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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 29  |  Issue : 4  |  Page : 961-970

Prognostic impact of immunohistochemical stratification of diffuse large B-cell lymphoma into germinal and nongerminal subtypes


Department of Pathology, Faculty of Medicine, Menoufia University, Shebin El Kom, Egypt

Date of Submission04-Apr-2015
Date of Acceptance16-Jun-2015
Date of Web Publication21-Mar-2017

Correspondence Address:
Mona A. H. Mohammed Kora
Department of Pathology, Menoufia University, Shebin El Kom, 32511
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-2098.202495

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  Abstract 

Objectives
The aim of this study was to investigate the difference between germinal and nongerminal diffuse large B-cell lymphoma (DLBCL) cases regarding their clinicopathological features, including survival and response to therapy.
Background
DLBCL is the most common subtype of non-Hodgkin's lymphoma in Egypt. It represents about 49% of non-Hodgkin's lymphoma cases according to the latest registry of National Cancer Institute, Cairo University. DLBCL is a heterogeneous group, especially as regards biological behavior, which includes response to chemotherapy and ultimate outcome. Previous studies suggested that classification of DLBCL into germinal and nongerminal subtypes had prognostic importance.
Patients and methods
This retrospective study included 61 de-novo DLBCL cases collected from the archival material of Pathology Department, Faculty of Medicine, Menoufia University, and treated at Menoufia Cancer Institute.
Results
Using Hans' algorithm, 31 (50.8%) cases were of germinal center B-cell (GCB) and 30 (49.8%) cases were of non-GCB subtype. Non-GCB cases showed significant association with splenic involvement (P = 0.01) and larger tumor size (P = 0.03). Overall, 90% of DLBCL cases with poor performance status were of GCB subtype. No significant difference regarding overall survival was noticed between GCB and non-GCB subtypes.
Conclusion
DLBCL should be classified into GCB and non-GCB subtypes because they differ prognostically. Hans' algorthim is a simple and reliable method for the classification of DLBCL, but it should be applied on a large number of cases to be used as a routine method for DLBCL evaluation.

Keywords: BCL6, CD10, diffuse large B-cell lymphoma, Hans' algorthim, MUM-1


How to cite this article:
Asaad NY, Abdel Wahed MM, Abdou AG, Serag El-Dien MM, Mohammed Kora MA. Prognostic impact of immunohistochemical stratification of diffuse large B-cell lymphoma into germinal and nongerminal subtypes. Menoufia Med J 2016;29:961-70

How to cite this URL:
Asaad NY, Abdel Wahed MM, Abdou AG, Serag El-Dien MM, Mohammed Kora MA. Prognostic impact of immunohistochemical stratification of diffuse large B-cell lymphoma into germinal and nongerminal subtypes. Menoufia Med J [serial online] 2016 [cited 2020 Apr 3];29:961-70. Available from: http://www.mmj.eg.net/text.asp?2016/29/4/961/202495


  Introduction Top


Malignant lymphoma represents a major health problem throughout the world. It is already the fourth common malignancy in Egypt out of all malignances and is continuing to increase rapidly. In Egypt, it constitutes 11.71% of total malignancies [1].

The Middle East Cancer Consortium showed that Egyptians and Israeli Jews had the highest rates of lymphoma and non-Hodgkin's lymphoma (NHL) among other Middle East Cancer Consortium populations. Egyptians had higher rates for NHL in age groups 0–14 years with a male-to-female ratio of 1.6: 1 [2]. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL in Egypt. It represents about 49% of NHL cases according to the latest registry of National Cancer Institute, Cairo University [3].

NHLs are the 12th most prevalent cancer in Europe. The most frequent lymphoma is DLBCL, with a male-to-female ratio of 1.2: 1, and is more frequent in 61–80-year-old patients [4].

DLBCL spans a broad age range and is heterogeneous in morphologic appearance, immunophenotype, and biologic behavior, including response to chemotherapy and ultimate outcome [5].

Management of DLBCL patients was guided by age-adjusted international prognostic index (AAIPI) score, which was considered the best available clinical tool for risk stratification. However, within each subgroup, marked heterogeneity was noticed regarding clinical outcomes. This may be due to biological parameters that are probably not taken into account by this index. Therefore, in the past years, many efforts have been made to find biological prognostic markers able to stratify DLBCL cases into prognostically different groups [6].

Gene expression profiling (GEP) studies have been performed to divide DLBCL into two major molecular subtypes: germinal center B-cell (GCB) like and non-GCB like. The latter was associated with inferior overall survival. However, to date, GEP has not been routinely feasible. Therefore, an attempt was made to correlate each of these two subtypes with immunohistochemical markers, which are CD10 and BCL6 for GCB type and MUM-1 for non-GCB [7].

Immunohistochemical expression of CD10, BCL6, and MUM-1 was used to divide DLBCL into GCB and non-GCB subtypes [8].


  Aim of the Work Top


The present study aimed to investigate the differences between germinal and nongerminal DLBCL cases with respect to their clinicopathological features, including survival and response to therapy.


  Patients and Methods Top


Sixty-one de-novo DLBCL cases were included in this selective retrospective study. The cases were retrieved from the archival material of Pathology Department, Faculty of Medicine, Menoufia University. They received treatment in Menoufia Cancer Institute between January 2009 and December 2014.

The clinical data were collected from patients' medical records and included age, sex, primary site of involvement (nodal or extranodal) [9], extent of nodal involvement (generalized or localized) [10], Ann-Arbor staging [11], splenic involvement, bone marrow involvement, lactate dehydrogenase (LDH) values [12], performance status (PS) [13], international prognostic index (IPI) score [14], revised IPI score [15], AAIPI [16], and recurrence [17].

All patients received six cycles of chemotherapy, CHOP-R (cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone – rituximab). After the completion of treatment, immediate clinical response was assessed on the basis of the criteria revised by the International Working Formulation Group [18].

Histopathological evaluation

Histopathological examination of hematoxylin and eosin-stained sections was performed, to confirm the diagnosis and evaluate the following:

  • Lymph node architecture: This was either partially or totally effaced [19]
  • Capsular invasion and perinodal fat involvement: This was evaluated for evidence of neoplastic invasion [14]
  • Extent of necrosis: This was expressed in percentage
  • Histopathological variants of DLBCL: These were centroblastic [9], immunoblastic [9], T-cell/histiocyte-rich DLBCL [20], and anaplastic large cell type [21]
  • Mitotic count [22].


Immunohistochemistry

The streptavidin–biotin amplified system was used for immunostaining. The slides were submitted to subsequent steps of deparaffinization and rehydration. Antigen retrieval was performed by boiling in citrate buffer saline (pH 6) for CD10 and MUM-1 and in EDTA buffer (pH 8) for BCL6, followed by cooling at room temperature. CD10 (Cat. # 081287), BCL6 (Cat. # MS-1114-R7), and MUM-1 (Cat. # MA1–25525) (mouse monoclonal antibodies; LabVision/Neomarkers, Fremont, California, USA) were used. CD10 and BCL6 were received as 7.0 ml ready-to-use form and MUM-1 was received as a 1.0 ml concentrate (diluted by using PBS at a dilution 1: 100). Incubation with primary antibodies was performed overnight at room temperature. Thereafter, the secondary antibody was applied with DAB as a chromogen substrate and Mayer's hematoxylin as a counterstain. Positive control (tonsil) for CD10, BCL6, and MUM-1 and negative control (omitting of primary antibody step) were included in each run of staining.

For all antibodies, cases were considered positive if more than 30% of tumor cells showed true expression (membranous expression for CD10 and nuclear expression for BCL6 and MUM-1) [8].

Depending on Hans' algorithm [8]: the case was considered GCB type when CD10 was positive or CD10 was negative, BCL6 was positive, and MUM-1 was negative.

The case was considered non-GCB type when CD10 was negative and BCL6 was positive or CD10 was negative, BCL6 was positive, and MUM-1 was positive.

Overall survival

Survival time was calculated in months from the date of diagnosis and ended with the death of the patient or the last follow-up visit. Overall survival time was available for 44/61 (72.13%) DLBCL cases (25 GCB and 19 non-GCB). The range of survival time was 1–105 months with a mean ± SD of 16.25 ± 17.87 months and a median of 9.5 months.

Statistical analysis

Data were collected, tabulated, and statistically analyzed using a personal computer with statistical package for the social sciences (SPSS Inc, Chicago, Illinois, USA), version 20. c 2 and Fisher's exact tests were used to compare qualitative variables. The Mann–Whitney (U) and Kruskal–Wallis (K) tests were used to compare quantitative variables. Log-rank and Cox regression analysis were used for life-table assessment. P values less than or equal to 0.05 were considered significant [23].


  Results Top


The clinicopathological data of the studied DLBCL cases are presented in [Table 1] and [Figure 1].
Table 1 The clinicopathological data of the studied DLBCL cases

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Figure 1: Histopathological variants of diffuse large cell B-cell lymphoma. (hematoxylin and eosin, ×400). (a) Centroblastic variant. (b) Immunoblastic variant. (c) Anaplastic variant. (d) T-cell histiocyte-rich cell variant.

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Immunohistochemical results of CD10, BCL6, and MUM-1 expression

Twenty-eight (28/61, 45.9%) cases were positive for CD10 [Figure 2]. Ten out of 33 (negative for CD10) cases were positive for BCL6 and 23 cases were negative [Figure 3]. Seven out of the 10 cases positive for BCL6 were positive for MUM-1 and three were negative [Figure 4]. Thus, the GCB group included 31/61 (50.8%) cases (28 cases CD10-positve and 31 cases CD10-negative, BCL6-positive, and MUM-1-negative) and the non-GCB group included 30/61 (49.2%) cases (23 cases CD10-negative and BCL6-negative and seven cases CD10-negative, BCL6-positive, and MUM-1-positive) [Figure 5].
Figure 2: (a) Case of DLBCL showing membranous expression for CD10 in more than 30% of malignant cells. (b) Another case negative for CD10 (immunohistochemistry, ×400). DLBCL, diffuse large B-cell lymphoma.

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Figure 3: (a) Case of DLBCL showing nuclear expression for BCL6 in more than 30% of malignant cells. (b) Another case negative for BCL6 (immunohistochemistry, ×400). DLBCL, diffuse large B-cell lymphoma.

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Figure 4: (a) Case of DLBCL showing nuclear expression for MUM-1 in more than 30% of malignant cells. (b) Another cases negative for MUM-1 (immunohistochemistry, ×200). DLBCL, diffuse large B-cell lymphoma.

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Figure 5: Classification of DLBCL into GCB and non.GCB using Hansf algorthim. DLBCL, diffuse large B.cell lymphoma; GCB, germinal center B.cell.

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Comparison between GCB and non-GCB groups regarding the studied clinical and pathological parameters

There were significant differences between GCB and non-GCB cases regarding tumor size, splenic involvement, and PS. The non-GCB group had significantly larger tumor sizes compared with the GCB group (P = 0.03). Fourteen out of 19 (14/19, 73.7%) DLBCL cases with splenic involvement were of non-GCB type (P = 0.01). Overall, 90% of cases with poor PS were of the GCB type (P = 0.01) ([Table 2]).
Table 2 Differences between GCB and non-GCB DLBCL cases regarding the clinicopathological data

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Comparison between CD10-negative and CD10-positive cases regarding the studied clinical and pathological parameters

CD10-positive cases were significantly associated with small tumor size (P = 0.03), absence of splenic involvement (P = 0.01), and poor PS (P = 0.03) in comparison with negative cases ([Table 3]).
Table 3 Differences between CD10 negative and positive cases regarding the clinicopathological data

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Response to therapy

Data on response to therapy were available for 49/61 (80.31%) DLBCL patients (25 GCB and 24 non-GCB). Thirty-six cases out of 49 (73.5%) showed complete response, whereas 13/49 (26.5%) showed partial response and stable disease. There was no significant difference between GCB and non-GCB subtypes regarding response to therapy (P = 0.21).

Univariate survival analysis

There was no significant difference between GCB and non-GCB subtypes regarding overall survival (P = 0.13, log-rank test = 2.25); however, absence of CD10 expression showed better overall survival (P = 0.04, log-rank test = 4.06) compared with positive cases [Figure 6].
Figure 6: Kaplan-Meier of overall survival for CD10-negative and CD10-positive groups (P = 0.04, log-rank test = 4.06).

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  Discussion Top


In this study, we classified DLBCL into GCB and non-GCB subtypes using three primary antibodies – CD10, BCL6, and MUM-1 – according to Hans' algorithm [7]. Many previous studies used Hans' algorithm to classify DLBCL [8],[24],[25],[26],[27],[28].

Other studies used Choi algorithm, which depends on CD10, BCL6, MUM-1, GCET1, and FOXP1 primary antibodies [29]. Although many algorithms were applied, such as modified Hans' (CD10 and MUM-1) [30], modified Choi (CD10, MUM-1, GCET1, and FOXP1) [30], Muris (CD10, MUM-1, and BCL2) [31], Nyman (MUM-1 and FOXP1) [32], Tally (CD10, MUM-1, GCET1, and FOXP1) [30], and Natkunam (LMO2) [33], Hans' algorithm is still the most valid and commonly used one [34],[35].

Half of our cases were of GCB subtype (50.8%). In previous studies, the percentage of GCB cases ranged from 45.2 to 65% [24],[25],[34],[36],[37],[38]. There is no specific reason known for this different distribution of prognostic subgroups. It may be due to different genetic makeup and specific genetic aberrations pertaining to different populations [28].

In the present study, we noticed that nongerminal cases carried bad prognostic impact. This was manifested by the association of non-GCB group with large tumor size (P = 0.03). This agreed with the results of Zizhen et al. [39], who found that the non-GCB primary gastric DLBCL was significantly associated with larger tumor size. However, van Imhoff et al. [25] stated that most GCB cases were more bulky.

Most nongerminal cases (73.7%) showed splenic involvement (P = 0.01), agreeing with Yeh et al. [40], who stated that DLBCL presenting initially in bone marrow, liver, or spleen was commonly of a nongerminal immunophenotype. Tanaka et al. [41] studied three cases of primary splenic lymphoma; two of them (66.6%) were of non-GCB subtype.

PS is a parameter included in the calculation of IPI and AAIPI [14]. Despite the absence of a significant relationship between the GCB and non-GCB subtypes regarding both IPI and AAIPI, 90% of cases with poor PS (2, 3, and 4) were of GCB group (P = 0.01). However, other studies did not show any significant differences between the two groups regarding PS [8],[24],[25].

Alizadeh and colleagues used GEP to classify DLBCL cases into GCB and non-GCB type. Although they used hundreds of genes to stratify the cases, they concluded that there was residual clinical heterogeneity that cannot be explained by their classification. They could not identify which of the genes that distinguish GCB from non-GCB cases were the most important determinants of response to therapy. In their study, although GCB cases had an overall favorable prognosis, five patients died within the first 2 years of diagnosis. On the other hand, three patients in the non-GCB subgroup were alive 5 years after treatment (despite the poor outcome of most patients in this subgroup) [42].

DLBCL with translocation of both MYC and BCL2, termed double-hit lymphoma, is characterized by an aggressive clinical course [43]. Moreover, the germinal center subtype patients with isolated BCL2 translocations had significantly worse outcome than the patients without BCL2 rearrangements (P = 0.0002), and their outcome was similar to that of patients with the nongerminal subtype [44].

Dybkaer and colleagues proposed a refined classification system based on subset-specific B-cell-associated gene signatures in the normal B-cell hierarchy and found that the centrocyte subtype had a superior prognosis compared with the centroblast subtype of GCB-like DLBCL. The centroblast subtype had a complex genotype, whereas the centrocyte subtype had high TP53 mutation and insertion/deletion frequencies and expressed LMO2, CD58, and stromal-1-signature and major histocompatibility complex class II-signature genes, which are known to have a positive impact on prognosis [45].

In this study, comparison between GCB and non-GCB cases as regards revised IPI, AAIPI (≤60 and > 60), tumor stage, and LDH values showed no significant differences (P = 0.36, 0.55, 0.33, 0.94, and 0.35, respectively), agreeing with Hans et al. [8], Berglund et al. [24] and van Imhoff et al. [25], in whose studies the two subtypes of DLBCL did not differ with respect to these clinical features.

The differences between GCB and non-GCB groups regarding clinicopathological features may be explained by the fact that DLBCL subgroups had distinct patterns of genomic alterations and particular chromosomal alterations that affect discrete biologic features of the tumors as defined by gene expression signatures. GCB DLBCL appeared to be derived from GCBs, and non-GCB DLBCL may be derived from a post-GCB undergoing plasmacytic differentiation [46].

Also, advances in molecular genetics have vastly improved our understanding of the biological diversity of DLBCL and have led to the discovery of key oncogenic pathways. In addition to the major molecular designations of GCB and activated B-cell subtypes, next-generation sequencing technologies have unveiled the remarkable complexity of DLBCL [47].

Regarding response to therapy, this study revealed no significant difference between the two groups (P = 0.21), agreeing with Borovecki et al. [44], Veelken et al. [48], and Fu et al. [49]. In contrast, Hassan et al. [28] stated that GCB gave a better immediate clinical response to chemotherapy compared with non-GCB.

In the present study, there was no significant difference regarding overall survival between germinal and nongerminal DLBCL (P = 0.13). Previous studies agreed with the results of the present study as regards the lack of significance of overall survival [50],[51]. However, some studies supported an excellent concordance between subgrouping of DLBCL into germinal and nongerminal subtypes and overall survival [39].

Several factors may account for this discrepancy, including the studied population, the methodology used, and interobserver discrepancies in the interpretations of the immunostaining slides [52]. Also, the differences may partly be explained by the differences in the cutoff value (10–30%) for a positive staining. In all, 10% is most commonly applied, but many studies found that this level might be too low to subdivide DLBCL into manageable subgroups with similar numbers of patients [24],[53].

CD10 is a membrane-associated, neutral endopeptidase that is expressed in a variety of human tissues but has a restricted expression in the germinal center cells of reactive lymphoid tissues [37]. The current study showed that CD10-negative cases carried poor prognostic impact. This was manifested by the association of CD10-negative cases with increased tumor size (P = 0.03) and involvement of the spleen (P = 0.01). However, CD10-negative cases were associated with good PS (P = 0.03) and longer overall survival on univariate analysis (P = 0.04). However, multivariate analysis revealed that CD10 positivity was not an independent prognostic factor (P = 0.07).

Harada et al. [54] and Veelken et al. [48] found that CD10 expression was associated with inferior overall survival. Previous studies using flow cytometry also suggested that CD10 expression in DLBCL may predict inferior survival [55],[56]. Other studies noticed no differences in the outcome for patients with DLBCL that express CD10 [57],[58].

Our results contradicted other studies, which found that CD10 expression was associated with improved overall survival [8],[59]. However, given the variability of outcomes in these retrospective studies, it is doubtful that CD10 alone can be used to predict survival in DLBCL.


  Conclusion Top


DLBCL should be classified into GCB and non-GCB subtypes because they prognostically differ. Hans' algorthim is a simple and reliable method for the classification of DLBCL, but it should be applied on a large number of cases to be used as a routine method for DLBCL evaluation. The similarity in the results of dividing DLBCL cases according to Hans' algorithm and by CD10 expression necessitates larger studies and longer follow-ups to verify whether CD10 alone can replace Hans' algorithm.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Mokhtar N, Gouda I, Adel I. Cancer pathology registry 2003–2004 and time trend analysis. In: Mokhtar N, Gouda I, Adel I, editors. Lympho-hematopoietic system tumors. Journal Department of Pathology, NCI; 2007: 46–54.  Back to cited text no. 1
    
2.
Freedman LS, Edwards BK, Ries LAG, Young JL, editors. Cancer Incidence in Four Member Countries (Cyprus, Egypt, Israel, and Jordan) of the Middle East Cancer Consortium (MECC) Compared with US SEER (Pub. No. 06-5873). Bethesda, MD: National Cancer Institute; 2006.  Back to cited text no. 2
    
3.
Abdelhamid T, Samra M, Ramadan H, Mehessin M, Mokhtar N. Clinical prognostic factors of diffuse large B cell non-Hodgkin's lymphoma: a retrospective study. J Egypt Nat Canc Inst. 2011; 23:17–24.  Back to cited text no. 3
    
4.
Novelli S, Briones J, Sierra J. Epidemiology of lymphoid malignancies: last decade update. Springerplus 2013; 2:70.  Back to cited text no. 4
    
5.
Korac P, Dominis M. Prognostic markers and gene abnormalities in subgroups of diffuse large B-cell lymphoma: single center experience. Croat Med J 2008; 49:618–624.  Back to cited text no. 5
    
6.
Karlin L, Coiffier B. Improving survival and preventing recurrence of diffuse large B-cell lymphoma in younger patients, current strategies and future directions. Onco Targets Ther 2013; 6:289–296.  Back to cited text no. 6
    
7.
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002; 346:1937–1947.  Back to cited text no. 7
    
8.
Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004; 103:275–282.  Back to cited text no. 8
    
9.
Swerdlow SH, Campo E, Harris NH, Jaffe ES, Pilerie SA, Stein H, et al. WHO classification of tumors of hematopoietic and lymphoid tissue, in World Health organization classification of tumors. Lyon, France: IARC; 2008: 9–17.  Back to cited text no. 9
    
10.
Ferrer R. Lymphadenopathy: differential diagnosis and evaluation. Am Fam Physician 1998; 58:1313–1320.  Back to cited text no. 10
    
11.
Armitage JO, Mauch P, Harris NL, Bierman P. Non-Hodgkin's lymphomas. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology. Philadelphia: Lippincott Williams and Wilkins; 2001. p. 2256-2277.  Back to cited text no. 11
    
12.
Yang L. Prognostic values of serum LDH and 2-MG in patients with non-Hodgkin lymphoma. Chin-German J Clin Oncol 2009; 8:353–355.  Back to cited text no. 12
    
13.
Oken MM. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5:649–655.  Back to cited text no. 13
    
14.
Mokhtar N, Khaled H. Lymphoma. Aventis Oncol 2002: (1):47–63.  Back to cited text no. 14
    
15.
Sehn LH. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 109:2007; 1857–1861.  Back to cited text no. 15
    
16.
Schot BW. Early FDG-PET assessment in combination with clinical risk scores determines prognosis in recurring lymphoma. Blood 2007; 109:486–491.  Back to cited text no. 16
    
17.
Damaj G, Bernard M, Legouill S. Late relapse of localized high-grade non-Hodgkin's lymphoma: clinical and biological features – ASH annual meeting, San Francisco. Blood 2008; 112:2603.  Back to cited text no. 17
    
18.
Cheson BD. New staging and response criteria for non-Hodgkin lymphoma and Hodgkin lymphoma. Radiol Clin North Am 2008; 46:213–223.  Back to cited text no. 18
    
19.
Gupta D. Small lymphocytic lymphoma with perifollicular, marginal zone, or interfollicular distribution. Mod Pathol 2000; 13:1161–1166.  Back to cited text no. 19
    
20.
Bouabdallah R. T-cell/histiocyte-rich large B-cell lymphomas and classical diffuse large B-cell lymphomas have similar outcome after chemotherapy: a matched-control analysis. J Clin Oncol 2003; 21: 1271–1277.  Back to cited text no. 20
    
21.
Gurbuxani S, Anastasi J, Hyjek E. Diffuse large B-cell lymphoma – More than a diffuse collection of large B cells: an entity in search of a meaningful classification. Arch Pathol Lab Med 2009; 133:1121–1134.  Back to cited text no. 21
    
22.
Baak JP. Mitosis counting in tumors. Hum Pathol 1990; 21:683–685.  Back to cited text no. 22
    
23.
Dawson B, Trapp RG. Basic and clinical biostatics. New York: Lange Medical Books/McGraw- Hill; 2004.  Back to cited text no. 23
    
24.
Berglund M, Thunberg U, Amini RM, Book M, Roos G, Erlanson M, et al. Evaluation of immunophenotype in diffuse large B-cell lymphoma and its impact on prognosis. Mod Pathol 2005; 18:1113–1120.  Back to cited text no. 24
    
25.
Van Imhoff GW, Boerma EJ, Vanderholt B, Schuuring E, Verdonck LF, Kluin-Nelemans HC, et al. Prognostic impact of germinal center-associated proteins and chromosomal breakpoints in poor-risk diffuse large B-cell lymphoma. J Clin Oncol 2006; 24:4135–4142.  Back to cited text no. 25
    
26.
Nyman H, Jerkeman M, Karjaainen-Lindsberg ML, Banham AH, Leppa S. Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Blood 2007; 109:4930–4935.  Back to cited text no. 26
    
27.
Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 2012; 30:3460–3467.  Back to cited text no. 27
    
28.
Hassan U, Mushtaq S, Mamoon N, Asghar AH, Ishtiaq S. Prognostic sub-grouping of diffuse large B-cell lymphomas into germinal centre and post germinal centre groups by immunohistochemistry after 6 cycles of chemotherapy. Asian Pac J Cancer Prev 2012; 13:1341–1347.  Back to cited text no. 28
    
29.
Choi WW, Weisenburger DD, Greiner TC, Piris MA, Banham AH, Delabie J, et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res 2009; 15:5494–5502.  Back to cited text no. 29
    
30.
Meyer PN, Fu K, Greiner TC, Smith LM, Delabie J, Gascoyne RD, et al. Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J Clin Oncol 2011; 29:200–207.  Back to cited text no. 30
    
31.
Muris JJ, Meijer CJ, Vos W, van Krieken JH, Jiwa NM, Ossenkoppele GJ, et al. Immunohistochemical profiling based on Bcl-2, CD10 and MUM1 expression improves risk stratification in patients with primary nodal diffuse large B cell lymphoma. J Pathol 2006; 208:714–723.  Back to cited text no. 31
    
32.
Nyman H, Jerkeman M, Karjalainen-Lindsberg ML, Banham AH, Leppa S. Prognostic impact of activated B-cell focused classification in diffuse large B-cell lymphoma patients treated with R-CHOP. Mod Pathol 2009; 22:1094–1101.  Back to cited text no. 32
    
33.
Natkunam Y, Farinha P, Hsi ED, Hans CP, Tibshirani R, Sehn LH, et al. LMO2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with anthracycline-based chemotherapy with and without rituximab. J Clin Oncol 2008:26:447–454.  Back to cited text no. 33
    
34.
Sahai K, Gangadharan V, Signh HP, Mani NS. A study of the newer prognostic markers in diffuse large B cell lymphomas. Med J Armed Forces India 2011; 67:41–45.  Back to cited text no. 34
    
35.
Hwang HS. High concordance of gene expression profiling-correlated immunohistochemistry algorithms in diffuse large B-cell lymphoma, not otherwise specified. Am J Surg Pathol 2014; 38:1046–1057.  Back to cited text no. 35
    
36.
Tzankov A, Meier C, Hirschmann P, Went P, Pileri SA, Dirnhofer S. Correlation of high numbers of intratumoral FOXP3+ regulatory T cells with improved survival in germinal center-like diffuse large B-cell lymphoma, follicular lymphoma and classical Hodgkin's lymphoma. Haematologica 2008; 93:193–200.  Back to cited text no. 36
    
37.
Dogan A, Murison P, Isaacon PG. CD10 and BCL6 expression in paraffin sections of normal lymphoid tissue and B cell lymphomas. Am J Surg Pathol 2000; 24:846–852  Back to cited text no. 37
    
38.
Habara T, Sato Y, Takata K, Iwaki N, Okumura H, Sonobe H, et al. Germinal center B-cell-like versus non-germinal center B-cell-like as important prognostic factor for localized nodal DLBCL. J Clin Exp Hematop 2012; 52:91–99.  Back to cited text no. 38
    
39.
Zizhen Z, Hui C, Yanying S, Danping S, Jiahua L, Chao H, et al. Correlation between immunophenotype classification and clinicopathological features in Chinese patients with primary gastric diffuse large B-cell lymphoma. Pathol Oncol Res 2013; 19:317–322.  Back to cited text no. 39
    
40.
Yeh YM, Chang KC, Chen YP, Kao LY, Tsai HP, Ho CL, et al. Large B cell lymphoma presenting initially in bone marrow, liver and spleen: an aggressive entity associated frequently with haemophagocytic syndrome. Histopathology 2010; 57:785–795.  Back to cited text no. 40
    
41.
Tanaka M, Tsunoda S, Inoue K, Izumi T, Yamamoto T, Hoshi S, et al. Clinical analysis of 3 cases with primary splenic diffuse large B-cell lymphoma. Rinsho Ketsueki. 2011; 52:703–707.  Back to cited text no. 41
    
42.
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403:503–511.  Back to cited text no. 42
    
43.
Friedberg JW. Double hit diffuse large B-cell lymphomas: diagnostic and therapeutic challenges. Chin Clin Oncol 2015; 4:9.  Back to cited text no. 43
    
44.
Borovecki A, Korac P, Nola M, Ivankovic D, Jaksic B, Dominis M. Prognostic significance of B-cell differentiation genes encoding proteins in diffuse large B-cell lymphoma and follicular lymphoma grade 3. Croat Med J 2008; 49:625–635.  Back to cited text no. 44
    
45.
Dybkaer K. Diffuse large B-cell lymphoma classification system that associates normal B-cell subset phenotypes with prognosis. J Clin Oncol 2015; 33:1379–1388.  Back to cited text no. 45
    
46.
Visco C. Patients with diffuse large B-cell lymphoma of germinal center origin with BCL2 translocations have poor outcome, irrespective of MYC status: a report from an International DLBCL rituximab-CHOP Consortium Program Study. Haematologica 2013; 98:255–263.  Back to cited text no. 46
    
47.
Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood 2015; 125:22–32.  Back to cited text no. 47
    
48.
Veelken H, Vik Dannheim S, Schulte Moenting J, Martens UM, Finke J, Schmitt-Graeff A. Immunophenotype as prognostic factor for diffuse large B-cell lymphoma in patients undergoing clinical risk-adapted therapy. Ann Oncol 2007; 18:931–939.  Back to cited text no. 48
    
49.
Fu K, Weisenburger DD, Choi WW, Perry KD, Smith LM, Shi X, et al. Addition of rituximab to standard chemotherapy improves the survival of both the germinal center B-cell-like and non-germinal center B-cell-like subtypes of diffuse large B-cell lymphoma. J Clin Oncol 2008; 26, 4587–4594.  Back to cited text no. 49
    
50.
Hwang HS, Yoon DH, Suh C, Park CS, Huh J. Prognostic value of immunohistochemical algorithms in gastrointestinal diffuse large B-cell lymphoma. Blood Res 2013; 48:266–273.  Back to cited text no. 50
    
51.
Chen Y, Xiao L, Zhu X, Lu C, Yu B, Fan D, et al. Immunohistochemical classification and prognosis of diffuse large B-cell lymphoma in China. Zhonghua Bing Li Xue Za Zhi 2014; 43:383–388.  Back to cited text no. 51
    
52.
Gutierrez-Garcia G, Cardesa-Salzmann T, Climent F, Gonzalez-Barca E, Mercadal S, Mate JL, et al. Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Blood 2011; 117:4836–4843.  Back to cited text no. 52
    
53.
Lossos IS, Jones CD, Warnke R, Natkunam Y, Kaizer H, Zehnder JL, et al. Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma. Blood 2001; 98:945–951.  Back to cited text no. 53
    
54.
Harada S, Suzuki R, Uehira K, Yatabe Y, Kagami Y, Ogura M, et al. Molecular and immunological dissection of diffuse large B cell lymphoma: CD5+, and CD5 − with CD10 + groups may constitute clinically relevant subtypes. Leukemia 1999; 13:1441–1447.  Back to cited text no. 54
    
55.
Uherova P, Ross CW, Schnitzer B, Singleton TP, Finn WG. The clinical significance of CD10 antigen expression in diffuse large B-cell lymphoma. Am J Clin Pathol 2001; 115:582–588.  Back to cited text no. 55
    
56.
Xu Y, McKenna RW, Molberg KH, Kroft SH. Clinicopathologic analysis of CD10 + and CD10 − Diffuse large B-cell lymphoma. Identification of a high-risk subset with coexpression of CD10 and bcl-2. Am J Clin Pathol 2001; 116:183–190.  Back to cited text no. 56
    
57.
Linderoth J, Jerkeman M, Cavallin-Stahl E, Kvaloy S, Torlakovic E. Immunohistochemical expression of CD23 and CD40 may identify prognostically favorable subgroups of diffuse large B-cell lymphoma: a Nordic Lymphoma Group Study. Clin Cancer Res 2003; 9:722–728.  Back to cited text no. 57
    
58.
McClure RF, Macon MR, Remstein ED, Dewald GW, Habermann TM, Kurtin PJ. Prognostic markers in adult, de novo, diffuse large B-cell lymphoma; CD10, bcl-6, bcl-2, and BCL2/IGH [abstract]. Mod Pathol 2003; 16:244a.  Back to cited text no. 58
    
59.
McClintock S, Perkins SL, Cleveland RP. Immunohistochemical expression pattern of germinal center and activation B-cell markers correlates with prognosis in diffuse large B-cell lymphoma [abstract]. Mod Pathol 2003; 16:244a.  Back to cited text no. 59
    


    Figures

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