Prognosis of diffuse large B cell lymphoma

INTRODUCTION — Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 25 percent of NHL cases [1,2]. (See "Classification of hematopoietic neoplasms".)

The diagnostic category of DLBCL is morphologically, genetically, and biologically heterogeneous. Several distinct clinicopathologic entities are now considered separate diagnostic categories, and are discussed below or separately:

●T cell histiocyte rich large B cell lymphoma. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'T cell histiocyte-rich large B cell lymphoma'.)

●Primary DLBCL of the mediastinum, also called primary mediastinal large B cell lymphoma. (See "Primary mediastinal large B cell lymphoma".)

●Intravascular lymphoma. (See "Intravascular large B cell lymphoma".)

●Lymphomatoid granulomatosis, an Epstein-Barr virus-positive large B cell lymphoma. (See "Pulmonary lymphomatoid granulomatosis" and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Lymphomatoid granulomatosis'.)

●ALK-positive large B cell lymphoma, associated with rearrangements in the ALK gene.

●Large B cell lymphoma associated with IRF4 rearrangement.

●Epstein-Barr virus-positive DLBCL.

●DLBCL associated with chronic inflammation.

●Human herpesvirus 8 (HHV8)-positive DLBCLs, included primary effusion lymphoma and tissue based HHV8-positive tumors.

In addition, the 2016 revision of the World Health Organization (WHO) classification system describes categories of NHL, which have morphologic features that may resemble DLBCL [2]:

●"High-grade B cell lymphoma." These tumors may have morphologic features that resemble DLBCL, Burkitt lymphoma (BL), or lymphoblastic lymphoma. Those with DLBCL or BL morphology are distinguished by the presence of MYC and BCL2 and/or BCL6 gene rearrangements, and are now classified as "high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 gene rearrangements." These lymphomas are no longer considered a type of DLBCL, but many would have been previously described (eg, in the 2008 WHO classification) as "B cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma," or "Burkitt-like" lymphoma, both of which were both eliminated from the 2016 revision. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Burkitt lymphoma'.)

Prognosis of high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 gene rearrangements is described below. (See 'Double hit lymphoma' below.)

●Mediastinal grey zone lymphoma, previously known as B cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Hodgkin lymphoma'.)

The prognosis of nodal DLBCL will be reviewed here. The pathobiology, staging, diagnosis, and treatment of this disorder are discussed separately.

●(See "Pathobiology of diffuse large B cell lymphoma and primary mediastinal large B cell lymphoma".)

●(See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma".)

●(See "Pretreatment evaluation and staging of non-Hodgkin lymphomas".)

●(See "Initial treatment of limited stage diffuse large B cell lymphoma".)

●(See "Initial treatment of advanced stage diffuse large B cell lymphoma".)

The prognosis of DLBCL that arises from transformation of a previously undiagnosed indolent lymphoid neoplasm is discussed separately. (See "Histologic transformation of follicular lymphoma", section on 'Prognosis and prognostic factors' and "Richter transformation in chronic lymphocytic leukemia/small lymphocytic lymphoma".)

OVERVIEW — DLBCL is curable in approximately half of cases with current therapy, particularly in those who achieve a complete remission with first-line treatment. Tumor-extrinsic factors that contribute to outcome include age, socioeconomic conditions, comorbid conditions, performance status, and various clinical features [3,4].

Prognosis in DLBCL is highly associated with the International Prognostic Index (IPI) score, which was proposed in 1993 to assign prognosis to patients with aggressive non-Hodgkin lymphoma undergoing treatment with doxorubicin-containing chemotherapeutic regimens (table 1 and figure 1). These findings have been confirmed in many series of patients with DLBCL.

Other prognostic factors appear to either complement or outperform the IPI in patients with DLBCL, including tumor-intrinsic variables such as cell of origin and certain genetic abnormalities, as described below. (See 'Molecular genetics' below.)

INTERNATIONAL PROGNOSTIC INDEX — The International Prognostic Index (IPI) and its variants are the main prognostic tools used in patients with DLBCL (table 1 and figure 1). These indices are significantly more accurate than standard staging criteria (which they incorporate) in predicting long-term survival.

Original IPI — The IPI was developed to evaluate pretreatment features that predict survival in patients with aggressive non-Hodgkin lymphoma (eg, DLBCL) following treatment with doxorubicin-containing chemotherapy regimens [5]. The following factors correlate significantly with shorter overall survival (OS) or relapse-free survival (RFS):

●Age >60 years

●Serum lactate dehydrogenase (LDH) concentration greater than normal

●Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (table 2)

●Clinical stage III or IV (table 3)

●>1 extranodal disease site

In this system, one point is given for each of the above characteristics present in the patient, for a total score ranging from zero to five, representing increasing degrees of risk (table 1 and figure 1):

●Low risk – IPI score of zero or one

●Low-intermediate risk – IPI score of two

●High-intermediate risk – IPI score of three

●High risk – IPI score of four or five

When applied to an initial group of 2031 patients with aggressive non-Hodgkin lymphoma treated with anthracycline-based regimens that did not include rituximab, five-year OS rates for patients with scores of zero to one, two, three, and four to five were 73, 51, 43, and 26 percent, respectively.

Revised IPI — The addition of rituximab to standard chemotherapy has resulted in improvements in OS rates in patients with CD20-positive tumors. Specifically, the combination of rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens is the most commonly employed treatment for DLBCL. The original IPI scoring system has been revalidated in this patient group [6,7].

An analysis of 1063 patients with aggressive B cell lymphoma who received rituximab plus CHOP or CHOP-like chemotherapy in the context of three prospective trials reassessed the prognostic value of the original IPI [6]. At a median observation time exceeding 30 months, three-year estimates for event-free survival (EFS), progression-free survival (PFS), and OS as divided by IPI score were (table 1 and figure 1):

●IPI score zero or one – Rates of 81, 87, and 91 percent, respectively

●IPI score two – Rates of 69, 75, and 81 percent, respectively

●IPI score three – Rates of 53, 59, and 65 percent, respectively

●IPI score four or five – Rates of 50, 56, and 59 percent, respectively

When patients from all three trials were analyzed as a single set, these four IPI groups differed significantly from each other in their estimates of EFS, PFS, and OS. These results support the use of the original IPI, rather than a revised IPI [8,9], for patient stratification and reporting of data from clinical trials of DLBCL using rituximab therapy.

One potential limitation to the use of the original IPI in patients receiving rituximab is that the difference in outcomes between patients in different IPI risk groups is relatively small. As described above, the estimated three-year survival rates among patients with the lowest and highest IPI scores were 91 and 59 percent, respectively. Despite this, the original IPI remains our preferred prognostic index for patients with DLBCL.

NCCN-IPI — The National Comprehensive Cancer Network (NCCN)-IPI incorporates more detailed information about the clinical variables used in the original IPI (ie, age, LDH, ECOG performance status, stage, and extranodal disease). Specifically, age and LDH are considered as continuous rather than dichotomous variables, and the location of extranodal disease is used rather than the number of extranodal sites. These changes make the NCCN-IPI more cumbersome than the original IPI to apply at the bedside. For now, the original IPI remains our preferred prognostic index for patients with DLBCL.

Clinical variables and outcomes of 1650 patients with de novo DLBCL treated at seven NCCN cancer centers from 2000 to 2010 were used to create the NCCN-IPI, which awards points for each of the following variables [10]:

●Age 41 to 60 years – 1 point

●Age >60 to 75 years – 2 points

●Age >75 years – 3 points

●LDH ratio >1 to 3 – 1 point

●LDH ratio >3 – 2 points

●ECOG PS ≥2 – 1 point

●Ann Arbor stage III to IV – 1 point

●Extranodal disease involving the bone marrow, central nervous system, liver/gastrointestinal tract, or lung – 1 point

The LDH variable is the ratio of the patient's LDH level to the upper limit of normal at the institution. The NCCN-IPI is the sum of these points. When applied to a separate cohort of 1138 patients in a registry from the British Columbia Cancer Agency treated with R-CHOP with curative intent since 2001, the NCCN-IPI was able to stratify patients into four risk groups with significantly different OS and PFS at five years:

●Low risk – 0 to 1 points (12 percent); OS 96 percent; PFS 94 percent

●Low-intermediate risk – 2 to 3 points (37 percent); OS 77 percent; PFS 72 percent

●High-intermediate risk – 4 to 5 points (37 percent); OS 56 percent; PFS 54 percent

●High risk – ≥6 points (14 percent); OS 38 percent; PFS 35 percent

Application of the original IPI to this same group of patients confirmed that the NCCN-IPI provided greater discrimination between risk groups. Whereas the five-year survival rates ranged from 43 to 84 percent with the original IPI, the NCCN-IPI rates ranged from 38 to 96 percent.

Other IPI variants

Age-adjusted IPI — An age-adjusted IPI was evaluated for the 1274 patients ≤60 years of age in the original study group [5]. For this score, all of the prognostic factors listed above, with the exception of age and number of extranodal sites, were given one point, for a score ranging from zero to three (table 1), representing increased degrees of risk:

●Low risk – Age-adjusted IPI score of zero

●Low-intermediate risk – Age-adjusted IPI score of one

●High-intermediate risk – Age-adjusted IPI score of two

●High risk – Age-adjusted IPI score of three

Five-year OS rates for patients ≤60 with age-adjusted scores of zero, one, two, and three were 83, 69, 46, and 32 percent, respectively. Five-year OS rates for those >60 with the same scores were 56, 44, 37, and 21 percent, respectively.

Stage-adjusted IPI — Modifications of the IPI have been made for patients with stage I or II aggressive non-Hodgkin lymphoma ("stage-adjusted" or "stage-modified" IPI) [11,12], since there are marked differences in prognosis among such patients. In one proposed scoring system, one point was given for each of the following pretreatment variables:

●Age >60

●Increased serum LDH levels

●Stage II or stage IIE disease (table 3)

●Performance status ≥2 (table 1)

As an example of the variability in prognosis among patients with stage I or II aggressive non-Hodgkin lymphoma undergoing similar treatment (ie, three courses of doxorubicin-containing chemotherapy plus involved region radiation therapy), patients with scores on the stage-modified IPI from zero to four had the following 10-year OS rates [13]:

●Score zero – 90 percent

●Score one or two – 56 percent

●Score three or four – 48 percent

The prognostic utility of this stage-modified IPI has also been shown for primary gastric and intestinal diffuse large B cell lymphoma [14,15]. It has been further noted that patients with bulky stage II aggressive non-Hodgkin lymphoma have an estimated five-year OS of 49 percent, similar to that of patients with stage III or IV disease [16]. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Gastric lymphoma' and "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)".)

MOLECULAR GENETICS

Cell of origin studies — We suggest that all cases of DLBCL undergo testing to determine the cell of origin. Gene expression profiling (GEP) is the gold standard for determining cell of origin, but has historically been performed on RNA obtained from fresh frozen tissues and is not routinely available in practice. Given their ease of use, immunohistochemistry algorithms (eg, Tally and Hans) (figure 2) are the most commonly used methods; concordance with GEP is approximately 80 percent. A focused gene expression profiling test (Lymph2Cx) can be performed on formalin-fixed paraffin-embedded tissue and is highly concordant (>95 percent) with conventional GEP using RNA from unfixed cells (eg, Affymetrix gene chip) [17]. Lymph2Cx has the potential to replace immunohistochemistry algorithms for cell of origin assignment in DLBCL, but it is not yet widely available.

Gene expression profiling — GEP by means of complementary DNA microarrays ("Lymphochip" microarrays) is an evolving approach to classification and diagnosis of non-Hodgkin lymphoma and other malignancies. DLBCL is a heterogeneous group of tumors that are diverse in terms of their underlying molecular pathogenesis and their clinical outcome. A number of studies have subclassified DLBCL based on GEP [18-28]. Several different classifications have been generated; the most widely used separates DLBCL into two major groups (figure 3):

●Germinal center B cell type (GCB) – These cases have a GEP that resembles a normal germinal center B cell. GCB tumors demonstrate t(14;18) translocations in approximately 30 to 40 percent of cases and a have a superior rate of five-year survival with standard R-CHOP therapy.

●Activated B cell type (ABC) – These cases have a GEP that resembles an activated B cell. These tumors are likely derived from a post-germinal-center B cell that has commenced early stages of plasmacytic differentiation. ABC tumors frequently demonstrate trisomy 3, deletion of CDKN2A, which encodes INK4A/ARF, and constitutive activation of the anti-apoptotic nuclear factor kappa B (NF-kB) pathway, and only rarely have t(14;18) translocations. When compared with GCB tumors, ABC tumors are associated with inferior rates of five-year survival following standard R-CHOP.

The GEP methods used evaluate the expression of 14 or 27 genes and use algorithms to produce a linear predictor score. The score has an assigned probability of identifying the case as ABC-type. If the probability of being ABC-type is >90 percent or <10 percent, cases are labeled ABC or GCB, respectively. Approximately 10 to 15 percent of cases do not meet these criteria and are identified as "unclassifiable." The role that GEP plays in the diagnosis and treatment of DLBCL is being refined. It is clear that these two subgroups have different underlying pathogenic mutations (discussed below) and different outcomes with standard R-CHOP therapy.

Additional profiling studies suggest that signatures of the surrounding stromal-cells also influence outcome [29,30]; while an area of active research, clinically actionable methods of assessing and quantifying host immune response in the DLBCL microenvironment are not yet available.

Hans and Tally methods — GEP is the gold standard for determining cell of origin, but current methods are not routinely available in practice. In an effort to avoid the need for GEP, panels of immunohistochemical markers have been proposed as an alternative means to identify the GCB and ABC subtypes of DLBCL [31]. No single immunohistochemical marker can differentiate between GCB and ABC subtypes, and immunohistochemistry-based methods therefore rely on the differential expression of multiple protein markers in the GCB and ABC subtypes. The two most popular methods are the Hans algorithm and the Tally method (figure 2) [32]:

●Hans algorithm – The Hans classifier uses CD10, BCL6, and MUM1 in a stepwise progression [22]. Cases that express CD10 are classified as GCB. Those that do not express CD10 are evaluated for BCL6 and, if negative, are classified as non-GCB. For those that express BCL6, MUM1 is used as a "tie-breaker." If positive, the cases are classified as non-GCB. If negative, they are classified as GCB. In the initial report, the Hans algorithm correctly assigned 112 of 142 tumors (79 percent concordance). Subsequent reports have estimated the sensitivity (85 to 90 percent), specificity (52 to 82 percent), positive predictive value (55 to 82 percent), and negative predictive value (83 to 90 percent) when compared with GEP [32].

●Tally method – The Tally method uses immunohistochemical markers to calculate a GCB score (CD10 and GCET1) and ABC score (MUM1 and FOXP1). Cases are classified as GCB or ABC if their GCB or ABC scores are greater, respectively. If the scores are equal, LMO2 is used as a "tie-breaker." If LMO2 is <30 percent, the case is classified as ABC. Otherwise, the case is GCB. An initial concordance of 93 percent was reported. Subsequent reports have estimated the sensitivity (80 to 99 percent), specificity (54 to 86 percent), positive predictive value (55 to 87 percent), and negative predictive value (79 to 99 percent) when compared with GEP [32].

Limitations of these methods include a reliance on markers that are not simply called "positive" or "negative," but which require the use of staining cutoffs (eg, >30 percent of cells positive). Because immunohistochemistry methods are not standardized across pathology departments, it may be difficult to use algorithms that rely on staining cutoffs in routine clinical practice, particularly at referral centers where cases and tissue blocks from multiple hospitals are seen in consultation.

Lymph2Cx platform — An alternative approach is the use of technologies that precisely quantify RNA transcript levels in formalin-fixed paraffin-embedded tissue sections. These technologies, which essentially permit transcripts to be counted, appear to be less sensitive to variations in tissue fixation and processing than immunohistochemistry, and correlate well with results obtained by GEP on gene chips [33]. The Lymph2Cx is an example of a digital gene expression test that is highly concordant with other methods of GEP.

An analysis of 344 patients with de novo DLBCL treated with R-CHOP reported the following estimated outcomes at five years according to molecular subtype as defined by Lymph2Cx [17]:

●GCB-type DLBCL – Freedom from progression (FFP) 76 percent; progression-free survival (PFS) 73 percent; disease-specific survival (DSS) 82 percent; overall survival (OS) 78 percent

●ABC-type DLBCL – FFP 51 percent; PFS 48 percent; DSS 61 percent; OS 56 percent

These results suggest that the Lymph2Cx is able to distinguish two prognostically distinct groups of DLBCL. When widely available, Lymph2Cx will likely replace immunohistochemistry algorithms and GEP for cell of origin assignment in DLBCL since it is more reliable than immunohistochemistry and more practical than GEP methods that require fresh, unfixed tissue.

MYC, BCL2, BCL6 abnormalities — The most common cytogenetic abnormalities in DLBCL involve MYC, BCL6, and BCL2.

●MYC – MYC is located at 8q24.21. Translocations involving MYC are seen in 5 to 15 percent of cases of DLBCL and confer a worse prognosis following treatment with doxorubicin-based combination chemotherapy (eg, R-CHOP) [34-36]. One series reported that inferior outcomes are primarily associated with cases in which MYC rearrangement involves immunoglobulin genes rather than other partner genes [37]. MYC amplification occurs in 2 percent of DLBCL and may also be associated with worse outcomes [38].

●BCL6 – BCL6 is located at 3q27.3. BCL6 translocations are found in up to one-third of DLBCL. There is a trend toward association with the ABC subtype, but the presence of this genetic aberration does not appear to have independent prognostic value [39].

●BCL2 – BCL2 is located at 18q21.33. BCL2 translocations are found in approximately one-third of DLBCL, mostly in the GCB molecular subtype. Translocations involving BCL2 do not appear to impact survival when present as the sole genetic abnormality (eg, not associated with concurrent MYC translocation) [40,41]. Expression of BCL2 protein in DLBCL does not correlate with the t(14;18). While the ABC subtype of DLBCL only rarely has the t(14;18), amplifications of 18q21 are seen in up to two-thirds of cases, providing a possible mechanism for BCL2 overexpression in these tumors. The impact of BCL2 protein expression on clinical outcomes is controversial [41,42], and additional studies are needed to clarify the prognostic impact of BCL2 expression in different subtypes of DLBCL.

Double hit lymphoma — The term double hit lymphoma is sometimes used colloquially to refer to cases of lymphoma that morphologically resemble DLBCL, but contain translocations of the MYC gene together with rearrangement of BCL2 and/or BCL6. This is no longer considered a type of DLBCL; in the 2016 World Health Organization (WHO) classification, double hit DLBCL was classified as high-grade B cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements [43]. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma".)

When treated with R-CHOP chemotherapy, double hit lymphomas have a worse prognosis than DLBCL (figure 4) [36,44-46]. Rare triple hit tumors with MYC, BCL2, and BCL6 rearrangements have also been described, and most data suggest that these genotypes are also associated with poor clinical outcomes [36].

Double expressor lymphoma — While all DLBCL with MYC translocation demonstrate increased MYC expression, some tumors have overexpression of MYC due to other mechanisms (eg, gene amplification). Overexpression of MYC and BCL2 can be identified with immunohistochemistry.

In several independent studies, co-expression of MYC and BCL2 was seen in 20 to 30 percent of cases of DLBCL and predicted a lower complete response rate and shorter PFS and OS [44,45,47]. Furthermore, in an analysis of 893 patients with de novo DLBCL treated with R-CHOP, multivariate analysis demonstrated that co-expression of MYC/BCL2 was associated with inferior OS (hazard ratio [HR] 2.52; 95% CI 1.73-3.67) and PFS (HR 2.45; 95% CI 1.71-3.51) [46]. However, while the presence of a MYC translocation conferred a poor prognosis independent of BCL2, MYC protein expression was only associated with worse outcome when accompanied by BCL2 expression.

Further studies are needed to clarify the prognosis of lymphomas that overexpress BCL2 and MYC based on immunohistochemistry. Cases with MYC overexpression identified by immunohistochemistry should undergo genetic testing for MYC translocations. Furthermore, since double hit DLBCLs have a particularly poor prognosis, testing for BCL2 and BCL6 rearrangements should also be considered in cases exhibiting high levels of MYC protein expression.

Identifying molecular subtype — In order to subtype DLBCL and to avoid misclassifying as DLBCL cases of high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 gene rearrangements, we suggest the following tests to assess molecular risk in all lymphomas that have the morphologic features of DLBCL:

●Evaluation of MYC, BCL2, and BCL6 gene status by fluorescence in situ hybridization (FISH) or cytogenetics. An acceptable alternative is to perform immunohistochemistry for MYC and BCL2; cases with MYC overexpression on immunohistochemistry should have further testing for MYC, BCL2, and BCL6 gene rearrangements by FISH. Our approach is to perform MYC FISH studies only when MYC staining is positive in >40 percent of tumor cell nuclei.

●Evaluation of cell of origin by GEP analysis, immunohistochemistry algorithms, or Lymph2Cx platform. Given their ease of use, immunohistochemistry algorithms (eg, Tally and Hans) (figure 2) are the most commonly used method; concordance with GEP is approximately 80 percent. While not yet widely available, the Lymph2Cx can be performed on formalin-fixed paraffin-embedded tissue and is highly concordant with other methods of GEP that require fresh, unfixed tissue. When available, Lymph2Cx may replace immunohistochemistry algorithms for cell of origin assignment in DLBCL.

Using this information, a lymphoma with DLBCL morphology may be subclassified as one of the following:

●Germinal center B cell (GCB) DLBCL – Cases of GCB DLBCL (as defined by GEP, immunohistochemistry algorithms, or Lymph2Cx) have a relatively good prognosis following standard therapy with R-CHOP.

●Activated B cell (ABC) DLBCL or non-GCB DLBCL – Cases with non-GCB DLBCL (identified by conventional GEP, immunohistochemistry algorithms, or Lymph2Cx) have high relapse rates and a less favorable prognosis following treatment with R-CHOP.

Deep sequencing — Deep sequencing of DLBCL genomic DNA has confirmed that heterogeneity in DLBCL extends to the tumor cell genome [48-50]. Studies that included nearly 2000 cases of DLBCL identified driver mutations that may identify genetically distinct subtypes of GCB and non-GCB DLBCL, with different clinical outcomes following standard therapy [51-53]. These observations must be confirmed before genomic testing is used to stratify patients and select therapy.

Cell-free plasma DNA — Circulating cell-free DNA can be quantified in plasma by next-generation sequencing of IgH gene segments derived from DLBCL [54-56]. In initial studies, tumor DNA load was reported to correlate with imaging-based tumor stage and to be a sensitive predictor of disease relapse. This modality requires further evaluation before using it clinically to assess disease burden and response to therapy.

SUMMARY

●Description – Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (approximately one-quarter of cases). DLBCL is morphologically, genetically, biologically, and prognostically heterogeneous.

●Prognostic factors – Outcomes are associated with both clinical features and pathologic aspects of DLBCL.

●Clinical features – Any of the following tools can be used to estimate prognosis for patients with DLBCL:

•International Prognostic Index (IPI) – The IPI (table 1) uses age, performance status (table 2), serum lactate dehydrogenase (LDH), disease stage (table 3), and number of extranodal sites to define prognostic categories. The IPI distinguishes two prognostic groups among patients treated with standard therapy (R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), although it defined four groups in the pre-rituximab era. (See 'International Prognostic Index' above.)

•Revised IPI – The revised IPI (R-IPI) uses the same risk factors and scoring system as the IPI, but it assigns patients to three risk groups.  

•National Comprehensive Cancer Network (NCCN)-IPI – The NCCN-IPI uses the same clinical variables, but age and LDH are considered as continuous, rather than dichotomous, variables and the location of extranodal disease is used rather than the number of extranodal sites.

●Pathologic features

•Mutations – Evaluation of MYC, BCL2, and BCL6 expression or mutation is used to exclude certain lymphomas that resemble DLBCL (eg, so-called “double-hit” lymphoma, which is no longer considered a DLBCL category) and may affect treatment prognosis or treatment. (See 'MYC, BCL2, BCL6 abnormalities' above.)

•Cell of origin status – Cell of origin (COO) studies using immunohistochemistry algorithms (eg, Tally and Hans) (figure 2) or molecular methods may predict responsiveness to therapy. (See 'Cell of origin studies' above.)

There are two major COO subtypes:

-Germinal center B cell type (GCB) – Malignant cells resemble normal germinal center B cells and have more favorable outcomes with standard chemoimmunotherapy (figure 3).

-Non-GCB or activated B cell type (ABC) – Malignant cells resemble activated B cells and are associated with inferior outcomes.