There are many clinically important prognostic factors in non-Hodgkin’s lymphoma, though only a few have consistently been shown to correlate with prognosis and outcome in multivariate analyses. These prognostic parameters (Table 1) have been incorporated into various proposed staging systems, such as the M. D. Anderson Tumor Score and the International Prognostic Index (IPI).[1,2] Unlike in Hodgkin’s disease, the Ann Arbor staging system is of limited use in predicting outcome in patients with non-Hodgkin’s lymphoma, primarily due to its inability to estimate tumor burden. The Ann Arbor staging system becomes more useful when used in combination with other parameters that estimate tumor burden and which might also reflect, directly or indirectly, the tumor’s biologic features.
Surrogate parameters for tumor burden include an elevated beta-2-microglobulin (ß2M), bulky disease, and the number of extranodal sites .[3-5] Bulky disease in the M. D. Anderson Tumor Score System is defined as any peripheral lymph node or mass ³ 7 cm, a T3 or T4 lesion (by the TNM system) in the sinus cavity or nasopharynx, or > two-thirds infiltration of the stomach, liver, or other extranodal sites that are difficult to measure. Such estimates of tumor burden, when combined with serum lactic dehydrogenase (LDH) levels and used as a prognostic model, have proven useful in predicting 5-year survival. For example, patients with poor-risk disease as defined by extensive nodal and/or extranodal disease and elevated LDH levels had a 5-year survival of 20%, in comparison with 87% for those good-risk patients with less extensive disease and normal LDH levels.
Beta-2-microglobulin seems to correlate with tumor burden as well, and is an independently significant and easily measured prognostic parameter. The ß2M level has been used together with LDH to identify patients with a poor prognosis; in combination with an elevated serum LDH, an elevated ß2M correlates with an inferior time to treatment failure and survival among patients with aggressive non-Hodgkin’s lymphoma, regardless of Ann Arbor stage.
Swan et al correlated these variables to identify a distinct high-risk group of patients with large-cell lymphoma whose 2-year survival was 19% compared with a 2-year survival of 100% in a low-risk group of patients. In this system, an intermediate prognostic category was observed and consisted of cases with either ß2M or LDH elevation, but not both. This intermediate category is considered undesirable for treatment planning because it is much easier to design or select treatment for patients with either a very favorable or a very unfavorable prognosis, but is more difficult for patients with an intermediate prognosis. The former could be treated with conventional regimens whereas the unfavorable group could be entered on experimental programs.
Estimates of tumor burden have proven to be significant in multivariate analyses and have found their way into some of the more recent staging systems. Ann Arbor stage, an increased ß2M and LDH, the presence of constitutional “B” symptoms and bulky disease were incorporated into a staging system known as the M. D. Anderson Tumor Score. One point is assigned for each adverse prognostic feature with the sum representing a “tumor score.” An estimate of tumor burden, the tumor score, correlates with response rates (Table 2).
In a study of 144 patients who were uniformly treated with the CHOP regimen (cyclophosphamide [Cytoxan, Neosar], doxorubicin [Adriamycin], vincristine [Oncovin], and prednisone), those patients with a tumor score of 0 to 2 had a time to treatment failure rate of 83% compared to 24% for those patients with a tumor score of 3 or more. This system incorporated tumor-dependent variables that had been found to be significant in multivariate analyses, were easily reproducible, and correlated with outcome. A major advantage of this system is the definition of only two prognostic categories with no intermediate categories.
Coiffier et al prospectively applied several of these prognostic systems from various single institutions to patients receiving the LNH-84 regimen and identified groups of good- and poor-risk patients. (The LNH-84 regimen includes doxorubicin, cyclophosphamide, vindesine [Eldisone, Enisone], bleomycin [Blenoxane], prednisone, and methotrexate.) Although the ability of each system to predict prognosis was roughly equivalent, a commonly accepted definition of tumor burden remained elusive. Serum LDH levels and Ann Arbor stage remained the most important variables, although ß2M was not included as a variable. Coiffier then proposed a prognostic index based on LDH and three measurements of tumor burden (tumor size, the number of extranodal sites, and Ann Arbor stage). Other prognostic variables such as serum albumin levels and bone marrow involvement did not seem to add to the prognostic capability beyond the aforementioned variables.
The International Non-Hodgkin’s Lymphoma Prognostic Factors Project also reviewed pretreatment clinical prognostic factors in order to develop a system that might correlate with future outcome for newly diagnosed patients with non-Hodgkin’s lymphoma. The resulting International Prognostic Index (IPI) has proven to be particularly useful in predicting outcome, and is widely used. Both prospective and retrospective analyses of other data have confirmed the utility of this prognostic model.
The IPI incorporates advanced age (defined as greater than 60 years old), advanced stage (Ann Arbor III or IV), elevated LDH, poor performance status, and greater than one extranodal disease site. For example, patients with only one or fewer adverse prognostic features are classified as being low risk, with a complete response rate of 87%, and a 5-year overall survival rate of 73%. Patients with low-intermediate and high-intermediate risk have complete response rates of 67% and 55%, and 5-year survival rates of 51% and 43%, respectively. Patients with high risk disease have a projected complete response rate of only 44%, with a 5-year survival rate of 26%. Variations of the IPI scale, such as an age-adjusted IPI score, have also been found to be quite sensitive.
The IPI has proven useful in predicting outcome in patients with both aggressive and low-grade lymphoma and has even proven to be useful among patients with mantle cell lymphoma. Both the M.D. Anderson tumor score and the IPI are shown in Table 2 and Table 3 along with projected response rates and survival estimates. The only drawback of the IPI is the fact that there are a large number of cases that fit into the intermediate risk categories, making treatment selection problematic.
Bone Marrow and Central Nervous System Involvement
Patients with lymphoma involving the bone marrow, testes, or those with a lymphoblastic or Burkitt’s lymphoma are at greatest risk for central nervous system (CNS) involvement. Given the poor prognosis of CNS or lepto-meningeal lymphoma, it is important to search for central nervous system involvement in such patients at presentation and to incorporate CNS prophylaxis into the treatment plan whenever indicated. Similarly, bone marrow involvement is considered to be an adverse feature and may occur in approximately 10% of all patients with histologically aggressive non-Hodgkin’s lymphoma at the initial staging evaluation. While bone marrow involvement has been shown to be prognostically important, it does not significantly add to the utility of existing prognostic models such as the IPI, and is therefore not generally included.
The presence of divergent histology in the marrow is an interesting phenomenon with prognostic ramifications. Robertson et al described 50 patients with diffuse large-cell lymphoma of lymph nodes and evidence of bone marrow involvement. Forty-eight percent had large-cell lymphoma, 38% had small cleaved-cell lymphoma, and 14% had mixed histology in the marrow. Those with large-cell lymphoma in the bone marrow had a low complete remission rate (16.7%), a high risk of CNS involvement (33%), and a poor 5-year overall survival (12%). Those with small-cleaved-cell lymphoma in the bone marrow had a higher complete remission rate (89.4%), a lower rate of CNS involvement (5%), and a better 5-year survival rate (79%). However, those patients with small-cleaved-cell lymphoma in the marrow had a continuous rate of relapse with a progression-free survival of only 30% at 5 years and 15% at 8 years, reminiscent of the situation with indolent non-Hodgkin’s lymphoma.
1. Rodriguez J, Cabanillas F, McLaughlin P, et al: A proposal for a simple staging system for intermediate-grade lymphoma and immunoblastic lymphoma based on the ‘tumor score.’ Ann Oncol 3:711-717, 1992.
2. Shipp MA, Harrington DP, Anderson JR, et al: A predictive model for aggressive NHL: The International NHL Prognostic Factors Project. N Engl J Med 329:987-994, 1993.
3. Ferraris AM, Giuntini P, Gaetani GF: Serum lactic dehydrogenase as a prognostic tool for non-Hodgkin’s lymphomas. Blood 54:928-932, 1979.
4. Schneider RJ, Seibert K, Passe S, et al: Prognostic significance of serum lactate dehydrogenase in malignant lymphoma. Cancer 46:139-143, 1980.
5. Jagannath S, Velasquez WS, Tucker SL, et al: Tumor burden assessment and its implication for a prognostic model in advanced diffuse large-cell lymphoma. J Clin Oncol 4:859-865, 1986.
6. Swan F Jr, Velasquez WS, Tucker S, et al: A new serologic staging system for large-cell lymphomas based on initial B2-microglobulin and lactate dehydrogenase levels. J Clin Oncol 7:1518-1527, 1989.
7. Levine EG, Arthur DC, Frizzera G, et al: Cytogenetic abnormalities predict clinical outcome in NHL. Ann Int Med 108:14-20, 1988.
8. Coiffier B, Lepage E: Prognosis of aggressive lymphomas: A study of five prognostic models with patients included in the LNH-84 regimen. Blood 74:558-564, 1989.
9. Coiffier B, et al: Fourth International Conference on Malignant Lymphoma, 1990, Lugano, Switzerland. Abstract T61.
10. Lopez-Guillermo A, Montserrat E, Basch F, et al: Applicability of the International Index for aggressive lymphomas to patients with large-cell lymphoma. J Clin Oncol 12:1343-1348, 1994.
11. Garcia-Conde J, Cabanillas F: Mantle cell lymphoma: A new lymphoproliferative entity with definite histopathological patterns, clinical characteristics and prognostic factors, and an investigational therapeutic approach. Ann Oncol 6:305-306, 1995.
12. Robertson LE, Redman JR, Butler JJ, et al: Discordant bone marrow involvement in diffuse large-cell lymphoma: A distinct clinical-pathologic entity associated with continuous risk of relapse. J Clin Oncol 9:236-242, 1991.
13. Ansell SM, Falkson G, van der Merwe R, et al: Chronological age is a multifactorial prognostic variable in patients with non-Hodgkin’s lymphoma. Ann Oncol 3:45-50, 1992.
14. Dixon DO, Neilan B, Jones SE, et al: Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: The Southwest Oncology Group experience. J Clin Oncol 4:295-305, 1986.
15. Vose JM, Armitage JO, Weisenburger DD, et al: The importance of age in survival of patients treated with chemotherapy for aggressive non-Hodgkin’s lymphoma. J Clin Oncol 6:1838-1844, 1988.
16. Armitage JO, Potter JF: Aggressive chemotherapy for diffuse histiocytic lymphoma in the elderly: Increased complications with advancing age. J Am Geriatr Soc 32:269-273, 1984.
17. Grogan L, Corbally N, Dervan PA, et al: Comparable prognostic factors and survival in elderly patients with aggressive non-Hodgkin’s lymphoma treated with standard-dose Adriamycin-based regimens. Ann Oncol 5(suppl 2):47-51, 1994.
18. d’Amore F, Brincker H, Christensen BE: Non-Hodgkin’s lymphoma in the elderly: A study of 602 patients aged 70 or older from a Danish population-based registry. The Danish LYEO-Study Group. Ann Oncol 3:379-386, 1992.
19. Coiffier B, Bryon PA, French M, et al: Intensive chemotherapy of aggressive lymphomas: Updated results of LNH-80 protocol and prognostic factors affecting response and survival. Blood 70:1394-1399, 1987.
20. Armitage JO, Weisenburger DD, Hutchins M, et al: Chemotherapy for diffuse large-cell lymphoma - rapidly responding patients have more durable remissions. J Clin Oncol 4:160-164, 1986.
21. Philip T, Armitage JO, Spitzer G, et al: High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin’s lymphoma. N Engl J Med 316:1493-1498, 1987.
22. Vose JM, Anderson JR, Kessinger A, et al: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin’s lymphoma. Clin Oncol 11:1846-1851, 1993.
23. Coiffier B, Gisselbrecht C, Vose JM, et al: Prognostic factors in aggressive malignant lymphomas: Description and validation of a prognostic index that could identify patients requiring a more intensive therapy. J Clin Oncol 9:211-219, 1991.
24. Kwak LW, Halpern J, Olshen RA, et al: Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: Results of a tree-structured survival analysis. J Clin Oncol 8:963-977, 1990.
25. Hoskins PJ, Ng V, Spinelli JJ, et al: Prognostic variables in patients with diffuse large-cell lymphoma treated with MACOP-B. J Clin Oncol 9:220-226, 1991.
26. Shipp MA, Harrington DP, Klatt MM, et al: Identification of major prognostic subgroups of patients with large-cell lymphoma treated with m-BACOD or M-BACOD. Ann Intern Med 104:757-765, 1986.
27. Coiffier B, Shipp MA, Cabanillas F, et al: Report of the first workshop on prognostic factors in large-cell lymphomas. Ann Oncol 2(suppl 2):213-217, 1991.
28. Kirn D, Mauch P, Shaffer K, et al: Large-cell and immunoblastic lymphoma of the mediastinum: prognostic features and treatment outcome in 57 patients. J Clin Oncol 11(suppl 1):1336-1343, 1993.
29. Mauch P, Leonard R, Skarin A, et al: Improved survival following combined radiation therapy and chemotherapy for unfavorable prognosis stage I-II non-Hodgkin’s lymphomas. J Clin Oncol 3:1301-1308, 1985.
30. Coiffier B, Brousse N, Peuchmaur M, et al: Peripheral T-cell lymphomas have a worse prognosis than B-cell lymphomas: A prospective study of 361 immunophenotyped patients treated with the LNH84 regimen. Ann Oncol 1:45-50, 1990.
31. Gasgoyne R, Tolcher A, Coupland R, et al: Prognostic significance of immunophenotype in diffuse large cell lymphomas. Lab Invest 70:109a.52-53, 1994.
32. Kwak LW, Wilson M, Weiss LM, et al: Similar outcome of treatment of B-cell and T-cell diffuse large cell lymphomas: The Stanford experience. J Clin Oncol 9:1426-1431, 1991.
33. Melnyk A, Rodriguez A, Pugh WC, et al: Evaluation of the revised European-American lymphoma classification confirms the clinical relevance of immunophenotype in 560 cases of aggressive non-Hodgkin’s lymphoma. Blood 89:4514-4520, 1997.
34. Gisselbrecht C, Gaulard P, Lepage E, et al: Prognostic significance of T-cell phenotype in aggressive non-Hodgkin’s lymphomas. Blood 92:76-82, 1998.
35. Miller TP, Grogan TM, Dahlberg S, et al: Prognostic significance of the Ki-67-associated proliferative antigen in aggressive non-Hodgkin’s lymphomas: A prospective Southwest Oncology Group trial. Blood 83:1460-1466, 1994.
36. Gascoyne RD, Adomat SA, Krajewski S, et al: Prognostic significance of bcl-2 protein expression and bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin’s lymphoma. Blood 90:244-251, 1997.
37. Yunis JJ, Mayer MG, Arnesen MA, et al: bcl-2 and other genomic alterations in the prognosis of non-Hodgkin’s lymphoma. N Engl J Med 320:1047-1054, 1989.
38. Miller TP, Levy N, Bailey NP, et al: The bcl-2 gene translocation (14;18) identifies a subgroup of patients with diffuse large cell lymphoma (DLCL) having an indolent clinical course with late relapse. Proc Am Soc Clin Oncol 13:370, 1994.
39. Hill ME, MacLennan KA, Cunningham DC, et al: Prognostic significance of BCL-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin’s lymphoma: A British National Lymphoma Investigation study. Blood 88:1046-1051, 1996.
40. Tang SC, Visser L, Hepperle B, et al: Clinical significance of bcl-2-MBR gene rearrangement and protein expression in diffuse large-cell non-Hodgkin’s lymphoma: an analysis of 83 cases. J Clin Oncol 12:149-154, 1994.
41. Piris MA, Pezella F, Martinez-Montero JC, et al: p53 and bcl-2 expression in high-grade B-cell lymphomas: Correlation with survival time. Br J Cancer 69:337-341, 1994.
42. Hermine O, Haioun C, Lepage E, et al: Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin’s lymphoma. Blood 87:265-272, 1996.
43. Kramer MHH, Hermans J, Parker J, et al: Clinical significance of bcl-2 and p53 protein expression in diffuse large B-cell lymphoma: A population-based study. J Clin Oncol 14:2131-2138, 1996.
44. Offit K, LeCoco F, Louie DC, et al: Rearrangement of the bcl-6 gene as a prognostic marker in diffuse large cell lymphoma. N Engl J Med 331:74-80, 1994.
45. Fisher RI, Dahlberg S, Nathwani BN, et al: A clinical analysis of two indolent lymphoma entities. Mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): A Southwestern Oncology Group study. Blood 85:1075-1082, 1995.
46. Leonard RCF: The identification of discrete prognostic groups in low grade NHL. Ann Oncol 2:655-662, 1991.
47. Soubeyran P, Richaud P, Hoerni B, et al: Low grade follicular lymphoma: Analysis of prognosis in a series of 281 patients. Eur J Cancer 27:1606-1613, 1991.
48. Romaguera JE, McLaughlin P, North L, et al: Multivariate analysis of prognostic factors in stage IV follicular low-grade lymphoma: A risk model. J Clin Oncol 9:762-769, 1991.
49. Sutcliffe SB, Gospodarowicz MK, Bush RS, et al: Role of radiation therapy in localized non-Hodgkin’s lymphoma. Radiother Oncol 4:211-223, 1985.
50. McLaughlin P, Fuller LM, Velasquez WS, et al: Stage III follicular lymphoma. Durable remissions with a combined chemotherapy-radiotherapy regimen. J Clin Oncol 6:867-874, 1987.
51. Litam P, Swan F, Cabanillas F, et al: Prognostic value of serum B2 microglobulin in low-grade lymphoma. Ann Int Med 114:805-810, 1991.
52. Macartney JC, Camplejohn RS, Morris R, et al: DNA flow cytometry of follicular non-Hodgkin’s lymphoma. J Clin Pathol 44:215-218, 1991.
53. Ezdlini EZ, Costello WG, Kucuk O, et al: Effects of the degree of nodularity on the survival of patients with nodular lymphoma. J Clin Oncol 5:413-418, 1987.
54. Strickler JG, Copenhaver CM, Rojas VA, et al: Comparison of “host cell infiltrates” in patients with follicular lymphoma with and without spontaneous regression. Am J Clin Pathol 90:257-261,1988.
55. Gallagher C, et al: Follicular lymphoma: Prognostic factors for response and survival. J Clin Oncol 4:1470-1480, 1986.
56. Diggs C, Wiernik P, Ostrow S: Nodular lymphoma: Prolongation of survival by CR. Cancer Clin Trials 4:107-114, 1981.
57. Lopez-Guillermo A, Montserrat E, Basch F, et al: Low grade lymphoma: Clinical and prognostic studies in a series of 143 patients from a single institution. Leuk Lymph 15:159-165, 1994.
58. Vuckovic J, Zemunik T, Forenpoher G, et al: Prognostic value of B-symptoms in low grade non-Hodgkin’s lymphoma. Leuk Lymph 13:357-358, 1994.
59. McLaughlin P, Fuller LM, Velasquez WS, et al: Stage I-II follicular lymphoma: Treatment results for 76 patients. Cancer 58: 1596-1602, 1986.
60. Cabanillas F, Grant G, Hagemeister F, et al: Refractoriness to chemotherapy and poor survival related to abnormalities of chromosome 17 and 7 in lymphoma. Am J Med 87:167-172, 1989.
61. Lee MS, Chang KS, Cabanillas F, et al: Detection of minimal residual disease cells carrying the t(14;18) by DNA sequence amplification. Science 237:175-178, 1987.
62. Pezella F, Jones M, et al: Evaluation of bcl-2 protein expression and t(14;18) translocation as prognostic markers in follicular lymphoma. Br J Cancer 65:87, 1992.
63. Gribben J, Freedman AF, Neuberg D: Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. N Engl J Med 325: 1525-1533, 1991.
64. Lopez-Guillermo A, Lee MS, Pugh W, et al: The molecular breakpoint site of bcl-2 gene has prognostic importance in indolent follicular lymphoma, FL, (abstract 1162). Blood 85:203a, 1996.
65. Melnyk A, Rodriguez MA: Intermediate- and high-grade non-Hodgkin’s lymphomas, in: Medical Oncology: A Comprehensive Review, Pazdur R (ed), pp 99-110. Huntington, NY, PRR Inc, 1995.