Abstract
Aim—To investigate the prognostic value of argyrophylic nucleolar organiser regions (AgNORs) in multiple myeloma.
Methods—Bone marrow aspirates from 55 newly diagnosed patients with multiple myeloma were stained with the one step AgNO3 technique. The mean number of AgNORs in each plasma cell nucleus (AgNOR count) was tested for a possible correlation with other clinical and laboratory variables at presentation (clinical stage, substage, heavy and light chain isotype, haemoglobin concentration, platelet count, marrow infiltration rate, degree of skeletal lesions, M protein concentration, plasma cell morphology, and serum concentrations of calcium, albumin, lactate dehydrogenase, C reactive protein, and ß2 microglobulin) and with outcome (response to first line treatment, first remission duration, and overall survival).
Results—A significant association between mean (SD) AgNOR count was found only for clinical stage (stage I, 3.09 (1.19); stage II, 3.80 (1.53); stage III, 5.28 (1.79); p < 0.005) and, from all stage determinants, only for M protein concentration (high, 5.92 (1.80); low, 4.01 (1.92); p < 0.001). There was a linear relation between AgNOR count and serum M protein concentration for patients with both IgG (r = 0.450; p < 0.01) and IgA (r = 0.768; p < 0.002) producing multiple myeloma.
Conclusions—Unlike previous investigations, no clear prognostic value for the AgNOR count was found in multiple myeloma. Instead, the results indicate that the AgNOR count might be an index for M protein synthesis rate. This is consistent with other findings in tissues with low proliferative potential and high protein synthetic activity, and calls for a cautious interpretation of AgNORs in malignancies with similar features.
Key Words: argyrophilic nucleolar organiser regions, multiple myeloma • M protein synthesis • prognosis
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Figure 1 AgNO3 stained bone marrow smear from a patient in our study (magnification, x1000). Argyrophilic nucleolar organiser regions (AgNORs) are visible as dark dots within the plasma cell nuclei.
Figure 2 Correlation between serum M protein concentration and argyrophilic nucleolar organiser region (AgNOR) count (dot diagram and best fitting line). (A) Patients with IgG producing multiple myeloma; (B) patients with IgA producing multiple myeloma.
Figure 3 Kaplan-Meier curves for the survival of patients, grouped according to argyrophilic nucleolar organiser region (AgNOR) count. Solid line, AgNOR > 4.4; dotted line, AgNOR ≤ 4.4. Circles represent censored observations.
Selected References
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- Bartl R., Frisch B., Fateh-Moghadam A., Kettner G., Jaeger K., Sommerfeld W. Histologic classification and staging of multiple myeloma. A retrospective and prospective study of 674 cases. Am J Clin Pathol. 1987 Mar;87(3):342–355. doi: 10.1093/ajcp/87.3.342. [DOI] [PubMed] [Google Scholar]
- Bryan R. L., Janmohamed R., Crocker J., Leyland M. J. Nucleolar organiser regions in myeloma and benign paraproteinaemia. Br J Cancer. 1990 Apr;61(4):645–645. doi: 10.1038/bjc.1990.144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Crocker J., Boldy D. A., Egan M. J. How should we count AgNORS? Proposals for a standardized approach. J Pathol. 1989 Jul;158(3):185–188. doi: 10.1002/path.1711580303. [DOI] [PubMed] [Google Scholar]
- 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]
- Derenzini M., Trerè D. Importance of interphase nucleolar organizer regions in tumor pathology. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;61(1):1–8. doi: 10.1007/BF02890399. [DOI] [PubMed] [Google Scholar]
- Durie B. G., Salmon S. E. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975 Sep;36(3):842–854. doi: 10.1002/1097-0142(197509)36:3<842::aid-cncr2820360303>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
- Egan M. J., Crocker J. Nucleolar organiser regions in pathology. Br J Cancer. 1992 Jan;65(1):1–7. doi: 10.1038/bjc.1992.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fakan S., Hernandez-Verdun D. The nucleolus and the nucleolar organizer regions. Biol Cell. 1986;56(3):189–205. doi: 10.1111/j.1768-322x.1986.tb00452.x. [DOI] [PubMed] [Google Scholar]
- Gall J. G., Pardue M. L. Formation and detection of RNA-DNA hybrid molecules in cytological preparations. Proc Natl Acad Sci U S A. 1969 Jun;63(2):378–383. doi: 10.1073/pnas.63.2.378. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Greipp P. R., Kyle R. A. Clinical, morphological, and cell kinetic differences among multiple myeloma, monoclonal gammopathy of undetermined significance, and smoldering multiple myeloma. Blood. 1983 Jul;62(1):166–171. [PubMed] [Google Scholar]
- Greipp P. R., Lust J. A., O'Fallon W. M., Katzmann J. A., Witzig T. E., Kyle R. A. Plasma cell labeling index and beta 2-microglobulin predict survival independent of thymidine kinase and C-reactive protein in multiple myeloma. Blood. 1993 Jun 15;81(12):3382–3387. [PubMed] [Google Scholar]
- Jozsa L., Kannus P., Järvinen M., Isola J., Kvist M., Lehto M. Atrophy and regeneration of rat calf muscles cause reversible changes in the number of nucleolar organizer regions. Evidence that also in nonproliferating cells the number of NORs is a marker of protein synthesis activity. Lab Invest. 1993 Aug;69(2):231–237. [PubMed] [Google Scholar]
- Korkolopoulou P., Angelopoulou M. K., Kontopidou F., Tsengas A., Patsouris E., Kittas C., Pangalis G. A. Prognostic implications of proliferating cell nuclear antigen (PCNA), AgNORs and P53 in non-Hodgkin's lymphomas. Leuk Lymphoma. 1998 Aug;30(5-6):625–636. doi: 10.3109/10428199809057575. [DOI] [PubMed] [Google Scholar]
- Kyle R. A. Why better prognostic factors for multiple myeloma are needed. Blood. 1994 Apr 1;83(7):1713–1716. [PubMed] [Google Scholar]
- Lorand-Metze I., Carvalho M. A., Metze K. Relationship between morphometric analysis of nucleolar organizer regions and cell proliferation in acute leukemias. Cytometry. 1998 May 1;32(1):51–56. doi: 10.1002/(sici)1097-0320(19980501)32:1<51::aid-cyto7>3.0.co;2-i. [DOI] [PubMed] [Google Scholar]
- Mamaev N. N., Medvedeva N. V., Shust V. F., Markochev A. B., Pasternak N. D. Nucleoli and AgNORs in Hodgkin's disease. Mol Pathol. 1997 Jun;50(3):149–152. doi: 10.1136/mp.50.3.149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marmont F., Pich A., Chiusa L., Locatelli F., Falda M., Boccadoro M., Resegotti L. Correlation between argyrophilic nucleolar organizer region counts and labelling index in multiple myeloma. Eur J Haematol. 1996 Jan-Feb;56(1-2):39–44. doi: 10.1111/j.1600-0609.1996.tb00291.x. [DOI] [PubMed] [Google Scholar]
- Morstyn G., Schechter G. P., Ihde D. C., Carney D. N., Eddy J. L., Cohen M. H., Minna J. D., Bunn P. A., Jr Therapy for multiple myeloma with alternating non-cross-resistant chemotherapy combinations: heterogeneity of tumor responsiveness. Cancer Treat Rep. 1984 Dec;68(12):1439–1446. [PubMed] [Google Scholar]
- Pich A., Chiusa L., Audisio E., Marmont F. Nucleolar organizer region counts predict complete remission, remission duration, and survival in adult acute myelogenous leukemia patients. J Clin Oncol. 1998 Apr;16(4):1512–1518. doi: 10.1200/JCO.1998.16.4.1512. [DOI] [PubMed] [Google Scholar]
- Pich A., Chiusa L., Marmont F., Navone R. Risk groups of myeloma patients by histologic pattern and proliferative activity. Am J Surg Pathol. 1997 Mar;21(3):339–347. doi: 10.1097/00000478-199703000-00011. [DOI] [PubMed] [Google Scholar]
- Pich A., Marmont F., Chiusa L., Cappello N., Resegotti L., Navone R. Argyrophilic nucleolar organizer region counts and prognosis in multiple myeloma. Br J Haematol. 1992 Dec;82(4):681–688. doi: 10.1111/j.1365-2141.1992.tb06944.x. [DOI] [PubMed] [Google Scholar]
- 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]
- Pollok A. Nucleolar organizer regions in exocrine pancreas in chronic pancreatitis and ductal adenocarcinoma. Diagnostic value and cytophysiologic correlate. Gen Diagn Pathol. 1997 Feb;142(3-4):199–209. [PubMed] [Google Scholar]
- Salmon S. E. Immunoglobulin synthesis and tumor kinetics of multiple myeloma. Semin Hematol. 1973 Apr;10(2):135–144. [PubMed] [Google Scholar]
- Skopelitou A., Tselenis S., Theocharis S., Agnantis N., Tsenga A., Elemenoglou J., Hadjiyannakis M., Kittas C. Expression of proliferating cell nuclear antigen (PCNA) and nucleolar organizer regions (NORs) in multiple myeloma. Anticancer Res. 1994 May-Jun;14(3A):787–792. [PubMed] [Google Scholar]
- Spiegelberg H. L. Biological activities of immunoglobulins of different classes and subclasses. Adv Immunol. 1974;19(0):259–294. doi: 10.1016/s0065-2776(08)60254-0. [DOI] [PubMed] [Google Scholar]
- Underwood J. C., Giri D. D. Nucleolar organizer regions as diagnostic discriminants for malignancy. J Pathol. 1988 Jun;155(2):95–96. doi: 10.1002/path.1711550203. [DOI] [PubMed] [Google Scholar]
- van Diest P. J., Brugal G., Baak J. P. Proliferation markers in tumours: interpretation and clinical value. J Clin Pathol. 1998 Oct;51(10):716–724. doi: 10.1136/jcp.51.10.716. [DOI] [PMC free article] [PubMed] [Google Scholar]