNA) and Ki67 (with MIB1). In 23/26 MPNST, 5%–65% of the tumour cell nuclei were immunoreactive for Ki67 with MIB1 while none of the 24 BPNST had nuclear staining exceeding 5%. Greater than 50% nuclear PCNA staining was detected in 25/26 MPNST compared with 8/24 BPNST; 17/26 MPNST showed 5–100% nuclear staining for p53 (13/26>20%), whereas none of the BPNST had nuclear staining exceeding 1%. The Ki67, PCNA and p53 immunostaining results correlated significantly with benign versus malignant (P<0.001, P<0.001 and P<0.005, respectively) as well as mitotic rate (P<0.001, P<0.05 and P<0.05). Ki67 immunostaining results correlated significantly with PCNA and p53, as did p53 with Ki67 and PCNA (P<0.001 in both). Stepwise (logistic regression forward) multivariate analysis of the variable, benign versus malignant, revealed the strongest correlations with PCNA (P=0.007) and Ki67 (P=0.021). Direct confirmation of the presence of p53 protein was obtained by western blot analysis of 3 MPNST and 5 BPNST. Two MPNST, showing 90% and 30% immunoreactivity, were positive for p53, while one MPNST with 5% immunoreactivity and all 5 BPNST were negative. Southern blot analysis performed on the two MPNST with high p53 protein levels revealed no amplification of the MDM2 gene, suggesting that high p53 levels in MPNST are likely to be due to mutation. The results also indicate that PCNA and Ki67 are potentially useful in distinguishing BPNST from MPNST, particularly in problematic cases of cellular schwannoma versus MPNST. The detection of p53 in a large percentage of cells of a plexiform neurofibroma giving rise to MPNST and Ki67 in 5% and 25% of cells of two similar cases suggests that malignant transformation may be detected in some cases by p53 and proliferation markers prior to overt histological evidence of malignancy.
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References
Amin MB, Ma CK, Linden MD, Kubus JJ, Zarbo RJ (1993) Prognostic value of proliferating cell nuclear antigen index in gastric stromal tumors — correlation with mitotic count and clinical outcome. Am J Clin Pathol 100:428–432
Andreassen Å, Øyjord T, Hovig E, Holm R, Flørenes VA, Nesland JM, Myklebost O, Høie J, Burland ØS, Børresen A-L, Fodstad Ø (1993) p53 abnormalities in different subtypes of human sarcomas. Cancer Res 53:468–471
Battifora H (1994) p53 immunohistochemistry: A word of caution (editorial). Hum Pathol 435–437
Bradley JW (1968) Distribution-free statistical tests. Prentice-Hall, London, pp 68–86
Bravo R, Frank R, Blundell PA, Macdonald-Bravo H (1987) Cyclin/PCNA is the auxiliary protein of DNA polymerase delta. Nature 326:515–517
Carmen C-W, Woods AL, Levison DA (1992) The assessment of cellular proliferation by immunohistochemistry: a review of currently available methods and their applications. Histochem 24:121–131
Casadei GP, Scheithauer BW, Hirose T, Manfrini M, Van Houton C, Wood MB (1995) Cellular schwannoma: A clinicopathologic, DNA flow cytometric and proliferation marker study of 71 cases. Cancer 75:1109–1119
Cattoretti G, Becker MHG, Key G, Duchrow M, Schlüter C, Galle J, Gerdes J (1992) Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol 168:357–363
Cristofolini M, Boi S, Girlando S, Zumiani G, Cristofolini P, Dalla-Palma P, Doglioni C, Barbareschi M (1993) p53 protein expression in nevi and melanomas. Arch Dermatol 129:739–743
Dei Tos AP, Doglioni C, Laurino L, Barbareschi M, Fletcher CDM (1993) p53 protein expression in non-neoplastic lesions and benign and malignant neoplasms of soft tissue. Histopathology 22:45–50
Deruaz JP, Janzer RC, Costa J (1993) Cellular schwannomas of the intracranial and intraspinal compartment: morphological and immunological characteristics compared with classical benign schwannomas. J Neuropathol Exp Neurol 52:114–118
Feinberg AP, Vogelstein B (1984) A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem 137:266–267
Finlay C, Hinds P, Levine A (1989) The p53 proto-oncogene can act as a suppressor of transformation. Cell 57:1083–1093
Frankel R, Bayonu W, Koslow M, Newcombe EW (1992) p53 mutations in human malignant gliomas: comparison of loss of heterozygosity with mutation frequency. Cancer Res 52:1427–1433
Gerdes J, Li L, Schlüter C, Duchrow M, Wohlenberg C, Gerlach C, Stahmer I, Kloth S, Brandt E, Flad H-D (1991) Immunochemical and molecular biologic characterization of the cell proliferation associated nuclear antigen that is defined by the monoclonal antibody Ki-67. Am J Pathol 138:867–873
Gerdes J, Becker MHG, Key G, Cattoretti G (1992) Immunohistochemical detection of tumour growth fraction (Ki-67 antigen) in formalin-fixed and routinely processed tissues (Letter to the Editor). J Pathol 168:85–87
Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53
Kawai A, Noguchi M, Beppu Y, Yokoyama R, Mukai K, Hirohashi S, Inoue H, Fukuma H (1994) Nuclear immunoreaction of p53 protein in soft tissue sarcomas. A possible prognostic factor. Cancer 73:2499–2505
Kindblom L-G, Ahldén M, Meis-Kindblom JM (1995) Proliferation markers (PCNA and Ki67) and p53 expression in PNST (abstract). Int J Surg Pathol [Suppl] 2:13
Kindblom L-G, Nelson JS, Meis-Kindblom JM (1995) Comparison of Ki67, PCNA, and p53 expression in pleomorphic xanthoastrocytoma and glioblastoma multiforme (GBM) (abstract). Int J Surg Pathol [Suppl] 2:418
Kindblom L-G, Meis-Kindblom JM (1995) Chondroid lipoma: An ultrastructural and immunohistochemical analysis with further observationsregarding its differentiation and pathogenesis. Hum Pathol 26:706–715
Lane DP (1994) On the expression of the p53 protein in human cancer. Mol Biol Rep 19:23–29
Latres E, Drobnjak M, Pollack D, Olivia MR, Ramos M, Karpeh M, Woodruff JM, Cordon-Cardo C (1994) Chromosome 17 abnormalities and TP53 mutations in adult soft tissue sarcomas. Am J Pathol 145:345–355
Leach FS, Tokino T, Meltzer P, Burrell M, Oliner JD, Smith S, Hill DE, Sidransky D, Kinzler KW, Vogelstein B (1993) p53 mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res 53:2231–2234
Levine AJ (1992) The p53 tumor suppressor gene. N Engl J Med 326:1350–1352
Levine AJ, Momand J, Finlay CA (1991) The p53 tumor suppressor gene. Nature 351:453–456
Lodding P, Kindblom L-G, Angervall L, Stenman G (1990) Cellular schwannoma. A clinicopathologic study of 29 cases. Virchows Arch [A] 416:237–248
Mayall FG, Goddard H, Gibbs AR (1992) p53 immunostaining in the distinction between benign and malignant mesothelial proliferations using formalin-fixed paraffin sections. J Pathol 168:377–381
Meis-Kindblom JM, Enzinger FM (1994) Plexiform malignant peripheral nerve sheath tumor of infancy and childhood. Am J Surg Pathol 18:479–485
Menon AG, Anderson KM, Riccardi VM, Chung RY, Whaley JM, Yandell DW, Farmer GE, Freiman RN, Lee JK, Li FP, Barker DF, Ledbetter DH, Kleider A, Martuza RL, Gusella JF, Seizinger BR (1990) Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proc Natl Acad Sci USA 87:5435–5439
Mulligan LM, Matlashewski GJ, Scrable HJ, Cavenee WK (1990) Mechanisms of p53 loss in human sarcomas. Proc Natl Acad Sci USA 87:5863–5867
Ng H-K, Lo K-W, Huang DP, Poon W-S (1994) p53 in low-grade gliomas. Int J Surg Pathol 1:163–170
Oliner JD, Kinzler KW, Meltzer PS, Georges DL, Vogelstein B (1992) Amplification of gene encoding a p53-associated protein in human sarcomas. Nature 358:80–83
Oshiro Y, Fukuda T, Tsuneyoshi M (1994) Fibrosarcoma versus fibromatoses and cellular nodular fasciitis. A comparative study of their proliferative activity using proliferating cell nuclear antigen, DNA flow cytometry, and p53. Am J Surg 18:712–719
Reifenberger G, Liu L, Ichimura K, Schmidt EE, Collins VP (1993) Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. Cancer Res 53:1–14
Sambrook J, Fritsch EF, Maniatis T (eds) (1989) Molecular cloning: A laboratory manual, 2nd edn. Cold Spring Harbor Laboratory Press, New York
Soini Y, Vähäkangas K, Nuorva K, Kamel D, Lane D, Pääkkö P (1992) p53 immunohistochemistry in malignant fibrous histiocytomas and other mesenchymal tumours. J Pathol 168:29–33
Stenman G, Sager R (1987) A conserved region in the human and Chinese hamster genomes contains genetically identified tumor-suppressor genes. Proc Natl Acad Sci USA 84:9099–9102
Stenman G, Sandros J, Mark J, Nordkvist A (1989) High p21RAS expression levels correlate with chromosome 8 rearrangements in benign human mixed salivary gland tumors. Genes Chrom Cancer 1:59–66
Toguchida J, Yamaguchi T, Ritchie B, Beauchamp RL, Dayton SH, Herrera GE, Yamamuro T, Kotoura Y, Sasaki MS, Little JB, Weichselbaum RR, Ishizaki K, Yandell DW (1992) Mutation spectrum of the p53 gene in bone and soft tissue sarcomas. Cancer Res 52:6194–6199
Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76:4350–4354
White W, Shiu MH, Rosenblum MK, Erlandson RA, Woodruff JM (1990) Cellular schwannoma. A clinicopathologic study of 57 patients and 58 tumors. Cancer 66:1266–1275
Wynform-Thomas D (1992) p53 in tumour pathology: Can we trust immunohistochemistry? (editorial). J Pathol 166:329–330
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Kindblom, LG., Ahldén, M., Meis-Kindblom, J.M. et al. Immunohistochemical and molecular analysis of p53, MDM2, proliferating cell nuclear antigen and Ki67 in benign and malignant peripheral nerve sheath tumours. Vichows Archiv A Pathol Anat 427, 19–26 (1995). https://doi.org/10.1007/BF00203733
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DOI: https://doi.org/10.1007/BF00203733