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. 1989 Sep;77(3):299–308.

Proliferation indices in malignant lymphomas.

J Crocker 1
PMCID: PMC1542062  PMID: 2680181

Abstract

In view of the importance of adjusting therapy to prognostic groups in malignant lymphomas, there have been numerous attempts over the past two decades to assess proliferation rates in these neoplasms. The techniques employed include radiolabelled thymidine uptake, DNA flow cytometry, the application of antibodies to proliferation-associated antigens and the enumeration of nucleolar organizer regions. The evolution of these methods is reviewed and their usefulness is evaluated.

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Selected References

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  1. Akerman M., Brandt L., Johnson A., Olsson H. Mitotic activity in non-Hodgkin's lymphoma. Relation to the Kiel classification and to prognosis. Br J Cancer. 1987 Feb;55(2):219–223. doi: 10.1038/bjc.1987.41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anastasi J., Bauer K. D., Variakojis D. DNA aneuploidy in Hodgkin's disease. A multiparameter flow-cytometric analysis with cytologic correlation. Am J Pathol. 1987 Sep;128(3):573–582. [PMC free article] [PubMed] [Google Scholar]
  3. Bauer K. D., Merkel D. E., Winter J. N., Marder R. J., Hauck W. W., Wallemark C. B., Williams T. J., Variakojis D. Prognostic implications of ploidy and proliferative activity in diffuse large cell lymphomas. Cancer Res. 1986 Jun;46(6):3173–3178. [PubMed] [Google Scholar]
  4. Boldy D. A., Crocker J., Ayres J. G. Application of the AgNOR method to cell imprints of lymphoid tissue. J Pathol. 1989 Jan;157(1):75–79. doi: 10.1002/path.1711570110. [DOI] [PubMed] [Google Scholar]
  5. Braylan R. C., Benson N. A., Nourse V., Kruth H. S. Correlated analysis of cellular DNA, membrane antigens and light scatter of human lymphoid cells. Cytometry. 1982 Mar;2(5):337–343. doi: 10.1002/cyto.990020511. [DOI] [PubMed] [Google Scholar]
  6. Braylan R. C., Diamond L. W., Powell M. L., Harty-Golder B. Percentage of cells in the S phase of the cell cycle in human lymphoma determined by flow cytometry. Cytometry. 1980 Nov;1(3):171–174. doi: 10.1002/cyto.990010302. [DOI] [PubMed] [Google Scholar]
  7. Braylan R. C., Fowlkes B. J., Jaffe E. S., Sanders S. K., Berard C. W., Herman C. J. Cell volumes and DNA distributions of normal and neoplastic human lymphoid cells. Cancer. 1978 Jan;41(1):201–209. doi: 10.1002/1097-0142(197801)41:1<201::aid-cncr2820410129>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  8. Buys C. H., Osinga J. Abundance of protein-bound sulfhydryl and disulfide groups at chromosomal nucleolus organizing regions: a cytochemical study on the selective silver staining of NORs. Chromosoma. 1980;77(1):1–11. doi: 10.1007/BF00292037. [DOI] [PubMed] [Google Scholar]
  9. Camplejohn R. S., Macartney J. C. Comparison of DNA flow cytometry from fresh and paraffin embedded samples of non-Hodgkin's lymphoma. J Clin Pathol. 1985 Oct;38(10):1096–1099. doi: 10.1136/jcp.38.10.1096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Celis J. E., Bravo R., Larsen P. M., Fey S. J. Cyclin: a nuclear protein whose level correlates directly with the proliferative state of normal as well as transformed cells. Leuk Res. 1984;8(2):143–157. doi: 10.1016/0145-2126(84)90135-8. [DOI] [PubMed] [Google Scholar]
  11. Chatterjee A., Freeman J. W., Busch H. Identification and partial characterization of a Mr 40,000 nucleolar antigen associated with cell proliferation. Cancer Res. 1987 Feb 15;47(4):1123–1129. [PubMed] [Google Scholar]
  12. Clevenger C. V., Bauer K. D., Epstein A. L. A method for simultaneous nuclear immunofluorescence and DNA content quantitation using monoclonal antibodies and flow cytometry. Cytometry. 1985 May;6(3):208–214. doi: 10.1002/cyto.990060306. [DOI] [PubMed] [Google Scholar]
  13. Costa A., Mazzini G., Del Bino G., Silvestrini R. DNA content and kinetic characteristics of non-Hodgkin's lymphoma: determined by flow cytometry and autoradiography. Cytometry. 1981 Nov;2(3):185–188. doi: 10.1002/cyto.990020310. [DOI] [PubMed] [Google Scholar]
  14. Crocker J., Burnett D. Granulocyte markers in histopathology: a review. J Pathol. 1986 Oct;150(2):77–88. doi: 10.1002/path.1711500202. [DOI] [PubMed] [Google Scholar]
  15. Crocker J., Egan M. J. Correlation between NOR sizes and numbers in non-Hodgkin's lymphomas. J Pathol. 1988 Nov;156(3):233–239. doi: 10.1002/path.1711560308. [DOI] [PubMed] [Google Scholar]
  16. Crocker J., Jenkins R. A quantitative study of histiocytic reticulum cells in diffuse and follicular non-Hodgkin's lymphomas. J Clin Pathol. 1984 Nov;37(11):1222–1226. doi: 10.1136/jcp.37.11.1222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Crocker J., Jones E. L., Curran R. C. A quantitative study of alpha-naphthyl acetate esterase-positive cells in Hodgkin's disease. J Clin Pathol. 1982 Dec;35(12):1301–1306. doi: 10.1136/jcp.35.12.1301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Crocker J., Macartney J. C., Smith P. J. Correlation between DNA flow cytometric and nucleolar organizer region data in non-Hodgkin's lymphomas. J Pathol. 1988 Feb;154(2):151–156. doi: 10.1002/path.1711540207. [DOI] [PubMed] [Google Scholar]
  19. Crocker J. Morphometric and related quantitative techniques in the study of lymphoid neoplasms. A review. J Pathol. 1984 Jun;143(2):69–80. doi: 10.1002/path.1711430202. [DOI] [PubMed] [Google Scholar]
  20. Crocker J., Nar P. Nucleolar organizer regions in lymphomas. J Pathol. 1987 Feb;151(2):111–118. doi: 10.1002/path.1711510203. [DOI] [PubMed] [Google Scholar]
  21. Diamond L. W., Braylan R. C. Flow analysis of DNA content and cell size in non-Hodgkin's lymphoma. Cancer Res. 1980 Mar;40(3):703–712. [PubMed] [Google Scholar]
  22. Diamond L. W., Nathwani B. N., Rappaport H. Flow cytometry in the diagnosis and classification of malignant lymphoma and leukemia. Cancer. 1982 Sep 15;50(6):1122–1135. doi: 10.1002/1097-0142(19820915)50:6<1122::aid-cncr2820500616>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  23. Diamond L. W., Weisenburger D. D., Rappaport H. The relationship between lymphocyte nuclear morphology and cell cycle stage in lymphoid neoplasia. Am J Hematol. 1981 Sep;11(2):165–173. doi: 10.1002/ajh.2830110208. [DOI] [PubMed] [Google Scholar]
  24. Dolbeare F., Gratzner H., Pallavicini M. G., Gray J. W. Flow cytometric measurement of total DNA content and incorporated bromodeoxyuridine. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5573–5577. doi: 10.1073/pnas.80.18.5573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. FLIEDNER T., KESSE M., CRONKITE E. P., ROBERTSON J. S. CELL PROLIFERATION IN GERMINAL CENTERS OF THE RAT SPLEEN. Ann N Y Acad Sci. 1964 Feb 28;113:578–594. doi: 10.1111/j.1749-6632.1964.tb40692.x. [DOI] [PubMed] [Google Scholar]
  26. Gatter K. C., Brown G., Trowbridge I. S., Woolston R. E., Mason D. Y. Transferrin receptors in human tissues: their distribution and possible clinical relevance. J Clin Pathol. 1983 May;36(5):539–545. doi: 10.1136/jcp.36.5.539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Gerdes J., Dallenbach F., Lennert K., Lemke H., Stein H. Growth fractions in malignant non-Hodgkin's lymphomas (NHL) as determined in situ with the monoclonal antibody Ki-67. Hematol Oncol. 1984 Oct-Dec;2(4):365–371. doi: 10.1002/hon.2900020406. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Gerdes J., Van Baarlen J., Pileri S., Schwarting R., Van Unnik J. A., Stein H. Tumor cell growth fraction in Hodgkin's disease. Am J Pathol. 1987 Sep;128(3):390–393. [PMC free article] [PubMed] [Google Scholar]
  30. Goodpasture C., Bloom S. E. Visualization of nucleolar organizer regions im mammalian chromosomes using silver staining. Chromosoma. 1975 Nov 20;53(1):37–50. doi: 10.1007/BF00329389. [DOI] [PubMed] [Google Scholar]
  31. Gratzner H. G. Monoclonal antibody to 5-bromo- and 5-iododeoxyuridine: A new reagent for detection of DNA replication. Science. 1982 Oct 29;218(4571):474–475. doi: 10.1126/science.7123245. [DOI] [PubMed] [Google Scholar]
  32. HANNA M. G., Jr AN AUTORADIOGRAPHIC STUDY OF THE GERMINAL CENTER IN SPLEEN WHITE PULP DURING EARLY INTERVALS OF THE IMMUNE RESPONSE. Lab Invest. 1964 Feb;13:95–104. [PubMed] [Google Scholar]
  33. Habeshaw J. A., Lister T. A., Stansfeld A. G., Greaves M. F. Correlation of transferrin receptor expression with histological class and outcome in non-Hodgkin lymphoma. Lancet. 1983 Mar 5;1(8323):498–501. doi: 10.1016/s0140-6736(83)92191-8. [DOI] [PubMed] [Google Scholar]
  34. Hall P. A., Crocker J., Watts A., Stansfeld A. G. A comparison of nucleolar organizer region staining and Ki-67 immunostaining in non-Hodgkin's lymphoma. Histopathology. 1988 Apr;12(4):373–381. doi: 10.1111/j.1365-2559.1988.tb01952.x. [DOI] [PubMed] [Google Scholar]
  35. Hall P. A., Richards M. A., Gregory W. M., d'Ardenne A. J., Lister T. A., Stansfeld A. G. The prognostic value of Ki67 immunostaining in non-Hodgkin's lymphoma. J Pathol. 1988 Mar;154(3):223–235. doi: 10.1002/path.1711540305. [DOI] [PubMed] [Google Scholar]
  36. Hemmaplardh D., Morgan E. H. Transferrin and iron uptake by human cells in culture. Exp Cell Res. 1974 Jul;87(1):207–212. doi: 10.1016/0014-4827(74)90543-6. [DOI] [PubMed] [Google Scholar]
  37. Hernandez-Verdun D., Hubert J., Bourgeois C. A., Bouteille M. Ultrastructural localization of Ag-NOR stained proteins in the nucleolus during the cell cycle and in other nucleolar structures. Chromosoma. 1980;79(3):349–362. doi: 10.1007/BF00327325. [DOI] [PubMed] [Google Scholar]
  38. Howell W. M., Denton T. E., Diamond J. R. Differential staining of the satellite regions of human acrocentric chromosomes. Experientia. 1975 Feb 15;31(2):260–262. doi: 10.1007/BF01990741. [DOI] [PubMed] [Google Scholar]
  39. Hsu T. C., Spirito S. E., Pardue M. L. Distribution of 18+28S ribosomal genes in mammalian genomes. Chromosoma. 1975 Nov 20;53(1):25–36. doi: 10.1007/BF00329388. [DOI] [PubMed] [Google Scholar]
  40. Jan-Mohamed R. M., Armstrong S. J., Crocker J., Leyland M. J., Hulten M. A. The relationship between number of interphase nors and nor-bearing chromosomes in non-Hodgkin's lymphoma. J Pathol. 1989 May;158(1):3–7. doi: 10.1002/path.1711580103. [DOI] [PubMed] [Google Scholar]
  41. Joensuu H., Klemi P. J., Korkeila E. Prognostic value of DNA ploidy and proliferative activity in Hodgkin's disease. Am J Clin Pathol. 1988 Dec;90(6):670–673. doi: 10.1093/ajcp/90.6.670. [DOI] [PubMed] [Google Scholar]
  42. Jordan G. At the heart of the nucleolus. Nature. 1987 Oct 8;329(6139):489–490. doi: 10.1038/329489a0. [DOI] [PubMed] [Google Scholar]
  43. Kruth H. S., Braylan R. C., Benson N. A., Nourse V. A. Simultaneous analysis of DNA and cell surface immunoglobulin in human B-cell lymphomas by flow cytometry. Cancer Res. 1981 Dec;41(12 Pt 1):4895–4899. [PubMed] [Google Scholar]
  44. Kvaløy S., Godal T., Marton P. F., Steen H., Brenhovd I. O., Abrahamsen A. F. Spontaneous (H)-thymidine uptake in histological subgroups of human B-cell lymphomas. Scand J Haematol. 1981 Mar;26(3):221–234. doi: 10.1111/j.1600-0609.1981.tb01650.x. [DOI] [PubMed] [Google Scholar]
  45. Kvaløy S., Marton P. F., Kaalhus O., Høie J., Foss-Abrahamsen A., Godal T. 3H-thymidine uptake in B cell lymphomas--relationship to treatment response and survival. Scand J Haematol. 1985 May;34(5):429–435. doi: 10.1111/j.1600-0609.1985.tb00773.x. [DOI] [PubMed] [Google Scholar]
  46. Lloyd R. V., Wilson B. S., Varani J., Gaur P. K., Moline S., Makari J. G. Immunocytochemical characterization of a monoclonal antibody that recognizes mitosing cells. Am J Pathol. 1985 Nov;121(2):275–283. [PMC free article] [PubMed] [Google Scholar]
  47. Macartney J. C., Camplejohn R. S., Alder J., Stone M. G., Powell G. Prognostic importance of DNA flow cytometry in non-Hodgkin's lymphomas. J Clin Pathol. 1986 May;39(5):542–546. doi: 10.1136/jcp.39.5.542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Macartney J. C. Proliferative activity in lymphomas. J Pathol. 1988 Sep;156(1):7–8. doi: 10.1002/path.1711560104. [DOI] [PubMed] [Google Scholar]
  49. Mathews M. B., Bernstein R. M., Franza B. R., Jr, Garrels J. I. Identity of the proliferating cell nuclear antigen and cyclin. Nature. 1984 May 24;309(5966):374–376. doi: 10.1038/309374a0. [DOI] [PubMed] [Google Scholar]
  50. Miyachi K., Fritzler M. J., Tan E. M. Autoantibody to a nuclear antigen in proliferating cells. J Immunol. 1978 Dec;121(6):2228–2234. [PubMed] [Google Scholar]
  51. Peckham M. J., Cooper E. H. Proliferation characteristics of the various classes of cells in Hodgkin's disease. Cancer. 1969 Jul;24(1):135–146. doi: 10.1002/1097-0142(196907)24:1<135::aid-cncr2820240118>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
  52. Peckham M. J., Cooper E. H. The pattern of cell growth in reticulum cell sarcoma and lymphosarcoma. Eur J Cancer. 1970 Oct;6(5):453–463. doi: 10.1016/0014-2964(70)90045-9. [DOI] [PubMed] [Google Scholar]
  53. Persson H., Hennighausen L., Taub R., DeGrado W., Leder P. Antibodies to human c-myc oncogene product: evidence of an evolutionarily conserved protein induced during cell proliferation. Science. 1984 Aug 17;225(4663):687–693. doi: 10.1126/science.6431612. [DOI] [PubMed] [Google Scholar]
  54. Ploton D., Menager M., Jeannesson P., Himber G., Pigeon F., Adnet J. J. Improvement in the staining and in the visualization of the argyrophilic proteins of the nucleolar organizer region at the optical level. Histochem J. 1986 Jan;18(1):5–14. doi: 10.1007/BF01676192. [DOI] [PubMed] [Google Scholar]
  55. Reeves B. R., Casey G., Honeycombe J. R., Smith S. Correlation of differentiation state and silver staining of nucleolar organizers in the promyelocytic leukemia cell line HL-60. Cancer Genet Cytogenet. 1984 Oct;13(2):159–166. doi: 10.1016/0165-4608(84)90057-8. [DOI] [PubMed] [Google Scholar]
  56. Robbins B. A., de la Vega D., Ogata K., Tan E. M., Nakamura R. M. Immunohistochemical detection of proliferating cell nuclear antigen in solid human malignancies. Arch Pathol Lab Med. 1987 Sep;111(9):841–845. [PubMed] [Google Scholar]
  57. Sasaki K., Matsumura K., Tsuji T., Shinozaki F., Takahashi M. Relationship between labeling indices of Ki-67 and BrdUrd in human malignant tumors. Cancer. 1988 Sep 1;62(5):989–993. doi: 10.1002/1097-0142(19880901)62:5<989::aid-cncr2820620525>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  58. Sasaki K., Ogino T., Takahashi M. Immunological determination of labeling index on human tumor tissue sections using monoclonal anti-BrdUrd antibody. Stain Technol. 1986 May;61(3):155–161. doi: 10.3109/10520298609110726. [DOI] [PubMed] [Google Scholar]
  59. Scarffe J. H., Crowther D. The pre-treatment proliferative activity of non-Hodgkin's lymphoma cells. Eur J Cancer. 1981 Jan;17(1):99–108. doi: 10.1016/0014-2964(81)90218-8. [DOI] [PubMed] [Google Scholar]
  60. Schrape S., Jones D. B., Wright D. H. A comparison of three methods for the determination of the growth fraction in non-Hodgkin's lymphoma. Br J Cancer. 1987 Mar;55(3):283–286. doi: 10.1038/bjc.1987.54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Shackney S. E., Levine A. M., Fisher R. I., Nichols P., Jaffe E., Schuette W. H., Simon R., Smith C. A., Occhipinti S. J., Parker J. W. The biology of tumor growth in the non-Hodgkin's lymphomas. A dual parameter flow cytometry study of 220 cases. J Clin Invest. 1984 Apr;73(4):1201–1214. doi: 10.1172/JCI111306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Simchen G., Winston F., Styles C. A., Fink G. R. Ty-mediated gene expression of the LYS2 and HIS4 genes of Saccharomyces cerevisiae is controlled by the same SPT genes. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2431–2434. doi: 10.1073/pnas.81.8.2431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Smetana K., Gyorkey F., Chan P. K., Tan E., Busch H. Proliferating cell nuclear antigen (PCNA) and human malignant tumor nucleolar antigens (HMTNA) in nucleoli of human hematological malignancies. Blut. 1983 Mar;46(3):133–141. doi: 10.1007/BF00320271. [DOI] [PubMed] [Google Scholar]
  64. Srigley J., Barlogie B., Butler J. J., Osborne B., Blick M., Johnston D., Kantarjian H., Reuben J., Batsakis J., Freireich E. J. Heterogeneity of non-Hodgkin's lymphoma probed by nucleic acid cytometry. Blood. 1985 May;65(5):1090–1096. [PubMed] [Google Scholar]
  65. Takasaki Y., Deng J. S., Tan E. M. A nuclear antigen associated with cell proliferation and blast transformation. J Exp Med. 1981 Dec 1;154(6):1899–1909. doi: 10.1084/jem.154.6.1899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Thornton J. G., Wells M., Hume W. J. Measurement of the S-phase duration in normal and abnormal human endometrium by in vitro double labelling with bromodeoxyuridine and tritiated thymidine. J Pathol. 1989 Feb;157(2):109–115. doi: 10.1002/path.1711570205. [DOI] [PubMed] [Google Scholar]
  67. Trowbridge I. S., Omary M. B. Human cell surface glycoprotein related to cell proliferation is the receptor for transferrin. Proc Natl Acad Sci U S A. 1981 May;78(5):3039–3043. doi: 10.1073/pnas.78.5.3039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Walker R. A., Day S. J. Transferrin receptor expression in non-malignant and malignant human breast tissue. J Pathol. 1986 Mar;148(3):217–224. doi: 10.1002/path.1711480305. [DOI] [PubMed] [Google Scholar]
  69. Young G. A., Hedley D. W., Rugg C. A., Iland H. J. The prognostic significance of proliferative activity in poor histology non-Hodgkin's lymphoma: a flow cytometry study using archival material. Eur J Cancer Clin Oncol. 1987 Oct;23(10):1497–1504. doi: 10.1016/0277-5379(87)90092-7. [DOI] [PubMed] [Google Scholar]
  70. de Capoa A., Baldini A., Marlekaj P., Natoli C., Rocchi M., Archidiacono N., Cianfarani S., Spadoni G. L., Boscherini B. Hormone-modulated rRNA gene activity is visualized by selective staining of the NOs. Cell Biol Int Rep. 1985 Sep;9(9):791–796. doi: 10.1016/0309-1651(85)90097-9. [DOI] [PubMed] [Google Scholar]

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