Skip to main content
NCBI home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1987 Jul;128(1):181–201.

Immunophenotypic criteria for the diagnosis of non-Hodgkin's lymphoma.

L J Picker, L M Weiss, L J Medeiros, G S Wood, R A Warnke
PMCID: PMC1899786  PMID: 3111266

Abstract

This study examines the immunohistologic profiles of a large series of histologically proven benign and malignant lymphoproliferative processes in order to define immunophenotypic criteria useful in the diagnosis of non-Hodgkin's lymphoma. Using a method of analysis relying solely on immunoarchitectural features of a given case, the authors were able to define immunologic criteria capable of differentiating benign from malignant lymphoid processes independent from conventional morphologic analysis. In general, these criteria involved identification of abnormal expression or loss of antigens in B- and T-lineage populations. Among B-lineage populations the following features were associated with malignant histology: 1) light-chain-restricted B lineage, 2) light chain -B lineage, 3) Leu-1+ B lineage, 4) L60+ B lineage, 5) 41H+, Ki-67+ B lineage, 6) loss of pan-B antigens, and 7) LFA-1-B lineage. Among T-cell populations outside the thymus, phenotypes associated with malignancy included 1) loss of pan-T antigens (including loss of the beta chain of the T-cell antigen receptor), 2) coexpression or loss of T-subset antigens, 3) Leu-6+ T-lineage, and 4) MB-1+ T lineage. Application of these criteria to a series of nearly 500 cases of lymphoma indicated that over 90% of B-lineage and about 80% of T-lineage neoplasms manifested immunophenotypic abnormalities that could distinguish them from benign, reactive lymphoid processes. It is concluded that immunophenotypic analysis of lymphoproliferative lesions is sufficiently sensitive and specific to confirm the histologic diagnosis of lymphoma in the vast majority of cases seen in clinical practice. Furthermore, in difficult cases or those with limited material or poor histology, immunophenotypic analysis may be the only means of making a definitive diagnosis.

Full text

PDF
181

Images in this article

186Figure 1
on p.186
188Figure 2
on p.188
189Figure 3
on p.189
190Figure 4
on p.190
192Figure 5
on p.192
194Figure 6
on p.194
196Figure 7
on p.196
197Figure 8
on p.197

Selected References

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

  1. Aisenberg A. C., Wilkes B. M., Harris N. L. Monoclonal antibody studies in non-Hodgkin's lymphoma. Blood. 1983 Mar;61(3):469–475. [PubMed] [Google Scholar]
  2. Antin J. H., Emerson S. G., Martin P., Gadol N., Ault K. A. Leu-1+ (CD5+) B cells. A major lymphoid subpopulation in human fetal spleen: phenotypic and functional studies. J Immunol. 1986 Jan;136(2):505–510. [PubMed] [Google Scholar]
  3. Arnold A., Cossman J., Bakhshi A., Jaffe E. S., Waldmann T. A., Korsmeyer S. J. Immunoglobulin-gene rearrangements as unique clonal markers in human lymphoid neoplasms. N Engl J Med. 1983 Dec 29;309(26):1593–1599. doi: 10.1056/NEJM198312293092601. [DOI] [PubMed] [Google Scholar]
  4. Bertness V., Kirsch I., Hollis G., Johnson B., Bunn P. A., Jr T-cell receptor gene rearrangements as clinical markers of human T-cell lymphomas. N Engl J Med. 1985 Aug 29;313(9):534–538. doi: 10.1056/NEJM198508293130902. [DOI] [PubMed] [Google Scholar]
  5. Bindl J. M., Warnke R. A. Advantages of detecting monoclonal antibody binding to tissue sections with biotin and avidin reagents in Coplin jars. Am J Clin Pathol. 1986 Apr;85(4):490–493. doi: 10.1093/ajcp/85.4.490. [DOI] [PubMed] [Google Scholar]
  6. Brenner M. B., McLean J., Scheft H., Warnke R. A., Jones N., Strominger J. L. Characterization and expression of the human alpha beta T cell receptor by using a framework monoclonal antibody. J Immunol. 1987 Mar 1;138(5):1502–1509. [PubMed] [Google Scholar]
  7. Burns B. F., Warnke R. A., Doggett R. S., Rouse R. V. Expression of a T-cell antigen (Leu-1) by B-cell lymphomas. Am J Pathol. 1983 Nov;113(2):165–171. [PMC free article] [PubMed] [Google Scholar]
  8. Caligaris-Cappio F., Gobbi M., Bofill M., Janossy G. Infrequent normal B lymphocytes express features of B-chronic lymphocytic leukemia. J Exp Med. 1982 Feb 1;155(2):623–628. doi: 10.1084/jem.155.2.623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Clark D. M., Boylston A. W., Hall P. A., Carrel S. Antibodies to T cell antigen receptor beta chain families detect monoclonal T cell proliferation. Lancet. 1986 Oct 11;2(8511):835–837. doi: 10.1016/s0140-6736(86)92870-9. [DOI] [PubMed] [Google Scholar]
  10. Cleary M. L., Chao J., Warnke R., Sklar J. Immunoglobulin gene rearrangement as a diagnostic criterion of B-cell lymphoma. Proc Natl Acad Sci U S A. 1984 Jan;81(2):593–597. doi: 10.1073/pnas.81.2.593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Doggett R. S., Wood G. S., Horning S., Levy R., Dorfman R. F., Bindl J., Warnke R. A. The immunologic characterization of 95 nodal and extranodal diffuse large cell lymphomas in 89 patients. Am J Pathol. 1984 May;115(2):245–252. [PMC free article] [PubMed] [Google Scholar]
  12. Foon K. A., Todd R. F., 3rd Immunologic classification of leukemia and lymphoma. Blood. 1986 Jul;68(1):1–31. [PubMed] [Google Scholar]
  13. Ford R. J., Cramer M., Davis F. M. Identification of human lymphoma cells by antisera to malignancy-associated nucleolar antigens. Blood. 1984 Mar;63(3):559–565. [PubMed] [Google Scholar]
  14. Garcia C. F., Weiss L. M., Warnke R. A. Small noncleaved cell lymphoma: an immunophenotypic study of 18 cases and comparison with large cell lymphoma. Hum Pathol. 1986 May;17(5):454–461. doi: 10.1016/s0046-8177(86)80034-x. [DOI] [PubMed] [Google Scholar]
  15. Grogan T. M., Fielder K., Rangel C., Jolley C. J., Wirt D. P., Hicks M. J., Miller T. P., Brooks R., Greenberg B., Jones S. Peripheral T-cell lymphoma: aggressive disease with heterogeneous immunotypes. Am J Clin Pathol. 1985 Mar;83(3):279–288. doi: 10.1093/ajcp/83.3.279. [DOI] [PubMed] [Google Scholar]
  16. Han T., Ozer H., Gavigan M., Gajera R., Minowada J., Bloom M. L., Sadamori N., Sandberg A. A., Gomez G. A., Henderson E. S. Benign monoclonal B cell lymphocytosis--a benign variant of CLL: clinical, immunologic, phenotypic, and cytogenetic studies in 20 patients. Blood. 1984 Jul;64(1):244–252. [PubMed] [Google Scholar]
  17. Harris N. L., Data R. E. The distribution of neoplastic and normal B-lymphoid cells in nodular lymphomas: use of an immunoperoxidase technique on frozen sections. Hum Pathol. 1982 Jul;13(7):610–617. doi: 10.1016/s0046-8177(82)80002-6. [DOI] [PubMed] [Google Scholar]
  18. Horning S. J., Doggett R. S., Warnke R. A., Dorfman R. F., Cox R. S., Levy R. Clinical relevance of immunologic phenotype in diffuse large cell lymphoma. Blood. 1984 May;63(5):1209–1215. [PubMed] [Google Scholar]
  19. Horning S. J., Weiss L. M., Crabtree G. S., Warnke R. A. Clinical and phenotypic diversity of T cell lymphomas. Blood. 1986 Jun;67(6):1578–1582. [PubMed] [Google Scholar]
  20. Howard D. R., Eaves A. C., Takei F. Two monoclonal antibodies defining unique antigenic determinants on human B-lymphoma cells. Cancer Res. 1985 Dec;45(12 Pt 1):6322–6327. [PubMed] [Google Scholar]
  21. Hsu S. M., Jaffe E. S. Phenotypic expression of T lymphocytes in thymus and peripheral lymphoid tissues. Am J Pathol. 1985 Oct;121(1):69–78. [PMC free article] [PubMed] [Google Scholar]
  22. Hsu S. M., Yang K., Jaffe E. S. Phenotypic expression of Hodgkin's and Reed-Sternberg cells in Hodgkin's disease. Am J Pathol. 1985 Feb;118(2):209–217. [PMC free article] [PubMed] [Google Scholar]
  23. Hsu S. M., Zhao X. Expression of interleukin-1 in Reed-Sternberg cells and neoplastic cells from true histiocytic malignancies. Am J Pathol. 1986 Nov;125(2):221–225. [PMC free article] [PubMed] [Google Scholar]
  24. Kadin M. E., Sako D., Berliner N., Franklin W., Woda B., Borowitz M., Ireland K., Schweid A., Herzog P., Lange B. Childhood Ki-1 lymphoma presenting with skin lesions and peripheral lymphadenopathy. Blood. 1986 Nov;68(5):1042–1049. [PubMed] [Google Scholar]
  25. Kadin M., Nasu K., Sako D., Said J., Vonderheid E. Lymphomatoid papulosis. A cutaneous proliferation of activated helper T cells expressing Hodgkin's disease-associated antigens. Am J Pathol. 1985 May;119(2):315–325. [PMC free article] [PubMed] [Google Scholar]
  26. Kansas G. S., Wood G. S., Fishwild D. M., Engleman E. G. Functional characterization of human T lymphocyte subsets distinguished by monoclonal anti-leu-8. J Immunol. 1985 May;134(5):2995–3002. [PubMed] [Google Scholar]
  27. Knowles D. M., 2nd, Halper J. P., Azzo W., Wang C. Y. Reactivity of monoclonal antibodies Leu 1 and OKT1 with malignant human lymphoid cells. Correlation with conventional cell markers. Cancer. 1983 Oct 15;52(8):1369–1377. doi: 10.1002/1097-0142(19831015)52:8<1369::aid-cncr2820520806>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  28. Krensky A. M., Sanchez-Madrid F., Robbins E., Nagy J. A., Springer T. A., Burakoff S. J. The functional significance, distribution, and structure of LFA-1, LFA-2, and LFA-3: cell surface antigens associated with CTL-target interactions. J Immunol. 1983 Aug;131(2):611–616. [PubMed] [Google Scholar]
  29. Kyle R. A. 'Benign' monoclonal gammopathy. A misnomer? JAMA. 1984 Apr 13;251(14):1849–1854. [PubMed] [Google Scholar]
  30. Lanier L. L., Ruitenberg J. J., Phillips J. H. Human CD3+ T lymphocytes that express neither CD4 nor CD8 antigens. J Exp Med. 1986 Jul 1;164(1):339–344. doi: 10.1084/jem.164.1.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Levy N., Nelson J., Meyer P., Lukes R. J., Parker J. W. Reactive lymphoid hyperplasia with single class (monoclonal) surface immunoglobulin. Am J Clin Pathol. 1983 Sep;80(3):300–308. doi: 10.1093/ajcp/80.3.300. [DOI] [PubMed] [Google Scholar]
  32. Levy R., Warnke R., Dorfman R. F., Haimovich J. The monoclonality of human B-cell lymphomas. J Exp Med. 1977 Apr 1;145(4):1014–1028. doi: 10.1084/jem.145.4.1014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Link M. P., Bindl J., Meeker T. C., Carswell C., Doss C. A., Warnke R. A., Levy R. A unique antigen on mature B cells defined by a monoclonal antibody. J Immunol. 1986 Nov 1;137(9):3013–3018. [PubMed] [Google Scholar]
  34. Marrack P., Kappler J. The antigen-specific, major histocompatibility complex-restricted receptor on T cells. Adv Immunol. 1986;38:1–30. doi: 10.1016/s0065-2776(08)60005-x. [DOI] [PubMed] [Google Scholar]
  35. Palutke M., Schnitzer B., Mirchandani I., Tabaczka P. M., Franklin R., Eisenberg L., So K., Carrillo G. Increased numbers of lymphocytes with single class surface immunoglobulins in reactive hyperplasia of lymphoid tissue. Am J Clin Pathol. 1982 Sep;78(3):316–323. doi: 10.1093/ajcp/78.3.316. [DOI] [PubMed] [Google Scholar]
  36. Reinherz E. L., Schlossman S. F. The differentiation and function of human T lymphocytes. Cell. 1980 Apr;19(4):821–827. doi: 10.1016/0092-8674(80)90072-0. [DOI] [PubMed] [Google Scholar]
  37. Rudders R. A., Ahl E. T., Jr, DeLellis R. A. Surface marker and histopathologic correlation with long-term survival in advanced large-cell non-Hodgkin's lymphoma. Cancer. 1981 Mar 15;47(6):1329–1335. doi: 10.1002/1097-0142(19810315)47:6<1329::aid-cncr2820470616>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  38. Sanchez-Madrid F., Krensky A. M., Ware C. F., Robbins E., Strominger J. L., Burakoff S. J., Springer T. A. Three distinct antigens associated with human T-lymphocyte-mediated cytolysis: LFA-1, LFA-2, and LFA-3. Proc Natl Acad Sci U S A. 1982 Dec;79(23):7489–7493. doi: 10.1073/pnas.79.23.7489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schwarting R., Stein H., Wang C. Y. The monoclonal antibodies alpha S-HCL 1 (alpha Leu-14) and alpha S-HCL 3 (alpha Leu-M5) allow the diagnosis of hairy cell leukemia. Blood. 1985 Apr;65(4):974–983. [PubMed] [Google Scholar]
  40. Spier C. M., Grogan T. M., Fielder K., Richter L., Rangel C. Immunophenotypes in "well-differentiated" lymphoproliferative disorders, with emphasis on small lymphocytic lymphoma. Hum Pathol. 1986 Nov;17(11):1126–1136. doi: 10.1016/s0046-8177(86)80418-x. [DOI] [PubMed] [Google Scholar]
  41. Stein H., Lennert K., Feller A. C., Mason D. Y. Immunohistological analysis of human lymphoma: correlation of histological and immunological categories. Adv Cancer Res. 1984;42:67–147. doi: 10.1016/s0065-230x(08)60456-x. [DOI] [PubMed] [Google Scholar]
  42. Stein H., Mason D. Y., Gerdes J., O'Connor N., Wainscoat J., Pallesen G., Gatter K., Falini B., Delsol G., Lemke H. The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood. 1985 Oct;66(4):848–858. [PubMed] [Google Scholar]
  43. Tubbs R. R., Fishleder A., Weiss R. A., Savage R. A., Sebek B. A., Weick J. K. Immunohistologic cellular phenotypes of lymphoproliferative disorders. Comprehensive evaluation of 564 cases including 257 non-Hodgkin's lymphomas classified by the International Working Formulation. Am J Pathol. 1983 Nov;113(2):207–221. [PMC free article] [PubMed] [Google Scholar]
  44. Uchiyama T., Broder S., Waldmann T. A. A monoclonal antibody (anti-Tac) reactive with activated and functionally mature human T cells. I. Production of anti-Tac monoclonal antibody and distribution of Tac (+) cells. J Immunol. 1981 Apr;126(4):1393–1397. [PubMed] [Google Scholar]
  45. Wang C. Y., Good R. A., Ammirati P., Dymbort G., Evans R. L. Identification of a p69,71 complex expressed on human T cells sharing determinants with B-type chronic lymphatic leukemic cells. J Exp Med. 1980 Jun 1;151(6):1539–1544. doi: 10.1084/jem.151.6.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Weiss L. M., Beckstead J. H., Warnke R. A., Wood G. S. Leu-6-expressing cells in lymph nodes: dendritic cells phenotypically similar to interdigitating cells. Hum Pathol. 1986 Feb;17(2):179–184. doi: 10.1016/s0046-8177(86)80291-x. [DOI] [PubMed] [Google Scholar]
  47. Weiss L. M., Crabtree G. S., Rouse R. V., Warnke R. A. Morphologic and immunologic characterization of 50 peripheral T-cell lymphomas. Am J Pathol. 1985 Feb;118(2):316–324. [PMC free article] [PubMed] [Google Scholar]
  48. Weiss L. M., Hu E., Wood G. S., Moulds C., Cleary M. L., Warnke R., Sklar J. Clonal rearrangements of T-cell receptor genes in mycosis fungoides and dermatopathic lymphadenopathy. N Engl J Med. 1985 Aug 29;313(9):539–544. doi: 10.1056/NEJM198508293130903. [DOI] [PubMed] [Google Scholar]
  49. Weiss L. M., Strickler J. G., Hu E., Warnke R. A., Sklar J. Immunoglobulin gene rearrangements in Hodgkin's disease. Hum Pathol. 1986 Oct;17(10):1009–1014. doi: 10.1016/s0046-8177(86)80084-3. [DOI] [PubMed] [Google Scholar]
  50. Weiss L. M., Trela M. J., Cleary M. L., Turner R. R., Warnke R. A., Sklar J. Frequent immunoglobulin and T-cell receptor gene rearrangements in "histiocytic" neoplasms. Am J Pathol. 1985 Dec;121(3):369–373. [PMC free article] [PubMed] [Google Scholar]
  51. Weiss L. M., Wood G. S., Trela M., Warnke R. A., Sklar J. Clonal T-cell populations in lymphomatoid papulosis. Evidence of a lymphoproliferative origin for a clinically benign disease. N Engl J Med. 1986 Aug 21;315(8):475–479. doi: 10.1056/NEJM198608213150802. [DOI] [PubMed] [Google Scholar]
  52. Wieczorek R., Burke J. S., Knowles D. M., 2nd Leu-M1 antigen expression in T-cell neoplasia. Am J Pathol. 1985 Dec;121(3):374–380. [PMC free article] [PubMed] [Google Scholar]
  53. Wood G. S., Abel E. A., Hoppe R. T., Warnke R. A. Leu-8 and Leu-9 antigen phenotypes: immunologic criteria for the distinction of mycosis fungoides from cutaneous inflammation. J Am Acad Dermatol. 1986 Jun;14(6):1006–1013. doi: 10.1016/s0190-9622(86)70124-2. [DOI] [PubMed] [Google Scholar]
  54. Wood G. S., Burns B. F., Dorfman R. F., Warnke R. A. In situ quantitation of lymph node helper, suppressor, and cytotoxic T cell subsets in AIDS. Blood. 1986 Mar;67(3):596–603. [PubMed] [Google Scholar]
  55. Wood G. S., Link M., Warnke R. A., Dilley J., Levy R. Pan-leukocyte monoclonal antibody L3B12. Characterization and application to research and diagnostic problems. Am J Clin Pathol. 1984 Feb;81(2):176–183. doi: 10.1093/ajcp/81.2.176. [DOI] [PubMed] [Google Scholar]
  56. Zipf T. F., Lauzon G. J., Longenecker B. M. A monoclonal antibody detecting a 39,000 m.w. molecule that is present on B lymphocytes and chronic lymphocytic leukemia cells but is rare on acute lymphocytic leukemia blasts. J Immunol. 1983 Dec;131(6):3064–3072. [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES