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. 1997 Jan;150(1):133–145.

Prognostic significance of the proliferative activity in neuroblastoma.

P Rudolph 1, T Lappe 1, B Hero 1, F Berthold 1, R Parwaresch 1, D Harms 1, D Schmidt 1
PMCID: PMC1858526  PMID: 9006330

Abstract

The prognostic significance of the immunohistochemically assessed growth fraction in neuroblastomas was determined in relation to tumor grade and tumor stage. A total of 101 cases of neuroblastoma were examined with the monoclonal antibodies PC10 against proliferating cell nuclear antigen (PCNA) and Ki-S5 against the Ki-67 protein. Patients were followed for a mean time of 4.8 years. Expression of both PC10 and Ki-S5 was found to be significantly linked to tumor grade and tumor stage. Prognostically favorable stage IVs was associated with low PCNA and Ki-S5 levels. For ganglioneuroblastoma, significant differences were found between the diffuse and the composite type. In univariate analysis of stage III and IV tumors, Ki-S5 and PCNA scores were significantly correlated with disease-free survival (P < 0.0015), allowing definition of a subset of cases with favorable outcome. As to Shimada's group with poor prognosis, significant differences in the clinical course were found for low and high Ki-S5 scores (P = 0.036) but not for PCNA. In multivariate analysis, only patient age, Shimada's grade, and Ki-S5 scores achieved prognostic significance. We conclude that proliferation marker Ki-S5 may provide substantial prognostic information and might become a useful adjunct for predicting the clinical courses of neuroblastoma.

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Selected References

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  1. Adam A., Hochholzer L. Ganglioneuroblastoma of the posterior mediastinum: a clinicopathologic review of 80 cases. Cancer. 1981 Jan 15;47(2):373–381. doi: 10.1002/1097-0142(19810115)47:2<373::aid-cncr2820470227>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  2. Ambros I. M., Ambros P. F. Schwann cells in neuroblastoma. Eur J Cancer. 1995;31A(4):429–434. doi: 10.1016/0959-8049(95)00051-j. [DOI] [PubMed] [Google Scholar]
  3. Ambros P. F., Ambros I. M., Strehl S., Bauer S., Luegmayr A., Kovar H., Ladenstein R., Fink F. M., Horcher E., Printz G. Regression and progression in neuroblastoma. Does genetics predict tumour behaviour? Eur J Cancer. 1995;31A(4):510–515. doi: 10.1016/0959-8049(95)00044-j. [DOI] [PubMed] [Google Scholar]
  4. Aoyama C., Qualman S. J., Regan M., Shimada H. Histopathologic features of composite ganglioneuroblastoma. Immunohistochemical distinction of the stromal component is related to prognosis. Cancer. 1990 Jan 15;65(2):255–264. doi: 10.1002/1097-0142(19900115)65:2<255::aid-cncr2820650213>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  5. Baak J. P. Mitosis counting in tumors. Hum Pathol. 1990 Jul;21(7):683–685. doi: 10.1016/0046-8177(90)90026-2. [DOI] [PubMed] [Google Scholar]
  6. Beckwith M., Ruscetti F. W., Sing G. K., Urba W. J., Longo D. L. Anti-IgM induces transforming growth factor-beta sensitivity in a human B-lymphoma cell line: inhibition of growth is associated with a downregulation of mutant p53. Blood. 1995 May 1;85(9):2461–2470. [PubMed] [Google Scholar]
  7. Berthold F., Kassenböhmer R., Zieschang J. Multivariate evaluation of prognostic factors in localized neuroblastoma. Am J Pediatr Hematol Oncol. 1994 May;16(2):107–115. [PubMed] [Google Scholar]
  8. Bove K. E., McAdams A. J. Composite ganglioneuroblastoma. An assessment of the significance of histological maturation in neuroblastoma diagnosed beyond infancy. Arch Pathol Lab Med. 1981 Jun;105(6):325–330. [PubMed] [Google Scholar]
  9. Bravo R., Frank R., Blundell P. A., Macdonald-Bravo H. Cyclin/PCNA is the auxiliary protein of DNA polymerase-delta. Nature. 1987 Apr 2;326(6112):515–517. doi: 10.1038/326515a0. [DOI] [PubMed] [Google Scholar]
  10. Bravo R., Macdonald-Bravo H. Existence of two populations of cyclin/proliferating cell nuclear antigen during the cell cycle: association with DNA replication sites. J Cell Biol. 1987 Oct;105(4):1549–1554. doi: 10.1083/jcb.105.4.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Brodeur G. M. Molecular basis for heterogeneity in human neuroblastomas. Eur J Cancer. 1995;31A(4):505–510. doi: 10.1016/0959-8049(95)00040-p. [DOI] [PubMed] [Google Scholar]
  12. Brodeur G. M., Pritchard J., Berthold F., Carlsen N. L., Castel V., Castelberry R. P., De Bernardi B., Evans A. E., Favrot M., Hedborg F. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993 Aug;11(8):1466–1477. doi: 10.1200/JCO.1993.11.8.1466. [DOI] [PubMed] [Google Scholar]
  13. COX D., YUNCKEN C., SPRIGGS A. I. MINUTE CHROMATIN BODIES IN MALIGNANT TUMOURS OF CHILDHOOD. Lancet. 1965 Jul 10;1(7402):55–58. doi: 10.1016/s0140-6736(65)90131-5. [DOI] [PubMed] [Google Scholar]
  14. Castresana J. S., Bello M. J., Rey J. A., Nebreda P., Queizán A., García-Miguel P., Pestaña A. No TP53 mutations in neuroblastomas detected by PCR-SSCP analysis. Genes Chromosomes Cancer. 1994 Jun;10(2):136–138. doi: 10.1002/gcc.2870100209. [DOI] [PubMed] [Google Scholar]
  15. Chatten J., Shimada H., Sather H. N., Wong K. Y., Siegel S. E., Hammond G. D. Prognostic value of histopathology in advanced neuroblastoma: a report from the Childrens Cancer Study Group. Hum Pathol. 1988 Oct;19(10):1187–1198. doi: 10.1016/s0046-8177(88)80151-5. [DOI] [PubMed] [Google Scholar]
  16. Christiansen H., Lampert F. Tumour karyotype discriminates between good and bad prognostic outcome in neuroblastoma. Br J Cancer. 1988 Jan;57(1):121–126. doi: 10.1038/bjc.1988.24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Christiansen H., Sahin K., Berthold F., Hero B., Terpe H. J., Lampert F. Comparison of DNA aneuploidy, chromosome 1 abnormalities, MYCN amplification and CD44 expression as prognostic factors in neuroblastoma. Eur J Cancer. 1995;31A(4):541–544. doi: 10.1016/0959-8049(95)00030-m. [DOI] [PubMed] [Google Scholar]
  18. Coltrera M. D., Gown A. M. PCNA/cyclin expression and BrdU uptake define different subpopulations in different cell lines. J Histochem Cytochem. 1991 Jan;39(1):23–30. doi: 10.1177/39.1.1670579. [DOI] [PubMed] [Google Scholar]
  19. Cowell J. K. Double minutes and homogeneously staining regions: gene amplification in mammalian cells. Annu Rev Genet. 1982;16:21–59. doi: 10.1146/annurev.ge.16.120182.000321. [DOI] [PubMed] [Google Scholar]
  20. Davidoff A. M., Pence J. C., Shorter N. A., Iglehart J. D., Marks J. R. Expression of p53 in human neuroblastoma- and neuroepithelioma-derived cell lines. Oncogene. 1992 Jan;7(1):127–133. [PubMed] [Google Scholar]
  21. Derenzini M., Sirri V., Trerè D., Ochs R. L. The quantity of nucleolar proteins nucleolin and protein B23 is related to cell doubling time in human cancer cells. Lab Invest. 1995 Oct;73(4):497–502. [PubMed] [Google Scholar]
  22. Dervan P. A., Magee H. M., Buckley C., Carney D. N. Proliferating cell nuclear antigen counts in formalin-fixed paraffin-embedded tissue correlate with Ki-67 in fresh tissue. Am J Clin Pathol. 1992 May;97(5 Suppl 1):S21–S28. [PubMed] [Google Scholar]
  23. Evans A. E., D'Angio G. J., Randolph J. A proposed staging for children with neuroblastoma. Children's cancer study group A. Cancer. 1971 Feb;27(2):374–378. doi: 10.1002/1097-0142(197102)27:2<374::aid-cncr2820270221>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
  24. Gansler T., Chatten J., Varello M., Bunin G. R., Atkinson B. Flow cytometric DNA analysis of neuroblastoma. Correlation with histology and clinical outcome. Cancer. 1986 Dec 1;58(11):2453–2458. doi: 10.1002/1097-0142(19861201)58:11<2453::aid-cncr2820581117>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
  25. Gerdes J., Lemke H., Baisch H., Wacker H. H., Schwab U., Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984 Oct;133(4):1710–1715. [PubMed] [Google Scholar]
  26. Gestblom C., Hoehner J. C., Påhlman S. Proliferation and apoptosis in neuroblastoma: subdividing the mitosis-karyorrhexis index. Eur J Cancer. 1995;31A(4):458–463. doi: 10.1016/0959-8049(95)00006-5. [DOI] [PubMed] [Google Scholar]
  27. Gillett C. E., Barnes D. M., Camplejohn R. S. Comparison of three cell cycle associated antigens as markers of proliferative activity and prognosis in breast carcinoma. J Clin Pathol. 1993 Dec;46(12):1126–1128. doi: 10.1136/jcp.46.12.1126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Hall P. A., Coates P. J. Assessment of cell proliferation in pathology--what next? Histopathology. 1995 Feb;26(2):105–112. doi: 10.1111/j.1365-2559.1995.tb00639.x. [DOI] [PubMed] [Google Scholar]
  29. Hall P. A., Levison D. A., Woods A. L., Yu C. C., Kellock D. B., Watkins J. A., Barnes D. M., Gillett C. E., Camplejohn R., Dover R. Proliferating cell nuclear antigen (PCNA) immunolocalization in paraffin sections: an index of cell proliferation with evidence of deregulated expression in some neoplasms. J Pathol. 1990 Dec;162(4):285–294. doi: 10.1002/path.1711620403. [DOI] [PubMed] [Google Scholar]
  30. Hall P. A., McKee P. H., Menage H. D., Dover R., Lane D. P. High levels of p53 protein in UV-irradiated normal human skin. Oncogene. 1993 Jan;8(1):203–207. [PubMed] [Google Scholar]
  31. Hayashi Y., Kanda N., Inaba T., Hanada R., Nagahara N., Muchi H., Yamamoto K. Cytogenetic findings and prognosis in neuroblastoma with emphasis on marker chromosome 1. Cancer. 1989 Jan 1;63(1):126–132. doi: 10.1002/1097-0142(19890101)63:1<126::aid-cncr2820630120>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  32. Hedborg F., Bjelfman C., Sparén P., Sandstedt B., Påhlman S. Biochemical evidence for a mature phenotype in morphologically poorly differentiated neuroblastomas with a favourable outcome. Eur J Cancer. 1995;31A(4):435–443. doi: 10.1016/0959-8049(95)00025-e. [DOI] [PubMed] [Google Scholar]
  33. Hemming A. W., Davis N. L., Kluftinger A., Robinson B., Quenville N. F., Liseman B., LeRiche J. Prognostic markers of colorectal cancer: an evaluation of DNA content, epidermal growth factor receptor, and Ki-67. J Surg Oncol. 1992 Nov;51(3):147–152. doi: 10.1002/jso.2930510304. [DOI] [PubMed] [Google Scholar]
  34. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  35. Huddart S. N., Muir K. R., Parkes S. E., Mann J. R., Stevens M. C., Raafat F., Smith K. Retrospective study of prognostic value of DNA ploidy and proliferative activity in neuroblastoma. J Clin Pathol. 1993 Dec;46(12):1101–1104. doi: 10.1136/jcp.46.12.1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Hughes M., Marsden H. B., Palmer M. K. Histologic patterns of neuroblastoma related to prognosis and clinical staging. Cancer. 1974 Nov;34(5):1706–1711. doi: 10.1002/1097-0142(197411)34:5<1706::aid-cncr2820340519>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  37. Joshi V. V., Cantor A. B., Altshuler G., Larkin E. W., Neill J. S., Shuster J. J., Holbrook C. T., Hayes F. A., Castleberry R. P. Recommendations for modification of terminology of neuroblastic tumors and prognostic significance of Shimada classification. A clinicopathologic study of 213 cases from the Pediatric Oncology Group. Cancer. 1992 Apr 15;69(8):2183–2196. doi: 10.1002/1097-0142(19920415)69:8<2183::aid-cncr2820690828>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  38. Joshi V. V., Cantor A. B., Altshuler G., Larkin E. W., Neill J. S., Shuster J. J., Holbrook C. T., Hayes F. A., Nitschke R., Duncan M. H. Age-linked prognostic categorization based on a new histologic grading system of neuroblastomas. A clinicopathologic study of 211 cases from the Pediatric Oncology Group. Cancer. 1992 Apr 15;69(8):2197–2211. doi: 10.1002/1097-0142(19920415)69:8<2197::aid-cncr2820690829>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  39. Kamel O. W., LeBrun D. P., Davis R. E., Berry G. J., Warnke R. A. Growth fraction estimation of malignant lymphomas in formalin-fixed paraffin-embedded tissue using anti-PCNA/Cyclin 19A2. Correlation with Ki-67 labeling. Am J Pathol. 1991 Jun;138(6):1471–1477. [PMC free article] [PubMed] [Google Scholar]
  40. Keim D. R., Hailat N., Kuick R., Reynolds C. P., Brodeur G. M., Seeger R. C., Hanash S. M. PCNA levels in neuroblastoma are increased in tumors with an amplified N-myc gene and in metastatic stage tumors. Clin Exp Metastasis. 1993 Jan;11(1):83–90. doi: 10.1007/BF00880069. [DOI] [PubMed] [Google Scholar]
  41. Key G., Becker M. H., Baron B., Duchrow M., Schlüter C., Flad H. D., Gerdes J. New Ki-67-equivalent murine monoclonal antibodies (MIB 1-3) generated against bacterially expressed parts of the Ki-67 cDNA containing three 62 base pair repetitive elements encoding for the Ki-67 epitope. Lab Invest. 1993 Jun;68(6):629–636. [PubMed] [Google Scholar]
  42. Kohl N. E., Kanda N., Schreck R. R., Bruns G., Latt S. A., Gilbert F., Alt F. W. Transposition and amplification of oncogene-related sequences in human neuroblastomas. Cell. 1983 Dec;35(2 Pt 1):359–367. doi: 10.1016/0092-8674(83)90169-1. [DOI] [PubMed] [Google Scholar]
  43. Kreipe H., Wacker H. H., Heidebrecht H. J., Haas K., Hauberg M., Tiemann M., Parwaresch R. Determination of the growth fraction in non-Hodgkin's lymphomas by monoclonal antibody Ki-S5 directed against a formalin-resistant epitope of the Ki-67 antigen. Am J Pathol. 1993 Jun;142(6):1689–1694. [PMC free article] [PubMed] [Google Scholar]
  44. Ladenstein R., Urban C., Gadner H., Fink F. M., Zoubek A., Emminger W., Grienberger H., Schmitt K., Ambros P. F., Ambros I. M. First experience with prognostic factors in unselected neuroblastoma patients. The Austrian Neuroblastoma 87 Study. Eur J Cancer. 1995;31A(4):637–641. doi: 10.1016/0959-8049(95)00069-u. [DOI] [PubMed] [Google Scholar]
  45. Linden M. D., Torres F. X., Kubus J., Zarbo R. J. Clinical application of morphologic and immunocytochemical assessments of cell proliferation. Am J Clin Pathol. 1992 May;97(5 Suppl 1):S4–13. [PubMed] [Google Scholar]
  46. Lopez F., Belloc F., Lacombe F., Dumain P., Reiffers J., Bernard P., Boisseau M. R. The labelling of proliferating cells by Ki67 and MIB-1 antibodies depends on the binding of a nuclear protein to the DNA. Exp Cell Res. 1994 Feb;210(2):145–153. doi: 10.1006/excr.1994.1022. [DOI] [PubMed] [Google Scholar]
  47. McCormick D., Hall P. A. The complexities of proliferating cell nuclear antigen. Histopathology. 1992 Dec;21(6):591–594. doi: 10.1111/j.1365-2559.1992.tb00454.x. [DOI] [PubMed] [Google Scholar]
  48. McGurrin J. F., Doria M. I., Jr, Dawson P. J., Karrison T., Stein H. O., Franklin W. A. Assessment of tumor cell kinetics by immunohistochemistry in carcinoma of breast. Cancer. 1987 May 15;59(10):1744–1750. doi: 10.1002/1097-0142(19870515)59:10<1744::aid-cncr2820591012>3.0.co;2-d. [DOI] [PubMed] [Google Scholar]
  49. Michitsch R. W., Montgomery K. T., Melera P. W. Expression of the amplified domain in human neuroblastoma cells. Mol Cell Biol. 1984 Nov;4(11):2370–2380. doi: 10.1128/mcb.4.11.2370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Prelich G., Tan C. K., Kostura M., Mathews M. B., So A. G., Downey K. M., Stillman B. Functional identity of proliferating cell nuclear antigen and a DNA polymerase-delta auxiliary protein. Nature. 1987 Apr 2;326(6112):517–520. doi: 10.1038/326517a0. [DOI] [PubMed] [Google Scholar]
  51. Prosperi E., Stivala L. A., Sala E., Scovassi A. I., Bianchi L. Proliferating cell nuclear antigen complex formation induced by ultraviolet irradiation in human quiescent fibroblasts as detected by immunostaining and flow cytometry. Exp Cell Res. 1993 Apr;205(2):320–325. doi: 10.1006/excr.1993.1092. [DOI] [PubMed] [Google Scholar]
  52. Quinn C. M., Wright N. A. The clinical assessment of proliferation and growth in human tumours: evaluation of methods and applications as prognostic variables. J Pathol. 1990 Feb;160(2):93–102. doi: 10.1002/path.1711600202. [DOI] [PubMed] [Google Scholar]
  53. Raschella G., Romeo A., Negroni A., Pucci S., Dominici C., Castello M. A., Bevilacqua P., Felsani A., Calabretta B. Lack of correlation between N-myc and MAX expression in neuroblastoma tumors and in cell lines: implication for N-myc-MAX complex formation. Cancer Res. 1994 Apr 15;54(8):2251–2255. [PubMed] [Google Scholar]
  54. Raschellà G., Negroni A., Giubilei C., Romeo A., Ferrari S., Castello M. A., Dominici C. Transcription of N-myc and proliferation-related genes is linked in human neuroblastoma. Cancer Lett. 1991 Jan;56(1):45–51. doi: 10.1016/0304-3835(91)90192-k. [DOI] [PubMed] [Google Scholar]
  55. Rudolph P., Lappe T., Schubert C., Schmidt D., Parwaresch R. M., Christophers E. Diagnostic assessment of two novel proliferation-specific antigens in benign and malignant melanocytic lesions. Am J Pathol. 1995 Dec;147(6):1615–1625. [PMC free article] [PubMed] [Google Scholar]
  56. Schlüter C., Duchrow M., Wohlenberg C., Becker M. H., Key G., Flad H. D., Gerdes J. The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins. J Cell Biol. 1993 Nov;123(3):513–522. doi: 10.1083/jcb.123.3.513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Schmidt D., Harms D., Carstensen S. Ganglioneuroblastom--Diagnose und Verlauf. Verh Dtsch Ges Pathol. 1988;72:292–295. [PubMed] [Google Scholar]
  58. Schröder R., Bien K., Kott R., Meyers I., Vössing R. The relationship between Ki-67 labeling and mitotic index in gliomas and meningiomas: demonstration of the variability of the intermitotic cycle time. Acta Neuropathol. 1991;82(5):389–394. doi: 10.1007/BF00296550. [DOI] [PubMed] [Google Scholar]
  59. Schwab M., Alitalo K., Klempnauer K. H., Varmus H. E., Bishop J. M., Gilbert F., Brodeur G., Goldstein M., Trent J. Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature. 1983 Sep 15;305(5931):245–248. doi: 10.1038/305245a0. [DOI] [PubMed] [Google Scholar]
  60. Schwab M. Amplification of N-myc as a prognostic marker for patients with neuroblastoma. Semin Cancer Biol. 1993 Feb;4(1):13–18. [PubMed] [Google Scholar]
  61. Schwab M. Human neuroblastoma: amplification of the N-myc oncogene and loss of a putative cancer-preventing gene on chromosome 1p. Recent Results Cancer Res. 1994;135:7–16. doi: 10.1007/978-3-642-85039-4_2. [DOI] [PubMed] [Google Scholar]
  62. Schwab M. Molecular cytogenetics of human neuroblastoma. Biochim Biophys Acta. 1992 Sep 14;1114(1):43–50. doi: 10.1016/0304-419x(92)90005-j. [DOI] [PubMed] [Google Scholar]
  63. Schwarting R. Little missed markers and Ki-67. Lab Invest. 1993 Jun;68(6):597–599. [PubMed] [Google Scholar]
  64. Shi S. R., Key M. E., Kalra K. L. Antigen retrieval in formalin-fixed, paraffin-embedded tissues: an enhancement method for immunohistochemical staining based on microwave oven heating of tissue sections. J Histochem Cytochem. 1991 Jun;39(6):741–748. doi: 10.1177/39.6.1709656. [DOI] [PubMed] [Google Scholar]
  65. Shimada H., Aoyama C., Chiba T., Newton W. A., Jr Prognostic subgroups for undifferentiated neuroblastoma: immunohistochemical study with anti-S-100 protein antibody. Hum Pathol. 1985 May;16(5):471–476. doi: 10.1016/s0046-8177(85)80085-x. [DOI] [PubMed] [Google Scholar]
  66. Shimada H., Chatten J., Newton W. A., Jr, Sachs N., Hamoudi A. B., Chiba T., Marsden H. B., Misugi K. Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst. 1984 Aug;73(2):405–416. doi: 10.1093/jnci/73.2.405. [DOI] [PubMed] [Google Scholar]
  67. Shimotake T., Iwai N., Tokiwa K., Deguchi E., Sawada T., Fushiki S. Increased numbers of argyrophilic nucleolar organizer regions between primary and metastatic sites predict tumor progression in stage IV and IV-S neuroblastoma. Cancer. 1994 Jun 15;73(12):3103–3107. doi: 10.1002/1097-0142(19940615)73:12<3103::aid-cncr2820731232>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  68. Taylor S. R., Locker J. A comparative analysis of nuclear DNA content and N-myc gene amplification in neuroblastoma. Cancer. 1990 Mar 15;65(6):1360–1366. doi: 10.1002/1097-0142(19900315)65:6<1360::aid-cncr2820650619>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  69. Van Roy N., Cheng N. C., Laureys G., Opdenakker G., Versteeg R., Speleman F. Molecular cytogenetic analysis of 1;17 translocations in neuroblastoma. Eur J Cancer. 1995;31A(4):530–535. doi: 10.1016/0959-8049(95)00004-3. [DOI] [PubMed] [Google Scholar]
  70. Versteeg R., Caron H., Cheng N. C., van der Drift P., Slater R., Westerveld A., Voûte P. A., Delattre O., Laureys G., Van Roy N. 1p36: every subband a suppressor? Eur J Cancer. 1995;31A(4):538–541. doi: 10.1016/0959-8049(95)00037-j. [DOI] [PubMed] [Google Scholar]
  71. Vogan K., Bernstein M., Leclerc J. M., Brisson L., Brossard J., Brodeur G. M., Pelletier J., Gros P. Absence of p53 gene mutations in primary neuroblastomas. Cancer Res. 1993 Nov 1;53(21):5269–5273. [PubMed] [Google Scholar]
  72. Waseem N. H., Lane D. P. Monoclonal antibody analysis of the proliferating cell nuclear antigen (PCNA). Structural conservation and the detection of a nucleolar form. J Cell Sci. 1990 May;96(Pt 1):121–129. doi: 10.1242/jcs.96.1.121. [DOI] [PubMed] [Google Scholar]
  73. Wenzel A., Schwab M. The mycN/max protein complex in neuroblastoma. Short review. Eur J Cancer. 1995;31A(4):516–519. doi: 10.1016/0959-8049(95)00060-v. [DOI] [PubMed] [Google Scholar]
  74. Wintzer H. O., Zipfel I., Schulte-Mönting J., Hellerich U., von Kleist S. Ki-67 immunostaining in human breast tumors and its relationship to prognosis. Cancer. 1991 Jan 15;67(2):421–428. doi: 10.1002/1097-0142(19910115)67:2<421::aid-cncr2820670217>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  75. Wirnsberger G. H., Becker H., Ziervogel K., Höfler H. Diagnostic immunohistochemistry of neuroblastic tumors. Am J Surg Pathol. 1992 Jan;16(1):49–57. [PubMed] [Google Scholar]
  76. Yu C. C., Filipe M. I. Update on proliferation-associated antibodies applicable to formalin-fixed paraffin-embedded tissue and their clinical applications. Histochem J. 1993 Dec;25(12):843–853. [PubMed] [Google Scholar]
  77. van Diest P. J., Baak J. P., Matze-Cok P., Wisse-Brekelmans E. C., van Galen C. M., Kurver P. H., Bellot S. M., Fijnheer J., van Gorp L. H., Kwee W. S. Reproducibility of mitosis counting in 2,469 breast cancer specimens: results from the Multicenter Morphometric Mammary Carcinoma Project. Hum Pathol. 1992 Jun;23(6):603–607. doi: 10.1016/0046-8177(92)90313-r. [DOI] [PubMed] [Google Scholar]

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