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ORIGINAL ARTICLE
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Immunohistochemical subtyping of diffuse large B-cell lymphoma into germinal center B-cell and activated B-cell subtype, along with correlation of the subtypes with extranodal involvement, serum lactate dehydrogenase, and positron emission tomography scan-based response assessment to chemotherapy


1 Department of Pathology, Max Super Speciality Hospital, Saket, New Delhi, India
2 Department of Urology, PGIMER, Chandigarh, India
3 Senior Resident, Department of Urology, PGIMER, Chandigarh, India

Date of Submission10-Jul-2020
Date of Decision07-Oct-2020
Date of Acceptance12-Jan-2021
Date of Web Publication30-Jul-2021

Correspondence Address:
Aarti Tyagi,
Department of Pathology, Max Super Speciality Hospital, Saket, New Delhi - 110 017
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_842_20

 > Abstract 


Context: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in Indian population and is divided into the prognostically important subtypes, germinal center B-cell (GCB) and activated B-cell-like (ABC), using immunohistochemistry-based algorithm.
Aim: The present study aims to evaluate the influence of immunohistochemical derived DLBCL subtype, GCB or ABC on prognostically significant variables – extranodal involvement and serum lactate dehydrogenase (LDH) level at presentation, and response to chemotherapy assessed on pre- and posttreatment fluorodeoxyglucose-positron emission tomography study.
Settings and Design: This was a retro-prospective, 2-year observational study at a tertiary health-care center, New Delhi.
Subjects and Methods: The study population includes a total 236 cases of DLBCL. According to the Hans algorithm, DLBCL cases were allocated to the GCB and ABC subgroups.
Statistical Analysis Used: For comparison of mean values, independent t-test and analysis of variance were used. For this purpose, we used SPSS 20.0 software. P < 0.05 was considered as statistically significant.
Results: Ninety-eight patients (41.5%) had GCB immunophenotype and 138 patients (58.5%) were ABC. A significant difference was observed between mean baseline level of LDH between GCB and ABC subtypes (P < 0.05). The proportion of cases with extranodal involvement was comparatively higher in ABC subtype (P < 0.05). Association between response to chemotherapy with DLBCL immunophenotypes was found to be highly significant (P < 0.00). The response rates were much better in GCB subtype.
Conclusions: The mean baseline level of LDH is significantly higher in ABC subtype. The proportion of cases with extranodal involvement was comparatively higher in ABC and shows poor response to chemotherapy as compared to GCB. Baseline LDH level was found to be important prognostic marker in the DLBCL.

Keywords: Diffuse large B-cell lymphoma, Hans algorithm, immunophenotype



How to cite this URL:
Tyagi A, Abrari A, Khurana A, Tyagi S. Immunohistochemical subtyping of diffuse large B-cell lymphoma into germinal center B-cell and activated B-cell subtype, along with correlation of the subtypes with extranodal involvement, serum lactate dehydrogenase, and positron emission tomography scan-based response assessment to chemotherapy. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 5]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=322712




 > Introduction Top


Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of large B-cells and is one of the most common types of non-Hodgkin lymphoma (NHL) which accounts for 55% of all NHLs in Indian population.[1] It is characterized by the rapid proliferation of large neoplastic B-cells, with nuclear size almost equal to or more than normal macrophage nuclei (even twice the size of a normal lymphocyte) having diffuse growth pattern. DLBCL displays centroblastic, immunoblastic, T-cell/histiocyte-rich, and anaplastic morphology.[2] It exhibits distinct biological heterogeneity at a pathological, morphological, immunophenotypic, and molecular level. Using gene expression profiling, DLBCL could be divided into the prognostically important subtypes of germinal center B-cell-like (GCB) and activated B-cell-like (ABC) lymphoma. Being expensive and not readily available, application of the molecular approaches in usual practice remains challenging. Therefore, immunohistochemistry (IHC)-based algorithm is used that is more user-friendly and feasible method to practice at any pathology laboratory. In 2004, Hans et al., classified DLBCL into GCB and non-GCB subtypes based on IHC findings using cDNA microarray data and three antibodies, namely CD10, polyclonal B-cell lymphoma 6 (BCL-6), and multiple myeloma oncogene-1 (MUM1). The immunostaining panel reproduced the gene expression results in 71% of GCB and 88% of non-GCB.[3]

Following the algorithm of Hans et al., several studies evaluated the proportion of GCB and non-GCB in different populations but yielded conflicting results regarding its prognostic significance.[3] Although a number of studies have reported significantly better survival for the GCB subgroup, others have found no difference in survival between the two groups.[4],[5] Prognostic significance of DLBCL subtyping has been evaluated in the rituximab era. No difference has been observed in survival between the two subtypes when rituximab was added to the chemotherapy, however, few studies have reported persistent disparity.[6],[7] Before the rituximab era, one of the common ways to identify NHL high-risk groups was the International Prognostic Index (IPI), which is based on clinical features such as age, performance status, stage, number of extranodal sites, and lactate dehydrogenase (LDH).[8] Currently, positron emission tomography (PET)–computed tomography (CT) with fluorine-18 fluorodeoxyglucose (18F-FDG) is recommended at diagnosis and at the end of treatment of DLBCL to ameliorate the accuracy of staging and response evaluation, respectively.[9] In 2007, the International Workshop Criteria integrated 18F-FDG PET results after completion of therapy into the response assessment for DLBCL,[9],[10] and thus, it is considered the best measure for initial staging and evaluation of response after treatment.

Rationale of study

Most of these studies have been performed in Western countries and only a few studies been reported from the Asian countries.[6],[7] and in India there is paucity of data with respect to immunophenotypes of DLBCL. With the preceding context, the present study will aim to evaluate the influence of immunohistochemical derived DLBCL subtype, GCB or ABC on prognostically significant variables– extranodal involvement and serum LDH level at presentation, and response to chemotherapy assessed on pre- and posttreatment FDG-PET study.


 > Subjects and Methods Top


A retro-prospective, observational study was carried out in the histopathology section of the Institute of Laboratory Services at a tertiary health-care center, New Delhi. Cases from May 2014 to December 2016 were evaluated retrospectively and from December 2016 to May 2018 were evaluated prospectively.

The study population involved in the study includes a total 236 cases (both males and females of all age groups) with primary diagnosis of DLBCL, with requisite IHC for allocation of GCB/ABC subtypes and in which LDH at presentation, extranodal involvement, and baseline and subsequent PET studies available were included in the study. Lymphoma cases with of non-DLBCL type or those in which requisite IHC was not performed or not possible due to suboptimal tissue and cases in which LDH value, status of extranodal involvement, and baseline and subsequent PET studies were not available were excluded from the study.

Post tissue processing, hematoxylin- and eosin-stained sections were prepared from the paraffin-embedded tissue blocks to identify diagnostic area. Formalin-fixed paraffin sections of 3 μm thick were used for IHC staining. Staining of tissue sections for BCL-6 was done manually, whereas immunoreaction for CD10 and MUM1 was performed in an automated Ventana autostainer. The staining for all the three antibodies was considered positive when more than 30% cells were stained with the respective antibody. For each case, the center with the highest percentage of tumor cells stained was used for analysis. The morphology of the tumor cells was also evaluated. Hans algorithm was used for the classification of subjects into two IHC subgroups.[6] According to the algorithm, cases were allocated to the GCB subgroup if CD10 alone was positive; CD10-negative cases were further tested for BCL-6. If BCL-6 was negative, then the case was assigned to the non-GCB subgroup. Cases with BCL-6 positivity were further stained with MUM1; if MUM1 was negative, then the case was assigned to the GCB subgroup and positive cases were grouped under the non-GCB subgroup.

Fluorine-18 fluorodeoxyglucose positron emission tomography–computed tomography scan protocol

PET-CT assessments were done at presentation, at mid-treatment, and at the end of the treatment. PET-CT analysis was reported as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) using the Deauville criteria.[11],[12]

Statistical analysis

A comparison of GCB and non-GCB groups with respect to raised LDH, involvements of extranodal sites, and assessment of PET findings was done by Chi-square test at 5% level of significance. For comparison of mean values of quantitative variable, independent t-test and analysis of variance[13] were used. For this purpose, we used SPSS 20.0 software(SPSS Inc., Chicago, IL, version 23.0 for Windows). P < 0.05 was considered as statistically significant.


 > Results Top


About 52.4% of the cases of DLBCL were <60 years followed by 47.5% of the cases more than 60 years (with 11.0% <30 years and 41.5% between 30 and 60 years). The mean age of the patients was 54.91 ± 17.25 years (with median 56 years) ranging between 13 and 87 years. Almost 56.2% of the cases were male with 43.2% of females. Almost 58.5% of the cases were of ABC subtype lymphoma (ABC) followed by 41.5% of the cases of germinal center BCL. Extranodal involvement was present in almost 55.9% of the cases followed by 44.1% without extranodal involvement. The mean LDH level was 385.9 ± 163.92 U/L ranging between 125 and 1688 U/L. Almost all the cases (96.2%) were having raised level of LDH. Furthermore, the mean Ki-67 proliferation index was 75.76% ± 15.24% ranging between 25 and 100. About one-third of the cases were having proliferation index more than 70% [Table 1].
Table1:DistributionofdiffuselargeB-celllymphomacasesonthebasisofage,sex,andclinicopathologicalprofile(n=236)

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The results showed that 98 patients (41.5%) had GCB immunophenotype and 138 patients (58.5%) had ABC phenotype. The majority of GCB cases (n = 63) were classified based on CD10 positivity, whereas CD10-negative cases (n = 35) were further classified as the GCB subtype based on combination of BCL-6 positivity and MUM1 negativity. The expression of CD10 was demonstrated in 26.6% of the cases (n = 63/236). Similarly, MUM1-positive cases were allocated as ABC subtype [Table 2].
Table2:DistributionofdiffuselargeB-celllymphomacasesintoimmunophenotypesaccordingtotheexpression(+)orabsence(-)ofthreeimmunohistochemicalmarkers(n=236)

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Association between DLBCL immunophenotypes (subtypes) was found to be statistically nonsignificant with age group and gender (P > 0.05). The proportion of both ABCs was more among males and patients aged <60 years (53.6% and 63.7%, respectively). On the other hand, GCB subtype was more common among patients aged ≥60 years and males (47.3% and 44.8%, respectively). A significant difference was observed between mean baseline level of LDH between GCB and ABC subtypes (P < 0.05). The mean baseline LDH level in GCB subtype was 339.19 ± 112.26 U/L ranging between 159 and 780 U/L whereas that in ABC subtype was 418.37 ± 185.87 U/L ranging between 125 and 1688 U/L. DLBCL subtype was found to be statistically associated with extranodal involvement (P < 0.05). Almost two-third (65.2%) of the cases with extranodal involvement were of ABC subtype followed by one-third (34.8%) of the cases of GCB subtype. Association between DLBCL immunophenotypes (subtypes) and Ki-67 proliferation index was found to be statistically significant (P < 0.05). About two-third (63.2%) of the cases of DLBCL with Ki-67 >70% were of ABC subtype followed by almost one-third (36.8%) of GCB subtype [Table 3].
Table3:AssociationbetweendiffuselargeB-celllymphomaimmunophenotypes(subtypes)withagegroup,gender,extranodalinvolvement,proliferationindex(Ki-67),andcomparisonofbaselinelactatedehydrogenaselevelatthetimeofpresentation

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Association between response to chemotherapy with DLBCL immunophenotypes was found to be highly significant (P < 0.00). The response rates were much better in GCB subtype as compared to ABC subtype. About two-third cases which completely responded to chemotherapy were of GCB subtype. On the other hand, prognosis and response to treatment were much poor in ABC subtype [Table 4]. Almost 92.7% of association between response to chemotherapy in DLBCL with extranodal involvement was found to be statistically nonsignificant (P > 0.05) [Table 5]. A significant difference was observed among when baseline LDH levels were compared in the different categories of response to treatment (P < 0.05). Baseline LDH level was found to be important prognostic marker in the DLBCL. The higher baseline LDH level at the initiation of treatment indicates poor prognosis [Table 6].
Table4:AssociationbetweendiffuselargeB-celllymphomaimmunophenotypes(subtypes)andclinicaloutcome

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Table5:AssociationbetweenextranodalinvolvementdiffuselargeB-celllymphomaimmunophenotypes(subtypes)withresponsetotreatment(n=236)

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Table6:Comparisonofbaselinelactatedehydrogenaselevelatthetimeofpresentationwithresponsetotreatment(n=236)

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 > Discussion Top


The study was carried out in the histopathology section of the Institute of Laboratory Services at a tertiary care center, New Delhi, with primary aim to subclassify the cases of DLBCL into GCB type [Figure 1] and ABC type [Figure 2] on the basis of IHC and evaluation of the influence of the subtype on prognostic variables and treatment response. The study was quite unique in its own kind as minimal studies are present in Indian context in relation to immunohistochemical classification of DLBCL and its further correlation with prognostic variables and treatment response. The present study was conducted among DLBCL patients treated with R-CHOP regimen of chemotherapy. The classification had been based according to Hans algorithm, in view of the fact that Hans algorithm had maintained its prognostic significance in most of the studies, performed using different algorithms in the same patient's subgroup.[14],[15]
Figure 1: Diffuse large B-cell lymphoma, liver lobe lesion, germinal center B-cell type: (a) Section shows diffuse infiltration by atypical large lymphoid cells with irregular nuclear contour, distinct nucleoli, and scant cytoplasm, H and E, ×400. (b) The large cell population express strong CD20, ×400. (c) The cells are immunoreactive for B-cell lymphoma 6 (nuclear positivity), ×400. (d) The large cell population express strong CD10 (membranous positivity), ×400. (e) No reactivity with an antibody to multiple myeloma oncogene-1, ×400. (f) Ki67 >95% cells are immunoreactive, ×100

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Figure 2: Diffuse large B-cell lymphoma, lymph node, activated B-cell-like type: (a) Section shows lymph node tissue comprising predominantly of intermediate-to-large-sized high N/C ratio, atypical lymphoid cells with conspicuous nucleoli, scant cytoplasm, and readily visible mitosis, H and E, ×400. (b) The large cell population express strong CD 20, ×400. (c) Strong nuclear expression of multiple myeloma oncogene-1 positivity in the tumor cell, ×400. (d) No reactivity with an antibody to CD10, ×400. (e) No reactivity with an antibody to B-cell lymphoma 6, ×400. (f) Ki67-immunoreactive in >75% cell population, ×400(f) Ki67-immunoreactive in >75% cell population, ×400(f) Ki67-immunoreactive in >75% cell population, ×400(f) Ki67-immunoreactive in >75% cell population, ×400

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In the studied group, almost 58.5% of the cases were of ABC subtype lymphoma (ABC) followed by 41.5% of the cases of germinal center BCL. However, the studies conducted in Western countries reported a proportion of GCB subtype of DLBCL to be significantly higher than the ABC subtype.[6],[16],[17] On the other hand, studies conducted in Asian countries reported GCB subtype less and ABC subtype to be more frequent[18],[19],[20],[21] [Table 7].{Figure 7}

This variation in the relative proportion of the DLBCL subtypes between countries might be due to differences in genetic, environmental, ethnic/demographic factors that have intervening role in lymphoma genesis. Apart from that, the differences in the study settings with inclusion criteria used for patient selection might be responsible for this variation.

In our studied group, the mean age of the DLBCL patients was 54.91 ± 17.25 years ranging between 13 and 87 years. About 52.4% of the cases of DLBCL were <60 years followed by 47.5% of the cases more than 60 years. An Indian study conducted by Dwivedi et al. reported similar results with a median age of the patients to be 56 years ranging between 15 and 83 years.[22] One of the Asian studies conducted by Oh et al. also reported the median age of patients at the time of diagnosis to be 59 years ranging between18 and 82 year, and about 54.0% of the cases of DLBCL were <60 years followed by 46.0% of the cases more than 60 years.[23] More specifically in Western countries, the median age of DLBCL patients has been reported 62 years (14–88 years).[3] Apart from that on reviewing studies conducted worldwide, the median age of the patients with DLBCL was found to be between 50 and 60 years.[3],[16],[17],[18],[19],[20]

In the studied group, almost 56.2% of the DLBCL patients were male whereas 43.2% were female. In a recent Indian study, the proportion of male and female DLBCL patients was reported 57% and 43%, respectively. In most of the studies conducted worldwide, the proportion of male patients was found comparatively more among DLBCL patients.[3],[16],[17],[19],[20]

The extranodal involvement was observed to be present in more than half (55.9%) of the cases of DLBCL. In a study conducted by Yao et al., 59% of the patients presented with extranodal involvement.[24] Similarly, another study conducted by Kasouha et al. reported 65.1% of the patients with DLBCL having extranodal involvement.[25] DLBCL is reported to be affected by the difference in proportions of nodal and extranodal cases.[26],[27]

In our studied group, 98 patients (41.5%) had GCB immunophenotype and 138 patients (58.5%) had ABC phenotype. The majority (64.2%) of GCB cases were classified based on CD10 positivity, whereas the rest CD10-negative cases (35.7%) were further classified as the GCB subtype based on combination of BCL-6 positivity and MUM1 negativity. Similarly, MUM1-positive cases were allocated as ABC subtype.

The association between DLBCL subtypes was found to be statistically significant with extranodal involvement. About 65.2% of the cases in present study with extranodal involvement were of ABC subtype followed by one-third (34.8%) of the cases of GCB subtype. About two-third (62.5%) of the cases of ABC subtype and almost half (46.9%) of the cases in GCB subtype showed extranodal involvement. Furthermore, about 70.4% of the cases of DLBCL aged <60 years with extranodal involvement were of ABC subtype. All these study findings are in concordance with the results of previous studies where it has been reported that most extranodal DLBCLs belong to ABC phenotype.[26],[28]

The mean LDH level observed was 385.9 ± 163.92 U/L ranging between 125 and 1688 U/L. Almost all the cases (96.2%) were having raised level of LDH. Among one of the Asian studies conducted by Oh et al., the raised LDH level has been reported in 73% of the cases.[23] As reported by Sehn et al., 53% of the patients of DLBCL were found to have elevated LDH level.[29] In the present study, a significant difference was observed between mean baseline level of LDH between GCB and ABC subtypes.

The significant difference was observed between baseline LDH levels. It was compared in the different categories of response to treatment, and the baseline LDH level was found to be one of the important prognostic markers in the DLBCL. In the present study, it was found that the higher baseline LDH level at the initiation of treatment indicates poor response to the treatment. The mean baseline LDH level among CR cases, PR cases, SD cases, and PD cases were found to be 354.73 ± 13.46, 365.34 ± 15.74, 397.98 ± 30.73, and 430.15 ± 22.69, respectively. As prognostic heterogeneity is suggested to exist among the patients, even within the same IPI risk group, Park et al. investigated the pattern of distribution and prognostic impact of five IPI factors within the same IPI score and reported that among five factors of IPI, elevated serum level of LDH seems to be the most frequently distributed and, more importantly, the most relevant IPI factor with the highest prognostic impact.[30]

The present study showed that no significant association was observed between extranodal involvement and response to chemotherapy in DLBCL and a varying response to chemotherapy was observed in relation to extranodal involvement among DLBCL cases. In concordance with the findings of our study, Hui D et al. also reported that primary extranodal presentation did not affect outcome of the chemotherapy among DLBCL patients.

The response to chemotherapy was assessed using FDG-PET studies. R-CHOP chemotherapy regimen was used among both the subgroups. PET-CT assessment was done taken at presentation, at mid-treatment, and at the end of the treatment. PET-CT analysis was reported according to the 5-PS using the Deauville criteria to CR, PR, SD, and PD.[11],[12] In the present study, association between response to chemotherapy with DLBCL immunophenotypes was found to be highly significant. The response rates were much better in GCB subtype as compared to ABC subtype. On the other hand, prognosis and response to treatment were much poor in ABC subtype. Almost 92.7% of the cases of DLBCL in progressive stage even after treatment were of ABC subtype. Majority of the studies have reported the ABC subtype to be definitely associated with inferior survival and comparatively poor treatment outcomes.[3],[4] Non-GCB subtype of DLBCL is characterized by constitutive activation of the nuclear factor-kappa B pathway, which can negatively impact the chemotherapeutic effect.[31] This might be the reason for poor treatment outcomes among patients of ABC subtype.


 > Conclusion Top


To summarize the salient findings, our study showed that the proportion of cases of ABC subtype lymphoma was higher as compared to germinal center BCL (58.5% vs. 41.5%, respectively). The mean baseline level of LDH in ABC subtype (418.37 ± 185.87 U/L) was significantly higher than GCB subtype (339.19 ± 112.26 U/L). The proportion of cases with extranodal involvement was comparatively higher in ABC subtype and showed poor response rates to chemotherapy as compared to GCB subtype. Baseline LDH level was found to be important prognostic marker in the DLBCL. The higher baseline LDH level at the initiation of treatment indicates poor response to the treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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