Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Dec;81(7):1213–1221. doi: 10.1038/sj.bjc.6690831

Immunocytochemical assessment of bone marrow aspirates for monitoring response to chemotherapy in small-cell lung cancer patients

G Pelosi 1, F Pasini 2, C Ottensmeier 4, F Pavanel 2, E Bresaola 3, A Bonetti 2, F Fraggetta 1, A Terzi 6, A Iannucci 5, G L Cetto 2
PMCID: PMC2374331  PMID: 10584884

Abstract

Recent reports have suggested that tumour cell immunodetection in bone marrow of small-cell lung cancer patients is by far more frequent than found cytohistologically and may have clinical relevance. This study evaluates primarily the efficacy of chemotherapy as method of in vivo purging, but also the relationship of marrow involvement with survival. A total of 112 bone marrow aspirates from 30 chemo-naïve patients were stained twice using anti-NCAM antibodies, first at diagnosis and then after chemotherapy (24 patients) or at disease progression (six patients). Marrow contamination was associated with lower survival (P = 0.002), and was also detected in 7/17 patients conventionally staged as having limited disease. At multivariate analysis, marrow involvement was an independent factor of unfavourable prognosis (P = 0.033). The amount of tumour contamination, before and after chemotherapy, remained unchanged also in responders and even in the subset of patients with apparent limited disease. Following chemotherapy, bone marrow became tumour negative only in 25% of initially positive responders and in none of non-responders. Our results indicate that (i) chemotherapy is not effective in purging bone marrow even in chemo-responsive patients and (ii) a subset of patients with limited disease and negative bone marrow aspirates might have a more favourable prognosis. © 1999 Cancer Research Campaign

Keywords: bone marrow, immunocytochemistry, micrometastases, SCLC, chemotherapy, prognosis

Full Text

The Full Text of this article is available as a PDF (222.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abrams J., Doyle L. A., Aisner J. Staging, prognostic factors, and special considerations in small cell lung cancer. Semin Oncol. 1988 Jun;15(3):261–277. [PubMed] [Google Scholar]
  2. Acheson A., Sunshine J. L., Rutishauser U. NCAM polysialic acid can regulate both cell-cell and cell-substrate interactions. J Cell Biol. 1991 Jul;114(1):143–153. doi: 10.1083/jcb.114.1.143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beiske K., Myklebust A. T., Aamdal S., Langholm R., Jakobsen E., Fodstad O. Detection of bone marrow metastases in small cell lung cancer patients. Comparison of immunologic and morphologic methods. Am J Pathol. 1992 Sep;141(3):531–538. [PMC free article] [PubMed] [Google Scholar]
  4. Berendsen H. H., de Leij L., Postmus P. E., Ter Haar J. G., Poppema S., The T. H. Detection of small cell lung cancer metastases in bone marrow aspirates using monoclonal antibody directed against neuroendocrine differentiation antigen. J Clin Pathol. 1988 Mar;41(3):273–276. doi: 10.1136/jcp.41.3.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brugger W., Bross K. J., Glatt M., Weber F., Mertelsmann R., Kanz L. Mobilization of tumor cells and hematopoietic progenitor cells into peripheral blood of patients with solid tumors. Blood. 1994 Feb 1;83(3):636–640. [PubMed] [Google Scholar]
  6. Carbone D. P., Koros A. M., Linnoila R. I., Jewett P., Gazdar A. F. Neural cell adhesion molecule expression and messenger RNA splicing patterns in lung cancer cell lines are correlated with neuroendocrine phenotype and growth morphology. Cancer Res. 1991 Nov 15;51(22):6142–6149. [PubMed] [Google Scholar]
  7. Cunningham B. A., Hemperly J. J., Murray B. A., Prediger E. A., Brackenbury R., Edelman G. M. Neural cell adhesion molecule: structure, immunoglobulin-like domains, cell surface modulation, and alternative RNA splicing. Science. 1987 May 15;236(4803):799–806. doi: 10.1126/science.3576199. [DOI] [PubMed] [Google Scholar]
  8. Dalseg A. M., Linnemann D., Bock E. Soluble neural cell adhesion molecule in brain, cerebrospinal fluid and plasma in the developing rat. Int J Dev Neurosci. 1989;7(2):209–217. doi: 10.1016/0736-5748(89)90071-3. [DOI] [PubMed] [Google Scholar]
  9. Davidoff M. S., Schulze W., Holstein A. F. Combination of alkaline phosphatase anti-alkaline phosphatase (APAAP)- and avidin-biotin-alkaline phosphatase complex (ABAP)-techniques for amplification of immunocytochemical staining of human testicular tissue. Andrologia. 1991 Sep-Oct;23(5):353–356. doi: 10.1111/j.1439-0272.1991.tb02579.x. [DOI] [PubMed] [Google Scholar]
  10. Doyle L. A., Borges M., Hussain A., Elias A., Tomiyasu T. An adherent subline of a unique small-cell lung cancer cell line downregulates antigens of the neural cell adhesion molecule. J Clin Invest. 1990 Dec;86(6):1848–1854. doi: 10.1172/JCI114915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Elias A. D. Small cell lung cancer: state-of-the-art therapy in 1996. Chest. 1997 Oct;112(4 Suppl):251S–258S. doi: 10.1378/chest.112.4_supplement.251s. [DOI] [PubMed] [Google Scholar]
  12. Everard M. J., Macaulay V. M., Min T., Millar J. L., Smith I. E. Small cell lung cancer cell line from histologically and immunocytochemically negative bone marrow. Eur J Cancer. 1990;26(6):766–767. doi: 10.1016/0277-5379(90)90141-f. [DOI] [PubMed] [Google Scholar]
  13. Frew A. J., Ralfkiaer N., Ghosh A. K., Gatter K. C., Mason D. Y. Immunocytochemistry in the detection of bone marrow metastases in patients with primary lung cancer. Br J Cancer. 1986 Apr;53(4):555–556. doi: 10.1038/bjc.1986.86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hay F. G., Ford A., Leonard R. C. Clinical applications of immunocytochemistry in the monitoring of the bone marrow in small cell lung cancer (SCLC). Int J Cancer Suppl. 1988;2:8–10. doi: 10.1002/ijc.2910410704. [DOI] [PubMed] [Google Scholar]
  15. Hirano T., Hirohashi S., Kunii T., Noguchi M., Shimosato Y., Hayata Y. Quantitative distribution of cluster 1 small cell lung cancer antigen in cancerous and non-cancerous tissues, cultured cells and sera. Jpn J Cancer Res. 1989 Apr;80(4):348–355. doi: 10.1111/j.1349-7006.1989.tb02318.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hirsch F. R., Hansen H. H. Bone marrow involvement in small cell anaplastic carcinoma of the lung: prognostic and therapeutic aspects. Cancer. 1980 Jul 1;46(1):206–211. doi: 10.1002/1097-0142(19800701)46:1<206::aid-cncr2820460134>3.0.co;2-a. [DOI] [PubMed] [Google Scholar]
  17. Hunter R. F., Broadway P., Sun S. L., Niell H. B., Mauer A. M. Detection of small cell lung cancer bone marrow involvement by discontinuous gradient sedimentation. Cancer Res. 1987 May 15;47(10):2737–2740. [PubMed] [Google Scholar]
  18. Keilhauer G., Faissner A., Schachner M. Differential inhibition of neurone-neurone, neurone-astrocyte and astrocyte-astrocyte adhesion by L1, L2 and N-CAM antibodies. Nature. 1985 Aug 22;316(6030):728–730. doi: 10.1038/316728a0. [DOI] [PubMed] [Google Scholar]
  19. Kelly B. W., Morris J. F., Harwood B. P., Bruya T. E. Methods and prognostic value of bone marrow examination in small cell carcinoma of the lung. Cancer. 1984 Jan 1;53(1):99–102. doi: 10.1002/1097-0142(19840101)53:1<99::aid-cncr2820530118>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  20. Kern W. F., Spier C. M., Hanneman E. H., Miller T. P., Matzner M., Grogan T. M. Neural cell adhesion molecule-positive peripheral T-cell lymphoma: a rare variant with a propensity for unusual sites of involvement. Blood. 1992 May 1;79(9):2432–2437. [PubMed] [Google Scholar]
  21. Komminoth P., Roth J., Lackie P. M., Bitter-Suermann D., Heitz P. U. Polysialic acid of the neural cell adhesion molecule distinguishes small cell lung carcinoma from carcinoids. Am J Pathol. 1991 Aug;139(2):297–304. [PMC free article] [PubMed] [Google Scholar]
  22. Lanier L. L., Spits H., Phillips J. H. The developmental relationship between NK cells and T cells. Immunol Today. 1992 Oct;13(10):392–395. doi: 10.1016/0167-5699(92)90087-N. [DOI] [PubMed] [Google Scholar]
  23. Ledermann J. A., Pasini F., Olabiran Y., Pelosi G. Detection of the neural cell adhesion molecule (NCAM) in serum of patients with small-cell lung cancer (SCLC) with "limited" or "extensive" disease, and bone-marrow infiltration. Int J Cancer Suppl. 1994;8:49–52. doi: 10.1002/ijc.2910570710. [DOI] [PubMed] [Google Scholar]
  24. Leonard R. C., Duncan L. W., Hay F. G. Immunocytological detection of residual marrow disease at clinical remission predicts metastatic relapse in small cell lung cancer. Cancer Res. 1990 Oct 15;50(20):6545–6548. [PubMed] [Google Scholar]
  25. MANTEL N., HAENSZEL W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959 Apr;22(4):719–748. [PubMed] [Google Scholar]
  26. Miettinen M., Cupo W. Neural cell adhesion molecule distribution in soft tissue tumors. Hum Pathol. 1993 Jan;24(1):62–66. doi: 10.1016/0046-8177(93)90064-n. [DOI] [PubMed] [Google Scholar]
  27. Molino A., Colombatti M., Bonetti F., Zardini M., Pasini F., Perini A., Pelosi G., Tridente G., Veneri D., Cetto G. L. A comparative analysis of three different techniques for the detection of breast cancer cells in bone marrow. Cancer. 1991 Feb 15;67(4):1033–1036. doi: 10.1002/1097-0142(19910215)67:4<1033::aid-cncr2820670428>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
  28. Moolenaar C. E., Muller E. J., Schol D. J., Figdor C. G., Bock E., Bitter-Suermann D., Michalides R. J. Expression of neural cell adhesion molecule-related sialoglycoprotein in small cell lung cancer and neuroblastoma cell lines H69 and CHP-212. Cancer Res. 1990 Feb 15;50(4):1102–1106. [PubMed] [Google Scholar]
  29. Moolenaar C. E., Pieneman C., Walsh F. S., Mooi W. J., Michalides R. J. Alternative splicing of neural-cell-adhesion molecule mRNA in human small-cell lung-cancer cell line H69. Int J Cancer. 1992 May 8;51(2):238–243. doi: 10.1002/ijc.2910510212. [DOI] [PubMed] [Google Scholar]
  30. Myklebust A. T., Godal A., Pharo A., Juell S., Fodstad O. Eradication of small cell lung cancer cells from human bone marrow with immunotoxins. Cancer Res. 1993 Aug 15;53(16):3784–3788. [PubMed] [Google Scholar]
  31. Myklebust A. T., Pharo A., Fodstad O. Effective removal of SCLC cells from human bone marrow. Use of four monoclonal antibodies and immunomagnetic beads. Br J Cancer. 1993 Jun;67(6):1331–1336. doi: 10.1038/bjc.1993.246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Nakamura S., Suchi T., Koshikawa T., Kitoh K., Koike K., Komatsu H., Iida S., Kagami Y., Ogura M., Katoh E. Clinicopathologic study of CD56 (NCAM)-positive angiocentric lymphoma occurring in sites other than the upper and lower respiratory tract. Am J Surg Pathol. 1995 Mar;19(3):284–296. doi: 10.1097/00000478-199503000-00006. [DOI] [PubMed] [Google Scholar]
  33. Pasini F., Pelosi G., Mostacci R., Santo A., Masotti A., Spagnolli P., Recaldin E., Cetto G. L. Detection at diagnosis of tumor cells in bone marrow aspirates of patients with small-cell lung cancer (SCLC) and clinical correlations. Ann Oncol. 1995 Jan;6(1):86–88. doi: 10.1093/oxfordjournals.annonc.a059056. [DOI] [PubMed] [Google Scholar]
  34. Pasini F., Pelosi G., Verlato G., Guidi G., Pavanel F., Tummarello D., Masotti A., Cetto G. L. Positive immunostaining with MLuC1 of bone marrow aspirate predicts poor outcome in patients with small-cell lung cancer. Ann Oncol. 1998 Feb;9(2):181–185. doi: 10.1023/a:1008226025229. [DOI] [PubMed] [Google Scholar]
  35. Patel K., Frost G., Kiely F., Phimister E., Coakham H. B., Kemshead J. T. Expression of the cluster 1 antigen (neural cell adhesion molecule) in neuroectodermal tumours. Br J Cancer Suppl. 1991 Jun;14:20–23. [PMC free article] [PubMed] [Google Scholar]
  36. Patel K., Moore S. E., Dickson G., Rossell R. J., Beverley P. C., Kemshead J. T., Walsh F. S. Neural cell adhesion molecule (NCAM) is the antigen recognized by monoclonal antibodies of similar specificity in small-cell lung carcinoma and neuroblastoma. Int J Cancer. 1989 Oct 15;44(4):573–578. doi: 10.1002/ijc.2910440402. [DOI] [PubMed] [Google Scholar]
  37. Patriarca C., Pruneri G., Alfano R. M., Carboni N., Ermellino L., Guddo F., Buffa R., Siccardi A. G., Coggi G. Polysialylated N-CAM, chromogranin A and B, and secretogranin II in neuroendocrine tumours of the lung. Virchows Arch. 1997 Jun;430(6):455–460. doi: 10.1007/s004280050055. [DOI] [PubMed] [Google Scholar]
  38. Perez E. A., Loprinzi C. L., Sloan J. A., Owens D. T., Novotny P. J., Bonner J. A. Utility of screening procedures for detecting recurrence of disease after complete response in patients with small cell lung carcinoma. Cancer. 1997 Aug 15;80(4):676–680. [PubMed] [Google Scholar]
  39. Pollard E. B., Tio F., Myers J. W., Clark G., Coltman C. A., Jr, Von Hoff D. D. Utilization of a human tumor cloning system to monitor for marrow involvement with small cell carcinoma of the lung. Cancer Res. 1981 Mar;41(3):1015–1020. [PubMed] [Google Scholar]
  40. Pollerberg G. E., Schachner M., Davoust J. Differentiation state-dependent surface mobilities of two forms of the neural cell adhesion molecule. Nature. 1986 Dec 4;324(6096):462–465. doi: 10.1038/324462a0. [DOI] [PubMed] [Google Scholar]
  41. Ross A. A., Cooper B. W., Lazarus H. M., Mackay W., Moss T. J., Ciobanu N., Tallman M. S., Kennedy M. J., Davidson N. E., Sweet D. Detection and viability of tumor cells in peripheral blood stem cell collections from breast cancer patients using immunocytochemical and clonogenic assay techniques. Blood. 1993 Nov 1;82(9):2605–2610. [PubMed] [Google Scholar]
  42. Rutishauser U., Acheson A., Hall A. K., Mann D. M., Sunshine J. The neural cell adhesion molecule (NCAM) as a regulator of cell-cell interactions. Science. 1988 Apr 1;240(4848):53–57. doi: 10.1126/science.3281256. [DOI] [PubMed] [Google Scholar]
  43. Skov B. G., Hirsch F. R., Bobrow L. Monoclonal antibodies in the detection of bone marrow metastases in small cell lung cancer. Br J Cancer. 1992 Apr;65(4):593–596. doi: 10.1038/bjc.1992.120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Stahel R. A., Gilks W. R., Lehmann H. P., Schenker T. Third International Workshop on Lung Tumor and Differentiation Antigens: overview of the results of the central data analysis. Int J Cancer Suppl. 1994;8:6–26. doi: 10.1002/ijc.2910570704. [DOI] [PubMed] [Google Scholar]
  45. Stahel R. A., Mabry M., Skarin A. T., Speak J., Bernal S. D. Detection of bone marrow metastasis in small-cell lung cancer by monoclonal antibody. J Clin Oncol. 1985 Apr;3(4):455–461. doi: 10.1200/JCO.1985.3.4.455. [DOI] [PubMed] [Google Scholar]
  46. Tome Y., Hirohashi S., Noguchi M., Matsuno Y., Kishi K., Uei Y., Shimosato Y. Immunocytologic diagnosis of small-cell lung cancer in imprint smears. Acta Cytol. 1991 Sep-Oct;35(5):485–490. [PubMed] [Google Scholar]
  47. Trillet V., Revel D., Combaret V., Favrot M., Loire R., Tabib A., Pages J., Jacquemet P., Bonmartin A., Mornex J. F. Bone marrow metastases in small cell lung cancer: detection with magnetic resonance imaging and monoclonal antibodies. Br J Cancer. 1989 Jul;60(1):83–88. doi: 10.1038/bjc.1989.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Veglio F., Schiavone D., Mengozzi G., Molino P., Chiandussi L. Levels of plasma neuropeptide Y and other vasoactive substances during head-up tilt in normal and essential hypertensive subjects. Clin Auton Res. 1995 Apr;5(2):67–70. doi: 10.1007/BF01827465. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES