Diffuse aggressive non-Hodgkin's lymphomas (NHL) encompass a diverse group of histologic subtypes that have a predominance of large neoplastic cells and lack any follicular architecture. This group of neoplasms demonstrates a spectrum of histologic, cytologic, immunophenotypic, and cytogenetic subtypes that are reflected by the marked biologic heterogeneity of diffuse large-cell lymphomas (DLCLs).<sup>19 Harris N.L., Jaffe E.S., Stein H. , e al. A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group Blood 1994 ;  84 : 1361

Cliccare qui per andare alla sezione Riferimenti, 66 Volpe G., Vitolo U., Carbone A. , e al. Molecular heterogeneity of B-lineage diffuse large cell lymphoma Genes Chromosom Cancer 1996 ;  16 : 21

Cliccare qui per andare alla sezione Riferimenti</sup> Although these are considered clinically aggressive tumors, the DLCLs are highly responsive to chemotherapy and are curable in approximately 40% to 55% of advanced-stage cases.<sup>61 Shipp M.A., Harrington D.P., Anderson J.R. , e al. A predictive model for aggressive NHL: The international non-Hodgkin's lymphoma prognostic factors project N Engl J Med 1993 ;  329 : 987

Cliccare qui per andare alla sezione Riferimenti</sup> Because the outcome for any individual patient is uncertain, prognostic models based on analysis of pretreatment variables are needed to facilitate treatment decisions. Those patients considered at high risk for treatment failure are potential candidates for alternative therapies, whereas those patients deemed to have a good prognosis may benefit from less aggressive approaches. This review focuses on a select group of pathologic, or so-called biologic, variables that may add additional prognostic information beyond that derived from an analysis of clinical factors.

Important clinical prognostic models have been developed that accurately predict the outcome of individual patients and have proven useful for studying risk-adjusted therapies.<sup>24 Hoskins P.J., Ng V., Spinelli J.J. , e al. Prognostic variables in patients with diffuse large-cell lymphoma treated with MACOP-B J Clin Oncol 1991 ;  9 : 220

Cliccare qui per andare alla sezione Riferimenti, 61 Shipp M.A., Harrington D.P., Anderson J.R. , e al. A predictive model for aggressive NHL: The international non-Hodgkin's lymphoma prognostic factors project N Engl J Med 1993 ;  329 : 987

Cliccare qui per andare alla sezione Riferimenti</sup> These factors are easily measured and are quantifiable. In general, they can be divided into four basic categories: (1) the tumor's growth and invasive potential (serum lactate dehydrogenase [LDH], stage, size of mass, number of nodal or extranodal sites of disease, bone marrow involvement); (2) the patient's response to the tumor (performance status, B symptoms); (3) the patient's ability to tolerate treatment (age, performance status, bone marrow involvement); and (4) a variety of treatment-related factors including time to achieve complete remission (CR) and dose delivery and intensity schedules.<sup>60 Shipp M.A. Prognostic factors in aggressive non-Hodgkin's lymphoma: Who has “high-risk” disease? Blood 1994 ;  83 : 1165

Cliccare qui per andare alla sezione Riferimenti, 61 Shipp M.A., Harrington D.P., Anderson J.R. , e al. A predictive model for aggressive NHL: The international non-Hodgkin's lymphoma prognostic factors project N Engl J Med 1993 ;  329 : 987

Cliccare qui per andare alla sezione Riferimenti</sup> An analysis of some of these variables led to the recent development of the International Prognostic Factor Index (IPI), which has proven to be an extremely useful model for predicting treatment failure risk in individual patients.<sup>61 Shipp M.A., Harrington D.P., Anderson J.R. , e al. A predictive model for aggressive NHL: The international non-Hodgkin's lymphoma prognostic factors project N Engl J Med 1993 ;  329 : 987

Cliccare qui per andare alla sezione Riferimenti</sup> Briefly, this large collaborative study of more than 3000 patients found that age, stage, LDH, performance status, and the number of extranodal sites of disease involvement were important clinical factors for predicting the outcome of patients with DLCLs. Each patient was assigned a score, and four relative-risk categories were determined including low, low-intermediate, high-intermediate, and high risk. The predicted 5-year survivals for these groups were 73%, 51%, 43%, and 26%, respectively. A separate age-adjusted model was also developed for those patients under age 60 years, considered potential candidates for intensive experimental regimens.<sup>61 Shipp M.A., Harrington D.P., Anderson J.R. , e al. A predictive model for aggressive NHL: The international non-Hodgkin's lymphoma prognostic factors project N Engl J Med 1993 ;  329 : 987

Cliccare qui per andare alla sezione Riferimenti</sup>

Importantly, these clinical variables are surrogates for the underlying biologic heterogeneity of the DLCLs. This has led both pathologists and basic researchers to search for the biologic correlates that underlie the clinical behavior of NHLs, with the hope that acquisition of new knowledge will not only improve our understanding of these entities but also lead to the recognition of independent factors that strengthen our ability to accurately predict prognosis in this group of patients.

Many pathologic prognostic factors have been studied in patients with DLCL, including cell lineage, growth fraction, chromosomal abnormalities, oncogene rearrangements, major histocompatibility antigen expression, cell adhesion molecule expression, and tumor-infiltrating lymphocyte responses, to name a few.<sup>14 Gascoyne R.D., Adomat S.A., Krajewski S. , e al. Prognostic significance of bcl-2 protein expression and bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma Blood 1997 ;  90 : 244

Cliccare qui per andare alla sezione Riferimenti, 17 Grogan T., Miller T. New biologic markers in non-Hodgkin's lymphomas Hematol Oncol Clin North Am 1991 ;  5 : 925

Cliccare qui per andare alla sezione Riferimenti, 45 Miller T.P., Grogan T.M., Dahlberg S. , e al. Prognostic significance of the Ki-67–associated proliferative antigen in aggressive non-Hodgkin's lymphomas: A prospective Southwest Oncology Group Trial Blood 1994 ;  83 : 1460

Cliccare qui per andare alla sezione Riferimenti</sup> This review will focus on four of these factors: cell lineage (B versus T cell); bcl-2 gene rearrangements; bcl-2 protein expression; and the role of p53 expression and mutations.