The Working Formulation was proposed in 1982 as a modification of the Rappaport classification of NHL based on morphology and biologic aggressiveness. Although many subtypes were not recognized, including T-cell lineage lymphomas, a revised European-American classification of lymphoid neoplasms (REAL classification) was introduced in 1994 incorporating T-cell malignancies, subtypes of Hodgkin lymphoma, and newer defined lymphoma-proliferative disorders. The WHO (World Health Organization) classification for lymphomas (introduced in 1999 and updated in 2008) uses the principles of the REAL classification defining each entity according to morphologic features, immunophenotype, genetic features, postulated normal counterpart, and clinical features.
The modifications in the 2008 WHO classification included incorporation of further site-specific lymphoma subtypes, recognition of age as a defining feature of some diseases, and inclusion of several borderline and provisional categories (Table 4). The most frequently occurring clinical entities recognized within the WHO classification are DLBCL (31%), follicular lymphoma (22%), marginal zone/MALT lymphoma (8%), SLL (7%), and MCL (6%), whereas all noncutaneous T-cell lymphomas represent approximately 10% of NHL diagnoses in the United States.
The WHO classification includes three types of follicular lymphoma (grades 1/2, 3a, and 3b). Grading of follicular lymphoma is based in part on the number of centroblasts or large cells per high-powered field. Notably, the presence of any diffuse areas (ie, nonfollicular pattern) with large B cells should be designated as DLBCL. Further, some cases may include a composite of different histologic subtypes within the same lymph node excision (eg, follicular lymphoma and DLBCL). Grade 3b follicular lymphoma indicates sheets of large cells within a follicle (ie, maintained follicular architecture). Grade 3b follicular lymphoma more closely resembles DLBCL at the molecular level. The WHO classification considers B-cell SLL to be synonymous with CLL.
In the updated WHO classification, further clinicopathologic subtypes were added, namely DLBCL associated with inflammation and EBV and DLBCL in the elderly. In terms of T-cell lymphomas (TCLs), anaplastic large cell lymphoma (ALCL), ALK-positive, is considered a distinct disease, which is distinguished from the provisional entity of ALCL, ALK-negative. In addition, three new variants of primary cutaneous TCL were introduced (Table 4).
Determining the extent of disease in patients with NHL provides prognostic information and is useful in treatment planning. However, histologic subclassification (WHO classification) is the primary determinant of survival and potential for cure. Compared with patients with limited disease, those with extensive disease usually require different therapy, and certain extranodal sites of involvement, such as the CNS and testes, require specific treatment modalities.
Ann Arbor system
Although initially devised for Hodgkin lymphoma, the Ann Arbor system has been routinely applied to NHL (Table 5). Because Hodgkin lymphoma commonly spreads via contiguous lymph node groups, this system is based primarily on the distribution of lymphatic involvement with respect to the diaphragm and the presence of extralymphatic organ involvement. The Ann Arbor system does not reflect the noncontiguous nature of disease spread in NHL, does not discriminate well between stages III and IV disease, and fails to account for tumor bulk or number of extranodal sites.
Some trials in Burkitt and Burkitt-like lymphoma use the St. Jude/Murphy staging system, in part to more completely describe the extent of extranodal disease. Unlike the current WHO classification, this staging system recognizes Burkitt leukemia as a separate entity. Moreover, this system was developed when surgery was used for diagnostic and therapeutic purposes. Patients are also typically stratified into two risk groups, with low-risk patients defined as having a normal LDH level and a single focus of disease measuring less than 10 cm and all others considered to be high risk.
Histology (by WHO classification) remains the major determinant of treatment outcome and prognosis. Newer pathologic technologic methods, such as gene expression profiling, have emerged as important determinants of outcome. However, these currently remain research-based; routine clinical factors continue to be prognostically important in indolent and aggressive NHLs.
The International Prognostic Index (IPI)
The International Prognostic Index (IPI) was developed by 16 institutions and cooperative groups in the United States, Europe, and Canada as a prognostic factor model for aggressive NHL treated with doxorubicin(Drug information on doxorubicin)-containing regimens. The IPI clinical features, which have been shown to be independently predictive of survival, are provided in Table 6.
This index appears to be a useful guide for selecting treatment for patients with aggressive DLBCL, by identifying subsets of patients in whom intensified primary or novel therapy may be warranted. Because younger and older patients have markedly different prognoses and younger patients are more likely to be considered for more intensive investigational regimens, an age-adjusted model for patients ≤ 60 years old has been proposed. In younger patients, stage (III or IV), high LDH level, and nonambulatory performance status are independently associated with decreased survival. Notably, the IPI has remained a valid prognostic index for R-CHOP (rituximab [Rituxan]-cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin], prednisone(Drug information on prednisone))–treated DLBCL. In the post-rituximab era, persons with no risk factors have a predicted 5-year overall survival of 94%, compared with 55% for high-risk patients with three to five risk factors.
A prognostic factor model was devised based on the study of 919 cases of follicular lymphoma, known as the Follicular Lymphoma IPI (FLIPI; Table 7). Multivariate analysis showed that age, Ann Arbor stage, number of nodal sites, LDH level, and hemoglobin level were predictors of overall survival.
An analysis of the FLIPI in the post-rituximab era has been reported (FLIPI-2). Multivariate analysis showed that elevated beta2-microglobulin, longest nodal diameter over 6 cm, bone marrow involvement, anemia, and age over 60 years independently predicted survival. Including all patients (n = 832) with 0, 1–2, or 3–5 factors, the 3-year progression-free survival was 91%, 69%, and 51% (P = .00001), whereas the 5-year progression-free survival was 79%, 51%, and 20%, respectively (P = .00001). Among patients treated with rituximab(Drug information on rituximab)-containing regimens only (n = 559), the FLIPI-2 remained predictive of outcome (3-year progression-free survival of 89%, 73%, and 57%, respectively; P = .001). The MCL International Prognostic Index (MIPI) was created from 455 advanced-stage MCL patients treated within three German clinical trials. It consisted of several clinical factors. The simplified MIPI (s-MIPI) is the sum of increasing points for grouped values of age, performance status, LDH level > the upper limit of normal, and leukocyte count and is scored as low (0–3 points), intermediate (4–5 points), and high risk (> 5 points; Table 8). Patients with low or intermediate risk according to the sMIPI had a 5-year overall survival > 75% to 80% compared with 38% for patients with high risk (> 5 factors).
Various immunobiologic factors have been suggested as predictors of outcome in NHL.
A number of studies have suggested that patients with aggressive T-cell NHL have a higher relapse rate and decreased overall survival compared with with B-cell disease, especially in the post-rituximab era.
Tumor cell proliferation
Studies using the Ki-67 antibody, a marker of nuclear proliferation, have shown that increased tumor cell proliferation is a poor prognostic factor in MCL.
Cytogenetic abnormalities and oncogene expression
Mutations of p53 are associated with histologic transformation in follicular NHL, which is a phenomenon frequently associated with a poor prognosis. Expression of bcl-2 in DLBCL has also been associated with inferior survival, whereas bcl-6 expression is a marker of germinal center derivation, a predictor of a favorable outcome with CHOP-like therapy. Expression of c-myc in DLBCL portends an inferior prognosis, while dual expression of bcl-2 and c-myc in B-cell lymphomas (the so-called double hit lymphomas) is a particularly poor prognostic sign.
DNA microarray technology for gene expression profiling has identified distinct prognostic subgroups in DLBCL and follicular NHL. Studies in DLBCL have characterized patients into the following subgroups: germinal center B-like DLBCL, activated B-like DLBCL, and a heterogeneous subgroup termed type-3 DLBCL. In the pre-rituximab era, patients with germinal center B-like DLBCL had a significantly improved overall survival compared with the other molecular profiles. In the post-rituximab era, this prognostic difference is less apparent, but still apparent. Studies in follicular NHL identified two gene expression signatures that predicted survival: immune-response 1 and immune-response 2. Interestingly, the genes that defined the prognostic signatures, however, were not expressed in the tumor cells but were expressed by the nonmalignant tumor microenvironment(primarily T cells, macrophages, and dendritic cells). A variety of immunologically active cell types, including specific T-cell subsets and tumor-associated macrophages, have been associated with prognosis in some studies. Similar data are available in DLBCL regarding gene-expressing studies of the surrounding (nonmalignant) microenvironment. Lenz et al showed that the stromal-1 signature (composed of extracellular-matrix deposition and histiocytic infiltration) was associated with a significantly improved outcome compared with stromal-2 (tumor blood-vessel density) in CHOP and R-CHOP treated populations.